GEM-01-15

Grupo Español Multidisciplinar de Melanoma (GEM)

C/ Secretari Coloma, nº 64-68. Escalera B, entresuelo 5ª, Barcelona, Spain, 08024

Juan Berges (Clinical Operations), Pivotal, S.L., +34 91 7801250 , juan.berges@pivotalcr.com

Claudio Savulsky MD, Pivotal, S.L., +34 617815564, claudio.savulsky@pivotalcr.com

No

No

No

Final

08 Jun 2020

No

Yes

30 Sep 2019

No

To evaluate the efficacy (in terms of PFS) of two schedules of administration of vemurafenib in combination with cobimetinib (continuous and intermittent) in previously untreated BRAFV600- mutation positive patients with unresectable locally advanced or metastatic melanoma.

This study was conducted under standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: Principles of the World Medical Association Declaration of Helsinki (2004 revision) ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Conference on Harmonization of Pharmaceuticals for Human Use Royal Decree 1090/2015, of December 4, which regulates clinical trials with drugs, the Research Ethics Committees with drugs and the Spanish Registry of Clinical Studies, and which fully incorporates the order of the Regulations ( EU) No. 536/2014 of the European Parliament and the Council, of April 16, 2014, on clinical trials of medicinal products for human use. Also applicable is Law 14/2007 on Biomedical Research and in Royal Decree 1716/2011, dated November 18, which establishes the minimum requirements for the authorization and operation of biobanks for biomedical research and treatment purposes. of biological samples of human origin. The investigator is aware when signing the protocol, to adhere to the instructions and procedures described in them and in this way, follow the principles of good clinical practices that they imply. In compliance with Royal Decree 1090/2015, the sponsor will submit the relevant documentation to the IECs of its choice for its evolution and subsequent report. The protocol, informed consent forms (ICF), and any appropriate related documents were submitted to the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) by the principal investigator (PI) for approval. The investigator submitted periodic reports and informed the IRB or IEC of any reportable adverse events (AEs) as per International Conference on Harmonization (ICH) of Technical Requirement.

02 Mar 2015

No

No

Spain: 70

70

70

0

0

0

0

0

0

46

23

1

Overall Trial (overall period)

Randomised - controlled

Yes

Cobimetinib

Cotellic®

Tablet

Oral use

Experimental Group A - Continuous Administration: Vemurafenib 960 mg orally twice daily on days 1-28 and cobimetinib 60 mg orally once a day on days 1-21 of each 28-day treatment cycle.

Vemurafenib

Zelboraf®

Tablet

Oral use

Experimental Group A - Continuous Administration:Vemurafenib 960 mg orally twice daily on days 1-28 and cobimetinib 60 mg orally once a day on days 1-21 of each 28-day treatment cycle.

Vemurafenib

Zelboraf®

Tablet

Oral use

Vemurafenib 960 mg orally twice daily on days 1-28 and cobimetinib 60 mg orally once a day on days 1-21 of each 28-day treatment cycle for 12 weeks. Then, both drugs were administered at the same doses previously indicated, but with an intermittent schedule: Vemurafenib days 1-28 followed by 14 days of rest (4 weeks on and 2 weeks off) and, Cobimetinib days 1-21 followed by 21 rest days. (3 weeks on and 3 weeks off)

Cobimetinib

Cotellic®

Tablet

Oral use

Vemurafenib 960 mg orally twice daily on days 1-28 and cobimetinib 60 mg orally once a day on days 1-21 of each 28-day treatment cycle for 12 weeks. Then, both drugs were administered at the same doses previously indicated, but with an intermittent schedule: Vemurafenib days 1-28 followed by 14 days of rest (4 weeks on and 2 weeks off) and, Cobimetinib days 1-21 followed by 21 rest days. (3 weeks on and 3 weeks off).

Group A (continuous administration)

Group B (intermittent administration)

Intention to treat Analyses

All 70 randomized subjects were included in the ITT analysis set. In the ITT population defined as all randomized patients, 35 subjects [50%] in the Group A – Continuous and 35 subjects [50%] in the Group B – Intermittent were included. Patients were analyzed according to the treatment group to which they have been assigned, regardless of the treatment received. All randomized subjects were included in the analysis. Of these 70 subjects, 51 subjects did not have any major protocol deviation and met criteria for inclusion in the PP analysis set.

