Optimizing Treatment Outcomes in Anal Cancer/media/Images/Swedish/CME1/SyllabusP… · Optimizing Treatment Outcomes in Anal Cancer 15th Annual West Coast Colorectal Cancer Symposium

15th Annual West Coast Colorectal Cancer Symposium Oct. 27, 2017

1

Optimizing Treatment Outcomes in Anal Cancer

15th Annual West Coast Colorectal Cancer Symposium

Lisa Kachnic, MD, FASTRO

Professor & Cornelius Vanderbilt Chair

Department of Radiation Oncology


2

Disclosures

UpToDateTM

EPICTM

INSYS Therapeutics

NCI Funding (NRG Oncology, SWOG)


3

Background

1. American Cancer Society. Anal cancer. http://www.cancer.org/cancer/analcancer/detailedguide/anal-cancer-what-is-key-statistics. Accessed 5/4/17.

2. American Cancer Society. Cancer Facts and Figures 2016. http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016/. Accessed 5/4/17.

3. Glynne-Jones R, et al. Ann Oncol. 2014;25 (suppl 3):iii10-iii20.

Anal cancer is fairly rare – much less common than cancer of

the colon or rectum1

– In 2016, approximately 8,080 individuals (5,160 women and

2,920 men) were diagnosed with anal cancer2

– 1,080 estimated deaths (640 women and 440 men)2

The number of new anal cancer cases has been rising for

many years1

Anal cancer is exclusively an HPV-driven disease3;

however, its low prevalence among other GI cancers (2.5%)

makes specialization in this tumor rare

Anal cancer is an area of relatively limited clinical research

focus

http://www.cancer.org/cancer/analcancer/detailedguide/anal-cancer-what-is-key-statistics

http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016/


4

NCCN Current Anal Cancer Treatment Guidelines

Demonstrate Limited Therapeutic Options

Localized Cancer Metastatic Cancer

5-FU + Mitomycin + RTContinuous-infusion 5-FU 1000 mg/m2/d IV days 1–4

and 29–32

Mitomycin 10 mg/m2/d IV bolus days 1 and 29

Concurrent radiotherapy (now IMRT)

5-FU + CisplatinContinuous-infusion 5-FU 1000 mg/m2 /d IV days 1–5

Cisplatin 100 mg/m2 IV day 2

Repeat every 4 weeks

+/– Capecitabine + Mitomycin + RT

Capecitabine 825 mg/m2 PO BID, Monday – Friday, on

each day that RT is given, throughout the duration of RT

(typically 28 treatment days)

Mitomycin 10 mg/m2 days 1 and 29

Concurrent radiotherapy (IMRT)

or

Capecitabine 825 mg/m2 PO BID days 1–5 weekly ×6

weeks

Mitomycin 12 mg/m2 IV bolus day 1

Concurrent radiotherapy (IMRT)

National Comprehensive Cancer Network. NCCN Guidelines. Anal Carcinoma. V. 1.2016.

?


5

Current Approaches

Metastatic

Localized


6

Historic Published Regimens for Met Anal SCCA

Author N Agents ORR Med PFS

(months)

Med OS

(months)

Wilking 1985 15 vincristine,

bleomycin & high-

dose methotrexate

3/12 (25%) 2M NR

Ajani

1989

3 5-FU/CDDP NA 17M (2 of 3) NA

Faivre 1999 18 5-FU/CDDP 65% (CR=15%) 4M NA

Jhawer

2006

20 mitomycin C,

adriamycin,

cisplatin,

bleomycin-CCNU

12/20 (60%) 8M 15

Alcindor

2008

5 taxol (1st and 2nd

line)

60% Range: 3-8M Range: 4-20M

Abbas

2011

7 taxol (2nd line) 57% Range: 2-8M Range: 5-14M

Kim

2013

8 DCF CR: 50%

(3/4 resected)

19-88M 1 yr: 62.5%

Eng

2014

77 42 5-FU/CDDP

24 – carbo/taxol

NA 7M NA


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IRCI/EORTC/ECOG EA2133: InterAACT1st Line Met SCCA of the Anal Canal to Establish a Standard

R

Arm A

Arm B

Cisplatin 75 mg/m2 day 1 +

5FU 1000mg/m2 infusion/24 hours/4 days

q28 days

Carboplatin (AUC = 5) +

Taxol (weekly) q 21 days

Objective: Identify best chemotherapy backbone to build for biologic

development

1) Primary endpoint: RR

2) Secondary endpoints: PFS, OS, correlatives, and QOL, etc.

