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Safety and Efficacy Study of Vemurafenib and High-dose Interferon Alfa-2b in Melanoma (12-107)

Primary Purpose

Melanoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
High-dose Interferon alfa-2b
Vemurafenib
Sponsored by
John Kirkwood
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Melanoma focused on measuring advanced, melanoma, Vemurafenib, High-dose Interferon alfa-2b

Eligibility Criteria

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

Inclusion Criteria:

  • Patients must have a written informed consent.
  • 18 years of age.
  • Patients must have histologically confirmed recurrent stage III or stage IV melanoma (AJCC 7th edition classification).
  • BRAF V600E and V600K mutated
  • Cutaneous squamous cell carcinomas (SCC) lesions identified at baseline must be excised. Adequate wound healing is required prior to study entry.
  • Patients must have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors v1.1.

  • Patients must have adequate hematologic, renal, and liver function:

    • WBC ≥ 3,000/mm3
    • ANC ≥ 1500
    • Hb ≥ 9g/dL (women) or ≥ 11g/dL (men) (supportive transfusions will be allowed during induction and maintenance phases to maintain these levels)
    • Platelets ≥ 100,000/mm3 (supportive transfusions will be allowed during induction and maintenance phases to maintain these levels)
    • Serum Creatinine ≤ 1.5 x upper limit of normal (ULN)
    • Serum Bilirubin ≤ 1.5 x ULN
    • Serum AST/ALT ≤ 2.5 x ULN
  • EKG documenting normal intervals.
  • Fully recovered from any effects of major surgery, and be free of significant detectable infection.
  • ECOG performance status of 0 or 1.
  • Free of active brain metastases by contrast-enhanced CT/MRI scans within 4 weeks prior to starting the study drugs.
  • Female patients of child bearing potential must have a negative pregnancy test (within 7 days from the time of randomization).

Exclusion Criteria:

  • Serious illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, uncontrolled hypertension, cardiac ischemia, myocardial infarction, and severe cardiac arrhythmia), bleeding disorders, symptomatic autoimmune diseases, severe obstructive or restrictive pulmonary diseases, uncontrolled endocrine disorders (hypothyroidism, hyperthyroidism and diabetes mellitus), retinopathy, active systemic infections, and inflammatory bowel disorders. This includes known HIV or AIDS-related illness, or active HBV and HCV.
  • Prior therapy (except for adjuvant immunotherapy) with a BRAF and/or MEK and/or ERK inhibitors.
  • Refractory nausea, vomiting, small bowel resection or any other gastrointestinal ailment that would preclude study drug absorption.

  • Cardiac abnormalities

    • Mean QTc interval ≥ 480 msec at screening.
    • Recent ACS/AMI - defined as within 24 weeks prior to screening.
    • Recent PCI/PTCA - defined as within 24 weeks prior to screening.
    • Recent malignant cardiac arrhythmias - all except sinus arrhythmia within 24 weeks prior to screening.
    • Symptomatic heart failure - NYHA Class ≥ II symptoms.
  • Active infection or antibiotics within one-week prior to study, including unexplained fever Any significant psychiatric disease, medical intervention, or other condition, which in the opinion of the principal investigator, could prevent adequate informed consent or compromise participation in the clinical trial.
  • Systemic steroid or other immunosuppressive therapy within 4 weeks of starting the study.
  • Lactating females or pregnant females.

Sites / Locations

  • Hillman Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Vemurafenib + IFNα-2b (10 MU/m2/d)

Vemurafenib + IFNα-2b(15 MU/m2/d)

Vemurafenib + IFNα-2b (20 MU/m2/d)

Arm Description

Vemurafenib + High-dose Interferon alfa-2b (10 MU/m2/d) IFNα-2b will be administered intravenously for 5 consecutive days (Monday through Friday) every week for 4 weeks (induction) Vemurafenib will be dosed continuously at the standard Food and Drug Administration (FDA) approved dose of 960mg twice a day orally without dose interruption except for toxicities attributable to this agent.

Vemurafenib + High-dose Interferon alfa-2b (15 MU/m2/d) IFNα-2b will be administered intravenously for 5 consecutive days (Monday through Friday) every week for 4 weeks (induction) Vemurafenib will be dosed continuously at the standard Food and Drug Administration (FDA) approved dose of 960mg twice a day orally without dose interruption except for toxicities attributable to this agent.

Vemurafenib + High-dose Interferon alfa-2b (20 MU/m2/d) IFNα-2b will be administered intravenously for 5 consecutive days (Monday through Friday) every week for 4 weeks (induction) Vemurafenib will be dosed continuously at the standard Food and Drug Administration (FDA) approved dose of 960mg twice a day orally without dose interruption except for toxicities attributable to this agent.

