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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:
Full description
This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied.
The FDA (the U.S. Food and Drug Administration) has not approved MSC110 as a treatment for any disease.
The FDA has approved dabrafenib and trametinib as treatment options for this disease.
Dabrafenib and trametinib attack different proteins that promote the growth of cancerous cells. These two treatments work in cancers with a mutation in the BRAF gene which alters a protein signaling pathway in cancer cells. The BRAF mutation status will be confirmed during this trial by review or procedure in order to make sure this clinical trial is right for the participant. Dabrafenib is a BRAF inhibitor that works by preventing altered BRAF proteins from stimulating the growth of the melanoma cancer cells. Trametinib works by blocking a protein related to BRAF called MEK that has been known to stimulate cells that also promote melanoma growth. In order to participate in the study, the participant disease needs to be tested positive for a mutation (a permanent change in the DNA sequence of a gene) of the BRAF gene that belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. Once the BRAF gene is mutated, the normal functioning of the BRAF protein may be changed. It is normal for patients with a BRAF mutation to receive these types of inhibitor therapies at some point in their treatment.
MCS110 is a colony-stimulating factor-1 (CSF-1) inhibitor. It is a human monoclonal antibody which binds CSF-1. A monoclonal antibody is a type of protein made in the laboratory that can locate and bind to substances in the body, including tumor cells. MCS110 is being developed as a treatment for patients with advanced cancer.
In this research study, the investigators are adding MCS110 to the treatment with dabrafenib and trametinib at the time when the participant's disease is growing despite these medications. The hope is that MCS110 will enhance how the cancer will respond to dabrafenib and trametinib and overcome any resistance to these medications that has developed. In previous laboratory studies performed by treating melanoma cancer cells with a CSF-1R (CSF-1 Receptor which interacts with the CSF-1 protien) inhibitor and a BRAF inhibitor, it was found that the CSF-1R inhibitor was successful in increasing efficacy.
Enrollment
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Inclusion criteria
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:
Participants must have a left ventricular ejection fraction (LVEF) ≥ 50%.
Participants must have a QTc of ≤ 470 msec for females and ≤ 450 for males on the screening EKG.
The effects of MCS110, trametinib and dabrafenib on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after the last dose of MCS110. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MCS110 administration. Highly Effective contraception methods include:
Ability to understand and the willingness to sign a written informed consent document.
Participants must have archival tumor tissue available. Participants without archival tissue may be enrolled at the discretion of the principal investigator.
All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 1) must be ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0; NCI, 2009) at the time of randomization
Exclusion criteria
Primary purpose
Allocation
Interventional model
Masking
6 participants in 5 patient groups
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Data sourced from clinicaltrials.gov
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