• Treatment for 6M and cont at the discretion of the investigator

• Substratification: HIV+/HIV-, HPV status, and prior XRT

• CT scans: q3M

• N=100/Closed

Study PIs UK - Rao, US - Eng


8

Future Approaches

Metastatic

Localized


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Immunotherapy May Fill this Unmet Need

APC T Cell

CTLA-4

PD-1

Anti–CTLA-4

Anti–PD-L1/PD-1

Cancer Cell

Tumor Lysis

• Chakravarty, Cancer Res

1999

• Demaria, Clin Cancer Res

2005

• Zeng, IJROBP 2013

• Bos, JEM 2013

• Deng, JCI 2014

DNA

Damage

Courtesy of A. Minn

AXAL Vaccine


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ADXS11-001 (AXAL) Immunotherapy

Live, highly attenuated gram + bacteria

bioengineered to secrete a HPV-16-E7

fusion protein targeting HPV

transformed cells

Biosafety level I-II. No fecal, urine

shedding or person-to- person

transmission; vector cleared with

antibiotics given for 7 days beginning 72

hours after injection

The Lm vector is infused IV and infects

antigen presenting cells where it cross

presents, stimulating MHC class 1 and 2

pathways resulting in specific T-cell

immunity to tumors

Hansen K, et al. EMBO J. 33:1654-1666, 2014.


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>3 doses

<3 doses

11

Presented by Huh W, et al. ASCO 2016. Abstract 5516.

Randomized Phase II AXAL Monotherapy in

Recurrent/Metastatic Cervical Cancer


12

Three Doses AXAL Yield Complete Responses

Presented by Huh W, et al. ASCO 2016. Abstract 5516.


13

Safety/Tolerability: Stage 1 Adverse Event Summary (n = 26)

Adverse event (AE) Grade 1–4 Grade 3 Grade 4

Patients with ≥1 treatment-related

AE (TRAE), n (%)

24 (92) 4 (15) 1 (4)*

TRAEs Occurring in ≥10% of PatientsFatigue 15 (58) - -

Chills 14 (54) - -

Fever 11 (42) - -

Nausea 10 (39) - -

Headache 9 (35) - -

Hypotension 7 (27) 2 (8) -

Vomiting 6 (23) - -

Cytokine release syndrome 5 (19) 3 (12) -

Myalgia 5 (19) - -

Abdominal pain 4 (15) - -

General pain 4 (15) - -

Flu-like symptoms 3 (11) - -

AST elevation 3 (11) - -

Safety findings among patients enrolled in Stage 2 are similar to those reported in detail for Stage 1.*The observed grade 4 TRAE recorded in 1 patient (lung infection and sepsis from Klebsiella pneumoniae) was considered possibly related to treatment.

13 Presented by Huh W, et al. ASCO 2016. Abstract 5516.


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Overall Survival

CI, confidence interval; NR, not reached.

All Patients

(N = 24)

>3 Doses of

ADXS11-001

(N = 12)

6-month OS 42% (n = 10/24) 67% (n = 8/12)

Median OS (95% CI) 4.8 months (3.8–NR) NR (3.5–NR)

Median PFS (95% CI) 2.6 months (2.0–3.2) –

All PatientsSTAGE 1

3 Doses of ADXS11-001

STAGE 2

14 Presented by Huh W, et al. ASCO 2016. Abstract 5516.


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Phase II FAWCETT Study of AXAL Monotherapy in

