MelanomaPhase 1NCT02818023
Dose-seeking Study of Pembrolizumab Plus Vemurafenib and Cobimetinib Advanced Melanoma
A Phase 1 study testing Pembrolizumab, Vemurafenib and Cobimetinib in people with Melanoma, run by Yana Najjar at 1 site in United States.
Trial summary
The study plans to treat patients with pembrolizumab and thus blocking the PD-1/PD-L1 axis would render tumor-infiltrating lymphocytes (TILs) in the tumor parenchyma more functional as a consequence of BRAF inhibition, such that T cell activation by BRAFi would not be dampened by the PD-1/PD-L1 interaction. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Pembrolizumab, Vemurafenib and Cobimetinib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- 13 Jul 2016to 23 Apr 2021
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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
- Provide written informed consent obtained prior to the initiation of study procedures.
- Male and female subjects who are at least 18 years of age.
- Histologically confirmed unresectable stage III or stage IV melanoma (AJCC 7th edition classification). Cutaneous melanoma and mucosal melanoma will be eligible.
- Only patients with BRAF V600E or V600K mutated tumors will be enrolled.
- Baseline skin exam is required for all patients. Note: Cutaneous squamous cell carcinoma (SCC) lesions identified at baseline must be excised.
- Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Baseline measurements must be obtained within 4 weeks prior to registration.
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- Adequate hematologic, renal, and liver function as evidenced by the following (within 4 weeks prior to starting the study drugs):
- WBC ≥ 3,000/mm3
- ANC ≥ 1500
- Hemoglobin ≥ 9g/dL (women) or ≥ 11g/dL (men) Platelets ≥ 100,000/mm3 Serum Creatinine ≤ 1.5 x upper limit of normal (ULN)
- Serum Bilirubin ≤ 1.5 x ULN
- Serum AST and ALT ≤ 2.5 x ULN
- Note: (supportive transfusions will be allowed during screening and during treatment as deemed necessary by the treating physician)
- EKG documenting QTc interval < 480 msec and no clinically significant arrhythmia
- Fully recovered from any effects of major surgery, and be free of significant infection.
- ECOG performance status of 0 or 1.
- Female patients of child bearing potential must have a negative pregnancy test within 7 days from the time of registration .
- Female subject of childbearing potential should have a negative urine or serum pregnancy 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.
- Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for greater than 1 year.
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
- Patients with brain metastases may be enrolled if brain metastases have been treated by surgery and/or radiation and are stable on 2 week repeat scan.
Who cannot join
- Serious clinically significant illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, uncontrolled hypertension, cardiac ischemia, myocardial infarction, and severe cardiac arrhythmia), bleeding disorders, symptomatic autoimmune diseases (such as inflammatory bowel disease, autoimmune hepatitis, uncontrolled hypo or hyperthyroidism), severe obstructive or restrictive pulmonary diseases, retinopathy, active systemic infections, and inflammatory bowel disorders.
- Known HIV or AIDS-related illness, or active HBV and HCV.
- Has a known history of active TB (Bacillus Tuberculosis)
- History of grade 4 immune-related adverse events requiring treatment with prednisone, or grade 3 immune-related adverse events requiring prednisone >10 mg/kg for >12 weeks, if previously treated with ipilimumab.
- Prior therapy with anti-PD-1 agent(s) in the metastatic setting. Treatment with anti-PD1 in the adjuvant setting is permitted.
- Prior therapy with a BRAF and/or MEK and/or ERK inhibitors in the metastatic setting. Treatment with BRAF/MEKi in the adjuvant setting is permitted.
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- Refractory nausea, vomiting, small bowel resection or any other gastrointestinal ailment that would preclude study drug absorption.
- Cardiac abnormalities
- Mean QTc interval ≥ 480 msec at screening.
- ACS/AMI -within 24 weeks prior to screening.
- PCI/PTCA -within 24 weeks prior to screening.
- Symptomatic heart failure - NYHA Class ≥ II symptoms.