Outcomes

Primary Outcome Measures

Number of Participants with Adverse Events to determine Ph II dose
At each dose level, the number of patients experiencing Adverse Events over their course of treatment will be characterized by type of Adverse Event and grade using NCI CTCAE (v4.0), and by time of onset in relation to the first day of therapy.

Secondary Outcome Measures

Progression Free and overall survival (Efficacy)
•Progression Free Survival will be evaluated at 6 months using the Kaplan-Meier method. Overall Survival will be measured from the initial date of treatment to the recorded date of death, and analyzed similarly to Progression Free Survival. Overall Survival will also be analyzed with the Kaplan-Meier method. The complete response rate and partial response rate will be estimated by the proportion of patients with a best response respectively by RECIST criteria.

Full Information

First Posted
August 27, 2013
Last Updated
April 1, 2018
Sponsor
John Kirkwood
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT01943422
Brief Title
Safety and Efficacy Study of Vemurafenib and High-dose Interferon Alfa-2b in Melanoma
Acronym
12-107
Official Title
Dose-seeking and Efficacy Study of the Combination of the BRAF Inhibitor Vemurafenib and High-dose Interferon Alfa-2b for Therapy of Advanced Melanoma
Study Type
Interventional

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Completed
Study Start Date
October 2013 (Actual)
Primary Completion Date
November 2016 (Actual)
Study Completion Date
December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
John Kirkwood
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a dose-seeking and efficacy study of combined BRAF Inhibitor Vemurafenib and High-dose Interferon alfa-2b for therapy of advanced melanoma.
Detailed Description
Dose-selection and dose-expansion study of combination therapy with high-dose interferon alfa-2b and vemurafenib. Vemurafenib at standard dosing with a 2 week lead-in period to exploit potential immunomodulatory effects. Concurrent HDI following this (week 2 onwards) at standard induction (4 weeks) and maintenance (48 weeks) doses. Modified Storer's "up and down" dose escalation schema using 3 fixed dose levels for HDI and a fixed sample size that allows efficient identification of recommended phase II dose. 36-63 patients will be enrolled depending on toxicity parameters. oIn the dose-selection portion, 3 patients will be enrolled per dose level, starting from the lowest dose level. Enrollment will occur serially allowing for the observation of toxicity during the observation period. oIterative enrollment of up to 3 subjects per cohort will be continued until a total of 30 evaluable subjects have been enrolled. oThe dose level at which the RLT rate is the closest to 1/3 will be considered as RP2D. oDuring the dose-expansion portion of the trial, depending on the number of patients treated at RP2D during the dose-selection portion, additional patients may be enrolled - the accrual target is 36 patients treated at RP2D.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma
Keywords
advanced, melanoma, Vemurafenib, High-dose Interferon alfa-2b

