LYMPHOMA COMMITTEE - SWOG Stat 2017/RoS Spring 2017... · APRIL 26 - 29, 2017 SWOG LYMPHOMA 7 S1001/II To estimate the rate of upstaging at baseline by PET among patients newly diagnosed

APRIL 26 - 29, 2017 SWOG LYMPHOMA 1

LYMPHOMA COMMITTEE


CONTENTS

S1001 Phase II ............................................................................................................................................................... 6

S1204 Surveillance ...................................................................................................................................................... 17

S1608 Phase II ............................................................................................................................................................. 18

EAY131 Master Protocol / Phase II ............................................................................................................................ 20


Patient Registrations to Studies

By 12 Month Intervals

LYMPHOMA COMMITTEE

Screening registrations and registrations to Biologic only studies are excluded

SWOG LAPS MEMBER NCORP NON-SWOG

178

304

121

7996

42

0

50

100

150

200

250

300

350

Time of Registration

Jan 2011Dec 2011

Jan 2012Dec 2012

Jan 2013Dec 2013

Jan 2014Dec 2014

Jan 2015Dec 2015

Jan 2016Dec 2016

58

29

76

27

84

53

140

39

38

37

29

24

26

3819

25


Patient Registrations by Study and Arm LYMPHOMA COMMITTEE

Jul 2016

Dec 2016

Jan 2016

Jun 2016

Jul 2015

Dec 2015

All

Patients

S1001 DLBCL, I-II, PET-Adapted Therapy

Initial registration

R-CHOP x 3 0 14 20 158

R-CHOP x 6 0 0 0 1

0 14 20 159

PET-Directed Therapy

Continued R-CHOP 2 19 17 136

IFRT + Zevalin 1 1 0 13

3 20 17 149

9177 NHL, Dose-adj. EPOCH+/-Rituximab*

Total Registrations 0 0 1 19

C51101 CNS, Myelo/Non-myelo Chemo, PhII*


E1411 MCL, RB+R, RBV+R, RB+LR, RBV+LR*


E1412 DLBCL, R2CHOP vs RCHOP*


* For non-SWOG coordinated studies only SWOG registrations are shown.


Non-SWOG Studies with SWOG-Credited Registrations

LYMPHOMA COMMITTEE

Studies with Accrual from July 2015 – December 2016

SWOG

Champion

Date

Activated

Date

Closed

Total

Accrual

9177 NHL, Dose-adj. EPOCH+/-Rituximab

M Fanale 04/13/12 160

No Progress Report Available

A051301 ABC DLBCL, Auto HCT and Ibrutinib/Placebo

P Stiff 07/15/16 0

No Progress Report Available

C51101 CNS, Myelo/Non-myelo Chemo, PhII

N Mohile 06/22/12 97

Most Recent Progress Report

E1411 MCL, RB+R, RBV+R, RB+LR, RBV+LR

B Till 06/08/12 09/09/16 373


E1412 DLBCL, R2CHOP vs RCHOP

J Amengual 01/22/14 01/17/17 343



S1001/II

S1001 Phase II

Coordinating Group: SWOG

A Phase II Trial of PET-Directed Therapy for Limited Stage Diffuse Large

B-Cell Lymphoma (DLBCL)

Participants:

SWOG, CTSU (Supported by Alliance, ECOG-ACRIN)

Study Chairs:

D Persky, S Park (Alliance), L Swinnen (ECOG-ACRIN)

Statisticians:

M LeBlanc, H Li

Data Coordinator:

J Jardine

Date Activated:

07/15/2011

Date Closed:

06/01/2016

SCHEMA

Objectives To assess the five-year progression-free survival

(PFS) rate in patients with newly diagnosed limited

stage diffuse large B-cell lymphoma using PET scan

to direct therapy after three cycles of R-CHOP.

To evaluate progression-free survival within the

PET+ and PET- subgroups of patients with newly

diagnosed limited stage diffuse large B-cell

lymphoma (DLBCL).

To evaluate the toxicity of this treatment regimen in

this patient population.

To evaluate the response probability in this patient

population.

To evaluate overall survival (OS) in the overall

population, and within the PET+ and PET- subgroups.

R

E

G

I

S

T

E

R

PET-

R-CHOPx 3*

*All patients who are early stage by CT but advanced stage by PET/CT at baseline

will receive R-CHOPx6

PET+

R-CHOPx1

IFRT + Zevalin


S1001/II

To estimate the rate of upstaging at baseline by PET

among patients newly diagnosed with limited stage

diffuse large B-cell lymphoma by CT imaging and

describe outcomes in patients upstaged by PET at

baseline to advanced DLBCL.

To evaluate the association of germinal center B-cell

subtype (GCB) vs stromal-1 vs stromal-2 gene

expression signatures with PFS and OS.

Patient Population Patients must have non-bulky Stage I or II de-novo

diffuse large B-cell non-Hodgkin's lymphoma

(DLBCL) which is positive for CD20. Patients who

have Stage I or II non-bulky disease based on

diagnostic CT scan, but are upstaged to Stage III or

IV based on FDG-PET evaluation, are also eligible.

Patients with primary mediastinal lymphoma,

testicular lymphoma, prior or simultaneous diagnosis

of indolent lymphoma, or post-transplant

lymphoproliferative disorder with DLBCL

morphology are not eligible. Patients may have either

measurable or evaluable limited-stage DLBCL.

Patients rendered free of measurable or evaluable

disease by virtue of biopsy (resection) are also

eligible. Patients with CNS involvement are not

eligible.

Patients must not have received prior chemotherapy,

radiation therapy, or antibody therapy for lymphoma.

Patients must be at least 18 years of age and have a

Zubrod performance status of 0-2. Patients must have

adequate renal, hepatic, cardiac and hematologic

function. Patients known to be HIV-positive are not

eligible.

Stratification/Descriptive Factors For registration step 1, patients will be described by

advanced stage based on local review of the baseline

PET/CT: yes vs no.

For registration step 2, patients will be described by

the positive PET/CT after three cycles of R-CHOP

based on centralized review: yes vs no.

Accrual Goals Assuming an ineligibility rate of 10%, we anticipate

needing to accrue 155 patients in order to obtain 140

eligible patients. Assuming that 15% of eligible

patients will have been upstaged at baseline by PET,

we expect that 120 patients will receive PET-directed

therapy. We further expect that 30 of these patients

will be PET-positive, assuming a PET-positive rate

of 25%. If the actual rate of PET-positivity is less

than 25%, accrual will continue until 30 eligible

patients in the FDG-PET-positive subgroup are

enrolled.

Summary Statement This study was closed to accrual on June 1, 2016,

after a total accrual of 159 patients, including one

patient who was upstaged to advanced stage DLBCL

based on local review of the baseline PET/CT. Two

patients are ineligible for initial registration, one due

to incorrect histology and one due to no required

baseline specimens submitted for pathology review.

One hundred fifty-four patients have been assessed

for toxicities on initial R-CHOPx3 therapy. One

patient died of sepsis five days after the last date of

treatment during the first cycle of treatment. Upon

review, this was found to be probably related to

protocol treatment. This patient also experienced

Grade 4 hematologic toxicities and febrile

neutropenia. An additional 27 patients experienced

Grade 4 hematologic toxicities, three of whom also

experienced Grade 4 non-hematologic toxicities

including febrile neutropenia (2), hyponatremia, and

sepsis.

The patient on R-CHOPx6 therapy did not experience

Grade 3 or greater toxicities.

One hundred forty-nine patients have been registered

to PET-directed therapy based on the availability of

the interim PET result, 137 of whom were interim

PET-negative and registered to the continued R-

CHOP therapy, and 12 of whom were interim PET-

positive and registered to the IFRT + Zevalin therapy.

One PET-negative patient is ineligible due to being

ineligible at Step 1. Major protocol deviations are

coded for two PET-negative patients who did not

received any PET-directed R-CHOP therapy; these

two patients are not evaluable for toxicities related to

PET-directed therapy.

Among 134 patients on the continued R-CHOP arm

that have been assessed for toxicities, one patient

died from hypoxia, which was possibly attributable to

treatment, and had also experienced Grade 4

neutropenia and respiratory, thoracic and mediastinal

disorders. Twelve additional patients on this arm

experienced treatment-related Grade 4 hematologic

toxicities, one of whom also experienced Grade 4

secondary leukemia. Two of the 12 patients assessed

for toxicities on the IFRT + Zevalin arm experienced

Grade 4 hematologic toxicities.


S1001/II

Registration by Institution

Initial Registration

Institutions

Total

Reg Institutions

Total

Reg

Alliance 40 Kentucky, U of 3

Rochester, Univ of 28 Fred Hutchinson CRC 2

ECOG-ACRIN 20 Greenville NCORP 2

Michigan CRC NCORP 8 Northwest NCORP 2

Arizona MC, U of 7 NRG 2

Upstate Carolina 7 St Luke's Mt State/PCRC NCORP 2

Kansas City NCORP 6 Virginia Mason MC/Northwest NCORP 2

Wichita NCORP 6 Essentia Hlth NCORP 1

Yale University 6 Montana NCORP 1

Loyola University 5 Southeast COR NCORP 1

City of Hope Med Ctr 4 Total (22 Institutions) 159

Hawaii MU-NCORP 4

Registration, Eligibility, and Evaluability


Data as of February 23, 2017

TOTAL R-CHOP x 3 R-CHOP x 6

NUMBER REGISTERED 159 158 1

INELIGIBLE 2 2 0

Insufficient Documentation 1 1 0

Irreversible 1 1 0

ELIGIBLE 157 156 1

Analyzable, Pend. Elig. 153 152 1

RESPONSE ASSESSMENT

Determinable 149 148 1

Not Determinable 2 2 0

Too Early 6 6 0

ADVERSE EVENT ASSESSMENT

Evaluable 155 154 1

Too Early 2 2 0


S1001/II

Patient Characteristics



R-CHOP x 3

(n=156)

R-CHOP x 6

(n=1)

AGE

Median 61.6 74.3

Minimum 18.5 74.3

Maximum 85.7 74.3

SEX

Males 80 51% 0 0%

Females 76 49% 1 100%

HISPANIC

Yes 7 4% 0 0%

No 142 91% 1 100%

Unknown 7 4% 0 0%

RACE

White 136 87% 1 100%

Black 6 4% 0 0%

Asian 10 6% 0 0%

Native American 1 1% 0 0%

Unknown 3 2% 0 0%

PET UPSTAGED

Yes 0 0% 1 100%

No 156 100% 0 0%

Treatment Summary



TOTAL R-CHOP x 3 R-CHOP x 6

NUMBER ON PROTOCOL TREATMENT 4 4 0

NUMBER OFF PROTOCOL TREATMENT

REASON OFF TREATMENT

153 152 1

Treatment completed as planned 148 147 1

Adverse Event or side effects 2 2 0

Refusal unrelated to adverse event 0 0 0

Other - not protocol specified 1 1 0

Reason under review 1 1 0

MAJOR PROTOCOL DEVIATIONS 0 0 0


S1001/II

Number of Patients with a Given Type and Grade of Adverse Event


Adverse Events Unlikely or Not Related to Treatment Excluded


R-CHOP x 3

(n=154)

