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