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Vemurafenib + IFNα-2b (10 MU/m2/d)
Arm Type
Experimental
Arm Description
Vemurafenib + High-dose Interferon alfa-2b (10 MU/m2/d) IFNα-2b will be administered intravenously for 5 consecutive days (Monday through Friday) every week for 4 weeks (induction) Vemurafenib will be dosed continuously at the standard Food and Drug Administration (FDA) approved dose of 960mg twice a day orally without dose interruption except for toxicities attributable to this agent.
Arm Title
Vemurafenib + IFNα-2b(15 MU/m2/d)
Arm Type
Experimental
Arm Description
Vemurafenib + High-dose Interferon alfa-2b (15 MU/m2/d) IFNα-2b will be administered intravenously for 5 consecutive days (Monday through Friday) every week for 4 weeks (induction) Vemurafenib will be dosed continuously at the standard Food and Drug Administration (FDA) approved dose of 960mg twice a day orally without dose interruption except for toxicities attributable to this agent.
Arm Title
Vemurafenib + IFNα-2b (20 MU/m2/d)
Arm Type
Experimental
Arm Description
Vemurafenib + High-dose Interferon alfa-2b (20 MU/m2/d) IFNα-2b will be administered intravenously for 5 consecutive days (Monday through Friday) every week for 4 weeks (induction) Vemurafenib will be dosed continuously at the standard Food and Drug Administration (FDA) approved dose of 960mg twice a day orally without dose interruption except for toxicities attributable to this agent.
Intervention Type
Drug
Intervention Name(s)
High-dose Interferon alfa-2b
Other Intervention Name(s)
IFNα-2b (HDI)
Intervention Description
•Vemurafenib at standard dosing with a 2 week lead-in period to identify potential effects. IFNα-2b following this (week 2 onwards) at standard induction (4 weeks) and maintenance (48 weeks) doses.
Intervention Type
Drug
Intervention Name(s)
Vemurafenib
Other Intervention Name(s)
Zelboraf
Intervention Description
Vemurafenib is a prescription medicine used to treat melanoma, that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene.
Primary Outcome Measure Information:
Title
Number of Participants with Adverse Events to determine Ph II dose
Description
At each dose level, the number of patients experiencing Adverse Events over their course of treatment will be characterized by type of Adverse Event and grade using NCI CTCAE (v4.0), and by time of onset in relation to the first day of therapy.
Time Frame
12-24 months from study start
Secondary Outcome Measure Information:
Title
Progression Free and overall survival (Efficacy)
Description
•Progression Free Survival will be evaluated at 6 months using the Kaplan-Meier method. Overall Survival will be measured from the initial date of treatment to the recorded date of death, and analyzed similarly to Progression Free Survival. Overall Survival will also be analyzed with the Kaplan-Meier method. The complete response rate and partial response rate will be estimated by the proportion of patients with a best response respectively by RECIST criteria.
Time Frame
48 months
Other Pre-specified Outcome Measures:
Title
Improve tumor STAT signaling
Description
Melanoma metastases removed from patients pretreatment, post-BRAFI alone and Post B-RAF+ will be analyzed for expression of IFNAR1 and immunologically relevant molecules such as HLA antigens, APM components and MA; these results will be correlated with T cell infiltration. In addition the metastases will be tested for extent of melanoma cell proliferation and apoptosis.
Time Frame
48 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have a written informed consent. 18 years of age. Patients must have histologically confirmed recurrent stage III or stage IV melanoma (AJCC 7th edition classification). BRAF V600E and V600K mutated Cutaneous squamous cell carcinomas (SCC) lesions identified at baseline must be excised. Adequate wound healing is required prior to study entry. Patients must have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors v1.1. Patients must have adequate hematologic, renal, and liver function: WBC ≥ 3,000/mm3 ANC ≥ 1500 Hb ≥ 9g/dL (women) or ≥ 11g/dL (men) (supportive transfusions will be allowed during induction and maintenance phases to maintain these levels) Platelets ≥ 100,000/mm3 (supportive transfusions will be allowed during induction and maintenance phases to maintain these levels) Serum Creatinine ≤ 1.5 x upper limit of normal (ULN) Serum Bilirubin ≤ 1.5 x ULN Serum AST/ALT ≤ 2.5 x ULN EKG documenting normal intervals. Fully recovered from any effects of major surgery, and be free of significant detectable infection. ECOG performance status of 0 or 1. Free of active brain metastases by contrast-enhanced CT/MRI scans within 4 weeks prior to starting the study drugs. Female patients of child bearing potential must have a negative pregnancy test (within 7 days from the time of randomization). Exclusion Criteria: Serious illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, uncontrolled hypertension, cardiac ischemia, myocardial infarction, and severe cardiac arrhythmia), bleeding disorders, symptomatic autoimmune diseases, severe obstructive or restrictive pulmonary diseases, uncontrolled endocrine disorders (hypothyroidism, hyperthyroidism and diabetes mellitus), retinopathy, active systemic infections, and inflammatory bowel disorders. This includes known HIV or AIDS-related illness, or active HBV and HCV. Prior therapy (except for adjuvant immunotherapy) with a BRAF and/or MEK and/or ERK inhibitors. Refractory nausea, vomiting, small bowel resection or any other gastrointestinal ailment that would preclude study drug absorption. Cardiac abnormalities Mean QTc interval ≥ 480 msec at screening. Recent ACS/AMI - defined as within 24 weeks prior to screening. Recent PCI/PTCA - defined as within 24 weeks prior to screening. Recent malignant cardiac arrhythmias - all except sinus arrhythmia within 24 weeks prior to screening. Symptomatic heart failure - NYHA Class ≥ II symptoms. Active infection or antibiotics within one-week prior to study, including unexplained fever Any significant psychiatric disease, medical intervention, or other condition, which in the opinion of the principal investigator, could prevent adequate informed consent or compromise participation in the clinical trial. Systemic steroid or other immunosuppressive therapy within 4 weeks of starting the study. Lactating females or pregnant females.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Kirkwood, MD
Organizational Affiliation
University of Pittsburgh Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hillman Cancer Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15232
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Safety and Efficacy Study of Vemurafenib and High-dose Interferon Alfa-2b in Melanoma

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