Grade

R-CHOP x 6

(n=1)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

ALT increased 130 21 3 0 0 0 1 0 0 0 0 0

AST increased 138 15 1 0 0 0 1 0 0 0 0 0

Abdominal pain 149 4 1 0 0 0 1 0 0 0 0 0

Agitation 152 1 1 0 0 0 1 0 0 0 0 0

Alkaline phosphatase increased 148 5 1 0 0 0 1 0 0 0 0 0

Allergic reaction 148 1 5 0 0 0 1 0 0 0 0 0

Alopecia 91 20 43 0 0 0 0 0 1 0 0 0

Anal hemorrhage 153 1 0 0 0 0 1 0 0 0 0 0

Anemia 74 59 13 8 0 0 0 1 0 0 0 0

Anorexia 134 14 5 1 0 0 0 1 0 0 0 0

Anxiety 148 2 4 0 0 0 1 0 0 0 0 0

Arthralgia 146 6 2 0 0 0 1 0 0 0 0 0

Back pain 150 3 1 0 0 0 1 0 0 0 0 0

Bloating 151 1 2 0 0 0 1 0 0 0 0 0

Blood bilirubin increased 152 2 0 0 0 0 1 0 0 0 0 0

Blurred vision 151 3 0 0 0 0 1 0 0 0 0 0

Bone pain 141 7 5 1 0 0 1 0 0 0 0 0

CD4 lymphocytes decreased 151 0 1 2 0 0 1 0 0 0 0 0

Catheter related infection 153 0 0 1 0 0 1 0 0 0 0 0

Chills 146 7 1 0 0 0 1 0 0 0 0 0

Concentration impairment 153 1 0 0 0 0 1 0 0 0 0 0

Confusion 153 1 0 0 0 0 1 0 0 0 0 0

Constipation 98 43 12 1 0 0 0 0 1 0 0 0

Cough 146 6 1 1 0 0 1 0 0 0 0 0

Creatinine increased 150 4 0 0 0 0 1 0 0 0 0 0

Dehydration 145 1 8 0 0 0 1 0 0 0 0 0

Depression 153 0 1 0 0 0 1 0 0 0 0 0

Diarrhea 135 15 1 3 0 0 1 0 0 0 0 0

Dizziness 142 12 0 0 0 0 1 0 0 0 0 0

Dry mouth 145 9 0 0 0 0 1 0 0 0 0 0

Dry skin 151 3 0 0 0 0 0 1 0 0 0 0

Dysgeusia 137 12 5 0 0 0 1 0 0 0 0 0

Dyspepsia 138 8 8 0 0 0 1 0 0 0 0 0

Dyspnea 141 8 2 3 0 0 0 1 0 0 0 0

Edema face 153 1 0 0 0 0 1 0 0 0 0 0

Edema limbs 145 7 1 1 0 0 0 1 0 0 0 0

Endocrine disorders-Other 153 0 0 1 0 0 1 0 0 0 0 0

Epistaxis 153 1 0 0 0 0 1 0 0 0 0 0

Eye disorders - Other, specify 152 2 0 0 0 0 1 0 0 0 0 0

Eye pain 153 1 0 0 0 0 1 0 0 0 0 0

Facial pain 152 2 0 0 0 0 1 0 0 0 0 0

Fall 153 0 1 0 0 0 1 0 0 0 0 0

Fatigue 48 81 21 4 0 0 0 1 0 0 0 0

Febrile neutropenia 140 0 0 11 3 0 1 0 0 0 0 0


S1001/II

R-CHOP x 3

(n=154)

Grade

R-CHOP x 6

(n=1)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

Fever 141 11 2 0 0 0 1 0 0 0 0 0

Flank pain 153 1 0 0 0 0 1 0 0 0 0 0

Flatulence 152 2 0 0 0 0 1 0 0 0 0 0

Flu like symptoms 153 0 1 0 0 0 1 0 0 0 0 0

GERD 147 4 3 0 0 0 1 0 0 0 0 0

GI disorders-Other, specify 152 2 0 0 0 0 1 0 0 0 0 0

Gastritis 153 0 1 0 0 0 1 0 0 0 0 0

Gen disorders/admin site cond 152 2 0 0 0 0 1 0 0 0 0 0

Generalized muscle weakness 145 6 2 1 0 0 1 0 0 0 0 0

Glucose intolerance 153 0 1 0 0 0 1 0 0 0 0 0

Headache 142 12 0 0 0 0 1 0 0 0 0 0

Hematuria 153 1 0 0 0 0 1 0 0 0 0 0

Hemoglobin increased 153 1 0 0 0 0 1 0 0 0 0 0

Hemorrhoids 153 1 0 0 0 0 1 0 0 0 0 0

Hiccups 153 1 0 0 0 0 1 0 0 0 0 0

Hoarseness 152 1 1 0 0 0 0 1 0 0 0 0

Hot flashes 152 2 0 0 0 0 1 0 0 0 0 0

Hyperglycemia 135 10 5 4 0 0 1 0 0 0 0 0

Hyperhidrosis 151 2 1 0 0 0 1 0 0 0 0 0

Hyperkalemia 153 0 1 0 0 0 1 0 0 0 0 0

Hypernatremia 153 1 0 0 0 0 1 0 0 0 0 0

Hypertension 147 2 2 3 0 0 1 0 0 0 0 0

Hypoalbuminemia 138 8 8 0 0 0 0 1 0 0 0 0

Hypocalcemia 143 8 3 0 0 0 1 0 0 0 0 0

Hypokalemia 143 7 2 2 0 0 1 0 0 0 0 0

Hypomagnesemia 148 6 0 0 0 0 1 0 0 0 0 0

Hyponatremia 146 7 0 0 1 0 1 0 0 0 0 0

Hypophosphatemia 153 0 1 0 0 0 1 0 0 0 0 0

Hypotension 149 3 2 0 0 0 1 0 0 0 0 0

Infusion related reaction 136 2 16 0 0 0 1 0 0 0 0 0

Injection site reaction 153 0 1 0 0 0 1 0 0 0 0 0

Insomnia 134 12 8 0 0 0 1 0 0 0 0 0

Irregular menstruation 153 1 0 0 0 0 1 0 0 0 0 0

Lip infection 153 1 0 0 0 0 1 0 0 0 0 0

Localized edema 152 2 0 0 0 0 1 0 0 0 0 0

Lower GI hemorrhage 153 1 0 0 0 0 1 0 0 0 0 0

Lung infection 152 0 0 2 0 0 1 0 0 0 0 0

Lymphocyte count decreased 89 24 21 15 5 0 0 0 1 0 0 0

Memory impairment 152 2 0 0 0 0 1 0 0 0 0 0

Menorrhagia 153 1 0 0 0 0 1 0 0 0 0 0

Mucosal infection 153 0 1 0 0 0 1 0 0 0 0 0

Mucositis oral 129 18 6 1 0 0 0 1 0 0 0 0

Myalgia 147 7 0 0 0 0 1 0 0 0 0 0

Nail discoloration 151 3 0 0 0 0 1 0 0 0 0 0

Nasal congestion 153 1 0 0 0 0 1 0 0 0 0 0

Nausea 82 51 20 1 0 0 0 1 0 0 0 0

Neck pain 151 2 1 0 0 0 1 0 0 0 0 0

Neutrophil count decreased 99 5 10 13 27 0 1 0 0 0 0 0

Oral pain 151 0 2 1 0 0 1 0 0 0 0 0

Pain 149 1 4 0 0 0 1 0 0 0 0 0

Pain of skin 153 1 0 0 0 0 1 0 0 0 0 0


S1001/II

R-CHOP x 3

(n=154)

Grade

R-CHOP x 6

(n=1)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

Papulopustular rash 153 1 0 0 0 0 1 0 0 0 0 0

Paresthesia 150 4 0 0 0 0 1 0 0 0 0 0

Peripheral motor neuropathy 149 4 1 0 0 0 1 0 0 0 0 0

Peripheral nerve infection 153 0 1 0 0 0 1 0 0 0 0 0

Peripheral sensory neuropathy 118 31 4 1 0 0 1 0 0 0 0 0

Phlebitis 153 0 1 0 0 0 1 0 0 0 0 0

Platelet count decreased 129 17 3 3 2 0 0 1 0 0 0 0

Postnasal drip 153 0 1 0 0 0 1 0 0 0 0 0

Presyncope 153 0 1 0 0 0 1 0 0 0 0 0

Productive cough 152 2 0 0 0 0 1 0 0 0 0 0

Proteinuria 153 1 0 0 0 0 1 0 0 0 0 0

Pruritus 150 3 1 0 0 0 1 0 0 0 0 0

Rash acneiform 152 2 0 0 0 0 1 0 0 0 0 0

Rash maculo-papular 146 7 1 0 0 0 0 1 0 0 0 0

Renal/urinary disorders-Other 152 2 0 0 0 0 1 0 0 0 0 0

Repro system/breast ds-Oth 152 1 1 0 0 0 1 0 0 0 0 0

Resp/thoracic/mediastinal ds 153 1 0 0 0 0 1 0 0 0 0 0

Scalp pain 153 1 0 0 0 0 1 0 0 0 0 0

Sepsis 152 0 0 0 1 1 1 0 0 0 0 0

Sinus bradycardia 152 2 0 0 0 0 1 0 0 0 0 0

Sinus tachycardia 152 2 0 0 0 0 1 0 0 0 0 0

Sinusitis 153 0 1 0 0 0 1 0 0 0 0 0

Skin infection 151 2 0 1 0 0 1 0 0 0 0 0

Skin/subq tissue ds-Other 149 5 0 0 0 0 1 0 0 0 0 0

Sore throat 148 5 1 0 0 0 1 0 0 0 0 0

Stomach pain 152 1 1 0 0 0 1 0 0 0 0 0

Stroke 153 0 0 1 0 0 1 0 0 0 0 0

Superficial thrombophlebitis 153 0 1 0 0 0 1 0 0 0 0 0

Thromboembolic event 153 0 1 0 0 0 1 0 0 0 0 0

Upper respiratory infection 147 0 7 0 0 0 1 0 0 0 0 0

Urinary frequency 144 9 1 0 0 0 1 0 0 0 0 0

Urinary incontinence 152 2 0 0 0 0 1 0 0 0 0 0

Urinary retention 153 1 0 0 0 0 1 0 0 0 0 0

Urinary tract infection 145 0 6 3 0 0 1 0 0 0 0 0

Urinary urgency 153 1 0 0 0 0 1 0 0 0 0 0

Urine discoloration 153 1 0 0 0 0 1 0 0 0 0 0

Vaginal infection 152 0 2 0 0 0 1 0 0 0 0 0

Voice alteration 152 1 1 0 0 0 1 0 0 0 0 0

Vomiting 141 8 5 0 0 0 0 1 0 0 0 0

Watering eyes 153 1 0 0 0 0 1 0 0 0 0 0

Weight gain 152 2 0 0 0 0 0 1 0 0 0 0

Weight loss 146 7 1 0 0 0 1 0 0 0 0 0

Wheezing 153 1 0 0 0 0 1 0 0 0 0 0

White blood cell decreased 97 15 11 17 14 0 0 0 1 0 0 0

Wound infection 153 0 1 0 0 0 1 0 0 0 0 0

MAX. GRADE ANY ADVERSE EVENT 2 21 65 38 27 1 0 0 1 0 0 0


S1001/II

Registration, Eligibility, and Evaluability



TOTAL

Continued R

-CHOP IFRT + Zevalin

NUMBER REGISTERED 149 137 12

INELIGIBLE 1 1 0

Insufficient Documentation 1 1 0

Irreversible 1 1 0

ELIGIBLE 148 136 12

Analyzable, Pend. Elig. 143 131 12

RESPONSE ASSESSMENT

Determinable 130 124 6

Not Determinable 1 1 0

Too Early 17 11 6

ADVERSE EVENT ASSESSMENT

Evaluable 146 134 12

Not Evaluable 2 2 0

Treatment Summary



TOTAL

Continued R

-CHOP IFRT + Zevalin

NUMBER ON PROTOCOL TREATMENT 3 3 0

NUMBER OFF PROTOCOL TREATMENT

REASON OFF TREATMENT

145 133 12

Treatment completed as planned 138 127 11

Adverse Event or side effects 1 1 0

Refusal unrelated to adverse event 1 1 0

Other - not protocol specified 0 0 0

Reason under review 5 4 1

MAJOR PROTOCOL DEVIATIONS 2 2 0


S1001/II

Number of Patients with a Given Type and Grade of Adverse Event


Adverse Events Unlikely or Not Related to Treatment Excluded


Continued R-CHOP

(n=134)

