MelanomaPhase 1NCT03026517
Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma
A Phase 1 study testing Dabrafenib, Trametinib and Phenformin in people with Melanoma, run by Memorial Sloan Kettering Cancer Center at 3 sites in United States.
Trial summary
The purpose of this study is to test whether it is safe to give phenformin with the standard drug combination of one of 3 FDA-approved combinations of BRAF inhibitor + MEK inhibitor which are standard treatments for patients with metastatic melanoma whose melanoma has a mutation in a gene called BRAF. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Dabrafenib, Trametinib and Phenformin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 3 sitesUnited States
- Study dates
- Jan 2017to 21 Jan 2025
- 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
- AJCC (2009) stage IV melanoma, or stage III melanoma not curable by surgery and which is progressing or in patients whom neo-adjuvant treatment is deemed acceptable. Patients must have at least 1 target lesion measurable by RECIST 1.1 criteria.
- The melanoma must harbor an activating BRAF V600 mutation. Prior therapy with a BRAF and/or MEK inhibitor is allowed in the dose-escalation phase only. However, patients who discontinued previous RAF inhibitor due to intolerance of the drug rather than due to progression will not be eligible.
- Histologic proof of melanoma reviewed and confirmed by the treating institution. The melanoma must have a documented BRAFV600E or BRAFV600K mutation by genotyping or IHC12 performed by a CLIA certified laboratory. At MSK, the Diagnostic Molecular Pathology laboratory has developed and implemented a targeted capture-based next-generation DNA sequencing assay, MSK-IMPACTTM, to profile all protein-coding exons and selected introns from 410 oncogenes and tumor suppressor genes in formalin-fixed paraffin embedded tissues (Cheng, D.T., et al., J Mol Diagn, 2015. 17(3): p. 251-64). MSK-IMPACTTM has been approved by the NY State Department of Health to be run as a clinical assay in the CLIA-compliant Diagnostic Molecular Pathology laboratory. MSK-IMPACTTM is capable of detecting mutations, copy number alterations, and structural variations. BRAF Exon15 was captured by the MSK-IMPACTTM panel and the c.1799T>A (p.V600E) mutation was fully validated as per NYS requirements. Detailed results of the validation of this mutation were included in the validation package submitted to NY State Department of Health.
- At MGH, samples will be tested using a multiplex polymerase chain reaction (PCR) technology called Anchored Multiplex PCR (AMP) for single nucleotide variant (SNV) and insertion/deletion (indel) detection in genomic DNA using next generation sequencing (NGS). Briefly, genomic DNA was isolated from a formalin-fixed paraffin embedded tumor specimen is sheared with the Covaris M220 instrument, followed by end-repair, adenylation, and ligation with an adapter. A sequencing library targeting hotspots and exons in 39 genes (including BRAF, exons 11 and 15) is generated using two hemi-nested PCR reactions. Illumina MiSeq 2 x 147 base paired-end sequencing results are aligned to the hg19 human genome reference using BWA-MEM (Li H and Durbin R. Bioinformatics 2009;25(14):1754-60). MuTect (Cibulskis K, et al. Nat Biotechnol 2013;31(3):213-9) and a laboratory-developed insertion/deletion analysis algorithm are used for SNV and indel variant detection, respectively. This assay has been validated to detect SNV and indel variants at 5% allelic frequency or higher in target regions with sufficient read coverage. This test was developed, and its performance characteristics were determined by the MGH Center for Integrated Diagnostics.
- Patients must be adequately recovered from surgery, radiation therapy, or any surgical complications prior to enrollment.
- Age ≥ 18 years old.
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- ECOG performance status of 0-2.
- The ability to swallow pills and otherwise follow the protocol.
- Patients with treated CNS metastases will be eligible if not symptomatic the CNS disease has been stable for a minium of 6 weeks and the patient requires less than or equal to the equivalent of 2 mg/day of dexamethasone.