- Active infection within one-week prior to study, including unexplained fever
- Systemic steroid or other immunosuppressive therapy within 4 weeks of starting the study.
- Lactating females and/or pregnant females.
- Any significant psychiatric disease, medical or other condition, which in the opinion of the principal investigator could prevent adequate informed consent or compromise participation in the clinical trial.
Trial locations and contacts
1 site in 1 country.
United States1 site
UPMC Cancer Center Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
About this study
Official title: Dose-seeking Study of Pembrolizumab Plus Vemurafenib and Cobimetinib for Therapy of Advanced Melanoma
The study plans to treat patients with pembrolizumab and thus blocking the PD-1/PD-L1 axis would render tumor-infiltrating lymphocytes (TILs) in the tumor parenchyma more functional as a consequence of BRAF inhibition, such that T cell activation by BRAFi would not be dampened by the PD-1/PD-L1 interaction. This combination would reverse dysfunction among T cells in the tumor parenchyma, maximizing T cell mediated immune anti-tumor efficacy. Progression free survival (PFS) with pembrolizumab in KEYNOTE-001 was 57% at 6 months, and 46.4% in the more recently reported phase III trial. PFS with vemurafenib treatment in BRIM-3 was ~50% at 6 months. Combined treatment with pembrolizumab, cobimetinib and vemurafenib for BRAF mutant melanoma is hypothesized to be safe and to improve the PFS compared to these recent historical controls. Because this combination has not yet been tested, and because the primary objective is to assess safety, the investigators are staging accrual in the first phase of the trial. The study aims to accrue up to 30 patients to the mTPI design of this study with the expectation that there will be at least 30 patients treated at RP2D. In case there are less than 30 patients on the RP2D, additional patients will be accrued. Patients will continue to receive treatment with pembrolizumab, vemurafenib and cobimetinib until disease progression or dose limiting toxicity. Patients with treatment response and no dose limiting toxicity may receive treatment with pembrolizumab for up to 24 months.
Read the detailed description
Pembrolizumab will be given at a dose of 200 mg q3 weeks (this is the standard dosage, ), and vemurafenib/cobimetinib will be given at 480 mg twice daily/20 mg daily, 720 mg twice daily/40 mg daily, or 960 mg twice daily/60 mg daily. Treatment with pembrolizumab, vemurafenib and cobimetinib will commence on the same day.
- Conditions
- Melanoma
- Being tested
- Pembrolizumab, Vemurafenib, Cobimetinib
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PembrolizumabDrug
Pembrolizumab will be given at a dose of 200 mg q3 weeks (this is the standard dosage, ). Treatment with pembrolizumab and vemurafenib will commence on the same day.
One cycle of treatment will be defined as one dose of pembrolizumab and 3 weeks of vemurafenib.
VemurafenibDrug
Vemurafenib will be given at 480 mg twice daily, 720 mg twice daily, or 960 mg twice daily. Treatment with pembrolizumab and vemurafenib will commence on the same day.
One cycle of treatment will be defined as one dose of pembrolizumab and 3 weeks of vemurafenib.
CobimetinibDrug
Cobimetinib will be given at 20 mg once daily, 40 mg once daily, or 60 mg once daily. Treatment with cobimetinib will commence on the same day. Cobimetinib will be given daily for 21 days, then held for 7 days.
| Study group | Role | What they receive |
|---|---|---|
| Pembrolizumab plus vemurafenib and Cobimetinib | Experimental | * Pembrolizumab will be given at a dose of 200 mg q3 weeks (this is the standard dosage, ), and vemurafenib/cobimetinib will be given at 480 mg twice daily/20 mg daily, 720 mg twice daily/40 mg daily, or 960 mg twice daily/60 mg daily. Treatment with pembrolizumab and vemurafenib will commence on the same day.
