Dose Finding Study of RAD001 (Everolimus, Afinitor®) in Combination With BEZ235 in Patients With Advanced Solid Tumors

Phase 1

Completed

• Conditions: Advanced Solid Tumors; Metastatic Breast Cancer; Metastatic Renal Cell Carcinoma
• Interventions: Drug: RAD001 + BEZ235

• Registration Number: NCT01482156
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

Study has two parts:

1. Dose-finding: to determine the maximum tolerated dose (MTD) and to evaluate the safety and tolerability of RAD001 (everolimus , Afinitor®) in combination with BEZ235 in patients with advanced solid tumors.

2. Dose-expansion: to assess safety and tolerability of RAD001 and BEZ235 at the MTD in patients with ER+/HER2- metastatic breast cancer and metastatic renal cell cancer

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2011-09-26
• Study First Submitted QC: 2011-11-29
• Study First Posted: 2011-11-30
• Study Start: 2012-01
• Primary Completion: 2015-02
• Study Completion: 2015-02
• Status Verified: 2015-11
• Last Update Submitted: 2020-12-17
• Last Update Posted: 2020-12-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

• Male and female patients age 18 years or older
• In the dose finding phase, patients with histologically or cytologically confirmed advanced solid malignancies that are metastatic or unresectable
• In the dose expansion phase, the enrollment will be limited to patients with:

Patients with metastatic renal cell carcinoma (mRCC) whose disease had progressed despite prior treatment with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine kinase inhibitor) therapy (at least one but no more than two lines of VEGFR-TKI therapy) Patients with metastatic breast cancer (MBC) which is ER+/HER2-, whose disease had progressed despite prior treatment with at least one but no more than two lines of chemotherapy and at least one prior line of endocrine therapy in the metastatic setting

• WHO performance status of 0-2
• Lab parameters within specifically defined criteria
• Patients with measurable disease per RECIST 1.0

Exclusion Criteria

• Patients who have previously received mTOR inhibitors or PI3K inhibitors
• Patients with CNS metastases unless previously treated with surgery, whole-brain radiation or stereotactic radiosurgery plus the disease having been stable for at least 2 months without steroid use for at least 1 month prior to the first dose of RAD001 and BEZ235. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs.
• Major surgery within 2 weeks prior to study enrollment
• Patient taking anti-cancer drug concomitantly
• Received radiation within 4 weeks prior to study enrollment (2 weeks if limited field radiation)
• Receive chemotherapy 4 weeks prior to study enrollment
• Received live attenuated vaccines within 1 week prior to study enrollment
• History of HIV
• Any other severe and/or uncontrolled medical condition

Other protocol-defined inclusion/exclusion criteria may apply

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
RAD001 + BEZ235	RAD001 + BEZ235	Patients will receive first dose of RAD001 at 2.5mg/5mg/10 mg weekly or 2.5mg/5mg daily in combination of BEZ235 at 50 mg/100 mg/200 mg/300 mg/400 mg twice a day. In the initial cohort of the dose finding phase, patients will receive a single 2.5 mg dose of RAD001 on Cycle 1 Day 1 and the combination therapy of RAD001 2.5 mg/week and BEZ235 200 mg bid starting on Cycle 1 Day 8. Dose escalation phase: patients will start RAD001 and BEZ235 on Cycle 1 Day 1 with both study drugs being administered at the center. Dose expansion phase: the first 15 patients enrolled at selected sites will take RAD001 as monotherapy from Day 1 to Day 7 (for PK sampling). The combination therapy of RAD001 and BEZ235 will start on Day 8. All remaining patients will receive the combination therapy of RAD001 and BEZ235 starting on Cycle 1 Day 1.

Primary Outcome Measures

Name	Time	Method
Probability of a Dose Limiting Toxicity (DLT) by the end of the first treatment cycle (DLT)	First treatment cycle (28 days)	The maximum tolerated dose (MTD) and the dose limiting toxicities during the first cycle of treatment
Incidence of DLT in patients by the end of the first treatment cycle in the co-administration of RAD001 and BEZ235	First treatment cycle (28 days)	Frequency of DLTs during the first cycle of treatment
Number of participants with adverse events and serious adverse events.	12 months	Measured by abnormal safety laboratory parameters, changes in electrocardiograms (ECGs), changes in vital signs and changes in physical examination parameters.

Secondary Outcome Measures

Name	Time	Method
Duration of response (DoR) according to local assessments by RECIST 1.0 for RCC and MBC in dose expansion phase	8 weeks	CT or MRI imaging parameters to determine the duration of response according to the RECIST 1.0 criteria
Time versus blood concentration profiles	First treatment cycle ( 28 days)	Analysis of pharmacokinetic parameters in blood samples
Overall Response Rate (ORR) (Complete Response (CR) + Partial Response (PR)) according to local assessments by RECIST 1.0 for renal cell carcinoma (RCC) and metastatic breast cancer (MBC) in dose expansion phase	8 weeks	CT or MRI imaging parameters to determine the overall response rate (complete response, partial response, stable disease, or progressive disease) according to the RECIST 1.0 criteria.
Progresive Free Survival (PFS) according to local assessments by RECIST 1.0 for renal cell carcinoma (RCC) and metastatic breast cancer (MBC) in dose expansion phase	8 weeks	CT or magnetic resonance imaging (MRI) imaging parameters to determine the PFS according to the RECIST 1.0 criteria

Trial Locations

Locations (4)

Washington University School of Medicine Washington University (16); 🇺🇸 Saint Louis, Missouri, United States

Medical University of South Carolina SC; 🇺🇸 Charleston, South Carolina, United States

Highlands Oncology Group Dept of Highlands Oncology Grp; 🇺🇸 Fayetteville, Arkansas, United States

Novartis Investigative Site; 🇬🇧 High Heaton, Newcastle Upon Tyne, United Kingdom