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ImmunoCobiVem

AcronymISRCTNEudraCTClinicaltrials.govDRKS
2015-005097-37

A Phase II, multicenter, open-Label, randomized-controlled Trial evaluating the efficacy and safety of a sequencing schedule of cobimetinib plus vemurafenib followed by immunotherapy wíth an anti-PD-L1 antibody atezolizumab for the Treatment in patients with unresectable or metastatic BRAF V600 Mutant melanoma.

Status: Active

Purpose / Objectives

Primary Outcome

Time to Second Objective Disease Progression (PFS2) defined as time from randomization to secont objective disease progressin according to RECIST v. 1.1 (PD2) follwoing randomization or death from any cause (Figure 2).

Secondary Outcomes

- Safety

- Overall Survival (OS) of a Patient defined as the time from randomization until documented date of death

- Overall survival rate at 12 months and 24 months defined as the rate of patients alive 12 months and 24 months, respectively after the date of randomization.

- 12 months and 24-months disease control rate (DCR). DCR is defined as the rate of patients showing complete Response (CR) or partial Response (PR) or stable disease (SD) at 12 months and at 24 months after the date of randomization. CR, PR, and SD are defined according to RECIST v1.1 Criteria.

- 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.

- From run-in Phase (Vemurafenib and Cobimetinib) to study Treatment in Arm A oder Arm B

- Vermurafenib and Cobimetinib to Atezolizumab (Arm A)

- From Atezolizumab to Vemurafenib + Cobimetinib (Arm B)

- PFS1 defined as time from randomization  and the first documented Tumor Progression date (PD1) or death by any cause.

- PFS3 defined as time from the first documented Tumor Progression date (PD2) after randomization or death bby any cause.

 

Exploratory objectives (addressed by the translational Research Project):

To evaluate the relationship of the Tumor immune and signaling biomarker landscape and efficacy.

To evaluate non-inherited genetic alterations of circulating free tumor-specific DNA in Plasma

To assess and Monitor the immunophenotype in pheripheral blood mononuclear cells.

 

Diagnosis

Patient attributes

Age

18-99

Inclusion criteria

1. Be willing and able to provide written informed consent for the Trial.

2. Male or female Patient being ≥ 18 years of Age on day of signing informed consent.

3. Histologically confirmed diagnosis of locally advanced, unresetable or metastatic melanoma AJCC 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 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 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.

4. Naive untreated Patient for locally advanced  or metastatic melanoma. Prior adjuvant therapy is permitted (e.g. IFN, IL-2-therapy, chemo- or radiotherapy). Patients who are in follow-up periodof a clinical Trial in adjuvant Setting and progressing may be enrolled/randomized.

5. Measurable disease , i.e., present with at least one measurable lesion per RECIST, Version 1.1, for the Definition of a measurable lesion.

6. Presence of BRAF Mutation (V600) in Tumor tissue from an archival tissue sample of newly obtained core or excisional biopsy of a Tumor lesion Prior to enrolment.

7. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a Tumor lesion.

8. Have a Performance Status of 0 or 1 on the ECOG Performance Scale.

9. Demonstrate adequate organ function as defined in the table (see protocol). All Screening labs should be performed within 14 days of Treatment Initiation.

10. Adequate cardiac function.

Left ventricular ejection fraction (LVEF) ≥ 50 % as determined by multigated acquisition (MUGA) scan or echocardiogram.

QTc intervals ≤ 480 MS

11. Able to take oral medications.

12. Patient is deemed by the investigator to have the initiative and means to be compliant with the protocol.

13. Female subject of childbearing potential should have a negative Serum pregnancy test within 72 hours Prior to receiving the first dose of study medication. If the Urine test ist positive or cannot be confirmed as negative, a Serum pregnancy test will be required.

14. Female patients of childbearing potential and male patients with Partners of childbearing potential must agree to always use 2 effective forms of contraception during the course of the study and at least 6 months after completion of study therapy.

Exclusion criteria

1. Use of any investigational or non-registered product within the 30 days before Registration.

2. Diagnosis of immunodeficiency or receiving systemic Steroid therapy or any other form of immunosuppressive therapy within 7 days Prior to study Day 1.

3. 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 costimulation or checkpoint pathways.

4. Prior therapy with a BRAF Inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib and / or Mek Inhibitor (including but not limited to trametinib, AZD6244, Binimetinib).

5. All Prior Treatment-related toxicities (except alopecia) must be ≤ Grade 1 according to the CTCAE (Version 4.0) at the time of randomization.
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

6. Note: If subject received Major surgery, the must have recovered adequately from the toxicity and/or complications from the Intervention Prior to starting therapy.

7. Known additional malignancy that is progressing or requires active Treatment. Exception include adequately treated basal cell carcinoma of the Skin, squamous cell carcinoma of the Skin, or in situ cervical cancer that has undergone potentially curative therapy without evidence or recurrence for at least 3 years Prior to the study.

8-27 (see Synopsis).

Trial design

  • Phase II
  • Multicenter
  • Randomized
  • Two-arm
  • Open Label

Documents (password protected)

Responsibilities in overall trial

Universitätsklinikum Essen

  • Tel. +49 (0)201/ 7 23 - 0
  • Fax +49 (0)201/ 7 23 - 46

National Coordinating Investigator

Prof Dirk Schadendorf

Study Sites

Klinik & Poliklinik für Dermatologie & Venerologie Köln

Study office

Status

Active

Principal Investigator

Univ.-Prof. Dr. med. Dr. Cornelia Mauch

Deputy of Principal Investigator

  • Dr. Nicole Kreuzberg

Subinvestigator

  • Dr. Nicole Kreuzberg
  • Bodo Bühler
  • Sarah Ramesh

Contact at Site