* One cycle of treatment will be defined as one dose of pembrolizumab and 3 weeks of vemurafenib. Receives: Drug: Pembrolizumab; Drug: Vemurafenib; Drug: Cobimetinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of participants that experience a dose-limiting toxicity
determine the safety and maximum tolerated dose of vemurafenib and cobimetinib with pembrolizumab
Measured: Up to 2 years
Secondary outcomes (3)
overall response rate (ORR)
Measured: Up to 2 years
progression free survival
Measured: Up to 2 years
overall survival
Measured: up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jun 2016 (estimated)
- Study start13 Jul 2016
- Primary completion10 Jun 2019
- Study completion23 Apr 2021
Why it stopped: Accrual to trial stopped due to high toxicity even at lowest dose of combination treatment. Patients on trial tolerating treatment at time of accrual closure still continued to receive treatment.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yana Najjar
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor-investigator, Yana Najjar, University of Pittsburgh
- Investigators
- Yana M. Najjar, MD, Principal investigator, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02818023
- Sponsor's protocol ID
- 15-131
- Status last verified
- Dec 2021
- First submitted
- 7 Jun 2016
- Last updated
- 3 Jan 2022
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dose-seeking Study of Pembrolizumab Plus Vemurafenib and Cobimetinib for Therapy of Advanced Melanoma
- ClinicalTrials.gov ID
- NCT02818023
- Acronym / sponsor ID
- 15-131
- Conditions
- Melanoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Accrual to trial stopped due to high toxicity even at lowest dose of combination treatment. Patients on trial tolerating treatment at time of accrual closure still continued to receive treatment.
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Yana NajjarUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 13 Jul 2016 (actual)
- Primary completion
- 10 Jun 2019 (actual)
- Study completion
- 23 Apr 2021 (actual)
- First posted
- 29 Jun 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study plans to treat patients with pembrolizumab and thus blocking the PD-1/PD-L1 axis would render tumor-infiltrating lymphocytes (TILs) in the tumor parenchyma more functional as a consequence of BRAF inhibition, such that T cell activation by BRAFi would not be dampened by the PD-1/PD-L1 interaction. This combination would reverse dysfunction among T cells in the tumor parenchyma, maximizing T cell mediated immune anti-tumor efficacy. Progression free survival (PFS) with pembrolizumab in KEYNOTE-001 was 57% at 6 months, and 46.4% in the more recently reported phase III trial. PFS with vemurafenib treatment in BRIM-3 was ~50% at 6 months. Combined treatment with pembrolizumab, cobimetinib and vemurafenib for BRAF mutant melanoma is hypothesized to be safe and to improve the PFS compared to these recent historical controls. Because this combination has not yet been tested, and because the primary objective is to assess safety, the investigators are staging accrual in the first phase of the trial. The study aims to accrue up to 30 patients to the mTPI design of this study with the expectation that there will be at least 30 patients treated at RP2D. In case there are less than 30 patients on the RP2D, additional patients will be accrued. Patients will continue to receive treatment with pembrolizumab, vemurafenib and cobimetinib until disease progression or dose limiting toxicity. Patients with treatment response and no dose limiting toxicity may receive treatment with pembrolizumab for up to 24 months.
Detailed description
Pembrolizumab will be given at a dose of 200 mg q3 weeks (this is the standard dosage, ), and vemurafenib/cobimetinib will be given at 480 mg twice daily/20 mg daily, 720 mg twice daily/40 mg daily, or 960 mg twice daily/60 mg daily. Treatment with pembrolizumab, vemurafenib and cobimetinib will commence on the same day.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Pembrolizumab plus vemurafenib and Cobimetinib | Experimental | Drug: Pembrolizumab, Drug: Vemurafenib, Drug: Cobimetinib* Pembrolizumab will be given at a dose of 200 mg q3 weeks (this is the standard dosage, ), and vemurafenib/cobimetinib will be given at 480 mg twice daily/20 mg daily, 720 mg twice daily/40 mg daily, or 960 mg twice daily/60 mg daily. Treatment with pembrolizumab and vemurafenib will commence on the same day. * One cycle of treatment will be defined as one dose of pembrolizumab and 3 weeks of vemurafenib. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- Provide written informed consent obtained prior to the initiation of study procedures.
