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

1. Sirolimus for NF1 Associated Plexiform Neurofibromas A Phase 2 Study of The mTOR Inhibitor Sirolimus in NF1 Related Plexiform Neurofibromas Brian Weiss, MD, Chair Michael Fisher, MD, Co-Chair Bruce Korf, MD, PhD, Co-Chair John Perentesis, MD, Co-Chair Brigitte Widemann, MD, Co-Chair NF Clinical Consortium

2. 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

3. 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

4. Mammalian Target of Rapamycin Brems, Lancet Oncol 2009; 10: 508–15.

6. 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

7. 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

8. 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

9. Treatment Plan • 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 • Target level reductions for certain toxicities • 7-10 ng/mL • 5-7 ng/mL

10. Duration of Treatment • 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 to6 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

11. Monitoring • 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

13. 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)

14. 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

15. 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

16. Toxicity Stopping Rules • >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

17. Stratum 1 Response n = 46 Stratum 1 Results p< 0.0001 Log Rank Test p = 0.14

18. Stratum 2 Response • 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.

19. Conclusions • Sirolimus, administered bid and targeted to 10-15 ng/mL, prolongs TTP by about 4 months in patients with progressive PNs • Sirolimusis not effective in shrinking non-progressive PN • No significant sirolimus toxicities were observed

20. Stratum 2: Self-report PedsQL domain scores p=.04 Mean scores p=.01 n=6 Course

21. 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