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

NCT ID: NCT01943422

Last Updated: 2018-04-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-10-31
• Study Completion Date: 2016-12-31

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.

Conditions

Melanoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Vemurafenib + IFNα-2b (10 MU/m2/d)

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.

Group Type: EXPERIMENTAL

High-dose Interferon alfa-2b

Intervention Type: DRUG

•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.

Vemurafenib

Intervention Type: DRUG

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.

Vemurafenib + IFNα-2b(15 MU/m2/d)

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.

Group Type: EXPERIMENTAL

High-dose Interferon alfa-2b

Intervention Type: DRUG

•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.

Vemurafenib

Intervention Type: DRUG

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.

Vemurafenib + IFNα-2b (20 MU/m2/d)

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.

Group Type: EXPERIMENTAL

High-dose Interferon alfa-2b

Intervention Type: DRUG

•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.

Vemurafenib

Intervention Type: DRUG

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.

Interventions

High-dose Interferon alfa-2b

•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

Vemurafenib

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.

Intervention Type: DRUG

Other Intervention Names

IFNα-2b (HDI); Zelboraf

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

John Kirkwood

OTHER

Sponsor Role: lead

Responsible Party

John Kirkwood

Director of Melanoma Program at UPCI

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

John Kirkwood, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh Medical Center

Locations

Hillman Cancer Center

Pittsburgh, Pennsylvania, United States

Countries

United States

Other Identifiers

12-107

Identifier Type: -

Identifier Source: org_study_id