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Evaluating the Efficacy and Safety of a Sequencing Schedule of Cobimetinib Plus Vemurafenib Followed by Immunotherapy With an Anti- PD-L1 Antibody in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma (ImmunoCobiVem)

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ClinicalTrials.gov Identifier: NCT02902029
Recruitment Status : Recruiting
First Posted : September 15, 2016
Last Update Posted : September 5, 2019
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen

Brief Summary:

Most patients with locally advanced or metastatic tumors succumb to their disease. Thus, there is a substantial need for novel therapeutic strategies to improve the outcome for patients with advanced or metastatic melanoma. Targeting the the Ras/Raf signalling pathway by BRAF and MEK inhibition as well as targeting immunologic checkpoint control with an antiPD-L1 antibody have emerged as treatment option.

In this study the best timing for sequential use of both treatment options (BRAF/MEK inhibition and antiPD-L1 antibody) in patients with unresectable or metastatic BRAFV600 mutant melanoma will be assessed.


Condition or disease Intervention/treatment Phase
Malignant Melanoma Drug: Vemurafenib Drug: Cobimetinib Drug: Atezolizumab Phase 2

Detailed Description:

At this time there is no experience concerning the sequencing strategy when using the two effective therapeutical approaches as targeting the Ras/Raf signalling pathway by BRAF and MEK inhibition or targeting immunologic checkpoint control with an antiPD-L1 antibody.

This is a prospective, open, multicenter, randomized phase II study in patients with unresectable or metastatic BRAFV600 mutant melanoma. In this study the scheduling of the treatment with a combined BRAF/MEK inhibition and the treatment with an anti-PD-L1 antibody will be assessed.

After a 3 months run-in period with vemurafenib and cobimetinib, all patients who did not show disease progression or treatment interruption for more than 28 days during run-in phase will be randomized in a 1:1 ratio:

  • either to proceed vemurafenib and cobimetinib until disease progression and subsequently cross-over to atezolizumab treatment until disease progression (Arm A).
  • or to receive the anti-PD-L1 antibody atezolizumab until disease progression and subsequently cross-back to vemurafenib and cobimetinib until disease progression (Arm B). In a translational research program tumor tissue, blood plasma and peripheral blood mononuclear cell will be analyzed to evaluate the biologic effects of treatment sequence on the molecular profile and biomarker expression in tissue and plasma.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 176 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Open-label, Randomized-controlled Trial Evaluating the Efficacy and Safety of a Sequencing Schedule of Cobimetinib Plus Vemurafenib Followed by Immunotherapy With an Anti- PD-L1 Antibody Atezolizumab for the Treatment in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma
Study Start Date : November 2016
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : June 2022


Arm Intervention/treatment
Experimental: Arm A

After a 3 months run-in period with vemurafenib and cobimetinib [960 mg vemurafenib twice daily (BID), 28/0; 60 mg cobimetinib daily (QD), 21/7], all patients who do not show disease progression or definite treatment interruption (e.g. due to unacceptable toxicity) for more than 28 days will be randomized.

Further treatment with vemurafenib and cobimetinib (960 mg vemurafenib BID, 28/0; 60 mg cobimetinib QD, 21/7).

After progression of disease patients in Arm A will subsequently receive atezolizumab treatment (1200 mg/ q3w).

Drug: Vemurafenib
960 mg vemurafenib BID until progression or unacceptable toxicity develops

Drug: Cobimetinib
60 mg cobimetinib QD, 21/7 until progression or unacceptable toxicity develops

Drug: Atezolizumab
1200 mg atezolizumab administered intravenously on day 1 of each 21 day-cycle. Will be given until progression or unacceptable toxicity develops

Experimental: Arm B

After a 3 months run-in period with vemurafenib and cobimetinib (960 mg vemurafenib BID, 28/0; 60 mg cobimetinib QD, 21/7), all patients who do not show disease progression or definite treatment interruption (e.g. due to unacceptable toxicity) for more than 28 days will be randomized.

Further treatment with atezolizumab. Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on day 1 of each 21 day-cycle.

After progression of disease patients in Arm B will cross back to vemurafenib and cobimetinib treatment (960 mg vemurafenib BID, 28/0; 60 mg cobimetinib QD, 21/7).