Grade

IFRT + Zevalin

(n=12)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

ALT increased 122 11 0 1 0 0 11 1 0 0 0 0

AST increased 127 7 0 0 0 0 11 1 0 0 0 0

Abdominal pain 133 0 0 1 0 0 11 1 0 0 0 0

Alkaline phosphatase increased 133 1 0 0 0 0 12 0 0 0 0 0

Allergic rhinitis 133 0 1 0 0 0 12 0 0 0 0 0

Alopecia 109 8 17 0 0 0 9 1 2 0 0 0

Anemia 86 33 13 2 0 0 7 3 1 1 0 0

Anorexia 130 2 1 1 0 0 9 2 1 0 0 0

Anxiety 133 1 0 0 0 0 11 0 1 0 0 0

Arthralgia 130 3 1 0 0 0 12 0 0 0 0 0

Arthritis 133 1 0 0 0 0 12 0 0 0 0 0

Blurred vision 133 1 0 0 0 0 11 1 0 0 0 0

Bone pain 132 2 0 0 0 0 12 0 0 0 0 0

Chills 133 1 0 0 0 0 11 1 0 0 0 0

Constipation 127 7 0 0 0 0 11 1 0 0 0 0

Cough 130 3 1 0 0 0 10 2 0 0 0 0

Creatinine increased 131 2 1 0 0 0 12 0 0 0 0 0

Dehydration 134 0 0 0 0 0 11 0 1 0 0 0

Depression 134 0 0 0 0 0 11 0 1 0 0 0

Dermatitis radiation 134 0 0 0 0 0 10 2 0 0 0 0

Diarrhea 129 5 0 0 0 0 11 1 0 0 0 0

Dizziness 134 0 0 0 0 0 11 1 0 0 0 0

Dry mouth 131 3 0 0 0 0 10 0 2 0 0 0

Dry skin 132 2 0 0 0 0 12 0 0 0 0 0

Dysgeusia 128 3 3 0 0 0 11 0 1 0 0 0

Dyspepsia 132 2 0 0 0 0 11 1 0 0 0 0

Dysphagia 134 0 0 0 0 0 9 2 1 0 0 0

Dyspnea 128 4 2 0 0 0 12 0 0 0 0 0

Ear pain 133 1 0 0 0 0 12 0 0 0 0 0

Edema limbs 131 3 0 0 0 0 12 0 0 0 0 0

Ejection fraction decreased 133 0 0 1 0 0 12 0 0 0 0 0

Esophagitis 134 0 0 0 0 0 11 0 1 0 0 0

Eye disorders - Other, specify 133 1 0 0 0 0 12 0 0 0 0 0

Eye pain 133 1 0 0 0 0 12 0 0 0 0 0

Fall 133 0 0 1 0 0 12 0 0 0 0 0

Fatigue 80 44 9 1 0 0 6 5 1 0 0 0

Febrile neutropenia 132 0 0 2 0 0 12 0 0 0 0 0

Fever 132 2 0 0 0 0 12 0 0 0 0 0

Flu like symptoms 133 1 0 0 0 0 12 0 0 0 0 0

GERD 129 4 1 0 0 0 12 0 0 0 0 0

Gastric ulcer 133 1 0 0 0 0 12 0 0 0 0 0

Gastritis 133 1 0 0 0 0 11 1 0 0 0 0

Gen disorders/admin site cond 133 1 0 0 0 0 12 0 0 0 0 0

Generalized muscle weakness 131 1 2 0 0 0 11 1 0 0 0 0


S1001/II

Continued R-CHOP

(n=134)

Grade

IFRT + Zevalin

(n=12)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

Glucose intolerance 133 0 1 0 0 0 12 0 0 0 0 0

Gum infection 133 1 0 0 0 0 12 0 0 0 0 0

Headache 133 1 0 0 0 0 12 0 0 0 0 0

Hearing impaired 133 1 0 0 0 0 12 0 0 0 0 0

Hot flashes 130 3 1 0 0 0 12 0 0 0 0 0

Hypercalcemia 133 1 0 0 0 0 12 0 0 0 0 0

Hyperglycemia 128 3 2 1 0 0 11 1 0 0 0 0

Hyperhidrosis 133 1 0 0 0 0 11 1 0 0 0 0

Hyperkalemia 132 2 0 0 0 0 12 0 0 0 0 0

Hypertension 128 4 0 2 0 0 12 0 0 0 0 0

Hyperuricemia 133 1 0 0 0 0 12 0 0 0 0 0

Hypoalbuminemia 131 3 0 0 0 0 12 0 0 0 0 0

Hypocalcemia 131 2 0 1 0 0 12 0 0 0 0 0

Hypoglycemia 133 1 0 0 0 0 12 0 0 0 0 0

Hypokalemia 128 3 1 2 0 0 12 0 0 0 0 0

Hypomagnesemia 133 1 0 0 0 0 11 1 0 0 0 0

Hyponatremia 131 2 0 1 0 0 12 0 0 0 0 0

Hypotension 133 0 0 1 0 0 12 0 0 0 0 0

Hypoxia 132 0 0 1 0 1 12 0 0 0 0 0

Infections/infestations-Other 132 0 2 0 0 0 12 0 0 0 0 0

Insomnia 132 2 0 0 0 0 10 0 2 0 0 0

Irregular menstruation 133 1 0 0 0 0 12 0 0 0 0 0

Laryngeal edema 134 0 0 0 0 0 11 1 0 0 0 0

Leukocytosis 133 0 0 1 0 0 12 0 0 0 0 0

Localized edema 133 0 1 0 0 0 12 0 0 0 0 0

Lymphedema 133 0 1 0 0 0 12 0 0 0 0 0

Lymphocyte count decreased 86 21 18 9 0 0 8 2 0 2 0 0

Malaise 133 0 1 0 0 0 12 0 0 0 0 0

Memory impairment 133 1 0 0 0 0 12 0 0 0 0 0

Mucositis oral 128 5 1 0 0 0 11 0 1 0 0 0

Muscle weakness lower limb 133 1 0 0 0 0 12 0 0 0 0 0

Muscle weakness upper limb 133 1 0 0 0 0 12 0 0 0 0 0

Myalgia 132 2 0 0 0 0 10 1 1 0 0 0

Nail discoloration 132 2 0 0 0 0 12 0 0 0 0 0

Nail loss 133 1 0 0 0 0 12 0 0 0 0 0

Nail ridging 131 3 0 0 0 0 12 0 0 0 0 0

Nasal congestion 132 0 2 0 0 0 12 0 0 0 0 0

Nausea 121 13 0 0 0 0 10 2 0 0 0 0

Neoplasms, all 133 1 0 0 0 0 12 0 0 0 0 0

Nervous sys disorders-Other 133 0 0 1 0 0 11 1 0 0 0 0

Neutrophil count decreased 114 2 5 4 9 0 7 1 2 1 1 0

Oral pain 132 1 1 0 0 0 12 0 0 0 0 0

Pain 131 3 0 0 0 0 12 0 0 0 0 0

Pain in extremity 130 2 2 0 0 0 11 0 1 0 0 0

Paresthesia 132 2 0 0 0 0 12 0 0 0 0 0

Peripheral motor neuropathy 132 2 0 0 0 0 12 0 0 0 0 0

Peripheral sensory neuropathy 109 22 2 1 0 0 10 2 0 0 0 0

Pharyngitis 133 0 1 0 0 0 11 0 1 0 0 0

Phlebitis 133 0 1 0 0 0 12 0 0 0 0 0

Platelet count decreased 117 13 0 2 2 0 8 0 1 2 1 0

Productive cough 133 1 0 0 0 0 12 0 0 0 0 0


S1001/II

Continued R-CHOP

(n=134)

Grade

IFRT + Zevalin

(n=12)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

Pruritus 132 2 0 0 0 0 12 0 0 0 0 0

Rash acneiform 133 1 0 0 0 0 12 0 0 0 0 0

Renal calculi 133 1 0 0 0 0 12 0 0 0 0 0

Resp/thoracic/mediastinal ds 132 1 0 0 1 0 12 0 0 0 0 0

Secondary Leukemia 133 0 0 0 1 0 12 0 0 0 0 0

Sinus bradycardia 133 1 0 0 0 0 12 0 0 0 0 0

Sinus tachycardia 132 2 0 0 0 0 12 0 0 0 0 0

Skin infection 131 1 1 1 0 0 12 0 0 0 0 0

Skin/subq tissue ds-Other 133 1 0 0 0 0 12 0 0 0 0 0

Small intestine infection 133 0 0 1 0 0 12 0 0 0 0 0

Sore throat 133 0 1 0 0 0 11 1 0 0 0 0

Telangiectasia 133 1 0 0 0 0 12 0 0 0 0 0

Thromboembolic event 133 0 0 1 0 0 12 0 0 0 0 0

Upper respiratory infection 131 0 3 0 0 0 12 0 0 0 0 0

Urinary frequency 133 1 0 0 0 0 12 0 0 0 0 0

Urinary tract infection 132 0 2 0 0 0 11 0 1 0 0 0

Urine discoloration 133 1 0 0 0 0 12 0 0 0 0 0

Voice alteration 133 0 1 0 0 0 12 0 0 0 0 0

Vomiting 133 1 0 0 0 0 12 0 0 0 0 0

Weight gain 131 2 1 0 0 0 12 0 0 0 0 0

Weight loss 131 1 1 1 0 0 10 2 0 0 0 0

White blood cell decreased 100 17 4 8 5 0 7 1 2 2 0 0

MAX. GRADE ANY ADVERSE EVENT 13 36 51 21 12 1 1 5 2 2 2 0


S1204

S1204 Surveillance

A Sero-Epidemiologic Survey and Cost-Effectiveness Study of Screening for

Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and

Hepatitis C Virus (HCV) Among Newly Diagnosed Cancer Patients

Study Chairs:

S Ramsey, D Hershman

Statisticians:

J Unger, K Arnold

Data Coordinator:

M Yee

Date Activated:

08/29/2013

Date Closed:

02/15/2017

Objectives Among newly diagnosed cancer patients presenting

to SWOG-affiliated community and academic

oncology clinics, estimate the prevalence of human

immunodeficiency virus (HIV), hepatitis B (HBV),

and hepatitis C (HCV) infection.

Evaluate known sociodemographic, clinical, and

behavioral factors that are significantly associated

with previously undiagnosed HIV, HBV, and/or

HCV infection in a population of people with newly

diagnosed cancer

Among patients who are identified as having HIV,

HBV, and/or HCV, evaluate the timing and type of

treatments received, both for the viral infections and

the cancers.

Evaluate type and rate of cancer treatment-related

adverse events in patients with HIV, HBV, and/or

HCV infection.

Determine the cost-effectiveness of (1) routine,

universal screening and (2) risk factor-directed

screening of newly diagnosed cancer patients for HIV,

HBV and/or HCV versus current care.

Patient Population Patients must be presenting for evaluation or

treatment for the first diagnosis of a new solid or

hematologic cancer malignancy. Confirmed diagnosis

date must be within 120 days prior to first clinic visit

as a newly diagnosed cancer patient at the registering

clinic. Patients presenting for "second opinions" of

confirmed malignancies are eligible, including those

who have started cancer treatment at other facilities.

Patients must be registered within 90 days after their

first clinic visit. Patients must not have been

diagnosed with a malignancy other than the current

malignancy within the past five years, with the

exception of basal cell or squamous cell skin cancer,

in situ cervical cancer, or in situ breast cancer.

Patients must have no evidence of disease for a prior

malignancy for at least five years prior to

randomization except as noted above.

Patients must be 18 years of age or older. Patients

must have had their blood drawn for viral status

testing for HIV, HBV and HCV or provide

acceptable viral status documentation prior to

registration, as defined in the protocol. Note that

patients must have blood drawn for testing prior to

registration for any of the three viruses not covered

by the documentation. Patients are allowed to

participate in other clinical trials.

Accrual Goals A total of 3,061 patients will be accrued to achieve

3,000 eligible patients.

Summary Statement For the current status of this study, please refer to the

Cancer Care Delivery chapter.


S1608/II

S1608 Phase II

Coordinating Group: SWOG

Randomized Phase II Trial in Early Relapsing or Refractory Follicular

Lymphoma

Participants:

SWOG, CTSU (Supported by Alliance and ECOG-ACRIN)

Study Chairs:

P Barr, B Link (Alliance), C Flowers (ECOG-ACRIN)

Statisticians:

H Li, M LeBlanc

Data Coordinator:

I Syquia

SCHEMA

Objectives To compare the complete response rate at 6 cycles

after randomization as defined by centrally read

PET/CT (integral biomarker) of two targeted

therapeutic regimens (obinutuzumab + TGR-1202 or

obinutuzumab + lenalidomide) with obinutuzumab +

CHOP in patients with early relapsing or refractory

follicular lymphoma.

To validate the prognostic association of the m7-

FLIPI model, demonstrating that the population of

follicular lymphoma patients who respond poorly to

chemoimmunotherapy are enriched for having a

high-risk m7-FLIPI score, and that the score is

associated with progression-free survival (integrated

biomarker).

To estimate the 30 month sustained complete

response rate (CR30) defined by centrally read

PET/CT with each of the regimens in this early

relapsing or refractory follicular lymphoma

population.

R

A

N

D

O

M

I

Z

A

T

I

O

N

TGR-1202 + Obinutuzumab

Lenalidomide + Obinutuzumab

CHOP + Obinutuzumab


S1608/II

To estimate best response at 12 cycles of therapy,

progression-free survival, duration of response, and

overall survival with each of the combinations in

early relapsing or refractory follicular lymphoma.