Recurrent/Metastatic Anal Cancer

Two-stage Trial Design Persistent/recurrent,

loco-regional

metastatic anal

cancer

Received at least

one line of therapy

for their metastatic

disease or

progressed after

platinum-based

therapy

Stage 1N = 31

AXAL monotherapy

Every 3 weeks for up

to 2 years

Stage 2N=24 additional patients

AXAL monotherapy

Every 3 weeks for up to 2 years

Interim Analysis

If ≥10% ORR or

≥20% 6-month PFS

Endpoints

Primary:

Best overall

response

6-month PFS

Other:

Safety and

tolerability

Duration of

response

Overall survival

PI: Eng

Courtesy of C. Eng


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NCI9673: Phase II Design of Nivolumab in

Metastatic Anal Cancer

patients with metastatic squamous cell carcinoma of the anal canal

- treated with at least one prior therapy for metastatic disease

- no prior immunotherapies received as part of cancer treatment

12 patients treated initially with nivolumab3 mg/kg IV every 2 weeks

patients were followed for best response using RECIST criteria 1.1

0 responses ≥ 1 response

stop trialexpand trial to include 25 additional patients with

metastatic SCCA

Simon Optimal, two-stage

phase II study, Ho: p ≤ 0.05

and an alternative

hypothesis Ha: p ≥ 0.20,

α = 0.10 and a β = 0.10

Diagnostic imaging was

completed every 6 wks

Morris et al: Lancet Oncology 4:446-453, 2017.

PI Eng


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-1 0 0-9 0-8 0-7 0-6 0-5 0-4 0-3 0-2 0-1 0

01 02 03 04 05 06 07 08 09 0

1 0 0

P a tie n t

% t

ar

ge

t le

sio

n r

ed

uc

tio

n

fro

m b

as

eli

ne

by

RE

CIS

T 1

.1 P ro g re s s iv e D is e a s e

S ta b le D is e a s e

P a rt ia l R e s p o n s e

P R

P D

NCI9673: Primary Endpoint of Response Rate

N=37 (ITT)

N=34 (evaluable)

2 CR’s

7 PR’s

ORR 24%

Patients

CR


Morris et al: Lancet Oncology, in press


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NCI9673: Progression-free & Overall Survival


PFS

OS


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NCI9673: Toxicities of Therapy

Toxicity (N=37) Grade (%)

1 2 3 4

Fatigue 17 (46) 7 (19) 1 (3) -

Anemia 13 (35) 11 (30) 2 (5) -

Rash 8 (22) 2 (5) 1 (3) -

Hypothyroidism 1 (3) 1 (3) 1 (3) -

Constipation 8 (22) 2 (5) - -

Diarrhea 8 (22) - - -

Anorexia 5 (14) 4 (11) - -

Weight loss 5 (14) 1 (3) - -

Arthralgia 3 (8) 3 (8) - -

Hyperglycemia 3 (8) 1 (3) - -

Lymphedema 1 (3) 1 (3) - -

Pneumonitis - 1 (3) - -

Nausea 2 (5) - - -



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Morris et al: AACR 2016; Eng et al: ASCO 2016.

Flow Cytometry Confirmation(Courtesy of IMT Platform)

Tumor Correlatives at Baseline by IHC (N=12)

Non-Responder

Responder

CD-8 PD-1 PD-L1


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Keynote-028: Phase Ib of Pembrolizumab for

Recurrent Anal Cancer

Reck et al: NEJM, 2016

IV pembro 10 mg/kg once every 2 wks up to

2 yrs or progression or toxicity

patients with PD-L1+ tumors

of 24 patients with scc anal:

4PR 10SD

ORR = 17%

median PFS 3 months

median OS 9 months

Ott et al: Annals Oncology 28: 1036-1041, 2017.


