Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation

NCT01959633 | Completed Phase 1 DMC

• 2 other identifiers: VEMUPLINT2013-003730-33
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

The hypothesis of this study is to evaluate the safety and the efficacy of Vemurafenib/PEG-interferon combination and the IFNAR1 upregulation lead by this treatment.

Conditions

Melanoma

Outcome Measures

Primary Outcomes (1)

• Number of participants with adverse events

  The NCI CTC-AE (Version 4) will be used to evaluate the clinical safety of the treatment in this study. Patients will be assessed for AEs at each clinical visit up to 24 weeks and as necessary throughout the study. Hematology and biochemistry will be done as part of regular safety assessments

  up to 24 weeks

Secondary Outcomes (1)

• Number of Objective tumor responses

  From date of randomization until the date of first documented progression or date of death for many cause, whichever came first, assessed up to week 32

Study Arms (1)

Vemurafenib+Cobimetinib + Peg-interferon

EXPERIMENTAL

Vemurafenib 960 mg b.i.d. + Cobimetinib 60 mg o.d.(21 days on followed by 7 days off) + Peg-interferon 1/2/3 micrograms/Kg once weekly

Drug: Vemurafenib; Drug: Peg-interferon; Drug: Cobimetinib

Interventions

Vemurafenib DRUG

Vemurafenib 960 mg b.i.d. for each course of treatment lasting 28 days

Also known as: Brand name= Zelboraf

Vemurafenib+Cobimetinib + Peg-interferon

Peg-interferon DRUG

In the Phase I are included 3 cohorts. Cohort 1) Peg-interferon 1 µg/Kg one time per week s.c. Cohort 2) Peg-interferon 2 µg/Kg one time per week s.c. Cohort 3) Peg-interferon 3 µg/Kg one time per week s.c. Interferon treatment should start after 15 days of Vemurafenib only In the Phase II is included the cohort selected by phase I due to MTD and expanded at RD.

Also known as: Brand name= Sylatron

Vemurafenib+Cobimetinib + Peg-interferon

Cobimetinib DRUG

Cobimetinib 60 mg o.d. (21 days on followed by 7 days off)

Also known as: Brand name=Cotellic

Vemurafenib+Cobimetinib + Peg-interferon

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients over 18
• Untreated and pretreated (no more than 1 treatment) patients with metastatic melanoma at stage unreseactable IIIb-IV, histologically confirmed, that show V600 type BRAF mutations. Patients eligible for Phase I may have been pretreated with the investigational study treatments.
• Patient with measurable disease by RECIST v 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 - 1
• Patients who have successfully completed all the secondary side effects to previous systemic therapy
• Patients with an appropriate hematologic, hepatic and renal functionality, assessed in the 7 days preceding the start of therapy, as well as:
• Absolute neutrophil count (ANC)\> 1.5 X 109 / L
• Absolute platelet count \> 100 X 109 / L
• Hemoglobin \> 9 g/dl
• Serum creatinine \< 1.5 times the normal maximum values or Creatinine Clearance \> 50 mL/hr (Cockroft-Gault formula)
• Transaminase level (AST and ALT) \< 2.5 times the normal maximum values
• Serum bilirubin \< 1.5 times the normal maximum values
• Negative pregnancy test performed within 7 days before beginning therapy (premenopausal women)
• Patients of childbearing age (or with partners of childbearing age) must use effective contraception during therapy and for at least 6 months after the effective treatment
• Absence of any psychological, familiar or social condition that may affect compliance with study protocol and scheduled follow-up

You may not qualify if:

• Presence of symptomatic brain metastases
• Previous malignant cancer during the 2 years preceding the signing of informed consent
• Investigational study treatment within 28 days or 5 half-lives, whichever is longer, preceding the first dose of study treatments in this study
• Pregnancy and/or breast feeding;
• Nausea and vomit refractory to therapy, malabsorption, external biliary shunt, previous bowel resection, which could impair an adequate absorption
• Any of these conditions occurring in the 6 months before the start of Vemurafenib therapy: heart attack, unstable angina and/or severe degree, congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, arterial hypertension not adequately controlled
• History of atrial or ventricular arrhythmia, symptomatic\> grade 2 (NCI CTCAE)
• Hystory of retinopathy
• Correct QT interval \> 450msec to baseline history of congenital long QT syndrome
• Uncontrolled medical condition among which endocrine disorders (such as hypothyroidism, hyperthyroidism and diabetes mellitus)
• Other severe medical or psychiatric conditions or abnormalities of laboratory tests that may increase the risk associated with study participation or the assumption of Vemurafenib, or that may interfere with the interpretation of study results, which in the judgment of the Investigator can make the patient not eligible for the study
• Unwillingness to practice adequate contraception
• Prior systemic treatment with BRAFi or MEKi, or interferon alpha

Sponsors & Collaborators

• Fondazione Melanoma Onlus: lead

Study Sites (1)

Fondazione G.Pascale

Napoli, 80131, Italy

Location

Related Publications (16)

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• Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, Punt CJ, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D; EORTC Melanoma Group. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005 Oct 1;366(9492):1189-96. doi: 10.1016/S0140-6736(05)67482-X.