- Male and female subjects who are at least 18 years of age.
- Histologically confirmed unresectable stage III or stage IV melanoma (AJCC 7th edition classification). Cutaneous melanoma and mucosal melanoma will be eligible.
- Only patients with BRAF V600E or V600K mutated tumors will be enrolled.
- Baseline skin exam is required for all patients. Note: Cutaneous squamous cell carcinoma (SCC) lesions identified at baseline must be excised.
Key exclusion criteria (16 listed)
- Serious clinically significant illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, uncontrolled hypertension, cardiac ischemia, myocardial infarction, and severe cardiac arrhythmia), bleeding disorders, symptomatic autoimmune diseases (such as inflammatory bowel disease, autoimmune hepatitis, uncontrolled hypo or hyperthyroidism), severe obstructive or restrictive pulmonary diseases, retinopathy, active systemic infections, and inflammatory bowel disorders.
- Known HIV or AIDS-related illness, or active HBV and HCV.
- Has a known history of active TB (Bacillus Tuberculosis)
- History of grade 4 immune-related adverse events requiring treatment with prednisone, or grade 3 immune-related adverse events requiring prednisone >10 mg/kg for >12 weeks, if previously treated with ipilimumab.
- Prior therapy with anti-PD-1 agent(s) in the metastatic setting. Treatment with anti-PD1 in the adjuvant setting is permitted.
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 |
|---|---|---|
| PembrolizumabPembrolizumab will be given at a dose of 200 mg q3 weeks (this is the standard dosage, ). Treatment with pembrolizumab and vemurafenib will commence on the same day. One cycle of treatment will be defined as one dose of pembrolizumab and 3 weeks of vemurafenib. | Drug | Pembrolizumab plus vemurafenib and Cobimetinib |
| VemurafenibVemurafenib will be given at 480 mg twice daily, 720 mg twice daily, or 960 mg twice daily. Treatment with pembrolizumab and vemurafenib will commence on the same day. One cycle of treatment will be defined as one dose of pembrolizumab and 3 weeks of vemurafenib. | Drug | Pembrolizumab plus vemurafenib and Cobimetinib |
| CobimetinibCobimetinib will be given at 20 mg once daily, 40 mg once daily, or 60 mg once daily. Treatment with cobimetinib will commence on the same day. Cobimetinib will be given daily for 21 days, then held for 7 days. | Drug | Pembrolizumab plus vemurafenib and Cobimetinib |
Primary outcome
Percentage of participants that experience a dose-limiting toxicity
Time frame: Up to 2 years
determine the safety and maximum tolerated dose of vemurafenib and cobimetinib with pembrolizumab
3 secondary outcomes
overall response rate (ORR)
Time frame: Up to 2 years
progression free survival
Time frame: Up to 2 years
overall survival
Time frame: up to 2 years
Results and safety
The study was stopped early (reason given: Accrual to trial stopped due to high toxicity even at lowest dose of combination treatment. Patients on trial tolerating treatment at time of accrual closure still continued to receive treatment.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jan 2022.
- Individual participant dataSharing planned: No
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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.
Yana M. Najjar, MD principal investigator
University of Pittsburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Pembrolizumab, Vemurafenib and Cobimetinib in people with Melanoma, run by Yana Najjar at 1 site in United States.
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 21 inclusion and 16 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: stopped early, as of the sponsor's last update on 3 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. 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?
The study was stopped early (reason given: Accrual to trial stopped due to high toxicity even at lowest dose of combination treatment. Patients on trial tolerating treatment at time of accrual closure still continued to receive treatment.). Results are not available in the source record.
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?
Percentage of participants that experience a dose-limiting toxicity (time frame: Up to 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 3 Jan 2022.