To evaluate the adverse effects of each of the

regimens in early relapsing or refractory follicular

lymphoma.

To evaluate the predictive performance of non-

invasive genotyping (m7-FLIPI in circulating tumor

DNA) of plasma at study entry relative to standard

tumor genotyping (m7-FLIPI) of formalin-fixed

paraffin-embedded tumor tissue.

To evaluate the association between the detection of

active lymphoma by PET/CT and the detection of

circulating tumor DNA in plasma at baseline, after 6

and 12 cycles, and at 30 months after initiation of

study therapy

Patient Population Patients must have follicular lymphoma (Grade I, II

or IIIa) confirmed at initial diagnosis and at relapse

with identifiable FDG avid disease on PET/CT.

Patients must not have involvement with large cell

lymphoma. Patients must have failed to achieve a

complete remission, or must have relapsed within

two years after completing one line of bendamustine-

containing chemoimmunotherapy. Patients must

have the components of Follicular Lymphoma

International Prognostic Index (FLIPI) available from

diagnosis and at time of registration. Patients must

not have clinical evidence of central nervous system

involvement by lymphoma.

Patients must have received at least three cycles

of bendamustine as first line therapy. Patients

may have additionally received maintenance anti-

CD-20 antibody based therapy or consolidative

radioimmunotherapy within two years of completing

the bendamustine therapy. Patients must have

completed systemic therapy at least 21 days prior to

registration or completed radioimmunotherapy at

least 84 days prior to registration. Patients must have

recovered from all treatment related toxicities prior to

registration. Patients must not have had prior

anthracycline based therapy, or any prior treatment

with any PI3K inhibitor or lenalidomide. Relapsed

patients must not have received any intervening

chemotherapy. Patients must be able and willing to

take prophylaxis as listed in the protocol.

Patients must be at least 18 years of age and have a

Zubrod performance status of 0-2. Patients must have

adequate renal, hepatic, cardiac and hematologic

function. Patients with Hepatitis B virus infection, or

Hepatitis C virus infection, or known HIV infection

are eligible with restrictions. Females of childbearing

potential (FCBP) must have a negative serum or

urine pregnancy test with a sensitivity of at least 25

mIU/mL within 10 - 14 days prior to registration.

Stratification/Descriptive Factors Patient randomization will be stratified according to

the following factors: (1) previous receipt of

maintenance therapy: yes vs no; and (2) refractory

status: lack of CR after completing first line

bendamustine-containing chemoimmunotherapy vs

disease relapse within two years of completing first

line bendamustine-containing chemoimmunotherapy.

Accrual Goals The accrual goal for this study is 150 patients to

achieve 135 eligible patients. Interim analyses are

planned after response data for six cycles of

treatment are available for the first half of patients on

each arm.


EAY131/II

EAY131 Master Protocol / Phase II

Coordinating Group: ECOG-ACRIN

NCI-MATCH: Molecular Analysis for Therapy Choice

Participants:

ECOG-ACRIN, CTSU

Study Chairs:

K Flaherty (ECOG-ACRIN), P O'Dwyer (ECOG-ACRIN),

A Chen (NCI), B Conley (NCI), V Villalobos (SWOG)

Date Activated:

08/12/2015

SCHEMA

Objectives To evaluate the proportion of patients with objective

response (OR) to targeted study agent(s) in patients

with advanced refractory

cancers/lymphomas/multiple myeloma.

To evaluate the proportion of patients alive and

progression free at six months of treatment with

targeted study agent in patients with advanced

refractory cancers/lymphomas/multiple myeloma.

To evaluate the time until death or disease

progression.

To identify potential predictive biomarkers beyond

the genomic alteration by which treatment is assigned

or resistance mechanisms using additional genomic,

RNA protein and imaging-based assessment

platforms.

To assess whether radiomic phenotypes obtained

from pre-treatment imaging and changes from pre-

through post-therapy imaging can predict objective

response and progression-free survival and to

evaluate the association between pre-treatment

radiomic phenotypes and targeted gene mutation

patterns of tumor biopsy specimens.

Patient Population Patients must have histologically documented solid

tumors or histologically confirmed diagnosis of

lymphoma or multiple myeloma that has progressed

following at least one line of standard systemic

therapy and/or for whose disease no standard

treatment exists that has been shown to prolong

Screening

Registration

Tissue Submission for

Molecular Profiling

No Molecular Profile

of Interest

Treatment for

Molecular Profile of

Interest

*Upon progression or inability to tolerate protocol treatment, patients may be re-screened for additional molecular profiles

of interest and corresponding protocol treatment.

Off Study

Toxicity or

Progression*


EAY131/II

survival. Patients must have measurable disease and

meet one of the criteria in the protocol regarding

tissue procurement.

Patients must not currently be receiving any other

investigational agents. Any prior therapy,

radiotherapy (except palliative radiation therapy of

30 Gy or less), or major surgery must have been

completed at least four weeks prior to treatment on

NCI-MATCH and patient must be recovered from

adverse events due to prior therapy (except alopecia

and lymphopenia). Palliative radiation therapy must

have been completed at least two weeks prior to

enrollment on a NCI-MATCH treatment subprotocol,

and patient must have recovered from any adverse

events of this therapy. Patients with brain metastases

or primary brain tumors must have completed

treatment , surgery, or radiation therapy at least four

weeks prior to start of treatment. Patients must not

require the use of full dose coumarin-derivative

anticoagulants. Factor X inhibitors are permitted.

Patients may receive non-protocol treatment after

biopsy (if clinically indicated) until they receive

notification of results, but patients may not enroll in

another investigational study during this time and the

therapy cannot be an arm in this trial.

Patients must be at least 18 years of age, have an

ECOG performance status of 0 or 1 and must be able

to swallow tablets. Patients must have adequate

hematologic, hepatic, renal, cardiac and marrow

function. Patients must not have any uncontrolled

intercurrent illness. HIV-positive patients are eligible

provided they meet protocol criteria. Each

subprotocol will have additional eligibility criteria

that will be outlined in Section 2.0 of the agent-

specific subprotocol.

Accrual Goals The target screening accrual for this study is

approximately 3,000 patients, with the goal of

accruing 35 patients in each treatment subprotocol. If

after screening 500 patients, the total number of

patients with actionable tumor alteration (therefore

qualifying for treatment) is below 50, results will be

presented to the steering committee for consideration

of terminating the trial. Within any given subprotocol,

if rate of enrollment is such that it is unlikely accrual

can reach 25 patients by the time the overall study

screening accrual goal is met, and if 13 patients have

been treated and no responses have been observed,

then the steering committee may consider terminating

accrual in that subgroup due to lack of feasibility.

After 500 patients are screened, the study design will

be reassessed to assure its appropriateness. An

interim analysis of the assay results will be

performed after biopsies from approximately the first

200 patients are processed.

Summary Statement This study activated on January 26, 2015, with 10

subprotocols included in the activation. Only sites

utilizing the CIRB as their IRB of record are able to

participate in the trial. The study was temporarily

closed to accrual on November 11, 2015, after rapid

accrual of 795 patients to the screening step in only

three months, including 119 SWOG registrations.

This pause in patient enrollment for assessment of

study design appropriateness was lifted on May 31,

2016, when this study reopened to enrollment with an

additional 14 new subprotocols. As of November 16,

2016, accrual to subprotocol N has been suspended

due to drug supply shortage.

ECOG-ACRIN reported a total of 4,121 screened

patients and 368 molecularly matched patients as of

December 31, 2016. This includes 512 screened and

46 molecularly matched SWOG registrations. The

complete Spring 2016 summary of this study from

ECOG-ACRIN is available on the SWOG web site.

ECOG-ACRIN Cancer Research Group E1412

Study Progress and Safety Report Spring 2016

Page 1

E1412 RANDOMIZED PHASE II STUDY OF LENALIDOMIDE R-CHOP (R2CHOP) VS R-

CHOP (RITUXIMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN, VINCRISTINE, AND

PREDNISONE) IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE LARGE B CELL

LYMPHOMA

Sponsor(s)

Coordinating Group ECOG-ACRIN

Chairperson(s) Dr. Grzegorz Nowakowski

Therapeutic Statistician Dr. Fangxin Hong

Imaging Statistician Dr. Fenghai Duan

Data Specialist Jannett Garrido

Phase of Study II

Type of Study Therapeutic

Committee Lymphoma

Accrual Objective 345 Patients

Participating Groups ECOG-ACRIN

DCP Treatment Credit 1.0

NSC# 10023, 26271, 67574, 687451, 703813, 725961

Clinicaltrials.gov Study ID NCT01856192

Study Status Open to Accrual

Date Proposed June 8, 2012

Date Activated August 27, 2013

Date Suspended May 22, 2015

Date Reactivated October 13, 2015

SCHEMA



Page 2

Purpose of the Study

Primary Endpoint (1) Progression-free survival (PFS) Secondary Endpoints (1) Response rate (RR) (2)

CR rate as defined by PET-CT criteria (3) Overall survival (OS) Correlative Endpoints (1) Impact of

DLBCL molecular subtype on outcome. (2) Interim PET scan results in relation to treatment outcome.

Study Population

Adult patients (age >/= 18) with untreated, histologically confirmed DLBCL expressing CD20 antigen,

stages IIB or II bulky measurable disease, ECOG PS 0-2, adequate organ function, able to receive aspirin

therapy. Pregnant or nursing women are excluded.

Summary of Study Design

In the revised design, a total of 345 patients will be enrolled to generate a total of 283 eligible DLBCL

cases, of which 102 cases are ABC-DLBCL. Patients will be randomized at 1:1 ratio to the control arm

(RCHOP) and the experimental arm (R2CHOP), stratified on IPI (2-3 vs. 4-5), age (<60 yrs. Vs >60 yrs).

The primary objective is to determine whether R2CHOP improves progression-free survival (PFS)

compared to RCHOP. A cure rate model was used for the PFS endpoint. It is expected that 2-year PFS

rate will be 64%, and cure rate is about 60% for the RCHOP arm. Assuming exponential distribution for

the PFS in the non-cure group, this translates into a median of 7.2 months (monthly failure rate of 0.096)

in the non-cure group. With a total accrual of 283 evaluable (eligible and treated) patients and total

information of 89 failures (additional 24 months follow-up); the study will have 89% to detect a 13%

increase in 2-year PFS rate from 64% to 77% in the R2CHOP arm, at one-sided 0.1 significance

level.With proportional hazard rate assumption, this difference corresponds to a hazard ratio of 0.59 and a

41% reduction in the PFS failure rate. A subset analysis within patients with ABC subtype is planned.

With 102 eligible ABC patients, the study will have 81% power to detect an 18% improvement to 74% 2-

year PFS rate for patients with ABC subtype, at one-sided 0.125 significance level. With proportional

hazard rate assumption, this difference corresponds to a hazard ratio of 0.52 and a 48% reduction in the

PFS failure rate. A correlative study of the results of interim PET scans, performed at prior to treatment,

prior to cycle 4 and after cycle 6 is also planned. These standard of care images will be archived at the

ACRIN Core PET Laboratory, and will be read centrally to examine these aims: 1) to evaluate the

association between a binary score of baseline SUV and PFS; 2) to evaluate the association of a binary

score of percent change in SUV from baseline to post-cycle 3; and 3) to compare percent change in SUV

from post-cycle 3 to baseline between the R2CHOP and RCHOP arims. Additional exploratory aims will

also be analyzed based on SUVs.

Progress to Date

This study was activated on August 27, 2013, suspended on May 22, 2015 after reaching its initial

accrual goal, and was reopened on October 13, 2015. A total of 244 patients have enrolled to the study as

of February 15, 2016. Accrual by ECOG-ACRIN institution and accrual by group are given in Tables 1a

and 1b, respectively. Projected accrual is listed in Table 1c. Expected cumulative accrual and actual

cumulative accrual are shown in Figure 1. Patient status as of February 15, 2016 is listed in Table 2.

Baseline patient demographic variables are listed in Table 3. Record status (number of forms due and

received) is listed in Table 4. Reasons off treatment are summarized in Table 5. Toxicity data is available

on 193 patients and incidence (hematologic toxicities included) is summarized in Table 6a. Grade 5

toxicity was observed in 5 patients. Off-treatment (treatment-related) toxicity is available on 175 patients

and incidence is presented in Table 6b. Nine lethal adverse events are listed in Table 7. One primary

secondary cancer was observed on Arm A (Table 8). Imaging status as of February 15, 2016 is listed in

Table 9.