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• Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Sales F, Gore M, MacKie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U; EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008 Jul 12;372(9633):117-126. doi: 10.1016/S0140-6736(08)61033-8.

  PMID: 18620949 BACKGROUND

• Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, Punt CJ, Sales F, Dummer R, Robert C, Schadendorf D, Patel PM, de Schaetzen G, Spatz A, Keilholz U. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012 Nov 1;30(31):3810-8. doi: 10.1200/JCO.2011.41.3799. Epub 2012 Sep 24.

  PMID: 23008300 BACKGROUND

• Glue P, Fang JW, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, Salfi M, Jacobs S. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther. 2000 Nov;68(5):556-67. doi: 10.1067/mcp.2000.110973.

  PMID: 11103758 BACKGROUND

• Hwu WJ, Panageas KS, Menell JH, Lamb LA, Aird S, Krown SE, Williams LJ, Chapman PB, Livingston PO, Wolchok JD, Houghton AN. Phase II study of temozolomide plus pegylated interferon-alpha-2b for metastatic melanoma. Cancer. 2006 Jun 1;106(11):2445-51. doi: 10.1002/cncr.21909.

  PMID: 16639739 BACKGROUND

• Helfrich I, Edler L, Sucker A, Thomas M, Christian S, Schadendorf D, Augustin HG. Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma. Clin Cancer Res. 2009 Feb 15;15(4):1384-92. doi: 10.1158/1078-0432.CCR-08-1615.

  PMID: 19228739 BACKGROUND

• Sumimoto H, Hirata K, Yamagata S, Miyoshi H, Miyagishi M, Taira K, Kawakami Y. Effective inhibition of cell growth and invasion of melanoma by combined suppression of BRAF (V599E) and Skp2 with lentiviral RNAi. Int J Cancer. 2006 Jan 15;118(2):472-6. doi: 10.1002/ijc.21286.

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• Leyton J, Smith G, Lees M, Perumal M, Nguyen QD, Aigbirhio FI, Golovko O, He Q, Workman P, Aboagye EO. Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901. Mol Cancer Ther. 2008 Sep;7(9):3112-21. doi: 10.1158/1535-7163.MCT-08-0264.

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• Forbes SA, Tang G, Bindal N, Bamford S, Dawson E, Cole C, Kok CY, Jia M, Ewing R, Menzies A, Teague JW, Stratton MR, Futreal PA. COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer. Nucleic Acids Res. 2010 Jan;38(Database issue):D652-7. doi: 10.1093/nar/gkp995. Epub 2009 Nov 11.

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• Rubinstein JC, Sznol M, Pavlick AC, Ariyan S, Cheng E, Bacchiocchi A, Kluger HM, Narayan D, Halaban R. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010 Jul 14;8:67. doi: 10.1186/1479-5876-8-67.

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• Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KY, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D'Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010 Sep 30;467(7315):596-9. doi: 10.1038/nature09454.

  PMID: 20823850 BACKGROUND

• Yang H, Higgins B, Kolinsky K, Packman K, Go Z, Iyer R, Kolis S, Zhao S, Lee R, Grippo JF, Schostack K, Simcox ME, Heimbrook D, Bollag G, Su F. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010 Jul 1;70(13):5518-27. doi: 10.1158/0008-5472.CAN-10-0646. Epub 2010 Jun 15.

  PMID: 20551065 BACKGROUND

• Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010 Aug 26;363(9):809-19. doi: 10.1056/NEJMoa1002011.

  PMID: 20818844 BACKGROUND

• Simeone E, Scognamiglio G, Capone M, Giannarelli D, Grimaldi AM, Mallardo D, Madonna G, Curvietto M, Esposito A, Sandomenico F, Sabbatino F, Bayless NL, Warren S, Ong S, Botti G, Flaherty KT, Ferrone S, Ascierto PA. A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation. J Transl Med. 2021 Jan 6;19(1):17. doi: 10.1186/s12967-020-02680-7.

  PMID: 33407577 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Vemurafenib; cobimetinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Paolo A Ascierto, MD

  Fondazione Melanoma Onlus

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 27, 2013
• First Posted: October 10, 2013
• Study Start: April 3, 2014
• Primary Completion: March 26, 2018
• Study Completion: March 26, 2018
• Last Updated: February 24, 2022

Record last verified: 2019-06

Locations

IT (1)