- Patients must have adequate organ and marrow function as defined below:
- Absolute Neutrophil Count ≥1.5 K/mcL
- Platelets ≥100 K/mcL
- Hemoglobin ≥ 9.0 g/dL
- Total Bilirubin ≤ 1.2 X institutional upper limit of normal (ULN) or ≤ 3.0 X institutional ULN if the patient has Gilbert's Syndrome
- AST (SGOT) and ALT (SGPT) ≤ 1.2 X institutional upper limit of normal (ULN)
- Creatinine ≤ 1.4 mg/dl
- Both men and women, and members of all races and ethnic groups are eligible for this trial.
Who cannot join
- Type I or Type II diabetes
- A history of renal failure (unless recovered for at least 6 months), lactic acidosis, recurrent or severe hypoglycemia, or significant chronic obstructive lung disease. Patients will not be excluded for reversible episodes of elevated creatinine due to hypovolemia.
- Acute or chronic liver or renal disease.
- Concurrent use of hypoglycemic agents or any systemic therapy for melanoma. Palliative limited-field radiation therapy will be allowed
- Current use of a prohibited medication.
- Vemurafenib
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- Avoid inducers and inhibitors of CYP3A4
- Careful with drugs metabolized by CTP1A2 (Clozapam, olanzapine, fluvoxamine, haloperidol, theophylline, caffeine).
- Encorafenib
- Avoid inducers and inhibitors of CYP3A4
- Avoid drugs that increase QTc interval
- Dabrafenib
- Avoid inducers and inhibitors of CYP3A4 or CYP2CA8 (Refer to Appendix C for specific drugs).
- Presence of conditions that will interfere significantly with the absorption of drugs.
- A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
- Pregnant and/or lactating women
- A prior or concurrent metastatic second malignancy within 3 years, even if it does not require active therapy. For example, patients with concomitant indolent B-cell malignancies will not be eligible. Patients with a prior resected in-situ or stage I malignancy felt to be cured will be eligible.
- Other uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. New York Heart Association class ≥2 will be an exclusion criterion.
- QTc interval > 500 msec unless a bundle branch block is also present.
- Patients with brain metastases unless they meet the criteria of section 6.1.8.
- Patients currently receiving other anti-melanoma treatment. Toxicities attributable to any prior therapy must have resolved to grade 1 or better prior to enrollment. Grade 2 endocrinopathies, except diabetes, that are ongoing from prior immunotherapy will not exclude the patient as long as the patient is on appropriate replacement doses of hormone.
- Patients receiving steroid treatment exceeding replacement dosing
- In the dose expansion phase of the trial, prior treatment with a BRAF inhibitor will be an exclusion criterion. This includes prior adjuvant dabrafenib/trametinib.
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
Memorial Sloan Kettering Westchester
Harrison, New York, 10604
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
About this study
Official title: Phase I Trial of Phenformin With Patients With Combination BRAF Inhibitor/MEK Inhibitor in Patients With BRAFV600E/K-mutated Melanoma
The purpose of this study is to test whether it is safe to give phenformin with the standard drug combination of one of 3 FDA-approved combinations of BRAF inhibitor + MEK inhibitor which are standard treatments for patients with metastatic melanoma whose melanoma has a mutation in a gene called BRAF.