Page 3

Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 0 Step 1

Aurora NCORP 0 4

Baystate Medical Center 0 1

Cancer Research Consortium of West Michigan NCORP 1 0

Cancer Research for the Ozarks NCORP 0 2

Carle Cancer Center NCORP 0 2

Case Western Reserve University 1 6

Colorado Cancer Research Program NCORP 0 3

Columbus NCORP 0 2

Dartmouth Hitchcock Medical Center 2 0

Delaware/Christiana Care NCORP 0 6

Emory University/Winship Cancer Institute 3 8

Essentia Health NCORP 0 1

Fox Chase Cancer Center 0 11

Froedtert and the Medical College of Wisconsin 0 3

Geisinger Cancer Institute NCORP 1 0

Georgia NCORP 0 1

Heartland Cancer Research NCORP 1 12

Indiana Univ/Melvin and Bren Simon Cancer Center 0 4

Iowa-Wide Oncology Research Coalition NCORP 0 5

Johns Hopkins Univ/Sidney Kimmel Cancer Center 0 10

Laura and Issac Perlmutter Ca Ctr at NYU Langone 0 1

Mayo Clinic 6 13

Metro Minnesota Community Oncology Res Consortium 1 8

Michigan Ca Res Consortium NCORP 0 12

Montana Cancer Consortium NCORP 1 0

Montefiore MU NCORP 0 2

Nevada Cancer Research Foundation NCORP 0 1

New Mexico MU NCORP 1 1

Northwestern University 2 2

Penn State Milton S Hershey Medical Center 1 3

Saint Luke's University Hospital-Bethlehem Campus 1 4

Sanford NCORP of the North Central Plains 1 5

Stanford Cancer Institute 1 1

Summa Akron City Hospital/Cooper Cancer Center 0 1

Thomas Jefferson University Hospital 0 7

Tufts Medical Center 0 1

UT Southwestern/Simmons Cancer Center-Dallas 0 8

University of Massachusetts Medical School 0 1

University of Michigan Comprehensive Cancer Center 1 1

University of Pennsylvania/Abramson Cancer Center 0 2

University of Wisconsin Hospital and Clinics 1 6

Vanderbilt University/Ingram Cancer Center 2 4

Wichita NCORP 2 3

Wisconsin NCORP 1 5

Total 31 173



Page 4

Table 1b. Accrual by Group

ECOG-ACRIN 31 173

SWOG 3 28

ALLIANCE 11 32

NRG 3 11

Total 48 244

Table 1c. Projected Accrual

Accrual goal 345

Planned accrual rate 144/yr

Accrual to date 244

Annual accrual rate

Overall 117/yr

Projected date of closure March 2017



Page 5

Table 2. Patient Status as of February 15, 2016

Cases Entered 244

Ineligible 0

Never Started Assigned Therapy 6

Reason for not starting assigned therapy (n=6)

Patient was hospitalized the day after registration (14024);

Patient withdrawal/refusal before beginning protocol therapy (14117, 14186);

Death before beginning protocol therapy (14196).

(14172, 14219)

Table 3. Demographics

Variable Level Arm A (n=121) Arm B (n=123) Total (n=244)

Sex Male 74 (61.2) 70 (56.9) 144 (59.0)

Female 47 (38.8) 53 (43.1) 100 (41.0)

Race White 111 (93.3) 104 (89.7) 215 (91.5)

African-American 5 (4.2) 9 (7.8) 14 (6.0)

Asian 3 (2.5) 3 (2.6) 6 (2.6)

Unknown/Unreported 2 7 9

Ethnicity Hispanic 4 (3.5) 5 (4.3) 9 (3.9)

Non-Hispanic 110 (96.5) 110 (95.7) 220 (96.1)

Unknown/Missing 7 8 15

Age Median 66 65 65

Minimum 23 22 22

Maximum 85 91 91

Table 4. Record Status

Form Name Forms Due Forms Received %

Demography 243 243 100.0

Patient Characteristics 243 238 97.9

Treatment Agent: Cyclophosphamide 1216 1198 98.5

Treatment Agent: Doxorubicin 1216 1198 98.5

Treatment Agent: Lenalidomide 608 596 98.0

Treatment Agent: Prednisone 1216 1179 97.0

Treatment Agent: Rituximab 1216 1198 98.5

Treatment Agent: Vincristine 1216 1198 98.5

Adverse Event Form 1216 1152 94.7

Disease Follow-Up Status Form 1800 1759 97.7

Off Treatment 209 206 98.6



Page 6

Table 5. Reasons Off Treatment

(Includes all patients who started treatment and

for whom off-treatment data have been received)

Reasons N %

Adverse event/side effects/complications 8 3.9

Alternative therapy 2 1.0

Death on study 7 3.4

Disease progression, relapse during active treatment 5 2.4

Other 6 2.9

Patient withdrawal/refusal after beginning protocol therapy 2 1.0

Treatment completed per protocol criteria 176 85.0

Total off treatment 206 99.5

Table 6a. Treatment-Related Toxicities

Toxicity Type

Treatment Arm

A (n=107) B (n=110)

Grade Grade

3 4 5 3 4 5

(%) (%) (%) (%) (%) (%)

Tinnitus 1 - - - - -

Anemia 21 5 - 21 2 -

Febrile neutropenia 18 3 - 7 - 1

Leukocytosis - - - - 1 -

Left ventricular systolic dysfunction 2 - - - - -

Fatigue 10 - - 6 - -

Fever 1 - - 1 - -

Edema limbs - - - 1 - -

Infusion related reaction 1 1 - - - -

Pruritus 1 - - - - -

Rash maculo-papular 1 - - - - -

Abdominal pain 1 - - - - -

Colonic obstruction 1 - - - - -

Diarrhea 7 - - - - -

Enterocolitis 1 - - - - -

Gastric perforation - - - 1 - -

Gastrointestinal disorders - Other, specify - - - 1 - -

Mucositis oral 2 - - 1 - -

Nausea 2 - - 1 - -

Vomiting 2 - - - - -

Lower gastrointestinal hemorrhage 1 - - - - -

Infections and infestations - Other, specify 2 - - - - -

Sepsis - 3 - - 2 2

Skin infection 2 - - - - -

Upper respiratory infection 1 - - - - -

Urinary tract infection 5 - - 2 - -

Enterocolitis infectious 1 - - - - -



Page 7

Table 6a. Treatment-Related Toxicities

Toxicity Type

Treatment Arm

A (n=107) B (n=110)

Grade Grade

3 4 5 3 4 5

(%) (%) (%) (%) (%) (%)

Lung infection 5 1 - 2 - 1

Pleural infection - - - 1 - -

Anorectal infection 1 - - - - -

Soft tissue infection 1 - - - - -

Fall - - - 1 - -

Alanine aminotransferase increased - - - 1 - -

Alkaline phosphatase increased 1 - - - - -

Creatinine increased 1 - - - - -

Lymphocyte count decreased 20 11 - 19 8 -

Neutrophil count decreased 9 49 - 13 43 -

Platelet count decreased 15 16 - 5 8 -

White blood cell decreased 11 29 - 9 22 -

Ejection fraction decreased 1 - - 1 - -

Anorexia 2 - - - - -

Dehydration 5 - - 3 - -

Hyperglycemia 1 - - - - -

Hypoalbuminemia 1 - - - - -

Hypocalcemia 2 - - 1 - -

Hypokalemia 7 - - 1 - -

Hyponatremia 5 - - 3 - -

Hypophosphatemia 4 - - 2 - -

Musculoskeletal and connective tissue disorder - Other, specify 1 - - - - -

Pain in extremity - - - 1 - -

Generalized muscle weakness 7 - - 2 - -

Dizziness 1 - - - - -

Peripheral sensory neuropathy 1 - - 1 - -

Syncope 2 - - 2 - -

Confusion 1 - - - - -

Delirium - - - 1 - -

Insomnia - - - 2 - -

Hiccups 1 - - - - -

Pleural effusion - - - 1 - -

Pneumonitis 1 - 1 - - -

Productive cough 1 - - - - -

Respiratory failure - 1 - - - -

Renal calculi 1 - - - - -

Acute kidney injury 1 - - - - -

Hypertension - - - 1 - -

Hypotension 2 - - 2 - -

Thromboembolic event 3 - - 1 - -

Vascular disorders - Other, specify 1 - - - - -

WORST DEGREE 22 53 1 17 45 4



Page 8

Table 6b Treatment-Related later (off treatment )Toxicities

Toxicity Type

Treatment Arm

OT (n=175)

Grade

3 4 5

(%) (%) (%)

Left ventricular systolic dysfunction 1 - -

Diarrhea 1 - -

Sepsis - - 1

Lymphocyte count decreased 1 - -

Neutrophil count decreased 1 1 -

White blood cell decreased 1 1 -

Ejection fraction decreased 1 - -

Dyspnea 1 - -

WORST DEGREE 3 1 1

Table 7. Lethal Adverse Events (regardless of treatment relation)

Case # Arm Description of Event

14039 B Death after cycle 6, last chemo 8/15/14. Admitted to hospital 4 months later

(12/16/14) with bilateral healthcare associated pneumonia, died 12/22 due to

sepsis/pneumonia. Reported as possibly related to treatment.

14052 B Cycle 6 day 8, weakness, neutropenic fever, UTI, pulmonary edema, elected

against aggressive treatment and discharged to hospice.

14103 B Cycle 1 day9, admitted for neutropenic fever, per report given neupogen. Blood

counts recovered, found to have pneumonia later in hospitalization, pleural

effusions,. Tried BiPAP, but declined intubation and died of respiratory failure,

on comfort measures. Reported as probable.

14129 B Cycle 2, day 19, hospitalized for neutropenic fever, blood count recovered, but

tracheoesophageal fistula documented by barium swallow with barium

aspiration, of note patient had exredodal lung involvement, patient not a

candidate for surgical repair, did not want stent, elected hospice. Death reported

as unrelated to treatment.

14130 B Cycle 1, day 5 with neutropenic fever, of note received prophylactic neulasta,

colitis and sepsis, had emergent surgery. Toxic megacolon, died after 5 day

hospitalization. Reported as probable.

14131 B Death after cycle 3, day 17, sudden death in patient with h/o CAD; asymptotic

the day before, sudden death during the night, no autopsy. Reported as unrelated

to treatment, definite to cardiac arrest.

14174 A Lung infection and febrile neutropenia followed by acute respiratory failure with

hypoxia. Patient died due to uncontrolled pneumonia

14195 B Sepsis secondary to proteus bacteremia and UTI. Possibly treatment related.

14214 A Sudden death NOS



Page 9

Table 8. Second Primary Cancers

(By arm during which event was reported)

Site Arm A Arm B

Lung 1 -

Table 9. Imaging Status

Status of PET PET Completed PET Received at Core Lab

n % n %

All 3 PET scans 145 61% 106 44%

PET3 and PET6, but not PET0 3 1% 1 0%



PET6, but not PET0 or PET3 1 0% 2 1%



No PET scans 15 6% 47 20%

Definitions

PET0 = Pre-treatment PET scan (Baseline)

PET3 = Post-cycle 3/Pre cycle 4 PET scan

PET6 = Post-cycle 6 PET scan

NOTE: Participant(s) who never started treatment have been omitted.



