A Phase 2 Study of The mTOR Inhibitor Sirolimus in NF1 Related Plexiform Neurofibromas

Brian Weiss, MD, ChairMichael Fisher, MD, Co-ChairBruce Korf, MD, PhD, Co-ChairJohn Perentesis, MD, Co-ChairBrigitte Widemann, MD, Co-ChairNF Clinical Consortium

Sirolimus for NF1 Associated Plexiform Neurofibromas

Plexiform Neurofibromas (PN)

• One of the most common tumors of NF1• Serious Morbidity

– Pain, impaired function, disfigurement– Life-threatening from compression of trachea,

large blood vessels, spinal cord

PN Therapy

• Complete excision is only known effective therapy– Limited by size / infiltrative nature of the tumor– May result in permanent neurological deficits– High rate of recurrence

• Radiotherapy and traditional chemotherapy agents given on traditional schedules have been ineffective

Brems, Lancet Oncol 2009; 10: 508–15.

Mammalian Target of Rapamycin

Sirolimus (rapamycin; Wyeth)

• Immunosupressant drug– FDA approved for the prevention of kidney allograft

rejection in adults and children >13 yrs

• Typically cytostatic, not cytotoxic

• Sirolimus attenuates mTOR signaling and tumor growth in in vitro and in vivo NF1 model

• Side effects include: dose-dependent reversible thrombocytopenia, leukopenia, mucositis, acneiform rash, hypercholesterolemia and hypertriglyceridemia

Primary Aims

• To determine whether sirolimus– Increases time to progression in subjects with

progressive PN– Results in objective radiographic responses

in subjects with non-progressive PN at trial entry

• To evaluate the feasibility and toxicity of chronic sirolimus administration in this patient population

• To characterize the pharmacokinetic profile of sirolimus when administered to this patient population

Eligibility• NF1• >3 years of age• PN: inoperable, measurable (>3cm), potential

to cause significant morbidity– Stratum 1: Evidence of tumor progression by MRI– Stratum 2: No progression but “high-risk”

• Adequate bone marrow, renal, hepatic function • Exclusions

– Taking strong inhibitors/inducers of CYP3A4 or EIACD

– Fasting LDL cholesterol > 160 mg/dL– Chronic treatment with systemic steroids or another

immunosuppressive agent

• Oral administration, 2x/day• 28 day cycles, no break between cycles• Starting dose = 0.8 mg/m2/dose bid• Pharmacokinetic dosing

– Initial target level = 10-15 ng/ml– Sirolimus levels: weekly during cycle 1. Subsequent cycles:

weekly until stable x 2 then after each cycle– Use both individual levels, full PK profile (of those that

consented), and published data

Treatment Plan

Target level reductions for certain toxicities

• 7-10 ng/mL • 5-7 ng/mL

• Stratum 1: Progressive PN– May continue on therapy up to 2 years unless

there is evidence of PD or unacceptable toxicity

• Stratum 2: No progression but “high-risk”– May continue on therapy for up to 6 cycles (24

wks) unless there is evidence of PD or unacceptable toxicity

– May stay on therapy past 6 cycles only if evidence of objective response

Duration of Treatment

• History, physical, and screening labs– end of cycle 1, 2, 3, then every 3 cycles

• MRI q 3 cycles until cycle 9, then q 6 cycles

• Volumetric MRI analysis– CR: complete resolution of all measurable or palpable

PNs– PR: ≥20% reduction in the volume of all index PNs– SD: <20% increase & <20% decrease in the volume of

all index PNs– PD: ≥ 20% increase in the volume of at least one index

PN

Monitoring

Toxicities Requiring Target Modification or Dose Interruption• Grade 3+ hematological toxicity • Grade 3+ non-hematological toxicity except

– Grade 3 N/V of < 3 days duration– Grade 3 ALT/AST elevation that resolves within 7 days and does not

recur– Grade 3+ fasting hypertriglyceridemia

• Grade 1+ GFR reduction• Grade 1+ fasting hypercholesterolemia unresponsive to diet/exercise• Grade 2+ allergic reaction attributable to sirolimus• Grade 2+ hypertension attributable to sirolimus• Grade 2 non-heme toxicity that persists for ≥ 7 days beyond start date of

next cycle (medically significant or sufficiently intolerable)

• Subjects requiring: • Mucositis (n=2; Gr 2 and Gr 3)• Elevated LDL (n=2)• Low ANC (n=2; Gr 3)

Toxicities Requiring Removal From Therapy

• “Severe” Toxicities– PJP or Grade 3+ opportunistic infection – Grade 2+ pneumonitis– Grade 4 rash– Grade 3+ hypertension– Grade 3+ allergic reaction– Poor renal function (CrCl or GFR <75% of nl for age)– Development of lymphoma or other cancers

• 1 subject developed Gr 2 pneumonitis in first 2 courses

Serious Adverse Events

• At least possibly related to sirolimus:– Grade 3 vomiting/headache (n=1)– Grade 3 AST/ALT elevation (n=2)– Grade 3 infection with normal ANC (n=1)– Grade 4 ARDS (n=1)

– All toxicities completely resolved

• >10% rate of severe toxicity in the first 2 courses

• >25% rate of subjects requiring target modification or removal from study for toxicity any time during Rx

• Neither stopping rule reached

Toxicity Stopping Rules

Stratum 1 Results

p< 0.0001

Log Rank Test p = 0.14

Stratum 1 Responsen = 46

• Simon 2 stage optimal design. – Stop after 12 subjects if number of responses = 0.

Otherwise accrue 25 more.– H0: response rate = 0.05 – HA: response rate = 0.20– α = 0.10, power = 90%

• No responses after 12 evaluable subjects. Stratum 2 closed.

Stratum 2 Response

Percent Volume Change Baseline to 6 Months

Minimum Maximum Mean Std Dev Median P Value-8.00 21.50 2.54 7.81 1.25 0.28

Conclusions

• Sirolimus, administered bid and targeted to 10-15 ng/mL, prolongs TTP by about 4 months in patients with progressive PNs

• Sirolimus is not effective in shrinking non-progressive PN

• No significant sirolimus toxicities were observed

Stratum 2: Self-report PedsQL domain scores

0 640

50

60

70

80

90

100

PhysicalEmotionalSocialSchool

Course

Mea

n sc

ores

p=.04

p=.01

n=6

Acknowledgements

• Alan Cantor, PhD (Statistician, UAB)• Eva Dombi, MD (NCI)• Sander Vinks, PharmD,PhD (CCMC)• Roger Packer, MD (Group Chair of NF Consortium)• NF Consortium Operations Center

• Bruce Korf, MD, PhD (NF Consortium PI)• Karen Cole-Plourde, BS (Program Manager)• Elizabeth Davis, RN (Clinical Coordinator)

• Department of Defense NF Research Program• NF Consortium Sites