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Next Steps for Metastatic Disease

Addition of immune therapy to winner of InterAACT trial

– agents/design still in discussion

– may be R phase II of systemic winner vs. systemic/immune

combo followed by maintenance immuno rx

– immuno rx likely to be nivo but could also consider AXAL pending

results of Fawcett trial

– primary endpoint would be PFS until progression

Reck et al: NEJM, 2016


23

Current Approaches

Metastatic

Localized


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Treatment Overview Localized Anal Cancer

Anal margin

– ~ skin cancer

– surgical excision or radiation alone

Adenocarcinoma

– ~ rectal cancer

SCCA of the anal canal

– T1 tumors: local excision, radiation alone or chemoradiation

– T2 and above: chemoradiation therapy with curative intent

– APR salvage for local recurrence


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Wayne State/Nigro Regimen

28 pts; single institution study

RT: 30 Gy in 15 fx via AP/PA fields to the pelvis, medial inguinal LN

and anal canal

Chemo: 5FU (1000 mg/m2/day) x 4 days + MMC (single 15 mg/m2

bolus)

APR planned; 5/6 initial pts had no residual tumor at APR; APR was

then reserved as salvage

Overall, 86% (24/28) clinical CR to chemo-RT

Follow-up series OS5 67%; CFS5 59%

Nigro et al: Cancer 51(10):1826-9, 1983;

Leichman et al: Am J Med 78(2):211-5, 1985.


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Role of Chemotherapy

Trial nGrade 4/5

Acute AEsLC CFS OS

UKCCCR1

RT

RT/5FU/MMC

585 39%

61%

58%*

65%*

EORTC2

RT

RT/5FU/MMC

110 39%

58%

40%

72%

65%*

72%*

RTOG 87-043

RT/5FU

RT/5FU/MMC

310 7%

23%

64%**

83%**

58%**

64%**

65%**

67%**

*3-yr; **5-yr; red denotes statistically significant

1UKCCCR, Lancet 1996; 2Bartelink, JCO 1997; 3Flam, JCO 1996.


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Sequelae of Conventional Nonconformal ChemoRT

Acute:– Anorectal dysfunction (frequency & urgency)

– GU

– Dermatitis (grade ¾ > 50%)

– Heme morbidity (grade ¾ > 50%), neutropenic sepsis

• 6 chemotherapy-related deaths in UKCCCR study

• 4 deaths in the RTOG/ECOG study

Chronic:– Anal incontinence/fibrosis (5-15%)

– Vaginal stenosis (30-80%)

– Small bowel obstruction (5-10%, but increases over time)

– Hip fracture (10-15%; more common in women)

– Sexual dysfunction

UKCCRC: Lancet 348:1049-54, 1996;

Flam et al: J Clin Oncol 14:1527-39, 1996.


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Strategies to Maintain Outcomes and Decrease

Morbidity

Substitution of MMC: RTOG 98-11

Technical improvements in RT: IMRT (RTOG

0529)


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RTOG 98-11 (T2-4 Nx M0; no HIV)

R

MMC 10 mg/m²

5FU 1g/m²

5FU 1g/m²

Cisplatin 75 mg/m²

RT: 45 Gy Boost 10-14 Gy

RT: 45 Gy Boost 10-14 Gy

T3/4;N+,

T2 with RD

T3/4;N+,

T2 with RD

Ajani et al: Jama 299 (16), 1914-21, 2008.


30

Study Endpoints

Primary: 5-year DFS increase from 63 to 73% (n=682)

/w CDDP

Secondary: Overall worst AEs


31

RTOG 98-11: Outcomes

5-Year Rates

CDDP/5FU –

RT/CDDP/5FU

n=320 (%)

RT+MMC/5FU

n=324 (%)p-Value

Disease-free Survival 54 60 0.17

Local Relapse 33 25 0.07

Colostomy 19 10 0.02

Distant Mets 19 15 0.14

Overall Survival 70 75 0.10

MEDIAN f/u 2.5 years

Ajani et al: JAMA 299 (16), 1914-21, 2008.


32

RTOG 98-11: Five Year Outcomes

5-Year Rates

CDDP/5FU –

RT/CDDP/5FU

n=320 (%)

RT+MMC/5FU

n=324 (%)p-Value

Disease-free Survival 57.8 67.8 0.006

Local Relapse 26.4 20 0.087

Colostomy 17.3 11.9 0.074

Distant Mets 18.1 13.1 0.12

Overall Survival 70.7 78.3 0.026

MEDIAN f/u = 5 years

Gunderson et al: JCO 30 (35), 4344-51, 2010.