Group A (continuous administration)

Group B (intermittent administration)

Intention to treat Analyses

All 70 randomized subjects were included in the ITT analysis set. In the ITT population defined as all randomized patients, 35 subjects [50%] in the Group A – Continuous and 35 subjects [50%] in the Group B – Intermittent were included. Patients were analyzed according to the treatment group to which they have been assigned, regardless of the treatment received. All randomized subjects were included in the analysis. Of these 70 subjects, 51 subjects did not have any major protocol deviation and met criteria for inclusion in the PP analysis set.

This study was designed to assess the efficacy, in terms of progression-free survival (PFS), of two regimens for the administration of the combination of vemurafenib and cobimetinib (continuous and intermittent), in the first-line treatment of patients with unresectable or metastatic advanced melanoma with the BRAF V600 mutation. The main variable is the PFS, defined as the time elapsed between the random allocation and the first appearance of disease progression, or death from any cause, whichever comes first. If a patient has not progressed and is still alive on the cutoff date for data analysis, they were censored on the date of the last tumor evaluation performed. Those patients without documentation of progression before a loss of follow-up were censored for PFS on the date of the last tumor evaluation before the loss of follow-up.

Primary

Time elapsed between randomization and the first occurrence of disease progression, as determined by the investigator using the RECIST criteria, V1.1 , or death from any cause, whichever comes first.

For an error α = 0.1 and an error β = 0.20, 34 evaluable pts recruited per group, using a Log-rank method (Tablecloth) Cox two-tailed . A power of 80% was obtained to detect a difference of 23% in the % PFS at 1 year (error α = 0.1) in the Kaplan-Meier curves, assuming 27 months of recruitment, 24 months of FU, a HR of 0.53 and a total of 61 events. A maximum loss of 10% of pts was estimated at follow-up and before progression, 38 pts per group, which gives an estimated total of 76 patients.

Group A (continuous administration) v Group B (intermittent administration)

70

Pre-specified

1.642

2-sided

Overall survival is defined as the time elapsed between randomization and death from any cause. If a patient is still alive on the cut-off date for data analysis, they were censored on the date of the last tumor evaluation performed. Those patients without documentation of death before the loss of followup were censored for the OS on the date of the last evaluation before the loss of follow-up. However, all the details about the censoring dates for the OS were specified in the statistical analysis plan. It was described using the median survival, as well as the 1 and 2-year survival rate, estimated using the Kaplan-Meier curve, along with their confidence intervals. The analysis between the two treatment groups was carried out similarly to that described for the PFS, using the Log-rank test, calculating the HRs, and their corresponding confidence intervals, using the Cox proportional hazards method.

Secondary

Overall survival is defined as the time elapsed between randomization and death from any cause.

The comparison between both curves was made using the Log-rank test, calculating the HRs, and their corresponding confidence intervals, through the Cox proportional hazards method, between the two arms Group B - Intermittent vs Group A - Continuous,

Group A (continuous administration) v Group B (intermittent administration)

70

Pre-specified

1.1092

2-sided

Standard deviation

The objective responses were evaluated following the RECIST V1.1 criteria. An estimate was made of the percentage of overall objective responses (defined as the proportion of patients with CR and RP), with its 95% confidence interval. The comparison between the groups of these parameters was made through the chi-square test

Secondary

The objective responses were evaluated following the RECIST V1.1 criteria.

All patients were closely monitored for safety and tolerability during all treatment cycles, at the end of study treatment visit and during the follow-up period.

Patients were screened for AEs every 2 weeks for the first 12 weeks of treatment and thereafter each cycle. The biweekly evaluation of adverse events during cycles 2 and 3 of treatment may be carried out through an evolutionary telephone monitoring if it is duly documented in the patient's medical history.

17.1

Group A (continuous administration)

Group B (intermittent administration)