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A Phase I/II Trial of Vemurafenib and Metformin to Melanoma Patients

Primary Purpose

Melanoma

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Vemurafenib

Metformin

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Unresectable melanoma, Stage IIIC and Stage IV BRAFV600E+ Melanoma

Eligibility Criteria

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

Inclusion Criteria:

Male or female patients ≥ 18 years of age;
Patients with histological confirmed BRAFV600E melanoma (Stage IIIC or Stage IV, American Joint Commission on Cancer);
Eastern Cooperative Oncology Group (ECOG) Performance Status(PS) of 0 to 2;
Life expectancy ≥ 3 months;
At least 1 site of radiographically measurable disease by RECIST 1.1
Adequate hematologic, renal, and liver function as defined by laboratory values performed within 42 days prior to initiation of dosing:
- Absolute neutrophil count (ANC) ≥ 1.0 x 109/L;
- Platelet count ≥ 50 x 109/L;
- Hemoglobin ≥ 8 g/dL;
- Serum creatinine ≤ 2 x upper limit of normal (ULN)
- Total serum bilirubin ≤ 3 x ULN;
- Serum aspartate transaminase (AST/SGOT) or serum alanine transaminase (ALT/SGPT) ≤ 3x ULN, and ≤ 4 x ULN if liver metastases are present.
Fertile males should use an effective method of contraception during treatment and for at least 3 months after completion of treatment, as directed by their physician;
Pre-menopausal females and females < 2 years after the onset of menopause should have a negative pregnancy test at Screening. Pre-menopausal females must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 90 days after the last dose of study drug. Females of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year;
Before study entry, written informed consent must be obtained from the patient prior to performing any study-related procedures.

Exclusion Criteria:

Prior treatment with Vemurafenib;
Known hypersensitivity to Metformin or any of its components;
Previous progression of melanoma while on Metformin;
Received radiotherapy for non CNS disease within the 2 weeks prior to commencing study treatment or have not recovered from side effects of all radiation-related toxicities to Grade ≤ 1, except for alopecia;
Pregnant, breast-feeding, or refusing double barrier contraception, oral contraceptives, or avoidance of pregnancy measures;
Have any other uncontrolled infection or medical condition that could interfere with the conduct of the study

Sites / Locations

James Graham Brown Cancer Center-University of LouisvilleRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Vemurafenib and Metformin

Arm Description

Outcomes

Primary Outcome Measures

Observation of CTCAE grade 4 or higher adverse events in six patients

In the phase I portion, six patients will be enrolled and observed for CTCAE grade 4 or higher events. If three or more grade 4 or higher adverse events are observed among the six patients, the study will be halted.

Secondary Outcome Measures

Overall Survival Follow up

Patients will be followed for up to three years following the last treatment administration. The Investigator or designees will make every possible attempt at least every 12 weeks (±7 days), for up to three years after the last treatment to contact the patient or family to obtain the survival information of the patient and, if applicable, the start date of additional anticancer treatment.

Number of adverse events

Descriptive statistics of all AEs observed during the study period.

type of adverse events

Descriptive statistics of all AEs observed during the study period.

Objective response rate (ORR)as measure of efficacy

Efficacy estimated as the objective response rate (ORR), which is the sum of Partial Responses (PR) and Complete Responses (CR) as determined by RECIST 1.1

Full Information

NCT ID

NCT01638676

First Posted

June 1, 2012

Last Updated

October 22, 2021

Sponsor

University of Louisville

Collaborators

James Graham Brown Cancer Center

1. Study Identification

Unique Protocol Identification Number

NCT01638676

Brief Title

A Phase I/II Trial of Vemurafenib and Metformin to Melanoma Patients

Official Title

A Phase I/II Trial of Vemurafenib and Metformin to Unresectable Stage IIIC and Stage IV BRAF.V600E+ Melanoma Patients

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Recruiting

Study Start Date

July 2012 (Actual)

Primary Completion Date

June 2025 (Anticipated)

Study Completion Date

June 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Louisville

Collaborators

James Graham Brown Cancer Center

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The main purpose of this study is to evaluate the safety of Vemurafenib in combination with Metformin in melanoma patients. The phase II part of the study will also evaluate the clinical activity of the combined regiment. Based on pre-clinical studies and a phase I trial, the investigators hypothesize that the combination of an FDA-approved non-toxic dose of oral Metformin with Vemurafenib will yield little toxicity and improve clinical outcomes in terms of objective response rates and survival in metastatic melanoma patients.

Detailed Description

This is a Phase I/II study. Phase I will be evaluating the safety of the FDA-approved Vemurafenib (960 mg orally, daily) in combination with Metformin (500 mg orally, twice daily for 2 weeks, then 850 mg orally,twice daily) in patients with unresectable Stage IIIC and Stage IV melanoma. Phase II will evaluate the clinical activity of the combined Vemurafenib/Metformin regimen. The safety profile of this combined Vemurafenib/Metformin regimen will be monitored during both phases. The treatment period consists of 28-day cycles until progression or unacceptable toxicity occurs.