Drug: Vemurafenib
960 mg vemurafenib BID until progression or unacceptable toxicity develops

Drug: Cobimetinib
60 mg cobimetinib QD, 21/7 until progression or unacceptable toxicity develops

Drug: Atezolizumab
1200 mg atezolizumab administered intravenously on day 1 of each 21 day-cycle. Will be given until progression or unacceptable toxicity develops




Primary Outcome Measures :
  1. Time to Second Objective Disease Progression [ Time Frame: 4 years ]
    Time to Second Objective Disease Progression (PFS2) defined as time from start of run-in phase (date of first intake of study drug) to second objective disease progression according to RECIST v. 1.1. (PD2) following randomization or death from any cause


Secondary Outcome Measures :
  1. Adverse events according to CTCAE Version 4.0 criteria (Safety / Toxicity) [ Time Frame: Until 90 days of discontinuation of dosing of the investigational product ]
    All adverse events according to CTCAE Version 4.0 criteria, that are related to the administration of the investigational agents will be assessed

  2. Overall survival [ Time Frame: 4 years ]
    Overall Survival (OS) of a patient defined as the time from start of run-in phase (date of first intake of study drug) until documented date of death

  3. Overall survival 12 months [ Time Frame: 1 year ]
    Overall survival rate at 12 months defined as the rate of patients alive 12 months after start of run-in phase (date of first intake of study drug)

  4. Overall survival 24 months [ Time Frame: 2 years ]
    Overall survival rate at 24 months defined as the rate of patients alive 24 months after start of run-in phase (date of first intake of study drug)

  5. 12-months disease control rate (DCR) [ Time Frame: 1 year ]
    DCR is defined as the rate of patients showing complete response (CR) or partial response (PR) or stable disease (SD) at 12 months after start of run-in phase (date of first intake of study drug).

  6. 24-months disease control rate (DCR). [ Time Frame: 2 years ]
    DCR is defined as the rate of patients showing complete response (CR) or partial response (PR) or stable disease (SD) at 24 months after start of run-in phase (date of first intake of study drug).

  7. Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status and/or brain metastases [ Time Frame: 4 years ]
    • From run-in phase (vemurafenib + cobimetinib) to study treatment in Arm A or Arm B
    • From vemurafenib + cobimetinib to atezolizumab (Arm A)
    • From atezolizumab to vemurafenib + cobimetinib (Arm B)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Be willing and able to provide written informed consent for the trial.
  • Male or female patient being ≥18 years of age on day of signing informed consent.
  • Histologically confirmed diagnosis of locally advanced, unresectable or metastatic melanoma AJCC (unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c) without active or untreated brain metastases; all known CNS lesions must have been treated with stereotactic therapy or surgery at least 4 weeks prior to the first dose of trial treatment AND the patient must be without evidence of clinical or radiographic disease progression in the CNS for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms must have returned to baseline, the patient must have no evidence of new or enlarging brain metastases, and the patient must not have used steroids for at least 3 weeks prior to trial treatment.
  • No previous therapy for the advanced or metastatic stage. Prior adjuvant therapy is permitted (e.g. Interferon, Interleukin-2-therapy, chemo- or radiotherapy). Prior adjuvant therapy has to be terminated (last dose) at least 28 days before enrolment. Patients who are in follow-up period of a clinical trial in adjuvant setting and progressing may be enrolled / randomized.
  • Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1, for the definition of a measureable lesion.
  • Presence of BRAF mutation (V600) in tumor tissue.
  • Performance status of 0 or 1 on the ECOG Performance Scale.
  • Adequate organ function.
  • Adequate cardiac function.
  • Able to take oral medications.
  • Female subject of childbearing potential should have a negative pregnancy test within 72 hours prior to receiving the first dose of study medication.
  • Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to CTFG during the course of this study and for at least 6 months after completion of study therapy.

Exclusion Criteria:

  • Use of any investigational or non-registered product within the 30 days before registration.
  • Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study Day 1.
  • Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  • Prior therapy with a BRAF inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib and / or MEK inhibitor
  • Prior major surgery.
  • Known additional malignancy that is progressing or requires active treatment within 5 years prior to the study.
  • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
  • History of leptomeningeal metastases.
  • History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to RVO or CSR.
  • History of retinal degenerative disease.
  • History of allogenic bone marrow transplantation or organ transplantation.
  • History of Gilbert's syndrome.
  • Impaired cardiovascular function or clinically significant cardiovascular diseases.
  • Uncontrolled arterial hypertension despite medical treatment.
  • Impairment of gastrointestinal function or gastrointestinal disease.
  • Evidence of interstitial lung disease or active, non-infectious pneumonitis.
  • Active infection requiring systemic therapy.
  • Positive test for Human Immunodeficiency Virus (HIV).
  • Positive test for Hepatitis B or Hepatitis C.
  • Known hypersensitivity reaction to any of the components of study treatment.
  • Medical, psychiatric, cognitive or other conditions, including known alcohol or drug abuse.
  • Patients having received a live, attenuated vaccine within 4 weeks prior to the first dose of trial treatment.
  • Legal incapacity or limited legal capacity.

