MCS110 With BRAF/MEK Inhibition in Patients With Melanoma

Study Overview
=================
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

Detailed 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.

Official Title
-----------------
A Phase I/II Study of MCS110 With BRAF/MEK Inhibition in Patients With Melanoma After Progression on BRAF/MEK Inhibition

Conditions
-----------------
Melanoma

Intervention / Treatment
-----------------
* Drug: MCS110
* Drug: Dabrafenib
* Drug: Trametinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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: 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) aPTT ≤ 1.5 × institutional ULN (for participants on anticoagulation therapy, ≤ 1.5 × their baseline value) 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: Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository). 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: 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. Participants with a history of or current evidence of retinal vein occlusion or retinal pigment epithelial detachment. Participants taking corticosteroids (≥ 10 mg of prednisone or equivalent). Exceptions may be discussed with the Overall PI on a case by case basis.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MCS110+ Trametinib + Dabrafenib<br>For Phase 1 MCS110 will be administered intravenously every 3 weeks. Dabrafenib is given orally every 12 hours. Trametinib is given orally daily | Drug: MCS110<br>* MCS110 is a colony-stimulating factor-1 (CSF-1) inhibitor. It is a human monoclonal antibody which binds CSF-1.<br>Drug: Dabrafenib<br>* Dabrafenib attack different proteins that promote the growth of cancerous cells<br>* Other names: Tafinlar;Drug: Trametinib<br>* Trametinib attack different proteins that promote the growth of cancerous cells<br>* Other names: Mekinist;|
| Experimental: MCS110 + Trametinib + Dabrafenib Phase 2<br>MCS110 will be administered intravenously every 3 weeks. The Dosage will be determine by the DLT of Phase 1 Dabrafenib is given orally every 12 hours. Trametinib is given orally daily | Drug: MCS110<br>* MCS110 is a colony-stimulating factor-1 (CSF-1) inhibitor. It is a human monoclonal antibody which binds CSF-1.<br>Drug: Dabrafenib<br>* Dabrafenib attack different proteins that promote the growth of cancerous cells<br>* Other names: Tafinlar;Drug: Trametinib<br>* Trametinib attack different proteins that promote the growth of cancerous cells<br>* Other names: Mekinist;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity | Any side effects or severe side effects that require the drug to be held or reduced | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | The percentage of patients that have a reduction of their disease on imaging that meets RECIST criteria | 2 years | 
| Complete Response rate | The percentage of patients who have a reduction of their disease on imaging to the point that it can no longer be measured. | 2 years | 
| Partial Response rate | The percentage of patients who have meet RECIST criteria for having a reduction in their disease on imaging but still have measurable disease. | 2 years | 
| Progression Free Survival | The length of time between participants starting study treatment and having growth of their disease | 2 years | 
| Overall Survival | The amount of time between participants starting study therapy and death | 2 years | 
| Toxicity (Safety and Tolerability) | Any side effects or severe side effects associated with study therapy | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Melanoma