- Conditions
- Melanoma
- Being tested
- Dabrafenib, Trametinib, Phenformin
- Keywords
- Phenformin, Dabrafenib, Trametinib, BRAF/MEKi, 15-318
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DabrafenibDrug
TrametinibDrug
PhenforminDrug
| Study group | Role | What they receive |
|---|---|---|
| Dabrafenib, Trametinib & Phenformin | Experimental | This is a multi-institution single-arm phase I trial with an expansion cohort at the MTD of Phenformin, in patients with metastatic BRAFV600E/K mutated melanoma. In the dose escalation phase, cohorts of patients will be treated with standard dose Dabrafenib (150 mg PO BID) plus Trametinib (2 mg PO QD) and increasing doses of Phenformin. In the dose-escalation phase of the trial, both patients who have already been treated with a BRAF and/or MEK inhibitor, and treatment-naïve patients will be eligible. The maximally tolerated Phenformin dose was determined to be 100 mg BID. The dose-expansion cohort will enroll up to 10 patients who are treatment- naïve for BRAF inhibitor. In this cohort, patients may be treated with any of the 3 FDA-approved BRAFi/MEKi combinations: dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib. Receives: Drug: Dabrafenib; Drug: Trametinib; Drug: Phenformin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Disease-free survival
The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used to determine treatment response.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2017 (estimated)
- Study startJan 2017
- Primary completion21 Jan 2025
- Study completion21 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by Memorial Sloan Kettering Cancer CenterThe 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Memorial Sloan Kettering Cancer Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Michael Postow, MD, Principal investigator, Memorial Sloan Kettering Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03026517
- Sponsor's protocol ID
- 15-318
- Status last verified
- Jan 2025
- First submitted
- 17 Jan 2017
- Last updated
- 23 Jan 2025
- Results posted
- No
Publications
Dalton KM, Lochmann TL, Floros KV, Calbert ML, Kurupi R, Stein GT, McClanaghan J, Murchie E, Egan RK, Greninger P, Dozmorov M, Ramamoorthy S, Puchalapalli M, Hu B, Shock L, Koblinski J, Glod J, Boikos SA, Benes CH, Faber AC. Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2009620118. doi: 10.1073/pnas.2009620118.
PubMed 33762304
Study at a glance
From the registry record, last updated by the sponsor on 23 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Trial of Phenformin With Patients With Combination BRAF Inhibitor/MEK Inhibitor in Patients With BRAFV600E/K-mutated Melanoma
- ClinicalTrials.gov ID
- NCT03026517
- Acronym / sponsor ID
- 15-318
- Conditions
- Melanoma
- Keywords
- Phenformin, Dabrafenib, Trametinib, BRAF/MEKi, 15-318
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Memorial Sloan Kettering Cancer CenterUniversity, hospital or other
- Collaborators
- Massachusetts General Hospital, Weill Medical College of Cornell University
- Study start
- Jan 2017 (actual)
- Primary completion
- 21 Jan 2025 (actual)
- Study completion
- 21 Jan 2025 (actual)
- First posted
- 20 Jan 2017 (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 purpose of this study is to test whether it is safe to give phenformin with the standard drug combination of one of 3 FDA-approved combinations of BRAF inhibitor + MEK inhibitor which are standard treatments for patients with metastatic melanoma whose melanoma has a mutation in a gene called BRAF.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Dabrafenib, Trametinib & Phenformin | Experimental | Drug: Dabrafenib, Drug: Trametinib, Drug: PhenforminThis is a multi-institution single-arm phase I trial with an expansion cohort at the MTD of Phenformin, in patients with metastatic BRAFV600E/K mutated melanoma. In the dose escalation phase, cohorts of patients will be treated with standard dose Dabrafenib (150 mg PO BID) plus Trametinib (2 mg PO QD) and increasing doses of Phenformin. In the dose-escalation phase of the trial, both patients who have already been treated with a BRAF and/or MEK inhibitor, and treatment-naïve patients will be eligible. The maximally tolerated Phenformin dose was determined to be 100 mg BID. The dose-expansion cohort will enroll up to 10 patients who are treatment- naïve for BRAF inhibitor. In this cohort, patients may be treated with any of the 3 FDA-approved BRAFi/MEKi combinations: dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- AJCC (2009) stage IV melanoma, or stage III melanoma not curable by surgery and which is progressing or in patients whom neo-adjuvant treatment is deemed acceptable. Patients must have at least 1 target lesion measurable by RECIST 1.1 criteria.
- The melanoma must harbor an activating BRAF V600 mutation. Prior therapy with a BRAF and/or MEK inhibitor is allowed in the dose-escalation phase only. However, patients who discontinued previous RAF inhibitor due to intolerance of the drug rather than due to progression will not be eligible.