6. Conditions and Keywords

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

Melanoma

Keywords

Unresectable melanoma, Stage IIIC and Stage IV BRAFV600E+ Melanoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

55 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Vemurafenib and Metformin

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Vemurafenib

Other Intervention Name(s)

Vemurafenib branded as Zelboraf

Intervention Description

Vemurafenib (960 mg PO daily) in patients with unresectable BRAFV600E positive Stage IIIC and Stage IV melanoma

Intervention Type

Drug

Intervention Name(s)

Metformin

Other Intervention Name(s)

Metformin hydrochloride branded as Glucophage

Intervention Description

Metformin (500 mg PO BID x 2 weeks, then 850 mg PO BID)

Primary Outcome Measure Information:

Title

Observation of CTCAE grade 4 or higher adverse events in six patients

Description

Time Frame

Duration of phase I portion, approximately six months

Secondary Outcome Measure Information:

Title

Overall Survival Follow up

Description

Time Frame

Every 12 weeks (+/- 7 days) after last drug dose, for up to 3 full years

Title

Number of adverse events

Description

Descriptive statistics of all AEs observed during the study period.

Time Frame

Duration of study, estimated to be approximately 60 months

Title

type of adverse events

Description

Descriptive statistics of all AEs observed during the study period.

Time Frame

Duration of study, estimated to be approximately 60 months

Title

Objective response rate (ORR)as measure of efficacy

Description

Efficacy estimated as the objective response rate (ORR), which is the sum of Partial Responses (PR) and Complete Responses (CR) as determined by RECIST 1.1

Time Frame

Duration of study (approximately 60 months)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female patients ≥ 18 years of age; Patients with histological confirmed BRAFV600E melanoma (Stage IIIC or Stage IV, American Joint Commission on Cancer); Eastern Cooperative Oncology Group (ECOG) Performance Status(PS) of 0 to 2; Life expectancy ≥ 3 months; At least 1 site of radiographically measurable disease by RECIST 1.1 Adequate hematologic, renal, and liver function as defined by laboratory values performed within 42 days prior to initiation of dosing: Absolute neutrophil count (ANC) ≥ 1.0 x 109/L; Platelet count ≥ 50 x 109/L; Hemoglobin ≥ 8 g/dL; Serum creatinine ≤ 2 x upper limit of normal (ULN) Total serum bilirubin ≤ 3 x ULN; Serum aspartate transaminase (AST/SGOT) or serum alanine transaminase (ALT/SGPT) ≤ 3x ULN, and ≤ 4 x ULN if liver metastases are present. Fertile males should use an effective method of contraception during treatment and for at least 3 months after completion of treatment, as directed by their physician; Pre-menopausal females and females < 2 years after the onset of menopause should have a negative pregnancy test at Screening. Pre-menopausal females must agree to use an acceptable method of birth control from the time of the negative pregnancy test up to 90 days after the last dose of study drug. Females of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year; Before study entry, written informed consent must be obtained from the patient prior to performing any study-related procedures. Exclusion Criteria: Prior treatment with Vemurafenib; Known hypersensitivity to Metformin or any of its components; Previous progression of melanoma while on Metformin; Received radiotherapy for non CNS disease within the 2 weeks prior to commencing study treatment or have not recovered from side effects of all radiation-related toxicities to Grade ≤ 1, except for alopecia; Pregnant, breast-feeding, or refusing double barrier contraception, oral contraceptives, or avoidance of pregnancy measures; Have any other uncontrolled infection or medical condition that could interfere with the conduct of the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jason A Chesney, MD PhD

Organizational Affiliation

James Graham Brown Cancer Center-U of Louisville

Official's Role

Principal Investigator

Facility Information:

Facility Name

James Graham Brown Cancer Center-University of Louisville

City

Louisville

State/Province

Kentucky

ZIP/Postal Code

40202

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jason A Chesney, MD PhD

Phone

502-562-3429

jason.chesney@louisville.edu

First Name & Middle Initial & Last Name & Degree

Sarah Lush, RN

Phone

502-540-1537

s.lush@louisville.edu

12. IPD Sharing Statement

Citations:

PubMed Identifier

24862830

Citation

Cerezo M, Tomic T, Ballotti R, Rocchi S. Is it time to test biguanide metformin in the treatment of melanoma? Pigment Cell Melanoma Res. 2015 Jan;28(1):8-20. doi: 10.1111/pcmr.12267. Epub 2014 Jun 26.

Results Reference

derived

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A Phase I/II Trial of Vemurafenib and Metformin to Melanoma Patients

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