Page 1

E1411 INTERGROUP RANDOMIZED PHASE II FOUR ARM STUDY IN PATIENTS WITH

PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA OF THERAPY WITH:

ARM A = RITUXIMAB+BENDAMUSTINE FOLLOWED BY RITUXIMAB

CONSOLIDATION (RB->R); ARM B =

RITUXIMAB+BENDAMUSTINE+BORTEZOMIB FOLLOWED BY RITUXIMAB

CONSOLIDATION (RBV->R), ARM C = RITUXIMAB+BENDAMUSTINE FOLLOWED

BY LENALIDOMIDE+RITUXIMAB CONSOLIDATION (RB->LR) OR ARM D =

RITUXIMAB+BENDAMUSTINE+BORTEZOMIB FOLLOWED BY

LENALIDOMIDE+RITUXIMAB CONSOLIDATION (RBV->LR)

Sponsor(s)

Coordinating Group ECOG-ACRIN

Chairperson(s) Dr. Mitchell Smith

Statistician Mr. Opeyemi Jegede

Data Specialist David Limjoco

Phase of Study II

Type of Study Therapeutic

Committee Lymphoma

Accrual Objective 332 Patients

Participating Groups ECOG-ACRIN, CALGB, SWOG, CTSU,

ALLIANCE, NRG

DCP Treatment Credit 2.0

DCP Cancer Control Credit 0.5

NSC# 138783, 681239, 687451, 703813

Clinicaltrials.gov Study ID NCT01415752

Study Status Open to Accrual

Date Proposed February 18, 2011

Date Activated May 22, 2012

Schema



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Purpose of the Study

1. Primary objectives: (1.1) To determine whether the addition of bortezomib (RBV) to an induction

regimen of rituximab-bendamustine (RB) improves progression-free survival (PFS) compared to RB alone

in patients with previously untreated mantle cell lymphoma. (1.2) To determine whether the addition of

lenalidomide to a consolidation regimen of rituximab following an induction regimen of RB or RBV

improves PFS compared to consolidation rituximab alone in this patient population. 2. Secondary

objectives: (2.1) To determine whether the addition of bortezomib to induction therapy improves the

PET-documented complete response rate compared to RB alone. (2.2) To determine the objective response

rate (ORR) for RB and RBV. (2.3) Among patients who do not have PET-documented CR at the end of

induction, to determine whether the addition of lenalidomide to consolidation therapy improves CR and

ORR compared with rituximab alone. (2.4) To determine overall survival (OS) in the treatment arms. (2.5)

To determine safety, with attention to the addition of bortezomib in the induction regimen and

lenalidomide-rituximab as consolidation therapy.

Study Population

Histologically confirmed untreated mantle cell lymphoma, ECOG PS 0-2, must have at least one objective

measurable disease parameter, must have adequate hematologic, liver and renal function, no evidence of

prior malignancy, no CNS involvement.

Summary of Study Design

The goals of the study are to determine if either bortezomib (Velcade, V) added to an induction regimen of

rituximab/ bendamustine (RB) or lenalidomide (L) added to rituximab (R) maintenance is associated with

improved outcome in patients with MCL and to identify arms suitable for evaluation in the Phase 3 setting.

332 patients, of whom 320 are expected to be eligible and to receive some protocol treatment, will be

stratified for balancing purposes according to MIPI risk status (low risk vs. intermediate vs. high risk) and

age (>/= 60 vs. < 60), and enrolled over 40 months and equally randomized to one of four arms: Arm A: RB

> R, Arm B: RBV ->R, Arm C: RB ->LR, Arm D: RBV ->LR.

Progress to Date

This study was activated on May 22, 2012. Accrual as of February 16, 2016 is 310. Tables 1a, 1b and 1c

show accrual by ECOG-ACRIN institution, accrual by group and projected accrual, respectively. Figure 1

shows cumulative accrual. Table 2 summarizes patient status as of February 16, 2016. Table 3 summarizes

demographics at study entry by arm. Record status is summarized in Table 4. Tables 5a and 5b show

off-treatment reasons for each step. Tables 6a and 6b show grade 3 and above treatment-related toxicity

data available for each step, and table 6c shows treatment-related late toxicities. Toxicity data are available

on 280 patients on step 1, 165 patients on step 2 and 47 patients for late toxicities. There were 3

treatment-related grade 5 toxicities observed in treatment step 1 and 1 treatment-related grade 5 toxicity in

step 2. These grade 5 events are listed in Table 7. List of cases with second primary cancer can be found in

Table 8. A summary of the collection of quality of life data is presented in Table 9.

Summary of New Study Design Proposal

Due to a lower than expected step 2 treatment accrual, an amendment to expand total accrual to 372, from

332, patients was proposed in February 2016. It was expected that 90% of accrued patients will proceed to

treatment step 2, but a landmark analysis conducted in December 2015, using as a cutoff the date the last

registered patient completed step 1 treatment per protocol, indicated that only 80% of accrued patients were

proceeding to treatment step 2. The revised design proposes to enroll these additional 40 patients over 4



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months with the same follow-up duration of 23 months. The original hypothesis of 37.4% reduction in the

hazard rate which corresponds to a 2-year PFS of 80% will remain the same for the new study design and

will be tested using a stratified logrank test with 1-sided Type I error of 10% for both induction and

consolidation treatments. Full information will exist for induction and consolidation treatments when 149

and 120 patients have progressed or died respectively.

Interim analysis will be conducted separately, at 25%, 50%, and 75% statistical information, for both

phases of the study (induction and consolidation) and monitored by the ECOG Data Monitoring Committee

(DMC) for early stopping for harm and futility.

Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 1 Step 2

Cancer Research Consortium of West Michigan NCORP 6 5

Cancer Research for the Ozarks NCORP 1 1

Carle Cancer Center NCORP 1 1

Case Western Reserve University 12 9

Catholic Health Initiatives NCORP 1 0

Colorado Cancer Research Program NCORP 7 4

Dartmouth Hitchcock Medical Center 3 0

Dayton NCORP 1 0

Delaware/Christiana Care NCORP 6 3

Essentia Health NCORP 5 2

Fox Chase Cancer Center 3 1

Fred Hutchinson Cancer Research Center 1 1

Froedtert and the Medical College of Wisconsin 7 5

Geisinger Cancer Institute NCORP 1 0

Heartland Cancer Research NCORP 2 2

Indiana Univ/Melvin and Bren Simon Cancer Center 1 1

Iowa-Wide Oncology Research Coalition NCORP 4 4

Mayo Clinic 11 6

Metro Minnesota Community Oncology Res Consortium 11 9

Michigan Ca Res Consortium NCORP 18 7

Montefiore MU NCORP 4 2

Northwestern University 7 1

Ochsner NCORP 2 2

Penn State Milton S Hershey Medical Center 1 0

Sanford NCORP of the North Central Plains 1 1

Stroger Hospital of Cook County MU NCORP 4 4

Summa Akron City Hospital/Cooper Cancer Center 0 1

Thomas Jefferson University Hospital 1 1

Tufts Medical Center 0 1

UT Southwestern/Simmons Cancer Center-Dallas 2 2

University of Pittsburgh Cancer Institute (UPCI) 2 0

University of Wisconsin Hospital and Clinics 4 2

VCU Massey Cancer Center MU NCORP 1 0

Vanderbilt University/Ingram Cancer Center 6 5

Washington University School of Medicine 7 6

Wichita NCORP 1 0

Wisconsin NCORP 7 5

Total 152 94



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Table 1b. Accrual by Group

Step 1 Step 2

ECOG-ACRIN 152 94

NCCTG 3 2

CALGB 12 5

NCIC-CTG 1 1

SWOG 74 43

NSABP 5 2

ALLIANCE 58 45

NRG 5 7

Total 310 199

Table 1c. Projected Accrual

Step 1 Step 2

Accrual goal 332

Planned accrual rate 100/yr

Accrual to date 310 199

Annual accrual rate

Overall 83/yr 53/yr

Last 6 months 112/yr 122/yr

Projected date of closure April 2016



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Table 2. Patient Status as of February 16, 2016

Step 1 Step 2

Cases Entered 310 199

Ineligible 2 0

Never Started Assigned Therapy 1 2

Reason for ineligibility Step 1:

Case 14022: Concurrent lung cancer malignancy, per study chair.

Case 14255: Baseline measurements and evaluations that confirm measurable disease

not obtained within 4 weeks of registration to the study.

Reason for not starting assigned therapy Step 1:

Case 14005: Patient ineligible

Reason for not starting assigned therapy Step 2:

Case 14060: Disease progression before protocol therapy

Case 14197: Patient withdrew before starting protocol therapy

Table 3a. Demographics Step 1

Variable Level Arm A

(n=80)

Arm B

(n=77)

Arm C

(n=77)

Arm D

(n=76)

Total

(n=310)

Sex Male 58 (72.5) 55 (71.4) 56 (72.7) 56 (73.7) 225 (72.6)

Female 22 (27.5) 22 (28.6) 21 (27.3) 20 (26.3) 85 (27.4)

Race White 72 (94.7) 74 (96.1) 69 (94.5) 68 (90.7) 283 (94.0)

African-American 3 (3.9) 1 (1.3) 0 (0.0) 4 (5.3) 8 (2.7)

Asian 1 (1.3) 2 (2.6) 4 (5.5) 1 (1.3) 8 (2.7)

Native Hawaiian 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.3) 1 (0.3)

Native American 0 (0.0) 0 (0.0) 0 (0.0) 1 (1.3) 1 (0.3)

Unknown/Unreported 4 0 4 1 9

Ethnicity Hispanic 1 (1.3) 2 (2.6) 3 (4.0) 1 (1.3) 7 (2.3)

Non-Hispanic 75 (98.7) 74 (97.4) 72 (96.0) 74 (98.7) 295 (97.7)

Unknown/Missing 4 1 2 1 8

Age Median 66 69 68 67 68

Minimum 46 43 47 42 42

Maximum 83 87 90 83 90



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Table 3b. Demographics Step 2

Variable Level Arm E

(n=47)

Arm F

(n=49)

Arm G

(n=54)

Arm H

(n=49)

Total

(n=199)

Sex Male 34 (72.3) 32 (65.3) 39 (72.2) 36 (73.5) 141 (70.9)

Female 13 (27.7) 17 (34.7) 15 (27.8) 13 (26.5) 58 (29.1)

Race White 41 (91.1) 48 (98.0) 50 (96.2) 45 (93.8) 184 (94.8)

African-American 3 (6.7) 1 (2.0) 0 (0.0) 2 (4.2) 6 (3.1)

Asian 1 (2.2) 0 (0.0) 2 (3.8) 0 (0.0) 3 (1.5)

Native American 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.1) 1 (0.5)

Unknown/Unreported 2 0 2 1 5

Ethnicity Hispanic 1 (2.3) 1 (2.0) 3 (5.7) 1 (2.1) 6 (3.1)

Non-Hispanic 43 (97.7) 48 (98.0) 50 (94.3) 47 (97.9) 188 (96.9)

Unknown/Missing 3 0 1 1 5

Age Median 68 70 69 66 68

Minimum 52 43 47 43 43

Maximum 83 88 90 84 90

Table 4. Record Status

Form Name Forms Due Forms Received %

Demography 310 310 100.0

Patient Characteristics 310 296 95.5

Treatment Agent: Bendamustine 1496 1440 96.3

Treatment Agent: Bortezomib 744 715 96.1

Treatment Agent: Lenalidomide 1019 926 90.9

Treatment Agent: Rituximab 3033 2927 96.5

Adverse Event Form 3485 3251 93.3

Disease Follow-up Status 3616 3397 93.9

Off Treatment (Step 1) 191 178 93.2

Off Treatment (Step 2) 118 54 45.8

Table 5a. Reasons Off-Treatment – Step 1

For Patients Not Registered to Subsequent Steps



Reasons N %




Disease progression- relapse during active treatment 8 16.7

Other 2 4.2

Patient off-treatment for other complicating disease 3 6.3






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Table 5b. Reasons Off-Treatment – Step 2



Reasons N %




Disease progression- relapse during active treatment 17 28.8

Other 4 6.8




Table 6a. Treatment-Related Toxicities – Step 1

Toxicity Type

Treatment Arm

A (n=71) B (n=72) C (n=69) D (n=68)

Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Anemia 4 - - 1 - - - - - 4 1 -

Blood and lymphatic system disorders - Other, specify 1 - - - - - - - - - - -

Febrile neutropenia - - - 2 - - - 1 - 2 - -

Thrombotic thrombocytopenic purpura - - - - - - - - - 1 - -

Atrial fibrillation 1 - - - - - - - - 1 - -

Cardiac arrest - - - - - 1 - - - - - -

Left ventricular systolic dysfunction 1 - - 1 - - - - - - - -

Fatigue - - - 1 - - 1 - - - - -

Fever - - - - - - - - - 1 - -

Edema limbs 3 - - 1 - - - - - - - -

Infusion related reaction - - - 3 - - - - - 2 - -

Pruritus 1 - - - - - 1 - - 1 - -

Rash acneiform 1 - - - - - - - - - - -

Rash maculo-papular 2 - - 4 - - 2 - - 4 - -

Skin and subcutaneous tissue disorders - Other, specify 1 - - - - - 1 - - - - -

Abdominal distension 1 - - - - - - - - - - -

Abdominal pain - - - - - - - - - 1 - -

Colitis - - - 1 - - - - - - - -

Dental caries - - - 1 - - - - - - - -

Diarrhea 1 - - 2 - - - - - 1 - -

Mucositis oral - - - 1 - - - - - - - -

Nausea 2 - - 1 - - - - - - - -

Vomiting 2 - - 2 - - - - - - - -

Hepatobiliary disorders - Other, specify - - - - - 1 - - - - - -

Allergic reaction 1 - - 3 - - - - - 1 - -

Anaphylaxis - - - 1 - - - - - - - -

Immune system disorders - Other, specify - - - - - - - - - 1 - -



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Toxicity Type

Treatment Arm

A (n=71) B (n=72) C (n=69) D (n=68)