- Histologic proof of melanoma reviewed and confirmed by the treating institution. The melanoma must have a documented BRAFV600E or BRAFV600K mutation by genotyping or IHC12 performed by a CLIA certified laboratory. At MSK, the Diagnostic Molecular Pathology laboratory has developed and implemented a targeted capture-based next-generation DNA sequencing assay, MSK-IMPACTTM, to profile all protein-coding exons and selected introns from 410 oncogenes and tumor suppressor genes in formalin-fixed paraffin embedded tissues (Cheng, D.T., et al., J Mol Diagn, 2015. 17(3): p. 251-64). MSK-IMPACTTM has been approved by the NY State Department of Health to be run as a clinical assay in the CLIA-compliant Diagnostic Molecular Pathology laboratory. MSK-IMPACTTM is capable of detecting mutations, copy number alterations, and structural variations. BRAF Exon15 was captured by the MSK-IMPACTTM panel and the c.1799T>A (p.V600E) mutation was fully validated as per NYS requirements. Detailed results of the validation of this mutation were included in the validation package submitted to NY State Department of Health.
- At MGH, samples will be tested using a multiplex polymerase chain reaction (PCR) technology called Anchored Multiplex PCR (AMP) for single nucleotide variant (SNV) and insertion/deletion (indel) detection in genomic DNA using next generation sequencing (NGS). Briefly, genomic DNA was isolated from a formalin-fixed paraffin embedded tumor specimen is sheared with the Covaris M220 instrument, followed by end-repair, adenylation, and ligation with an adapter. A sequencing library targeting hotspots and exons in 39 genes (including BRAF, exons 11 and 15) is generated using two hemi-nested PCR reactions. Illumina MiSeq 2 x 147 base paired-end sequencing results are aligned to the hg19 human genome reference using BWA-MEM (Li H and Durbin R. Bioinformatics 2009;25(14):1754-60). MuTect (Cibulskis K, et al. Nat Biotechnol 2013;31(3):213-9) and a laboratory-developed insertion/deletion analysis algorithm are used for SNV and indel variant detection, respectively. This assay has been validated to detect SNV and indel variants at 5% allelic frequency or higher in target regions with sufficient read coverage. This test was developed, and its performance characteristics were determined by the MGH Center for Integrated Diagnostics.
- Patients must be adequately recovered from surgery, radiation therapy, or any surgical complications prior to enrollment.
Key exclusion criteria (23 listed)
- Type I or Type II diabetes
- A history of renal failure (unless recovered for at least 6 months), lactic acidosis, recurrent or severe hypoglycemia, or significant chronic obstructive lung disease. Patients will not be excluded for reversible episodes of elevated creatinine due to hypovolemia.
- Acute or chronic liver or renal disease.
- Concurrent use of hypoglycemic agents or any systemic therapy for melanoma. Palliative limited-field radiation therapy will be allowed
- Current use of a prohibited medication.
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 |
|---|---|---|
| Dabrafenib | Drug | Dabrafenib, Trametinib & Phenformin |
| Trametinib | Drug | Dabrafenib, Trametinib & Phenformin |
| Phenformin | Drug | Dabrafenib, Trametinib & Phenformin |
Primary outcome
Disease-free survival
Time frame: 2 years
The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used to determine treatment response.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jan 2025.
- Derived from this study: PubMed 33762304Dalton KM, Lochmann TL, Floros KV, Calbert ML, Kurupi R, Stein GT, McClanaghan J, Murchie E, Egan RK, Greninger P, Dozmorov M, Ramamoorthy S, Puchalapalli M, Hu B, Shock L, Koblinski J, Glod J, Boikos SA, Benes CH, Faber AC. Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2009620118. doi: 10.1073/pnas.2009620118.
- Memorial Sloan Kettering Cancer CenterLink provided by the sponsor.
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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.
Michael Postow, MD principal investigator
Memorial Sloan Kettering Cancer Center
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Dabrafenib, Trametinib and Phenformin in people with Melanoma, run by Memorial Sloan Kettering Cancer Center at 3 sites 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 17 inclusion and 23 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 23 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites 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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Disease-free survival (time frame: 2 years). 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 NCT03026517, which also lists 1 linked publication.
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 23 Jan 2025.