A Phase I/II Study of RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma
Patient population Phase I portion: Metastatic colorectal cancer. A total of 3 patients on
each cohort. Additional 3 patients on the tolerable cohort. Total patient number: Minimum 6,
Maximum: 12 Phase II portion: Metastatic colorectal cancer: A total of 33 patients will be
treated in this portion. This will include the patients treated on the tolerable dose level
from the phase I trial. The statistical justification is indicated in the Statistics section
Overall study design Phase I Study: A three cohort dose escalation will be used. Cycle
length will be 28 days.
Bevacizumab FOLFOX-6 RAD001 Cohort 1: 5 mg/ kg Q 2weeks Standard Dose FOLFOX-6 2.5 mg PO
qd Cohort 2: 5 mg/ kg Q 2weeks Standard Dose FOLFOX-6 5 mg PO qd Cohort 3: 5mg/kg Q 2 weeks
Standard Dose FOLFOX-6 10 mg PO qd
Phase II Study:
For the Phase II portion the primary endpoint is Progression Free Survival at 6 months.
Study Objectives Primary
1. To evaluate the progression free survival (PFS) for a combination of FOLFOX+
Bevacizumab + RAD001 in previously untreated metastatic or advanced colorectal cancers
2. To evaluate the safety of the combination at a daily dosing of 2.5mg RAD001, 5 mg
RAD001 or 10 mg RAD001 (Phase 1 part) Secondary
1. To study the toxicity profile of the combination 2. To study the Response Rate (RR) of
the combination 3. To determine the serum proteomic profiles of patients treated with
combination therapy (Both phase I and II portions)
Dose selection for RAD001 In phase 1 clinical studies of RAD001 as a monotherapy agent in
oncology patients, the side-effect profile is essentially mild to moderate adverse events
with a low frequency of DLT at the daily dose of 10 mg/d. Based on the PK/PD model, a daily
dose of 10mg RAD001 is assumed to provide a persistently high degree of target inhibition in
the tumor [Investigators' Brochure-Section 220.127.116.11]. In addition, preliminary data from
phase 1 studies, in which changes in molecular characteristics of tumor induced by treatment
with RAD001 at the doses of 5 and 10 mg/d were investigated, confirm the pharmacodynamic
activity predicted previously by PK/PD modeling [Investigators' Brochure-Section 18.104.22.168].
Therefore, a dose of 10 mg/d should ensure adequate drug target inhibition for most
patients, taking into consideration the known inter-patient variability in drug levels (CV
of approx 50%). In this study, we will begin with a RAD001 dose of 2.5 mg which is the
lowest dose that can be administered on a daily basis. If the dose is tolerable (<1/6 DLTs),
we will escalate to the dose of RAD001 (5 mg) and a third cohort of 10 mg. If cohort 1 is
intolerable, study will be closed without any further expansion. On any dose level, 3
patients would be enrolled. If there are 0/3 DLTs, we would be able to escalate the dose
level. If 1/3 DLTs are observed, 3 additional patients will be enrolled on the same dose
level. The intent is to escalate dose levels only if < 1/6 DLTs are observed. In case 2 or
more DLTs are observed on a particular dose level, no further dose escalation is possible.
This dose level would be deemed intolerable and the lower dose level would be expanded. The
definition of the Maximum Tolerated Dose (MTD) is the highest dose level at which RAD001 can
be combined with FOLFOX/ Bevacizumab with < 1/6 DLTs.
FOLFOX/ Bevacizumab: FOLFOX6 and Bevacizumab will be given as previously described 28.
mFOLFOX6 (oxaliplatin 85 mg/m2 IV with LV 350 mg IV over 2 hours plus FU 400 mg/m2 IV bolus
and 2,400 mg/m2continuous infusion over 46 hours every 2 weeks) will be combined with
Bevacizumab given at 5 mg/kg every 2 weeks. Dose modifications will be carried out for
chemotherapy as per the label for oxaliplatin, fluorouracil and bevacizumab.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Evaluate PFS for combination of FOLFOX+ Bevacizumab + RAD001 in previously untreated metastatic or advanced colorectal cancers
Sunil Sharma, MD
Huntsman Cancer Institute
United States: Food and Drug Administration
|Huntsman Cancer Institute||Salt Lake City, Utah 84112|
|Utah Cancer Specialists||Salt Lake City, Utah 84106|