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MelanomaPhase 1/2VEMUPLINTNCT01959633

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

A Phase 1/2 study testing Vemurafenib, Peg-interferon and Cobimetinib in people with Melanoma, run by Fondazione Melanoma Onlus at 1 site in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Melanoma
What is being tested?
Vemurafenib, Peg-interferon and Cobimetinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
11 participants
Where
1 siteItaly
Study dates
3 Apr 2014to 26 Mar 2018
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
Show all 16Show fewer
  • 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
  • Dated and signed informed consent before any study procedure

Who cannot join

  • 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
Show all 13Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

Italy1 site

  • Fondazione G.Pascale

    Naples, 80131

Other trials in Italy

About this study

Official title: Phase I-II Study of the Combination Vemurafenib Plus Cobimetinib Plus PEG-interferon in Advanced Melanoma Patients Harboring the V600BRAF Mutation

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.

Read the detailed description

Phase I A cohort of 3 consecutive patients will be treated at each dose level (first step). Patients are scheduled to receive at least two courses of therapy (cycle every 28 days) at the same dose level. Escalation of the dose to the next higher level proceeds in absence of dose-limiting toxicity (DLT). Drug-related toxicities will be evaluated during each cycle of therapy and graded according to the NCI Common Toxicity Criteria.

Adverse events (AEs) and the activity of the treatment in terms of ORR, will be assessed as primary endpoints, respectively for phase I and phase II; other variables will be compared as secondary endpoints.

The treatment scheme is Peg-Interferon 1/2/3 micrograms/Kg (lyophilized powder 296 and 444 μg vials) one time per week + Vemurafenib film-coated capsules 960 mg b.i.d. + Cobimetinib tablets 60 mg o.d. 21 days on followed by 7 days off.

Interferon treatment should start after 15 days of Vemurafenib + Cobimetinib only.

Phase I will be conducted at Istituto Nazionale per lo Studio e la Cura dei Tumori - Fondazione G. Pascale (PI Paolo Antonio Ascierto) and a minimum of 3 patients per cohort will be enrolled. Groups of 3 patients will be entered at each dose level (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). DLT will be determined after 2 courses of therapy: if all 3 patients treated at a dose level have been observed for 2 courses of therapy without DLT, then the dose will be escalated. If at least 2/3 patients have DLT after the first 2 courses of therapy in each cohort, then the previous dose level will be considered as the MTD. If 1/3 patients have DLT, then 3 more patients will be treated at this dose level. If none of these patients has DLT, then the dose will be escalated. If at least one of the 3 additional patients has DLT, then the previous dose will be considered the MTD.

The maximum tolerated dose (MTD) is then considered the recommended dose for further evaluation (next step).

Patients experiencing toxicities that were not dose-limiting can be retreated at the same dose level upon full recovery.

Special case is represented by patients with liver metastases for whom ALT or AST increases >3xULN (i.e., Grade 2 of the CTCAE) requires a closer monitoring of the liver tests. In such cases patients with AT up to 5xULN may be allowed to participate in the trial. Therefore, a threshold level of ALT or AST >3xBaseline value (vs. the standard >3xULN threshold) is considered to prompt closer monitoring for the whole duration of the treatment. Patients with rapidly rising or high serum ALT or AST or with ALT or AST elevations accompanied by jaundice require urgent evaluation to find treatable causes of hepatocellular necrosis.

Patients will be treated until progression if the MTD is not reached.

Phase II Phase II will be conducted in approximately 10 Investigational sites located in Italy and 42 patients will be enrolled in total (including 3 patients from the phase I).

Treatment will be continued until progression or unacceptable toxicity.

Conditions
Melanoma
Being tested
Vemurafenib, Peg-interferon, Cobimetinib
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VemurafenibDrug

    Also called Brand name= Zelboraf

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

  • Peg-interferonDrug

    Also called Brand name= Sylatron

    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.

  • CobimetinibDrug

    Also called Brand name=Cotellic

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

Study groups in NCT01959633
Study groupRoleWhat they receive
Vemurafenib+Cobimetinib + Peg-interferonExperimentalVemurafenib 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
Receives: Drug: Vemurafenib; Drug: Peg-interferon; Drug: Cobimetinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: up to 24 weeks

Secondary outcomes (1)

  1. Number of Objective tumor responses

    Objective tumor response will be measured according to the modified RECIST 1.1 criteria. Response criteria are essentially based on a set of measurable lesions identified at baseline as target lesions, and followed until disease progression. Durable response rate (DRR) will be identified as the percentage of patients that is still in CR and PR at week 32. The results will be tabulated with Clopper-Pearson 95%CI for response rates

    Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Oct 2013 (estimated)
  2. Study start3 Apr 2014
  3. Primary completion26 Mar 2018
  4. Study completion26 Mar 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
11 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01959633
Sponsor's protocol ID
VEMUPLINT
Other IDs
2013-003730-33
Acronym
VEMUPLINT
Status last verified
Jun 2019
First submitted
27 Sep 2013
Last updated
24 Feb 2022
Results posted
No
Data monitoring committee
Yes

Publications

  • Bukowski RM, Tendler C, Cutler D, Rose E, Laughlin MM, Statkevich P. Treating cancer with PEG Intron: pharmacokinetic profile and dosing guidelines for an improved interferon-alpha-2b formulation. Cancer. 2002 Jul 15;95(2):389-96. doi: 10.1002/cncr.10663.

    PubMed 12124839

  • 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.

    PubMed 16198768

  • 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.

    PubMed 18620949

  • 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.

    PubMed 23008300

  • 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.

    PubMed 11103758

  • 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.

    PubMed 16639739

  • 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.

    PubMed 19228739

  • 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.

    PubMed 16052531

  • Artale S, Sartore-Bianchi A, Veronese SM, Gambi V, Sarnataro CS, Gambacorta M, Lauricella C, Siena S. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol. 2008 Sep 1;26(25):4217-9. doi: 10.1200/JCO.2008.18.7286. No abstract available.

    PubMed 18757341

  • 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.

    PubMed 18790789

  • 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.

    PubMed 19906727

  • 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.

    PubMed 20630094

  • 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.

    PubMed 20823850

  • 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.

    PubMed 20551065

  • 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.

    PubMed 20818844

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Vemurafenib, Peg-interferon and Cobimetinib in people with Melanoma, run by Fondazione Melanoma Onlus at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of participants with adverse events (time frame: up to 24 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01959633, which also lists 16 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Feb 2022.

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