MCS110 With BRAF/MEK Inhibition in Patients With Melanoma

NCT03455764 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: 17-656
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation. The interventions involved in this study are:

• MCS110
• Dabrafenib
• Trametinib

Conditions

Melanoma

Keywords

Melanoma

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Dose Limiting Toxicities (DLT) [Phase I]

  A DLT was defined as an adverse event that (a) was possibly, probably, or definitely related to the study medication regimen and (b) experienced during the first cycle of treatment, and (c) met any of the following criteria: ≥ Grade 3 non-hematological toxicity; grade 3 thrombocytopenia with clinically significant bleeding; grade 4 thrombocytopenia; ≥ grade 3 febrile neutropenia; grade 4 anemia; holding of any study medication due to toxicity for a period of greater than 8 consecutive days or two separate periods of any duration during the first cycle, any other significant toxicity deemed by the principal investigator to be dose limiting.

  Participants were followed up to 21 days.

• Maximum Tolerated Dose of MCS110 [Phase I]

  The trial used 3+3 design to determine maximum tolerated dose (MTD), escalating on 0/3 or 1/6 DLTs, and de-escalating if two DLTs were encountered. See subsequent primary outcome measure for the DLT definition. MTD was the highest dose level at which 0/3 or 1/6 subjects experienced a DLT.

  Participants were followed up to 21 days.

Secondary Outcomes (2)

• Overall Response Rate (ORR) [Phase I]

  Participants were followed up to 30 months.

• Median Progression Free Survival [Phase I]

  Participants were followed up to 30 months.

Study Arms (5)

MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 1]

EXPERIMENTAL

* MCS110 2.5mg/kg will be administered intravenously every 3 weeks. * Dabrafenib 150mg is given orally every 12 hours. * Trametinib 2mg is given orally daily

Drug: MCS110; Drug: Dabrafenib; Drug: Trametinib

MCS110 + Trametinib + Dabrafenib [Phase 2]

EXPERIMENTAL

* MCS110 will be administered intravenously every 3 weeks. The Dosage will be determined by the DLT of Phase 1 * Dabrafenib 150mg is given orally every 12 hours. * Trametinib 2mg is given orally daily

Drug: MCS110; Drug: Dabrafenib; Drug: Trametinib

MCS110+ Trametinib + Dabrafenib [Phase I Dose Level -1]

EXPERIMENTAL

* MCS110 1.25 mg/kg was administered intravenously every 3 weeks. * Dabrafenib 150mg is given orally every 12 hours. * Trametinib 2mg is given orally daily

Drug: MCS110; Drug: Dabrafenib; Drug: Trametinib

MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 2]

EXPERIMENTAL

* MCS110 5mg/kg was administered intravenously every 3 weeks. * Dabrafenib 150mg is given orally every 12 hours. * Trametinib 2mg is given orally daily

Drug: MCS110; Drug: Dabrafenib; Drug: Trametinib

MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 3]

EXPERIMENTAL

* MCS110 10mg/kg was administered intravenously every 3 weeks. * Dabrafenib 150mg is given orally every 12 hours. * Trametinib 2mg is given orally daily

Drug: MCS110; Drug: Dabrafenib; Drug: Trametinib

Interventions

MCS110 DRUG

MCS110 is a colony-stimulating factor-1 (CSF-1) inhibitor. It is a human monoclonal antibody which binds CSF-1.

MCS110 + Trametinib + Dabrafenib [Phase 2]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level -1]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 1]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 2]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 3]

Dabrafenib DRUG

Dabrafenib attack different proteins that promote the growth of cancerous cells

Also known as: Tafinlar

MCS110 + Trametinib + Dabrafenib [Phase 2]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level -1]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 1]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 2]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 3]

Trametinib DRUG

Trametinib attack different proteins that promote the growth of cancerous cells

Also known as: Mekinist

MCS110 + Trametinib + Dabrafenib [Phase 2]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level -1]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 1]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 2]; MCS110+ Trametinib + Dabrafenib [Phase I Dose Level 3]

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective.
• For enrollment to the phase II portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and have had progression of disease on prior BRAF and MEK inhibitor therapy.
• Participants enrolling to the phase I portion of the trial must have evaluable or measurable disease.
• Participants enrolling to the phase II portion of the trial must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
• Age ≥ 18 years. As no dosing or adverse event data are currently available in participants \< 18 years of age, children are excluded from this study but will be eligible for future pediatric trials.
• ECOG performance status 0 - 2 (see Appendix A).
• Life expectancy of greater than 8 weeks.
• Participants must have normal organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1.5 K/uL
• Platelets ≥ 100 K/uL
• Hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN
• Serum creatinine ≤ 1.5 × institutional ULN
• PT-INR ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤ 1.5 × their baseline value)

You may not qualify if:

• Participants who have had chemotherapy, radiotherapy, biologic therapy, major surgery, or another investigational agent within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Previous BRAF/MEK inhibitor use is allowed with no washout period for the phase I and II portions.
• Participants who have not recovered to ≤ CTCAE grade 1 or baseline from toxicity as a result of previous cancer treatment prior to entering the study (with the exception of alopecia and peripheral neuropathy which can be ≤ grade 2).
• For enrollment to the phase II portion: participants who have not received prior BRAF or MEK inhibitor therapy.
• Participants with known untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with a history of brain metastases that have been treated, are no longer taking corticosteroids, and have been stable on imaging for ≥ 4 weeks following the last date of treatment are permitted.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MCS110, dabrafenib, or trametinib.
• 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.
• Pregnant women are excluded from this study because MCS110, dabrafenib and trametinib are anti-cancer agents with the potential for teratogenic or abortifacient effects. Pregnancy status will be verified at various points in the trial and a serum pregnancy test will be required. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MCS110, dabrafenib or trametinib, breastfeeding should be discontinued if the mother is treated with MCS110, dabrafenib or trametinib.
• Participants with a known history of HIV are ineligible because of the potential for pharmacokinetic interactions with MCS110, dabrafenib, and trametinib with antiretroviral agents. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy.
• Participants with a personal or family history of long QT syndrome.
• Participants with a history of a second primary malignancy. Exceptions include: patients with a history of malignancies that were treated curatively and have not recurred within 3 years prior to study entry; resected basal and squamous cell carcinomas of the skin, and completely resected carcinoma in situ of any type.
• Participants with impairment of GI function or GI disease that may significantly alter the absorption of dabrafenib and trametinib in the opinion of the treating investigator (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
• Participants who are unable to swallow or retain oral medication.
• Participants that require co-administration of strong or moderate CYP3A inhibitors, as these medications may alter dabrafenib and trametinib concentrations.
• Participants who require treatment with medications that are strong or moderate CYP3A inducers, as these medications may alter the concentration of trametinib.
• Participants with evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Novartis: collaborator

Study Sites (1)

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Limitations and Caveats

Early termination resulted from the drug manufacturer's decision to stop drug development.

Results Point of Contact

• Title: Dr. Elizabeth Buchbinder
• Organization: Dana-Farber Cancer Institute

elizabeth_buchbinder@dfci.harvard.edu

6176325055

Study Officials

• Elizabeth I Buchbinder, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 28, 2018
• First Posted: March 7, 2018
• Study Start: September 10, 2018
• Primary Completion: September 5, 2023
• Study Completion: September 5, 2023
• Last Updated: July 31, 2024
• Results First Posted: July 31, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)