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 with an anti- PD-L1 antibody atezolizumab for the treatment in patients with unresectable or metastatic BRAF V600 mutant melanoma

Phase 1

• Conditions: Patients with locally advanced, unresectable or metastatic BRAFV600 mutant melanoma.; MedDRA version: 21.1Level: PTClassification code 10025650Term: Malignant melanomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: LLTClassification code 10025667Term: Malignant melanoma site/stage unspecifiedSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: PTClassification code 10027480Term: Metastatic malignant melanomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-005097-37-DE
• Lead Sponsor: niversity Hospital Essen

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-03-21
• Last Update Posted: 29 April 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 176

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, unresectable or metastatic melanoma AJCC 7th edition (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 in dosing exceeding 10 mg daily of prednisone equivalent for at least 3 weeks prior to trial treatment .

4. No previous therapy for the advanced or metastatic stage. Prior adjuvant therapy is permitted (e.g. IFN, IL-2-therapy, chemo- or radiotherapy). Prior adjuvant therapy has to be terminated (last dose) at least 28 days before enrollment. Patients who are in follow-up period of 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 measureable lesion.

6. Presence of BRAF mutation (V600) in tumor tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion prior to enrollment.

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 as following. All screening labs should be performed within 28 days of treatment initiation.
9.1 Hematological:
• Absolute neutrophil count =1,500 /mcL
• Platelets =100,000 / mcL
• Hemoglobin =9 g/dL OR =5.6 mmol/L
• INR and aPTT < 1.5 x ULN
9.2 Renal:
• Serum creatinine =1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) =50 mL/min for subject with creatinine levels > 1.5 X institutional ULN
9.3 Hepatic:
• Serum total bilirubin = 1.5 X ULN
• AST (SGOT) and ALT (SGPT) = 2.5 X ULN OR = 5 X ULN for subjects with liver metastases

10. Adequate cardiac function:
• Left ventricular ejection fraction (LVEF) = 50% as determined by multigated acquisition (MUGA) scan or echocardiogram
• QTc interval = 450 ms

11. All prior treatment-related toxicities (except alopecia) following adjuvant therapy must be = Grade 1 according tothe CTCAE (version 4.03) at the time of: randomization.
Note: Subjects with = Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

12. Able to take oral medications.

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

14. 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 is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

15. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to a

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 in dosing exceeding 10 mg daily of prednisone equivalent 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 co-stimulation or checkpoint pathways) also in an adjuvant setting.
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, Cobimetinib) also in an adjuvant setting.
5.Prior major surgery.
6.Known additional malignancy that is progressing or requires active treatment within 3 years prior to the study. Exceptions 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.
7.Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Note: Subjects with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 3 weeks prior to trial treatment.
8.History of leptomeningeal metastases
9.History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history of hyperviscosity or hypercoagulability syndromes).
10.History of retinal degenerative disease.
11.History of allogenic bone marrow transplantation or organ transplantation.
12.History of Gilbert’s syndrome
13.Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
•History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6 months prior to screening.
•Symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and / or conduction abnormality < 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia.
•History of congenital long QT syndrome or mean (average of triplicate measurements) QTc measured using Fridericia’s method > 450 ms at baseline or uncorrectable abnormalities in serum electrolytes.
14.Uncontrolled arterial hypertension despite medical treatment.
15.Patients who have neuromuscular disorders which are associated with elevated CK (e. g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
16.Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, small bowel resection).
17.Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids in dosing exceeding 10 mg daily of prednisone equivalent or immunosuppressive agents. Note: Subjects with vitiligo or controlled asthma/atopy would b

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified