Malignant MelanomaPhase 1NCT01271803

A Study of Vemurafenib and GDC-0973 (Cobimetinib) in Participants With BRAFV600E Mutation-Positive Metastatic Melanoma

A Phase 1 study testing Cobimetinib and vemurafenib in people with Malignant Melanoma, run by Hoffmann-La Roche at 10 sites in 2 countries.

Completed

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

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Malignant Melanoma
What is being tested?: Cobimetinib and vemurafenib
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 131 participants
Where: 10 sitesin 2 countries
Study dates: 17 Feb 2011to 12 Dec 2017
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

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

Participants with histologically confirmed melanoma (unresectable Stage IIIc and Stage IV metastatic melanoma, as defined by American Joint Committee on Cancer [AJCC])
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1
Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to (</=) 1
Participants must
be previously untreated for locally advanced/unresectable or metastatic melanoma or
previously treated but without prior exposure to any BRAF or MEK inhibitor therapy or

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progressed on vemurafenib while participating in a Phase I (including clinical pharmacology studies), II, or III clinical study or expanded access programs (EAP) immediately prior to enrollment in this study or
progressed on vemurafenib administered in a postmarketing setting immediately prior to enrollment in this study.
Life expectancy >/=12 weeks

Who cannot join

History of prior significant toxicity from another RAF or MEK pathway inhibitor requiring discontinuation of treatment
Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment
Experimental therapy within 4 weeks prior to first dose of study drug treatment except vemurafenib
Major surgery within 4 weeks of first dose of study drug treatment or planning a major surgery during the study

Trial locations and contacts

10 sites in 2 countries.

Country

City, postcode or hospital

10 sites in 2 countries

United States9 sites

University of Colorado; Anschutz Cancer Pavilion
Aurora, Colorado, 80045
University of Chicago
Chicago, Illinois, 60637
Karmanos Cancer Inst. ; Hudson Webber; Cancer Research Building
Detroit, Michigan, 48201
Indiana University - Department of Medicine, Division of Gastroenterology/Hepatology
Indianapolis, Indiana, 46202
UCLA Department of Medicine
Los Angeles, California, 90024
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
New York University Medical Center
New York, New York, 10036
University of California at San Francisco
San Francisco, California, 94115
The Angeles Clinic and Research Institute, Santa Monica Office
Santa Monica, California, 90025

Other trials in United States

Australia1 site

Peter Maccallum Cancer Institute; Medical Oncology
Melbourne, Victoria, 3000

Other trials in Australia

About this study

Official title: A Phase IB, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of Vemurafenib in Combination With GDC-0973 (Cobimetinib) When Administered in BRAFV600E Mutation-Positive Patients Previously Treated (But Without Prior Exposure to BRAF or MEK Inhibitor Therapy) or Previously Untreated for Locally Advanced/Unresectable or Metastatic Melanoma or Those Who Have Progressed After Treatment With Vemurafenib

This open-label, dose-escalation study of vemurafenib in combination with cobimetinib will evaluate the safety, tolerability and pharmacokinetics in participants with BRAFV600 mutation-positive metastatic melanoma. Participants with previously untreated, BRAFV600E mutation-positive, locally advanced/unresectable or metastatic melanoma or those who have progressed on vemurafenib monotherapy immediately prior to enrolling in this trial are eligible. Participants will be assigned to different cohorts with escalating oral doses of vemurafenib and cobimetinib. This study consists of 2 stages, Stage 1 (Dose Escalation Stage [DES] and Cohort Expansion Stage [CES]) and the anticipated time on study treatment is until disease progression, unacceptable toxicity or any other discontinuation criterion is met.

Conditions: Malignant Melanoma
Being tested: Cobimetinib, vemurafenib
Medical subject headings: Melanoma

What participants receive

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

CobimetinibDrug
Also called GDC-0973
Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
vemurafenibDrug
Participants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Study groups in NCT01271803
Study group	Role	What they receive
DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Participants will receive oral 60 milligrams (mg) cobimetinib once daily (QD) on Days 1-14, followed by 14 days off on Days 15-28 (14/14 dosing schedule) and oral 720 mg vemurafenib twice daily (BID) on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Participants will receive oral 60 mg cobimetinib QD on Days 1-21, followed by 7 days off on Days 22-28 (21/7 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Participants will receive oral 60 mg cobimetinib QD on Days 1-28 (28/0 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Participants will receive oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Participants will receive oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Participants will receive oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Participants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
Cobimetinib Monotherapy (100 mg or 60 mg)	Experimental	Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib
CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib
CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Participants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Receives: Drug: Cobimetinib; Drug: vemurafenib

What is being measured

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

Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts
DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade less than or equal to (≤) 1 within 7 days, b) Grade 3 rash or photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cutaneous squamous cell carcinoma (cuSCC) that was subsequently resected, d) Grade greater than or equal to (≥) 3 fatigue or hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum creatine phosphokinase (CPK) levels, which is asymptomatic, deemed by the investigator to be clinically insignificant and that returned to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (absolute neutrophil count [ANC] less than <500/microliter [μL]), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.
Measured: 28 Days
Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES
The highest dose level(s) at which fewer than one-third of participants experienced a DLT was declared the MTD. DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade ≤1 within 7 days, b) Grade 3 rash/photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cuSCC that was subsequently resected, d) Grade ≥3 fatigue/hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum CPK levels, which is asymptomatic, deemed to be clinically insignificant and returns to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (ANC <500/ μL), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.
Measured: 28 Days
Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1
Measured: Cycle 1: predose (0 hours [hr]) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3
Measured: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1
Measured: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1
Measured: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3
Measured: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1
Measured: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1
Measured: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
AUC0-24 of Cobimetinib on Day 14, Cycle 1
Measured: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Measured: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
Measured: Predose (0 hr) on Days -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Cmax of Vemurafenib on Day -1, Cycle 1 of Cohorts 1C and 2A in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
Measured: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
Measured: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
Measured: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants
Measured: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
Measured: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Vemurafenib on Day 14, Cycle 1
Measured: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14
Tmax of Vemurafenib on Day 14, Cycle 1
Measured: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14

Secondary outcomes (6)

Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1
Tumor response of CR or PR is considered as objective response. CR: disappearance of all target lesions, reduction in short axis <10 millimeters in pathological lymph nodes (target and non-target lesions); PR: at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Responses were confirmed by repeat assessments ≥4 weeks after initial documentation.
Measured: Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression (up to 82 months)
Percentage of Participants With Disease Progression According to RECIST V 1.1
Progressive disease (PD) according to RECIST V 1.1: at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (nadir), including baseline; in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm; appearance of 1 or more lesions is also considered as progression.
Measured: Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months)
Median Duration of Response (DOR)
Duration of response, defined as the time from first occurrence of a documented objective response until the time of disease progression, as determined by investigator review of tumor assessments using RECIST v 1.1, or death from any cause during the study (that is within 30 days after the last dose of study treatment).
Measured: Time from first occurrence of objective response until the time of disease progression or death from any cause (up to 82 months)
Overall Survival (OS)
OS was defined as the time from the date of randomization to the date of death due to any cause. Participants were censored at the last date of tumor measurement, the last date in the study drug log, or the date of last follow-up. OS analyzed using Kaplan-Meier estimate.
Measured: Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months)
Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2
The pharmacodynamic effect of cobimetinib in combination with vemurafenib was assessed by measuring changes in FDG uptake as characterized by the lean body mass corrected (LBM) maximum standardized uptake value (SUV max) measurement using FDG-PET. Post-baseline timepoint Cycle 1 was averaged between Days 10 to 14 and Cycle 2 for Days 14+7.
Measured: Cycle 1 (Days 10 to 14), Cycle 2 (Days 14+7)
Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC)
Changes in effector molecules of the MAPK pathway that are directly or indirectly affected by BRAF and MEK inhibition (including but not limited to ERK and phosphorylated ERK and MEK) by IHC using biopsies at baseline, between Days 10-14 of Cycle 1, and at disease progression. IHC is a staining process performed on fresh/frozen tumor tissue samples.
Measured: At baseline; Cycle 1: Day 14; at disease progression (Up to 32 months)

Timeline

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

17 Feb 201112 Dec 2017

First posted7 Jan 2011 (estimated)
Study start17 Feb 2011
Primary completion1 Oct 2013
Study completion12 Dec 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (3)Papers the sponsor has linked to this study.
Other trials for Malignant MelanomaStudies of the same condition, open and under way.
More trials run by Hoffmann-La RocheThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

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
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 131 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01271803
Sponsor's protocol ID: NO25395
Status last verified: Jul 2019
First submitted: 5 Jan 2011
Last updated: 29 Jul 2019
Results posted: Yes, on ClinicalTrials.gov

Publications

Ascierto PA, Ribas A, Larkin J, McArthur GA, Lewis KD, Hauschild A, Flaherty KT, McKenna E, Zhu Q, Mun Y, Dreno B. Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib +/- cobimetinib: a pooled analysis of four clinical trials. J Transl Med. 2020 Aug 3;18(1):294. doi: 10.1186/s12967-020-02458-x.
PubMed 32746839
Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K, Kee D, Boasberg P, Yin M, Chan I, Musib L, Choong N, Puzanov I, McArthur GA. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014 Aug;15(9):954-65. doi: 10.1016/S1470-2045(14)70301-8. Epub 2014 Jul 15.
PubMed 25037139
Baudy AR, Dogan T, Flores-Mercado JE, Hoeflich KP, Su F, van Bruggen N, Williams SP. FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973. EJNMMI Res. 2012 May 31;2(1):22. doi: 10.1186/2191-219X-2-22.
PubMed 22651703

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
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Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
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Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 29 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase IB, Open-Label, Dose-Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of Vemurafenib in Combination With GDC-0973 (Cobimetinib) When Administered in BRAFV600E Mutation-Positive Patients Previously Treated (But Without Prior Exposure to BRAF or MEK Inhibitor Therapy) or Previously Untreated for Locally Advanced/Unresectable or Metastatic Melanoma or Those Who Have Progressed After Treatment With Vemurafenib
ClinicalTrials.gov ID: NCT01271803
Acronym / sponsor ID: NO25395
Conditions: Malignant Melanoma
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 131 participants (actual)
Lead sponsor: Hoffmann-La RocheIndustry (pharma, biotech, devices)
Study start: 17 Feb 2011 (actual)
Primary completion: 1 Oct 2013 (actual)
Study completion: 12 Dec 2017 (actual)
First posted: 7 Jan 2011 (estimated)
Results: Posted 17 Jun 2016

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 12

Arm	Type	Receives
DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 60 milligrams (mg) cobimetinib once daily (QD) on Days 1-14, followed by 14 days off on Days 15-28 (14/14 dosing schedule) and oral 720 mg vemurafenib twice daily (BID) on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 60 mg cobimetinib QD on Days 1-21, followed by 7 days off on Days 22-28 (21/7 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 60 mg cobimetinib QD on Days 1-28 (28/0 dosing schedule) and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 60 mg cobimetinib QD on 28/0 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 100 mg cobimetinib QD on 14/14 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 60 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 80 mg cobimetinib QD on 14/14 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
Cobimetinib Monotherapy (100 mg or 60 mg)	Experimental	Drug: CobimetinibParticipants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule, or oral 100 mg cobimetinib QD on 14/14 dosing schedule of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 720 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.
CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib	Experimental	Drug: Cobimetinib, Drug: vemurafenibParticipants will receive oral 60 mg cobimetinib QD on 21/7 dosing schedule and oral 960 mg vemurafenib BID on Days 1-28 of every cycle (1 Cycle=28 Days), until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (9 listed)

Participants with histologically confirmed melanoma (unresectable Stage IIIc and Stage IV metastatic melanoma, as defined by American Joint Committee on Cancer [AJCC])
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1
Eastern Cooperative Oncology Group (ECOG) Performance Status of less than or equal to (</=) 1
Participants must
Life expectancy >/=12 weeks

Key exclusion criteria (4 listed)

History of prior significant toxicity from another RAF or MEK pathway inhibitor requiring discontinuation of treatment
Palliative radiotherapy within 2 weeks prior to first dose of study drug treatment
Experimental therapy within 4 weeks prior to first dose of study drug treatment except vemurafenib
Major surgery within 4 weeks of first dose of study drug treatment or planning a major surgery during the study

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
CobimetinibAlso: GDC-0973Participants will receive cobimetinib 60 to 100 mg at any of the 3 dosing schedules with or without vemurafenib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.	Drug	CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib, CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib, Cobimetinib Monotherapy (100 mg or 60 mg), DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib, DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib, DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib, DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib
vemurafenibParticipants will receive vemurafenib 720 or 960 mg along with cobimetinib in cycles of 28 days each until disease progression, unacceptable toxicity, or any other discontinuation criteria are met.	Drug	CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib, CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib, DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib, DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib, DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib, DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib, DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib

Primary outcome

Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts
Time frame: 28 Days
DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade less than or equal to (≤) 1 within 7 days, b) Grade 3 rash or photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cutaneous squamous cell carcinoma (cuSCC) that was subsequently resected, d) Grade greater than or equal to (≥) 3 fatigue or hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum creatine phosphokinase (CPK) levels, which is asymptomatic, deemed by the investigator to be clinically insignificant and that returned to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (absolute neutrophil count [ANC] less than <500/microliter [μL]), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.
Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES
Time frame: 28 Days
The highest dose level(s) at which fewer than one-third of participants experienced a DLT was declared the MTD. DLT is defined as 1 of the following toxicities considered by the investigator to be related to study treatment: a) Grade 3 nausea, vomiting or diarrhea that resolved to Grade ≤1 within 7 days, b) Grade 3 rash/photosensitivity that resolved to Grade ≤2 within 7 days, c) Grade 3 cuSCC that was subsequently resected, d) Grade ≥3 fatigue/hyperuricemia that resolved to Grade ≤2 within 7 days, e) Grade 3 fever, f) Grade 3 or 4 elevation of serum CPK levels, which is asymptomatic, deemed to be clinically insignificant and returns to Grade ≤2 during the 14-day cobimetinib treatment holiday, g) Grade ≥3 febrile neutropenia, h) Grade ≥4 neutropenia (ANC <500/ μL), i) Grade ≥4 thrombocytopenia, j) Grade ≥4 anemia, k) Grade ≥3 elevation of total bilirubin, hepatic transaminase or alkaline phosphatase.
Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1
Time frame: Cycle 1: predose (0 hours [hr]) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3
Time frame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Time Taken to Reach Maximum Plasma Concentration (Tmax) of Cobimetinib on Day 1, Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Area Under Concentration Versus Time Curve (AUC) Over a Period of 24 Hours (AUC0-24) of Cobimetinib on Day 1, Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
AUC0-24 of Cobimetinib on Day 1, Cycle 1 of Cohort 3
Time frame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Cobimetinib on Day 14 (Steady State), Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Tmax of Cobimetinib on Day 14 (Steady State), Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
AUC0-24 of Cobimetinib on Day 14, Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Clearance (CL) of Cobimetinib on Day 14 (Steady State), Cycle 1
Time frame: Cycle 1: predose (0 hr) on Days 8, 14; 0.5, 1, 2, 4, 6 hr postdose on Day 14
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Cmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
Time frame: Predose (0 hr) on Days -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Cmax of Vemurafenib on Day -1, Cycle 1 of Cohorts 1C and 2A in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
Time frame: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Tmax of Vemurafenib on Day -1, Cycle 1 in Participants Previously Treated With Vemurafenib Prior to Enrollment Into This Study
Time frame: Predose (0 hr) on Day -1, 1; 2, 4, 6, 8 hr postdose on Day -1
Cmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
Time frame: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Vemurafenib on Day 1, Cycle 1 in Cohort 1A in BRAFi-naïve Participants
Time frame: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Tmax of Vemurafenib on Day 1, Cycle 1 in BRAFi-naïve Participants
Time frame: Predose (0 hr) on Day 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1
Cmax of Vemurafenib on Day 14, Cycle 1
Time frame: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14
Tmax of Vemurafenib on Day 14, Cycle 1
Time frame: Predose (0 hr) on Days 14, 15; 0.5, 1, 2, 4, 6, 8 hr postdose on Day 14

6 secondary outcomes

Percentage of Participants With an Objective Response of Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1
Time frame: Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression (up to 82 months)
Percentage of Participants With Disease Progression According to RECIST V 1.1
Time frame: Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months)
Median Duration of Response (DOR)
Time frame: Time from first occurrence of objective response until the time of disease progression or death from any cause (up to 82 months)
Overall Survival (OS)
Time frame: Assessed at screening (within 28 days prior to initiation of Cycle 1), every 6 weeks thereafter until disease progression or death (up to 82 months)
Average Percent Change From Baseline in Fluorodeoxyglucose-positron Emission Tomography (FDG-PET) at Cycle 1 and Cycle 2
Time frame: Cycle 1 (Days 10 to 14), Cycle 2 (Days 14+7)
Pharmacodynamics: Number of Participants With Mitogen-Activated Protein Kinase (MAPK) Inhibition, as Assessed by Immunohistochemistry (IHC)
Time frame: At baseline; Cycle 1: Day 14; at disease progression (Up to 32 months)

Results and safety

Results posted to the registry on 17 Jun 2016, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Vemurafenib PD Participants	66	11
BRAFi-naïve Participants	63	24
Cobimetinib Monotherapy (100 mg or 60 mg)	2	0

Primary outcome: Number of Participants With Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts

Time frame: 28 Days. Number. Unit: participants

Measure	DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib n = 5	DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib n = 8	DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib n = 27	DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib n = 3	DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib n = 4	DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib n = 4	DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib n = 4	DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib n = 3	DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib n = 5
Value	0	0	1	0	2	0	0	0	1

Population analysed: Safety-evaluable population (SEP) included all participants who received at least one dose of study drug. SEP participants who received combination study treatment (cobimetinib + Vemurafenib) were included in the analysis of this outcome. Here, number of participants analyzed = participants who were evaluable for this outcome.

Primary outcome: Maximum Tolerated Doses (MTD) of Vemurafenib and Cobimetinib When Administered in Combination in DES

Time frame: 28 Days. Number. Unit: mg

Measure	Dose Escalation Stage (Stage 1) n = 63
Cobimetinib dose (21/7 dosing schedule)	60
Vemurafenib dose (21/7 dosing schedule)	960

Population analysed: Safety-evaluable population. Here, number of participants analyzed = participants who were evaluable for this outcome.

Primary outcome: Maximum Plasma Concentration (Cmax) of Cobimetinib on Day 1, Cycle 1

Time frame: Cycle 1: predose (0 hours [hr]) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1. Geometric mean (Geometric Coefficient of Variation). Unit: nanograms per milliliter (ng/mL)

Measure	DES (Cohort 1): 60 mg Cobimetinib + 720 mg Vemurafenib n = 5	DES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib n = 8	DES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib n = 26	DES (Cohort 1C): 60 mg Cobimetinib + 720 mg Vemurafenib n = 3	DES (Cohort 1D): 60 mg Cobimetinib + 960 mg Vemurafenib n = 4	DES (Cohort 2): 80 mg Cobimetinib + 720 mg Vemurafenib n = 4	DES (Cohort 2A): 100 mg Cobimetinib + 720 mg Vemurafenib n = 4	DES (Cohort 4): 80 mg Cobimetinib + 960 mg Vemurafenib n = 5	CES (Cohort 1A): 60 mg Cobimetinib + 720 mg Vemurafenib n = 27	CES (Cohort 1B): 60 mg Cobimetinib + 960 mg Vemurafenib n = 38
Value	159 (110)	146 (100)	121 (96)	136 (81)	130 (53)	133 (37)	146 (79)	93.6 (26)	84.3 (67)	105 (64)

Population analysed: PK population included all participants who received study treatment and had at least one vemurafenib and cobimetinib plasma concentration available. Here, number of participants analyzed = participants who were evaluable for this outcome.

Primary outcome: Cmax of Cobimetinib on Day 1, Cycle 1 in Cohort 3

Time frame: Cycle 1: predose (0 hr) on Days 1, 2; 0.5, 1, 2, 4, 6 hr postdose on Day 1. Mean (Standard Deviation). Unit: ng/mL

Measure	DES (Cohort 3): 60 mg Cobimetinib + 960 mg Vemurafenib n = 2
Value	51.6 (50.1)

Population analysed: PK population. Here, number of participants analyzed = participants who were evaluable for this outcome.

6 secondary outcomes are reported in the full results.

Adverse events

Time frame: Up to 82 months. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Vemurafenib PD Participants	21 of 66 (31.8%)	64 of 66 (97%)	Not reported
BRAFi-naïve Participants	36 of 63 (57.1%)	63 of 63 (100%)	Not reported
Cobimetinib Monotherapy (100 mg or 60 mg)	0 of 2 (0%)	2 of 2 (100%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 32746839Ascierto PA, Ribas A, Larkin J, McArthur GA, Lewis KD, Hauschild A, Flaherty KT, McKenna E, Zhu Q, Mun Y, Dreno B. Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib +/- cobimetinib: a pooled analysis of four clinical trials. J Transl Med. 2020 Aug 3;18(1):294. doi: 10.1186/s12967-020-02458-x.
Derived from this study: PubMed 25037139Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K, Kee D, Boasberg P, Yin M, Chan I, Musib L, Choong N, Puzanov I, McArthur GA. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014 Aug;15(9):954-65. doi: 10.1016/S1470-2045(14)70301-8. Epub 2014 Jul 15.
Derived from this study: PubMed 22651703Baudy AR, Dogan T, Flores-Mercado JE, Hoeflich KP, Su F, van Bruggen N, Williams SP. FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973. EJNMMI Res. 2012 May 31;2(1):22. doi: 10.1186/2191-219X-2-22.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Clinical Trials study director

Hoffmann-La Roche

10 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Cobimetinib and vemurafenib in people with Malignant Melanoma, run by Hoffmann-La Roche at 10 sites in 2 countries.

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 9 inclusion and 4 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 29 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in United States, Australia. 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 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.

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

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Jun 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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 Dose-Limiting Toxicities (DLTs) During DES in Combination Cohorts (time frame: 28 Days). The study lists 19 primary outcomes in all. 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 NCT01271803, which also lists 3 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 29 Jul 2019.