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): NCT02902029


Contacts
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Contact: Dirk Schadendorf, Prof. Dr. dirk.schadendorf@uk-essen.de

Locations
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France
Hôpital Ambroise-Paré Recruiting
Boulogne-Billancourt, France, 92104
Contact: Philippe Saiag, Prof.       philippe.saiag@apr.aphp.fr   
Hospital Claude Huriez Recruiting
Lille, France, 59000
Contact: Laurent Mortier, Prof.       laurent.mortier@chru-lille.fr   
Hôpital de la Timone Recruiting
Marseille, France, 13885
Contact: Jean J Grob, Prof.       jean-jacques.grob@ap-hm.fr   
CHU de Nantes Recruiting
Nantes, France, 44093
Contact: Brigitte Dreno, Prof.       brigitte.dreno@wanadoo.fr   
Centre Hospitalier Lyon Sud Recruiting
Pierre-Bénite, France, 69310
Contact: Stéphane Dalle, Dr.       stephane.dalle@chu-lyon.fr   
Germany
SLK-Kliniken Heilbronn GmbH Recruiting
Heilbronn, Baden-Wuerttemberg, Germany, 74078
Contact: Uwe Martens, Prof. Dr.       uwe.martens@slk-kliniken.de   
Principal Investigator: Uwe Martens, Prof. Dr.         
Sub-Investigator: Jamil Akkad         
University Hospital Mannheim, Clinic for Dermatology Recruiting
Mannheim, Baden-Wuerttemberg, Germany, 68167
Contact: Jochen Utikal, Prof. Dr.       jochen.utikal@umm.de   
Principal Investigator: Jochen Utikal, Prof. Dr.         
Sub-Investigator: Maria Rita Gaiser, PD Dr. med.         
National Centre for Tumour Diseases (NCT) Recruiting
Heidelberg, BW, Germany, 69120
Contact: Jessica Hassel, Dr. med.       jessica.hassel@med.uni-heidelberg.de   
Principal Investigator: Jessica Hassel, Dr. med.         
Sub-Investigator: Martin Hartmann, Dr. med         
University Hospital Essen, Department of Dermatology, Skin Cancer Center Recruiting
Essen, North Rhine-Westphalia, Germany, 45122
Contact: Dirk Schadendorf, Prof. Dr.       dirk.schadendorf@uk-essen.de   
Principal Investigator: Dirk Schadendorf, Prof. Dr.         
Sub-Investigator: Elisabeth Livingstone, Dr.         
Sub-Investigator: Lisa Zimmer, Dr.         
HELIOS Klinikum Erfurt Recruiting
Erfurt, Thuringia, Germany, 99089
Contact: Rudolf Herbst, Prof. Dr.       rudolf.herbst@helios-kliniken.de   
Principal Investigator: Rudolf Herbst, Prof. Dr.         
Sub-Investigator: Ivonne Kellner, Dr. med.         
Charité-Universitätsmedizin Berlin Recruiting
Berlin, Germany, 10117
Contact: Felix Kiecker, Dr. med.       felix.kiecker@charite.de   
Principal Investigator: Felix Kiecker, Dr. med.         
Sub-Investigator: Claas Ulrich, Dr. med.         
Elbe Kliniken Stade - Buxtehude Not yet recruiting
Buxtehude, Germany, 21614
Contact: Peter Mohr, Dr. med.       Peter.Mohr@elbekliniken.de   
Principal Investigator: Peter Mohr, Dr. med.         
Universitätsklinik Dresden Recruiting
Dresden, Germany, 01307
Contact: Friedegund Meier, Prof. Dr.       friedegund.meier@uniklinikum-dresden.de   
Principal Investigator: Friedegund Meier, Prof. Dr.         
Sub-Investigator: Marlene Garzarolli         
Medizinische Hochschule Hannover Recruiting
Hannover, Germany, 30625
Contact: Ralf Gutzmer, Prof. Dr.       gutzmer.ralf@mh-hannover.de   
Principal Investigator: Ralf Gutzmer, Prof. Dr.         
Sub-Investigator: Imke Satzger, Pd Dr.         
Universitätsklinikum des Saarlandes Not yet recruiting
Homburg/Saar, Germany, 66421
Contact: Claudia Pföhler, Prof. Dr.       Claudia.Pfoehler@uniklinikum-saarland.de   
Principal Investigator: Claudia Pföhler, Prof. Dr.         
Sub-Investigator: Thomas Vogt, Prof. Dr.         
Universitäts-Hautklinik Kiel Recruiting