3 4 5 3 4 5 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Cytokine release syndrome - - - 1 - - - - - - - -

Infections and infestations - Other, specify - - - 2 - - - - - 1 - -

Sepsis - 1 - - - - - 1 - - 2 -

Sinusitis 1 - - - - - - - - - - -

Skin infection - - - - - - - - - 1 - -

Upper respiratory infection - - - - - - - - - 1 - -

Lung infection 1 - - - - - 2 - - 1 - -

Alanine aminotransferase increased 1 - - - - - - - - - - -

Aspartate aminotransferase increased 1 - - - - - - - - - - -

CD4 lymphocytes decreased - - - 1 - - - - - - - -

Creatinine increased - - - - - - 1 - - - - -

INR increased - - - 1 - - - - - - - -

Lymphocyte count decreased 25 13 - 28 15 - 24 15 - 33 15 -

Lymphocyte count increased 1 - - - - - - - - - - -

Neutrophil count decreased 8 5 - 12 5 - 8 4 - 17 5 -

Platelet count decreased 5 - - 9 - - 5 - - 4 2 -

Weight gain 2 - - - - - - - - - - -

Weight loss - - - - - - - - - 1 - -

White blood cell decreased 9 1 - 12 5 - 7 1 - 14 2 -

Dehydration - - - - - - 1 - - - - -

Hyperglycemia - - - 1 - - - - - 2 - -

Hyperuricemia - - - - - - - - - - 1 -

Hypoalbuminemia - - - - - - 1 - - - - -

Hypocalcemia - - - 1 - - - - - - - -

Hypokalemia 2 - - - - - - - - - - -

Hypomagnesemia - - - - - - - - - 1 - -

Hyponatremia 2 - - 1 - - 1 1 - 1 - -

Hypophosphatemia - - - 1 - - - - - - - -

Tumor lysis syndrome - - - - - - - 1 1 - - -

Back pain - - - 2 - - - - - - - -

Generalized muscle weakness - - - - - - 1 - - - - -

Dizziness - - - - - - - - - 1 - -

Peripheral sensory neuropathy - - - 3 - - - - - 2 - -

Vasovagal reaction - - - 1 - - - - - - - -

Cataract - - - - - - - - - 1 - -

Insomnia - - - 2 - - - - - - - -

Dyspnea - - - - 1 - - - - - - -

Hypoxia 1 - - - 1 - - - - 1 - -

Pulmonary edema - - - - 1 - - - - - - -

Respiratory failure - - - - 1 - - - - - - -

Chronic kidney disease 1 - - 1 - - - - - - - -

Acute kidney injury - - - - - - 1 - - - - -

Flushing - - - - - - 1 - - - - -

Hypertension 3 - - 6 - - 3 - - 2 - -



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Toxicity Type

Treatment Arm

A (n=71) B (n=72) C (n=69) D (n=68)


3 4 5 3 4 5 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Hypotension 1 - - 2 - - 2 - - 2 - -

Thromboembolic event - - - 1 - - - - - - - -

Vascular disorders - Other, specify - - - - - - - - - 1 - -

WORST DEGREE 34 19 - 41 18 2 29 19 1 33 24 -

Table 6b. Treatment-Related Toxicities – Step 2

Toxicity Type

Treatment Arm

E (n=39) F (n=42) G (n=41) H (n=43)


3 4 5 3 4 5 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Anemia - - - - - - - - - 1 - -

Febrile neutropenia - - - 2 1 - 2 - - 2 1 -

Myocardial infarction - - - - - - - - 1 - - -

Fatigue - - - - - - 1 - - 2 - -

Fever - - - - - - - - - - 1 -

Pain - - - - - - 1 - - - - -

Rash maculo-papular - - - - - - 2 - - - - -

Palmar-plantar erythrodysesthesia syndrome - - - - - - 1 - - - - -

Diarrhea - - - - - - - - - 3 - -

Nausea - - - - - - - - - 1 - -

Allergic reaction - - - - - - - - - 1 - -

Infections and infestations - Other, specify 1 - - 1 - - - - - - - -

Skin infection 1 - - - - - - - - - - -

Lung infection 1 - - - - - 1 - - 2 1 -

Alanine aminotransferase increased - - - - - - - - - 1 - -

CPK increased - - - - 1 - - - - - - -

Creatinine increased - - - 1 - - - - - - - -

INR increased - - - - - - - - - 1 - -

Lymphocyte count decreased 12 6 - 14 4 - 18 3 - 21 6 -

Neutrophil count decreased 4 1 - 1 4 - 4 12 - 11 8 -

Platelet count decreased - - - - 1 - 1 - - 1 - -

Weight loss - - - - - - - - - 2 - -

White blood cell decreased 5 - - 2 3 - 12 4 - 12 - -

Anorexia - - - - - - - - - 1 - -

Dehydration - - - 1 - - - - - - - -

Hypokalemia - - - 1 - - 1 - - - - -

Hyponatremia - - - 1 - - - - - - - -

Generalized muscle weakness - - - 1 - - - - - - - -

Paresthesia - - - - - - - - - 1 - -



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Table 6b. Treatment-Related Toxicities – Step 2

Toxicity Type

Treatment Arm

E (n=39) F (n=42) G (n=41) H (n=43)


3 4 5 3 4 5 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Peripheral sensory neuropathy - - - 1 - - - - - 1 - -

Syncope - - - - - - - - - 1 - -

Vasovagal reaction - - - - - - - - - 1 - -

Treatment related secondary malignancy - - - - - - 1 - - 1 - -

Cough - - - - - - - - - 2 - -

Dyspnea - - - - - - - - - 1 - -

Hypoxia - - - - - - 1 - - - - -

Pneumonitis - - - - - - 1 - - - - -

Chronic kidney disease - - - 1 - - - - - - - -

Hypertension - - - 2 - - 1 - - 1 - -

Hypotension - - - 1 - - - - - - - -

Thromboembolic event - - - - - - - - - 2 - -

WORST DEGREE 14 7 - 13 7 - 13 15 1 22 13 -

Table 6c. Treatment-Related Late Toxicities

Toxicity Type

Treatment Arm

OT (n=47)

Grade

3 4 5

(n) (n) (n)

Neutrophil count decreased - 1 -

White blood cell decreased 1 - -

WORST DEGREE - 1 -

Table 7. Lethal Adverse Events

Case Arm Description of Event

14208 B Hepatobiliary disorders

14247 C Tumor lysis syndrome

14279 B Cardiac arrest

14028 G Myocardial infarction



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Table 8. Second Primary Cancer

Cancer Site Treatment Arm

C D E G H

Basal cell carcinoma 1 - 1 - 3

Breast - - - - 1

Lung cancer - - - - 1

Melanoma - 1 - - 1

Skin cancer not melanoma 2 - - 2 -

Thyroid - - - - 1

Total 3 1 1 2 7

Table 9. Quality of Life Compliance

QOL Timepoint Patients Reaching Timepoint % Forms Completed

Baseline (Step 1) 302 99.67

6 Month QOL + End of Induction 210 88.57

12 Month QOL 101 81.19

Off Treatment Consolidation QOL

(due to reason other than progression) 43 69.77

Progression 26 65.38

51101 November 2016

Template Version Date: September 24, 2013

Alliance Study 51101 – A Randomized Phase II Trial Of Myeloablative Versus Non-Myeloablative Consolidation Chemotherapy For Newly Diagnosed Primary CNS B-Cell Lymphoma

Committee: Lymphoma Study Statisticians: Sin-Ho Jung, PhD Study Chair: Tracy Batchelor, MD, MPH Brandelyn N. Pitcher, MS 1.0 OBJECTIVES Primary

To compare the two-year progression-free survival (PFS) of patients treated with the myeloablative consolidation treatment strategy of HDT/ASCT versus those treated with non-myeloablative consolidation chemotherapy with cytarabine and etoposide

Secondary 1. To compare the two-year event-free survival (EFS) of patients treated with

consolidation HDT/ASCT versus those treated with consolidation chemotherapy consisting of etoposide and cytarabine

2. To compare the overall survival (OS) of patients treated with the consolidation HDT/ASCT versus those treated with consolidation chemotherapy consisting of etoposide and cytarabine

3. To assess the toxicities associated with consolidation HDT/ASCT versus consolidation consisting of etoposide and cytarabine

4. To determine diffusion MRI metrics (ADCmini, ADC25%, and ADCmean) prior to induction chemotherapy, after one full induction chemotherapy cycle, and at the end of induction chemotherapy as a predictor of response and outcome (CALGB 581101)

5. To determine brain FDG-PET metrics (tumor SUV and tumor versus background SUV) prior to induction chemotherapy, after one full induction chemotherapy cycle, and at the end of induction chemotherapy as a predictor of response and outcome (CALGB 581101)

6. To determine whether low baseline ADC measurements are associated with shorter PFS and OS (CALGB 581101)

7. To determine whether reduction in tumor SUV by > 25% on brain FDG-PET/CT after one cycle of induction therapy is associated with improved PFS and OS (CALGB 581101)

8. To determine which IHC-based biomarkers are predictive of an adverse prognosis (CALGB 151113)

9. To determine which IHC-based biomarkers are predictive of a favorable prognosis (CALGB 151113) for BCL6 (B-cell CLL/lymphoma 6), and STAT 6 (signal transducer and activator of transcription 6, interleukin-4 induced)

10. To analyze tumor tissue for gene expression profiles, and to correlate these profiles with treatment outcomes (CALGB 151113)

11. To determine whether CSF proteome is a predictor of outcomes (prognostic marker) irrespective of treatment arm [43] (CALGB 151113) for (IL-10 (interleukin 10) and C3 (complement component 3)

12. To assess the neurocognitive function of patients treated with consolidation HDT/ASCT versus those treated with consolidation chemotherapy (etoposide and cytarabine) as measured by serial administration of the International PCNSL Collaborative Group (IPCG) neurocognitive battery and evaluate the long-term survivorship differences between the two arms (CALGB 71105)

13. To assess the quality of life of patients treated with consolidation HDT/ASCT versus those treated with consolidation etoposide and cytarabine as measured by the EORTC Quality of Life Questionnaire-Core 30/Brain Cancer Module-20 (EORTC-QLQ30/BCM20), and to evaluate the long-term survivorship differences between the two arms (CALGB 71105)

51101 November 2016


2.0 CURRENT SCHEMA

. 3.0 ELIGIBILITY CRITERIA

• Diffuse large B-cell lymphoma confined to the CNS; diagnosis by brain biopsy or resection, CSF, or vitreous fluid.

• No evidence of NHL outside of CNS; no history of NHL • No isolated ocular or leptomeningeal lymphoma • No prior chemotherapy or radiation therapy for lymphoma • At least one measurable, contract-enhancing brain lesion (≥ 1 cm in length) • Age 18-75 years • Karnofsky performance scale ≥ 30 (≥ 50 for patients ages 60-70) • Non-pregnant and non-nursing • Negative HIV serology • Negative HBV and HCV serology • No history of organ transplantation or ongoing immunosuppressant therapy • ANC ≥ 1500/mcL • AST & ALT ≤ 2 x ULN • Total bilirubin ≤ 3 mg/dL • Platelets ≥ 100,000/mcL • CrCl ≥ mL/min

4.0 TREATMENT SCHEDULE

The treatment schedule is described in detail in the Study Schema (Section 2.0 of this report).

51101 November 2016


5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors This is a randomized phase II study. Patients will be randomized to HDT/ASCT or chemotherapy.

The intent to treat (ITT) analysis using the log-rank test with a one-sided alpha=10% will have 90% power to compare two-year PFS of 50% and 70% between the two arms. The final analysis will be conducted when 60 events (progressions or deaths) are observed from the patients who proceed to either HDT/ASCT or chemotherapy (or about 95 events from all the eligible patients). All randomized patients will be included in the final data analysis based on intent-to-treat analysis. The experimental therapy will be accepted for further investigation if the one-sided p-value is smaller than 0.1. The critical value c at the final analysis will be obtained by solving 1-alpha=P(Z1 > c1, Z > c) with respect to c, where (Z1, Z) is a bivariate normal random vector with means 0, variances 1 and correlation coefficient r=(v1/v)1/2, and v1 and v are variance estimates of the log-rank test at the interim and final analyses, respectively. Through simulations, the two-stage design is found to have about 9.7% of type I error and 87% power.

