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 Sirolimus for NF1 Associated Plexiform Neurofibromas
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A Phase 2 Study of The mTOR Inhibitor Sirolimus in NF1 Related Plexiform Neurofibromas
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 - PowerPoint PPT Presentation
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A Phase 2 Study of The mTOR Inhibitor Sirolimus in NF1 Related Plexiform Neurofibromas
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
– 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.