Bevacizumab in Patients With Metastatic Renal Cell Carcinoma or Others Advanced Solid Tumors
The primary endpoint is the occurrence of limiting toxicities leading to definitive
discontinuation of the study drugs during the first 24 weeks in absence of progression of
Secondary endpoints included the occurrence of Dose Limiting Toxicities (DLTs) evaluated
during the first two cycles; overall response rate (ORR), 6-months progression-free survival
rate and Pharmacokinetic assessments.
The following definitions will be used:
The Dose Limiting Toxicities (DLTs) are defined as the occurrence during the first two
cycles of any grade 4 toxicity, and of any following events:
- clinical evidence of congestive heart failure,
- any arterial thromboembolic event,
- grade 3 venous thrombosis,
- grade 3 thrombocytopenia >=7 days or associated with bleeding,
- grade 3 hypertension uncontrolled (>=160/90 mmHg) with medications,
- grade 3 elevations in AST/ALT or total bilirubin. Any other grade 3 toxicity >=7 days
is also considered as a DLT, with exception of fatigue.
The determination of the maximum-tolerated dose (MTD) will be conducted on a 3 + 3 + 3
design. Cohorts of 3 to 9 patients will be sequentially enrolled in 3 steps to receive one
of four escalated doses of Pazopanib in combination with Bevacizumab to establish the MTD
(step 1: patients 1 to 3; step 2: patients 4 to 6; step 3: patients 7 to 9).
The MTD is considered to be exceeded if DLT is observed during the first 2 cycles (i.e., 56
days) in at least 2 out of 3 or 3 out of 6 patients evaluable for MTD in the two first
steps, then in at least 3 out of 9 patients after completion of enrolment (step 3).
When the MTD will be established, patients already involved in the follow-up phase at a dose
level above the MTD should decrease to the MTD.
Note: in an exploratory way (i.e., with simulation) the possibility to take into account for
the determination of the MTD the occurrence of recurrent grade 2 events or the combination
of synergic grade 2-3 toxicities as "1/2 DLT" will be investigated in the study.
Optimal Long Exposure Dose (OLED):
To determine the Optimal Long Exposure Dose (OLED), all patients which will not experience a
Dose Limiting Toxicity (DLT) during the first two cycles will continue the treatment and
will be followed until week 24, in order to record toxic reactions of lesser severity or
mixed toxicities leading to definitive discontinuation of the study drug, in the absence of
progression of the disease.
The OLED is defined as the dose level (less than or equal to the MTD) for which the
occurrence of sub-acute limiting toxicities leading to definitive discontinuation of the
study drug is compatible with further phase II studies.
In practice, if <=2/7-8 patients or <=3/9 patients treated at a dose level <=MTD and
followed until week 24 experience sub-acute limiting toxicities, that dose level will be
considered as the OLED.
The overall response rate (ORR) is defined as the proportion of patients with a complete
response (CR) or partial response (PR) - target lesions and tumor response according to
Progression-Free Survival (PFS):
Progression-free survival (PFS) is defined as the time from the date of first study drug
administration to the date of the first observation of documented disease progression or
death due to any cause. PFS will be determined based on tumor assessment (RECIST criteria)
and survival information.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determination of the Optimal Long Exposure Dose (OLED)
The primary endpoint is the occurrence of an interruption of one drug of the association of a duration superior to 4 weeks during the first 24 weeks in absence of progression of the disease.
24 weeks for each patient
SYLVIE NEGRIER, Phd
Centre Léon Bérard; Lyon; FRANCE
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)