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Acute Toxicity RT/5FU/MMC

Induction

5FU/CDDP →

RT/5FU/CDDP

P-value

G3/4 hematologic 61% 42% <0.001

G3/4 non-hematologic 74% 74% NS

Worst overall 87% 83% 0.19

Similar rates of severe long-term side effects: 11% vs. 10%

RTOG 98-11: Toxicity

Ajani et al: JAMA 299 (16), 1914-21, 2008.


34

RTOG 98-11 Conclusions

Not a direct comparison between arms

Difference in DFS, OS with 5 year follow-up in favor of standard arm

Cumulative colostomy rate significantly worse in CDDP arm; ? delay in radiation

with induction chemo ? different radiosensitization on two arms

No overall toxicity savings in CDDP arm

Induction chemotherapy is not of additional benefit

Is CDDP inferior to MMC – cannot determine with 98-11

From this trial - RT plus 5FU/MMC remains the standard of care for

patients with anal canal carcinoma


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RTOG 98-11 Acute Toxicity Anal Cancer

9811* Gd 1 Gd 2 Gd 3 Gd 4

Heme 10% 23% 35% 26%

Derm 9% 35% 43% 5%

GI 17% 38% 32% 4%

GU 16% 19% 3% 1%

*5FU, MMC arm

Ajani et al: JAMA 299 (16), 1914-21, 2008.

2D RT

**


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RTOG 0529: Phase II Dose Painted IMRT

R

E

G

I

S

T

E

R

Mitomycin-C 10 mg/m² IV bolus on days

1 & 29 IMRT

5-FU 1000 mg/m²/day by CI on days 1-4

& 29-32 IMRT

T2 and above

*HIV pts eligible

DP-IMRT – Real Time Review

T2N0: 50.4 Gy tumor; 42 Gy elective nodes in 28

fxs over 5.5 weeks

T3N0 or T4N0: 54 Gy tumor; 45 Gy elective

nodes in 30 fxs over 6 weeks

N+: 50.4 Gy < 3 cm or 54 Gy > 3 cm in 30 fxs

over 6 weeks

Kachnic et al: Int J Radiat Oncol Biol Phys 86(1):27-33, 2013.


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Study Endpoints

Primary: Reduce combined grade 2+ GI/GU toxicities by 15%,

as compared to 98-11 5FU/MMC arm (n=59 pts)

Secondary: all AEs vs. 98-11

Secondary: feasibility (< 5 cases with major deviations)

Secondary: two year outcomes


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Survival analyzed via Kaplan-Meier;

failure endpoints with cumulative

incidence methods; endpoints were

measured from study entry

Median DP-IMRT duration 43 days

(range 32-59) vs. 49 days (range 4-

100) on the 5FU/MMC arm of 9811

(P < 0.0001)

Methods/Accrual

T2N0M0; Patient prone on a bowel displacement device.

VMAT plan using 10 MV beams and 270° arcs. Primary PTV

(PTVA50.4) received 50.4 Gy (red) and the elective nodal

PTV (PTVN42) received 42 Gy (blue) in 28 fractions.

63 patients accrued; 52 evaluable



39

**Acute Toxicity: 0529 vs. 98-11

010

2030

4050

607080

90100

Grade 2+

GI/GU

Grade 3+

GI/GU

Grade 2+

Skin

Grade 3+

Skin

Grade 2+

Hem.

Grade 3+

Hem.

RTOG 9811 RTOG 0529

p=0.5

p=0.0052

p=0.10

p<0.0001

p=0.032

p=0.29


NCI CTCAE version 3


40

Long-term Outcomes

RTOG 0529

(n=52)

RTOG 9811-MMC Arm

(n=325)

Endpoint

Total

Events

5y-%

(95% C.I.)

8y-%

(95% C.I.)

Total

Events

5y-%

(95% C.I.)

8y-%

(95% C.I.)

