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Trial record 9 of 1269 for:    IFNA2

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

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ClinicalTrials.gov Identifier: NCT01943422
Recruitment Status : Completed
First Posted : September 17, 2013
Last Update Posted : April 3, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
John Kirkwood, University of Pittsburgh

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.

Condition or disease Intervention/treatment Phase
Melanoma Drug: High-dose Interferon alfa-2b Drug: Vemurafenib Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 2013
Actual Primary Completion Date : November 2016
Actual Study Completion Date : December 2016


Arm Intervention/treatment
Experimental: 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.
Drug: 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.
Other Name: IFNα-2b (HDI)

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.
Other Name: Zelboraf

Experimental: 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.
Drug: 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.
Other Name: IFNα-2b (HDI)

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.
Other Name: Zelboraf

Experimental: 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.
Drug: 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.
Other Name: IFNα-2b (HDI)

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.
Other Name: Zelboraf




Primary Outcome Measures :
  1. Number of Participants with Adverse Events to determine Ph II dose [ Time Frame: 12-24 months from study start ]
    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 :
  1. Progression Free and overall survival (Efficacy) [ Time Frame: 48 months ]
    •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.


Other Outcome Measures:
  1. Improve tumor STAT signaling [ Time Frame: 48 months ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01943422


Locations
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United States, Pennsylvania
Hillman Cancer Center
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
John Kirkwood
Merck Sharp & Dohme Corp.
Investigators
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Principal Investigator: John Kirkwood, MD University of Pittsburgh Medical Center

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Responsible Party: John Kirkwood, Director of Melanoma Program at UPCI, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01943422     History of Changes
Other Study ID Numbers: 12-107
First Posted: September 17, 2013    Key Record Dates
Last Update Posted: April 3, 2018
Last Verified: April 2018

Keywords provided by John Kirkwood, University of Pittsburgh:
advanced
melanoma
Vemurafenib
High-dose Interferon alfa-2b

Additional relevant MeSH terms:
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Interferon alpha-2
Interferon-alpha
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Interferons
Vemurafenib
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action