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Richard Gorlick and George Demetri, Co-PIs

SARC 014: A PHASE I STUDY OF RAPAMYCIN AND R1507, A RECOMBINANT HUMAN MONOCLONAL ANTIBODY TO THE INSULIN-LIKE GROWTH FA CTOR-1 RECEPTOR FOR THE TREATMENT OF PATIENTS WITH SARCOMA. Richard Gorlick and George Demetri, Co-PIs. Inhibition of mTOR with rapamycin may enhance IGF-1R signal dependency.

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Richard Gorlick and George Demetri, Co-PIs

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  1. SARC 014: A PHASE I STUDY OF RAPAMYCIN AND R1507, A RECOMBINANT HUMAN MONOCLONAL ANTIBODY TO THE INSULIN-LIKE GROWTH FA CTOR-1 RECEPTOR FOR THE TREATMENT OF PATIENTS WITH SARCOMA Richard Gorlick and George Demetri, Co-PIs

  2. Inhibition of mTOR with rapamycin may enhance IGF-1R signal dependency Manning and Cantley, Cell, 2007 Courtesy of EA Kolb, CTOS oral presentation, Friday session

  3. OS2 The combination of rapamycin and R1507 inhibits both AKT and S6Kinase phosphorylation and shows at least additive activity in vivo IGF-1R AKT P-AKT S6 P-S6 GAPDH COMBO RAPA D7 RAPA D2 R1507 D7 R1507 D2 CONTROL OS2 Courtesy of EA Kolb, CTOS oral presentation, Friday session

  4. Objectives • Primary • To determine the recommended phase 2 doses for R1507 and rapamycin in combination • To determine the DLTs/MTD for the combination (if it exists) • To characterize the PKs of the combination • Secondary • To assess PD endpoints in PBMC • To determine biomarkers of response to the extent feasible in the context of a Phase I trial

  5. Eligibility • Histologically proven sarcoma patients for whom treatment on a phase 1 trial would be appropriate • Two age-based cohorts (≥2, ≤18 and >18) • Adequate bone marrow, liver and renal function • Adequate recovery from prior therapy • Adequate performance status • Negative pregnancy test for females of childbearing potential • No prior IGF-1R or mTOR inhibitor • No hypersensitivity reaction to Ab treatment • No active infections • Signed informed consent

  6. Treatment Plan – Dose Level 1 and 2(Discontinuous Schedule)

  7. Treatment Plan – Dose Level 3 and 4(Discontinuous Schedule)

  8. Study Design • Two independent cohorts – age 2 to 18 and >18 • Standard toxicity definitions • Observation for 12 weeks to define toxicity • With SD, response or clinical benefit continued treatment permitted for two years • Standard 3 + 3 design • Will consider further dose escalation (of R1507 and rapamycin) beyond dose level 4 if PK reveals markedly decreased exposure to either drug when given in combination • Expanded cohort to total of 25 patients treated at the recommended phase 2 dose

  9. Conclusion • It is anticipated this phase 1 trial will establish the doses for a phase 2 trial of the R1507 and rapamycin combination in all (sarcoma) patients greater than 2 years of age. • The pharmacokinetics of R1507 and rapamycin when given in combination should be established. • A preliminary assessment of PD markers and markers of response (to the extent possible within the confines of a phase 1 trial) will be performed.

  10. Participating Sites • Pediatric • Memorial Sloan-Kettering Cancer Center • National Cancer Institute • The Children’s Hospital at Montefiore • Medical • MD Anderson Cancer Center • Dana Farber Cancer Institute • University of Michigan • Anticipate as administration of phase 1 trials improves additional institutions will be added and other combinations can be considered for phase 1 testing.

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