Local-regional

Failure 8 16 (7, 27) 16 (7, 27) 67 20 (16, 25) 22 (17, 27)

Colostomy

Failure*6 10 (4, 20) 12 (5, 23) 38 12 (9, 16) 12 (9, 16)

Distant

Failure11 16 (7, 27) 22 (12, 34) 46 13 (10, 17) 16 (12, 21)

Disease-free

Survival19 70 (56, 81) 62 (47, 74) 122 68 (62, 73) 57 (50, 63)

Colostomy-

free

Survival

17 74 (59, 84) 66 (51, 77) 106 72 (67, 77) 63 (57, 69)

Overall

Survival16 76 (61, 86) 68 (53, 79) 87 78 (73, 83) 69 (62, 74)

Median follow-up all pts 0529 = 7.9 years (0.02-9.2)

*In 0529, 5 out of 6 colostomies were performed for local-regional failures

In 9811, colostomies were performed for:

• Disease - 26/38; Treatment complications - 10/38; Both - 2/38

Kachnic et al: Int J Radiat Oncol Biol Phys ASTRO 2017.


41

RTOG 0529 Late Sexual Function Definitely, Probably, or Possibly Related to Pr

otocol Treatment (n=51)

Number of Patients by Grade

1 2 3 4 5

Sexual Function 2 6 3 0 0Erectile Dysfunction 0 1 1 0 0

Libido Decreased 1 0 0 0 0

Menses Irregular 0 0 2 0 0

Reproduction 1 1 0 0 0

Vaginal Stenosis 1 5 0 0 0

Vaginal Discharge 0 1 0 0 0

Vulvovaginal Dryness 2 3 0 0 0

NCI CTCAE version 3

Kachnic et al: Int J Radiat Oncol Biol Phys ASTRO 2017.


42

Chemoradiation using DP-IMRT for anal canal cancer provides

comparable long-term efficacy, with reduced acute morbidity, as

compared to non-conformal radiation delivery.

Rates of severe long-term effects were very low; comparisons to

98-11 are limited due to the different toxicity scoring systems

(0529 NCI CTCAE; 98-11 RTOG/EORTC).

DP-IMRT has become the platform for the next generation of

locally advanced anal trials (UK ACT 5).

RTOG 0529 Conclusions


43

Strategies to Improve Outcome in

Localized Disease Have Failed

Adjuvant chemotherapy: RTOG 98-111, UK ACT II2

Increased radiation doses: ACCORD 33

EGFR inhibition: AMC 045/ECOG 32054

1. Ajani et al: Jama 299 (16), 1914-21, 2008.

2. James RD et al: Lancet Oncol 14(6): 516-24, 2013.

3. Peiffert et al: J Clin Oncol 30 (16): 1941-8, 2012.

4. Sparano et al: J Clin Oncol 2016 Epub.


44

Opportunity for Treatment Improvements in

Locally Advanced Anal Cancer

High risk locally advanced anal cancer includes T2 > 4cm, T3,

T4 and/or node positive disease

Five year DFS of RTOG 98-11 (5FU/MMC/RT):

– 45% T4

– 59% T3

– 63% T2 > 4cm

– 53% N+

Ajani JA, et al. JAMA. 2008;299:1914-1921; From 98-11, Gunderson et al.: ASCO GI, 2010.


45

53.2Gy

28F

58.8Gy

28F

61.6Gy

28F

N=640

Ph II

Ph III

Pilot

T3/4 Nany,T2N1-3

Pilot/Ph II/PhIII

Leads – Hawkins and Sebag-Montefiore

ACT5

Primary Endpoint: 3yr locoregional failure

ACT3

Obsn

Margin

≤1mm

41.4Gy

23F

T1 N0 Anal marginLocal excision

Phase II trialN=90

Lead – Renehanand Muirhead

50.4Gy

28F

41.4Gy

23F

ACT4

T1,T2<4cm N0/X

Randomized 2:1R Phase II trial

N=162

Leads – Adams and Harrison

PLATO‘PersonaLising RadioTherapy dOse for Anal Cancer’

Chief investigator – Sebag-Montefiore


46

Future Approaches

Metastatic

Localized


47

ADXS11-001 (AXAL) with Mitomycin/5-FU/IMRT for Locally

Advanced Anal Cancer: Brown University

• Premeds with naproxen (500 mg BID, day –1 and 0) and promethazine (25 mg BID, predose 8 hr)