5.2 Primary Endpoint

The primary endpoint of this trial is to compare the two-year progression-free survival (PFS) of patients treated with the myeloablative consolidation treatment strategy of HDT/ASCT versus those treated with non-myeloablative consolidation chemotherapy with cytarabine and etoposide.

5.3 Target Accrual

A total of 160 patients (80 per arm) will be randomized between the control and experimental arms with 50:50 allocation proportions. The randomization will be conducted at registration, i.e. before induction therapy. Assuming that 80% of randomized subjects will achieve a radiographic response (CR, CRU, or PR) or stability (SD) and 5% will withdraw or will be ineligible, approximately 120 patients will be eligible for proceeding to either HCT/ASCT or chemotherapy. We expect an accrual rate of 6 patients per month.

6.0 CURRENT ACCRUAL

Study Activation Date 06/15/2012 Target Accrual (n) 160 Current Accrual (n) 81 Accrual Rate – Since activation 1.59/month Accrual Rate – Past 12 months (if applicable) 2.25/month Projected closure date for a trial open for more than one year (based on accrual rate from past 12 months)

09/08/2019

51101 November 2016


7.0 CURRENT STUDY STATUS

This study was activated on 06/15/2012. The accrual as of 9/07/2016 was 81. 8.0 PATIENT CHARACTERISTICS Table 8a. Demographics

A

(N=40) B

(N=41) Total

(N=81) Age N 40 41 81 Mean (SD) 58.3 (10.0) 58.9 (10.4) 58.6 (10.2) Median 61.0 59.0 61.0 Q1, Q3 52.5, 66.0 55.0, 68.0 54.0, 67.0 Range (34.0-74.0) (34.0-75.0) (34.0-75.0) Race White 38 (95.0%) 39 (95.1%) 77 (95.1%) Asian 1 (2.5%) 1 (2.4%) 2 (2.5%) Not reported: patient refused or not available 0 (0.0%) 1 (2.4%) 1 (1.2%)

0 000 0 1 0

11 3 1 0 2 2 2 2 1 0 1 1 1 1 2

7 1 0 2 2 1 24 1 0 3 1 2 1 2 3 1 2 3 1 0 1

5 04 2 2

5 1 0

Expected Accrual 160 Patients

51101 November 2016


A

(N=40) B

(N=41) Total

(N=81) Unknown: Patient unsure 1 (2.5%) 0 (0.0%) 1 (1.2%) Gender f 17 (42.5%) 17 (41.5%) 34 (42.0%) m 23 (57.5%) 24 (58.5%) 47 (58.0%)

Table 8b. Stratification Factors

A

(N=40) B

(N=41) Total

(N=81) Stratification#Factor Age < 51 years 8 (20.0%) 8 (19.5%) 16 (19.8%) Age >= 51 years and KPS >= 70 23 (57.5%) 24 (58.5%) 47 (58.0%) Age >= 51 years and KPS < 70 9 (22.5%) 9 (22.0%) 18 (22.2%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary 66 (81.5%) patients are evaluable for adverse event (AE) analysis. Overall, 12 (18.2%) experienced a maximum grade 3 adverse event, 41 (62%) experienced a maximum grade 4 adverse event and 2 patient2 (3%) experienced a grade 5. The most commonly occurring grade 3/4 AEs include: neutrophil count decreased (60% Arm A, 59% Arm B), platelet count decreased (60% Arm A, 59% Arm B), lymphocyte count decreased (47% Arm A, 33% Arm B), anemia (50% Arm A, 38% Arm B), aspartate aminotransferase increased (30% Arm A; 27% Arm B) alanine aminotransferase increased (40% Arm A; 33% Arm B) and febrile neutropenia (43% Arm A, 15% Arm B), and hyperglycemia (17% Arm A; 29% Arm B).

Table 9a. Summary of Grade 3+ Adverse Events

Regardless of Attribution Number of Evaluable Patients:

Arm A=32 Arm B=34

Patients with a maximum: Arm n (%)

Total

Grade 3 Event A 7 (21.9%)

B 5 (14.7%)


B 21 (61.8%)


B 1 (2.9%)

Hematologic Adverse Events


51101 November 2016


Summary of Grade 3+ Adverse Events Regardless of Attribution

Number of Evaluable Patients: Arm A=32 Arm B=34

Patients with a maximum: Arm n (%)

B 4 (11.8%)


B 20 (58.8%)


B 0 (0.0%)

Non-Hematologic Adverse Events


B 14 (41.2%)


B 9 (26.5%)


B 1 (2.9%)

Note: Summaries are based on available patient data Table 9b.

Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event


Arm A=32 Arm B=34 Grade of AdverseEvent

Arm 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)

Hematologic Adverse Events Blood/Bone Marrow

Anemia A 15 ( 50%) 0 ( 0%) 0 ( 0%) B 13 ( 38%) 0 ( 0%) 0 ( 0%) Blood and lymphat sys disord - Oth spec

A 1 ( 3%) 1 ( 3%) 0 ( 0%)

B 0 ( 0%) 1 ( 3%) 0 ( 0%) Leukocytosis A 2 ( 7%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Lymphocyte count decreased A 6 ( 20%) 8 ( 27%) 0 ( 0%) B 6 ( 18%) 5 ( 15%) 0 ( 0%) Lymphocyte count increased A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Neutrophil count decreased A 1 ( 3%) 17 ( 57%) 0 ( 0%)

51101 November 2016






B 2 ( 6%) 18 ( 53%) 0 ( 0%) Platelet count decreased A 5 ( 17%) 13 ( 43%) 0 ( 0%) B 0 ( 0%) 17 ( 50%) 0 ( 0%) White blood cell decreased A 2 ( 7%) 7 ( 23%) 0 ( 0%) B 3 ( 9%) 5 ( 15%) 0 ( 0%)

Non-Hematologic Adverse Events Blood and lymphatic sys disord

Febrile neutropenia A 12 ( 40%) 1 ( 3%) 0 ( 0%) B 5 ( 15%) 0 ( 0%) 0 ( 0%)

Cardiac disorders Supraventricular tachycardia A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 3%) 0 ( 0%)

Ear and labyrinth disorders Hearing impaired A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 3%) 0 ( 0%)

Gastrointestinal disorders Abdominal pain A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Colitis A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Dental caries A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Diarrhea A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Dysphagia A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Mucositis oral A 7 ( 23%) 0 ( 0%) 0 ( 0%) B 5 ( 15%) 0 ( 0%) 0 ( 0%) Nausea A 3 ( 10%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Pancreatic duct stenosis A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Rectal hemorrhage A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Vomiting A 1 ( 3%) 0 ( 0%) 0 ( 0%)

51101 November 2016






B 0 ( 0%) 1 ( 3%) 0 ( 0%) Gen disord and admin site cond

Fatigue A 3 ( 10%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Gait disturbance A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 3 ( 9%) 0 ( 0%) 0 ( 0%) Sudden death NOS A 0 ( 0%) 0 ( 0%) 1 ( 3%) B 0 ( 0%) 0 ( 0%) 0 ( 0%)

Infections and infestations Abdominal infection A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Catheter related infection A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Encephalitis infection A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Enterocolitis infectious A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Infections and infestations - Oth spec

A 2 ( 7%) 1 ( 3%) 0 ( 0%)

B 1 ( 3%) 0 ( 0%) 0 ( 0%) Lung infection A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 3 ( 9%) 0 ( 0%) 0 ( 0%) Mucosal infection A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Sepsis A 0 ( 0%) 1 ( 3%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 1 ( 3%) Sinusitis A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Urinary tract infection A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 2 ( 6%) 0 ( 0%) 0 ( 0%) Wound infection A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%)

Investigations Actvtd prtl thromboplastin tm prolonged

A 0 ( 0%) 0 ( 0%) 0 ( 0%)

51101 November 2016






B 1 ( 3%) 0 ( 0%) 0 ( 0%) Alanine aminotransferase increased

A 12 ( 40%) 0 ( 0%) 0 ( 0%)

B 8 ( 24%) 3 ( 9%) 0 ( 0%) Aspartate aminotransferase increased

A 9 ( 30%) 0 ( 0%) 0 ( 0%)

B 7 ( 21%) 2 ( 6%) 0 ( 0%) Blood bilirubin increased A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Creatinine increased A 2 ( 7%) 0 ( 0%) 0 ( 0%) B 3 ( 9%) 0 ( 0%) 0 ( 0%) Investigations - Other, specify A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Urine output decreased A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Weight loss A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%)

Metabol and nutrition disord Alkalosis A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Anorexia A 3 ( 10%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Dehydration A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Glucose intolerance A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 2 ( 6%) 0 ( 0%) 0 ( 0%) Hyperglycemia A 5 ( 17%) 0 ( 0%) 0 ( 0%) B 10 ( 29%) 0 ( 0%) 0 ( 0%) Hyperkalemia A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Hyperuricemia A 0 ( 0%) 1 ( 3%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypoalbuminemia A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Hypocalcemia A 0 ( 0%) 0 ( 0%) 0 ( 0%)

51101 November 2016






B 1 ( 3%) 0 ( 0%) 0 ( 0%) Hypoglycemia A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypokalemia A 4 ( 13%) 1 ( 3%) 0 ( 0%) B 5 ( 15%) 0 ( 0%) 0 ( 0%) Hyponatremia A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 3 ( 9%) 2 ( 6%) 0 ( 0%) Hypophosphatemia A 6 ( 20%) 0 ( 0%) 0 ( 0%) B 2 ( 6%) 0 ( 0%) 0 ( 0%)

Musculosk and conn tiss disord Arthritis A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Avascular necrosis A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Generalized muscle weakness A 4 ( 13%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%)

Nervous system disorders Ataxia A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Cognitive disturbance A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Edema cerebral A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 3%) 0 ( 0%) Encephalopathy A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Headache A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Seizure A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 3%) 0 ( 0%) Somnolence A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Syncope A 2 ( 7%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%)

Psychiatric disorders Confusion A 1 ( 3%) 0 ( 0%) 0 ( 0%)

51101 November 2016






B 3 ( 9%) 0 ( 0%) 0 ( 0%) Delirium A 0 ( 0%) 1 ( 3%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Depression A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Insomnia A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%)

Renal and urinary disorders Acute kidney injury A 2 ( 7%) 0 ( 0%) 0 ( 0%) B 3 ( 9%) 0 ( 0%) 0 ( 0%)

Reprod sys and breast disord Menorrhagia A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%)

Respirat, thor, mediast disord Dyspnea A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypoxia A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 3%) 0 ( 0%) Respiratory failure A 0 ( 0%) 1 ( 3%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%)

Surgical and medical proced Surgical and medical proced - Oth spec

A 1 ( 3%) 0 ( 0%) 0 ( 0%)

B 0 ( 0%) 0 ( 0%) 0 ( 0%) Vascular disorders

Hematoma A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 0 ( 0%) 0 ( 0%) Hypertension A 3 ( 10%) 0 ( 0%) 0 ( 0%) B 6 ( 18%) 0 ( 0%) 0 ( 0%) Hypotension A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 3%) 0 ( 0%) Thromboembolic event A 1 ( 3%) 0 ( 0%) 0 ( 0%) B 1 ( 3%) 1 ( 3%) 0 ( 0%)

10.0 IMBEDDED CORRELATIVES

51101 November 2016


CALGB 151113, Exploratory Analyses of Biomarkers as Potential Predictors of Outcome for Primary CNS B-cell Lymphoma Participation to imbedded correlative 151113 was optional for all patient registered to 51101. As of September 8, 2016, there are 472 patients who consented. Samples are being collected and banked for future analysis. CALGB 581101, Imaging Markers of Outcome After Chemotherapy in Patients with Newly Diagnosed Primary CNS B-cell Lymphoma Participation to imbedded correlative 581101 was optional for all patient registered to 51101 at limited institutions. As of September 8, 2016, there are 11 patients who consented. Images are being collected and banked for future analysis. CALGB 71105, Neurocognitive Function and Quality of Life in Patients with Primary CNS B-cell Lymphoma Participation to imbedded correlative 71005 was optional for all patient registered to 51101. As of September 8, 2016, there are 56 patients who consented. QOL assessments are being collected and will be analyzed future analyses.

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