Vemurafenib in Combination With Everolimus or Temsirolimus With Advanced Cancer

• ClinicalTrials.gov Identifier: NCT01596140
• Recruitment Status: Active, not recruiting
• First Posted: May 10, 2012
• Last Update Posted: May 29, 2019
• Sponsor: M.D. Anderson Cancer Center
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Study Description

Brief Summary:

The goal of this clinical research study is to find the highest tolerable dose of vemurafenib that can be given in combination with either everolimus or temsirolimus. The safety of these drug combinations will also be studied.

Vemurafenib is designed to block BRAF inside the cancer cells, which is a mutation that is involved in cancer cell growth.

Temsirolimus and everolimus are designed to block the growth of cancer cells, which may cause cancer cells to die.

Condition or disease	Intervention/treatment	Phase
Advanced Cancer; Solid Tumor	Drug: Vemurafenib; Drug: Everolimus; Drug: Temsirolimus	Phase 1

  Show Detailed Description

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 114 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Dose-Escalation Study of the BRAF Inhibitor Vemurafenib (Zelboraf®) in Combination With an mTOR Inhibitor, Everolimus (Afinitor®) or Temsirolimus (Torisel®), in Subjects With Advanced Cancer
• Actual Study Start Date: December 2012
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: December 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Vemurafenib + Oral Everolimus; Vemurafenib starting dose 720 mg orally twice day (morning/evening) for 28-day cycle plus Oral Everolimus starting dose 5 mg daily.	Drug: Vemurafenib; Starting dose 720 mg by mouth twice a day (3 tablets in the morning and 3 tablets in the evening) for 28-day study cycle.; Other Names: Zelboraf®; PLX4032; RO5185426; Drug: Everolimus; Starting dose 5.0 mg by mouth daily for 28-day study cycle.; Other Names: Afinitor®; RAD001
Experimental: Vemurafenib + Intravenous Temsirolimus; Vemurafenib starting dose 720 mg orally twice day (morning/evening) for 28-day cycle plus Intravenous Temsirolimus starting dose 15 mg daily on Days 1, 8, 15, and 22 of each cycle.	Drug: Vemurafenib; Starting dose 720 mg by mouth twice a day (3 tablets in the morning and 3 tablets in the evening) for 28-day study cycle.; Other Names: Zelboraf®; PLX4032; RO5185426; Drug: Temsirolimus; Starting dose 15 mg daily over 30-60 minutes on Days 1, 8, 15, and 22 of each 28-day cycle.; Other Name: Temodar

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) of Combination Vemurafenib [ Time Frame: First cycle of 28 day cycle ]
   The MTD of combination Vemurafenib and Everolimus or Vemurafenib and Temsirolimus is defined as the highest dose studied in which the incidence of dose limiting toxicity (DLT) was less than one third (33%) of the participants at that dose level. DLT defined as any Grade 3 or 4 non-hematologic toxicity, as defined in NCI CTC v4.0, even if expected and believed related to study medications, any Grade 4 hematologic toxicity lasting two weeks or longer despite supportive care; Grade 3 nausea/vomiting > 48 hours or any Grade 4 nausea/vomiting; and any other Grade 3 non-hematologic toxicity, including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in NCI-CTCAE that is attributable to therapy.

Secondary Outcome Measures :

1. Tumor Response [ Time Frame: 4 months ]
   Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by RECIST criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a >/= 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to Choi criteria, i.e., decrease in size by 10% or more, or a decrease in tumor density, as measured in Hounsfield units (HU), by more than or equal to 15%.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Confirmation of BRAF mutation-positive malignancy is required for selection of patients for vemurafenib therapy
2. Measurable or non-measurable disease by RECIST 1.1.
3. Patients with advanced cancer should be refractory to standard therapy, relapsed after standard therapy, or have no standard therapy available that improves survival by at least three months.
4. Patients must be at least 3 weeks past receiving cytotoxic therapy and at least 5 half-lives after their previous treatment or 3 weeks, whichever is shorter, after biologic therapy. Patients may receive palliative radiotherapy immediately or during treatment provided that not all target lesions are radiated.
5. ECOG performance status </= 2 (Karnofsky >/= 60%; Lansky Score >/= 50).
6. Patients must have normal organ and marrow function defined as: absolute neutrophil count >/=1,000/mL; platelets >/=50,000/mL; creatinine < 2.0; total bilirubin < 2.0; ALT(SGPT) </= 3 X ULN; Exception for patients with liver metastasis: ALT(SGPT) </= 5 X ULN.
7. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days after the last dose.
8. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients with uncontrolled concurrent illness, including but not limited to: ongoing or active infection requiring hospitalization; psychiatric illness/social situations that would limit compliance with study requirements.
2. Exclusion of patients with creatinine >2.0 and bilirubin > 2.0.
3. Pregnant or lactating women.
4. Patients with a history of bone marrow transplant within the previous two years.
5. Patients with a known hypersensitivity to any of the components of the drug products.
6. Patients with major surgery within 30 days prior to entering the study.
7. Patients with a baseline QTc > 500 ms.
8. Patients who are unable to swallow pills.

Contacts and Locations

Locations

United States, Texas

University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Vivek Subbiah, MD; M.D. Anderson Cancer Center

More Information

Additional Information:

University of Texas MD Anderson Cancer Center Website 

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT01596140 History of Changes
• Other Study ID Numbers: 2012-0153; NCI-2012-00789 ( Registry Identifier: NCI CTRP )
• First Posted: May 10, 2012
• Last Update Posted: May 29, 2019
• Last Verified: May 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:

Vemurafenib; Everolimus; Afinitor; RAD001; temsirolimus; BRAF gene mutation; solid tumor; relapsed BRAF mutation positive malignant melanoma; refractory BRAF mutation positive malignant melanoma

Additional relevant MeSH terms:

Neoplasms; Sirolimus; Everolimus; Vemurafenib; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antifungal Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action