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

Manning and Cantley, Cell, 2007

Courtesy of EA Kolb, CTOS oral presentation, Friday session

IGF-1R

AKT

P-AKT

S6

P-S6

CO

MB

O

RA

PA

D7

RA

PA

D2

R1507 D

7 R

1507 D2

CO

NT

RO

L

The combination of rapamycin and R1507 inhibits both AKT and S6Kinase phosphorylation and shows at least

additive activity in vivo

RTV

0.0

1.0

2.0

3.0

4.0

0 1 2 3 4 5 6 7

Time (Weeks)

Re

lativ

e T

um

or

Vo

lum

e

CONTROL

Rapa

R1507

Combo

OS2

GAPDH

OS2Courtesy of EA Kolb, CTOS oral presentation, Friday session

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

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

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

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

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

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.

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.