Kiel, Germany, 24105
Contact: Katharina Kähler, Dr. med.       kckaehler@yahoo.de   
Principal Investigator: Katharina Kähler, Dr. med.         
Sub-Investigator: Axel Hauschild, Prof. Dr.         
Universitätsklinikum Köln Recruiting
Köln, Germany, 50937
Contact: Cornelia Mauch, Prof. Dr.       cornelia.mauch@uk-koeln.de   
Principal Investigator: Cornelia Mauch, Prof. Dr.         
Universitätsklinikum Leipzig Recruiting
Leipzig, Germany, 04103
Contact: Jan Christoph Simon, Prof. Dr.       jan.simon@medizin.uni-leipzig.de   
Principal Investigator: Jan Christoph Simon, Prof. Dr.         
Sub-Investigator: Mirjana Ziemer, Dr. med.         
Gesellschaft für Klinische Forschung Ludwigshafen mbH Recruiting
Ludwigshafen, Germany, 67063
Contact: Edgar Dippel, Prof. Dr.       dippele@klilu.de   
Principal Investigator: Edgar Dippel, Prof. Dr.         
Sub-Investigator: Evelyn Dabrowski, Dr. med.         
Universitätsklinikum Schleswig-Holstein Recruiting
Lübeck, Germany, 23538
Contact: Patrick AM Terheyden, PD Dr. med.       patrick.terheyden@uksh.de   
Principal Investigator: Patrick AM Terheyden, PD Dr. med.         
Sub-Investigator: Diamant Thaci, Prof.         
Universitätsklinikum Mainz Recruiting
Mainz, Germany, 55131
Contact: Carmen Loquai, Prof. Dr.       carmen.loquai@unimedizin-mainz.de   
Principal Investigator: Carmen Loquai, Prof. Dr.         
Sub-Investigator: Stephan Grabbe, Prof. Dr.         
Sub-Investigator: Heidrun Karin Mitzel-Rink, Dr.         
Johannes Wesling Klinikum Minden Recruiting
Minden, Germany, 32429
Contact: Rudolf Stadler, Prof. Dr.       rudolf.stadler@muehlenkreiskliniken.de   
Principal Investigator: Rudolf Stadler, Prof. Dr.         
Sub-Investigator: Jörg Böttjer, Dr.         
Klinikum der Universität München Recruiting
München, Germany, 80337
Contact: Carola Berking, Prof. Dr.       Carola.Berking@med.uni-muenchen.de   
Principal Investigator: Carola Berking, Prof. Dr.         
Sub-Investigator: Julia Katharina Tietze, Dr. med.         
Universitätsklinikum Tübingen Recruiting
Tübingen, Germany, 72076
Contact: Claus Garbe, Prof. Dr.       claus.garbe@med.uni-tuebingen.de   
Principal Investigator: Claus Garbe, Prof. Dr.         
Sub-Investigator: Thomas Kurt Eigentler, PD Dr. med.         
Sub-Investigator: Benjamin Matthias Weide, Dr. med.         
Uniklinikum Würzburg Recruiting
Würzburg, Germany, 97080
Contact: Anja Heike Gesierich, MD       Gesierich_A@ukw.de   
Principal Investigator: Anja Heike Gesierich, MD         
Sub-Investigator: Marion Wobser, Dr.         
Greece
"LAIKO" General Hospital of Athens Recruiting
Athens, Greece, 11527
Contact: Helen Gogas, Prof.       hgogas@hol.gr   
Serbia
Military Medical Academy Recruiting
Belgrad, Serbia, 11000
Contact: Lidija Kandolf-Sekulovic, Prof.       lkandolfsekulovic@gmail.com   
Sponsors and Collaborators
University Hospital, Essen
Investigators
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Principal Investigator: Dirk Schadendorf, Prof. Dr. University Hospital, Essen

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Responsible Party: Prof. Dr. med. Dirk Schadendorf, Prof. Dr. med., University Hospital, Essen
ClinicalTrials.gov Identifier: NCT02902029     History of Changes
Other Study ID Numbers: ImmunoCobiVem_2015
First Posted: September 15, 2016    Key Record Dates
Last Update Posted: September 5, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen:
unresectable stage IIIB, IIIC, IV melanoma
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Atezolizumab
Vemurafenib
Antibodies
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action