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

Primary Purpose

Advanced Solid Tumors, Metastatic Breast Cancer, Metastatic Renal Cell Carcinoma

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

RAD001 + BEZ235

About this trial

This is an interventional treatment trial for Advanced Solid Tumors focused on measuring Advanced solid tumors, Metastatic renal cell carcinoma (mRCC), ER+/HER2-Metastatic breast cancer (MBC), Dose finding study, mTOR, Pl3K, BEZ235, RAD001, Everolimus, Afinitor®, ER+/HER2- metastatic breast cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Highlands Oncology Group Dept of Highlands Oncology Grp
Washington University School of Medicine Washington University (16)
Medical University of South Carolina SC
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

RAD001 + BEZ235

Arm Description

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.

Outcomes

Primary Outcome Measures

Probability of a Dose Limiting Toxicity (DLT) by the end of the first treatment cycle (DLT)

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

Frequency of DLTs during the first cycle of treatment

Number of participants with adverse events and serious adverse events.

Measured by abnormal safety laboratory parameters, changes in electrocardiograms (ECGs), changes in vital signs and changes in physical examination parameters.

Secondary Outcome Measures

Time versus blood concentration profiles

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

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

CT or magnetic resonance imaging (MRI) imaging parameters to determine the PFS according to the RECIST 1.0 criteria

Duration of response (DoR) according to local assessments by RECIST 1.0 for RCC and MBC in dose expansion phase

CT or MRI imaging parameters to determine the duration of response according to the RECIST 1.0 criteria

Full Information

NCT ID

NCT01482156

First Posted

September 26, 2011

Last Updated

December 17, 2020

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT01482156

Brief Title

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

Official Title

An Open-label, Multi-center Phase I Dose-finding Study of RAD001 (Everolimus, Afinitor®) in Combination With BEZ235 in Patients With Advanced Solid Tumors

Study Type

Interventional

2. Study Status

Record Verification Date

November 2015

Overall Recruitment Status

Completed

Study Start Date

January 2012 (undefined)

Primary Completion Date

February 2015 (Actual)

Study Completion Date

February 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

5. Study Description

Brief Summary

Study has two parts: 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. 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Advanced Solid Tumors, Metastatic Breast Cancer, Metastatic Renal Cell Carcinoma

Keywords

Advanced solid tumors, Metastatic renal cell carcinoma (mRCC), ER+/HER2-Metastatic breast cancer (MBC), Dose finding study, mTOR, Pl3K, BEZ235, RAD001, Everolimus, Afinitor®, ER+/HER2- metastatic breast cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

46 (Actual)

8. Arms, Groups, and Interventions

Arm Title

RAD001 + BEZ235

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

RAD001 + BEZ235

Other Intervention Name(s)

Afinitor

Intervention Description

RAD001 is formulated as tablets of 2.5 mg and 5 mg strength, blistered in units of 10 tablets (for oral use) each. Blisters should be opened only at the time of dministration as the drug is both hygroscopic and light-sensitive. RAD001 should be administered immediately after a meal with a large glass of water. BEZ235 is supplied as 50-mg, 200-mg, 300-mg and 400-mg sachets (for oral use). BEZ235 is packaged in aluminum foil bags. Bags are packaged in a box. Patients will receive RAD001 in combination with BEZ235.

Primary Outcome Measure Information:

Title

Probability of a Dose Limiting Toxicity (DLT) by the end of the first treatment cycle (DLT)

Description

The maximum tolerated dose (MTD) and the dose limiting toxicities during the first cycle of treatment

Time Frame

First treatment cycle (28 days)

Title

Incidence of DLT in patients by the end of the first treatment cycle in the co-administration of RAD001 and BEZ235

Description

Frequency of DLTs during the first cycle of treatment

Time Frame

First treatment cycle (28 days)

Title

Number of participants with adverse events and serious adverse events.

Description

Measured by abnormal safety laboratory parameters, changes in electrocardiograms (ECGs), changes in vital signs and changes in physical examination parameters.

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Time versus blood concentration profiles

Description

Analysis of pharmacokinetic parameters in blood samples

Time Frame

First treatment cycle ( 28 days)

Title

Description

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.

Time Frame

8 weeks

Title

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

Description

CT or magnetic resonance imaging (MRI) imaging parameters to determine the PFS according to the RECIST 1.0 criteria

Time Frame

8 weeks

Title

Duration of response (DoR) according to local assessments by RECIST 1.0 for RCC and MBC in dose expansion phase

Description

CT or MRI imaging parameters to determine the duration of response according to the RECIST 1.0 criteria

Time Frame

8 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Highlands Oncology Group Dept of Highlands Oncology Grp

City

Fayetteville

State/Province

Arkansas

ZIP/Postal Code

72703

Country

United States

Facility Name

Washington University School of Medicine Washington University (16)

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Facility Name

Medical University of South Carolina SC

City

Charleston

State/Province

South Carolina

ZIP/Postal Code

29425

Country

United States

Facility Name

Novartis Investigative Site

City

Wilrijk

ZIP/Postal Code

2610

Country

Belgium

Facility Name

Novartis Investigative Site

City

Bordeaux Cedex

ZIP/Postal Code

33075

Country

France

Facility Name

Novartis Investigative Site

City

Montellier Cedex 5

ZIP/Postal Code

34298

Country

France

Facility Name

Novartis Investigative Site

City

Verona

State/Province

ZIP/Postal Code

37126

Country

Italy

Facility Name

Novartis Investigative Site

City

Auckland

Country

New Zealand

Facility Name

Novartis Investigative Site

City

Barcelona

State/Province

Catalunya

ZIP/Postal Code

08035

Country

Spain

Facility Name

Novartis Investigative Site

City

High Heaton

State/Province

Newcastle Upon Tyne

ZIP/Postal Code

NE7 7DN

Country

United Kingdom

12. IPD Sharing Statement

Links:

URL

https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=14406

Description

Results for CRAD001X2109 can be found on the Novartis Clinical Trial Results Website

Learn more about this trial

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

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