• Ampicillin is given day 3–9 after each ADXS11-001 dose (now amended to 60 days)

• N = 25

• Primary stage II–III anal cancer

• High risk of recurrence

• HPV positive

ADXS11-001

1×109 CFU × 4 (1 prior to chemoRT and 3 post, q28 days) as a 500-mL infusion over 30

min

ADXS11-001 #1

Day –10 to 14

Mito/5-FU

ADXS11-001 #2

Day +10 post-IMRT

5.5 weeks IMRT 28 days

Open-Label Phase I/II Study

Primary efficacy

endpoint:

6-month CR rateMito/5-FU

28 days Follow-up

ADXS11-001 #3 ADXS11-001 #4

Biopsy

DiagnosisBiopsy

6 months

https://www.clinicaltrials.gov/ct2/show/NCT02002182.

PIs Safran & Perez


48

AXAL Phase I/II BrUOG Study in Anal Cancer: Preliminary

Results Show Early Response & Lack of Recurrence

Perez K et al. IANS 2015; Abstract 23.

Results Summary

• Well tolerated safety profile

• All patients who have completed RT and received treatment achieved a CR at six months (N = 9)

• Expected CR rate at 6 months ~50%; 90% 6-month CR rate in this study (9 of 10 treated patients)

• Only one recurrence to date at a median f/u of over 3 years

• Historical 3-year recurrence rate in similar patient population = ~45%

Adverse EventGrade

2

Grad

e 3

Flu-like symptoms 1

Migraine 1

Hypotension 1

Hypokalemia* 1

Chills/rigors 3 2

Nausea 2

Back Pain 1 1

Fever 2

There were no Grade 4 adverse events.

Relapse Free Survival Data


49

AXAL Adjuvant Monotherapy (AIM2CERV):

Phase III Study to Prevent Recurrence in

High-Risk Cervical Cancer

Primary Endpoint: Disease-free survival

Secondary Endpoint: Overall survival, safety

R A N D O M I Z E ( N = 4 5 0 )

Reference Group

Placebo IV up to 1 year

Treatment Group

ADXS11-001

(1×109 CFU) up to 1 year

High-risk locally advanced cervical cancer

• FIGO Stage IB2–II with positive pelvic

nodes

• FIGO Stage III–IV

• Any FIGO stage with para-aortic nodes

Total sites: 150 in 20 countries

• GOG is supporting AIM2CERV by acting

as a Site Management Organization

Trial timeline (estimated)

• First patient enrollment: 3Q16

• Last patient enrollment: 1Q18

• Final data readout: 3Q19

Randomization 1:2 Between Reference and Treatment Groups

Cisplatin (at least 4 weeks of exposure) and

radiation (minimum 40 Gy external beam radiation therapy)

1:2

FDA SPA issued July 2016

Fast-Track Designation for FDA Review

Advanced-Therapy Medicinal Product (ATMP) from EMA CAT


50

EA2165: Randomized Phase II Assessing

Nivolumab Maintenance in Locally Advanced

Anal Cancer

High Risk Locally Advanced Anal

Cancer

T3/4, N+

5FU or Capecitabine+ Mitomycin + RT

+/- Nivolumab

x 6 months

Primary Endpoint is DFS; N = 180/270

PI Rajdev


51

Anal Cancer Summary

Multidisciplinary treatment modality is imperative

Chemoradiation with curative intent remains gold standard for previously untreated localized patients

- 5-FU & MMC still recommended; IMRT now standard

- Adjuvant chemotherapy & EGFRi all ineffective

- Future US studies to evaluate immune modulation

For metastatic disease, no standard therapy exists

– InterAACT will provide the optimal systemic therapy

– This systemic platform will be used to develop future trials of immune

modulation


52

QUESTIONS

Documents

Optimizing Treatment Outcomes in Anal Cancer/media/Images/Swedish/CME1/SyllabusP… · Optimizing Treatment Outcomes in Anal Cancer 15th Annual West Coast Colorectal Cancer Symposium