Overcoming Primary Resistance to Immunotherapy in Metastatic Melanoma

NCT05304546 | Completed Phase 2

• 1 other identifier: 9222-22-SMC
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

This study will enroll metastatic (Stage IV or inoperable stage III) melanoma (MM) patients carrying a BRAF V600E/K mutation with confirmed primary resistance to standard of care immunotherapy (single agent PD-1 or a combination of CTLA-4/PD-1 blockade). Patients must be naïve to therapy with BRAF+MEK inhibitors, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Conditions

Malignant Melanoma; Metastatic Melanoma; Immunotherapy; BRAF V600E; Malignant Melanoma Stage IV

Keywords

Melanoma; Primary Resistance to Immunotherapy; Neoplasm

Outcome Measures

Primary Outcomes (4)

• Decrease in nuclear c-MYC levels in situ by 50%

  Results of IHC with readout of intensity and percentage with nuclear localization will be used to evaluate this outcome. C-MYC will be evaluated on the basis of intensity (0 to +3).

  48 months

• Increase in mitochondrial proteins ACAT1 and HADHA in the tumor cells in situ by 50%

  HADHA and ACAT1 will be evaluated on the basis of intensity (0 to +3) and percentage of positive cells

  48 months

• Increase in CD8+ counts in situ by 50%

  Results of IHC enabling CD8 counts will be used to evaluate this outcome

  48 months

• Best overall response rate (BORR) to pembrolizumab

  Assessed by RECIST 1.1

  48 months

Secondary Outcomes (4)

• Progression-free survival (PFS)

  48 months

• Duration of response (DoR)

  48 months

• Response rate to targeted therapy upon progression

  48 months

• Number of participants with Treatment-Related Adverse Events as Assessed by CTCAE v5.0

  48 months

Study Arms (1)

Single Arm MK3475, encorafenib and binimetinib

EXPERIMENTAL

Intravenous pembrolizumab 400 mg Q6W + oral encorafenib 450 mg QD + oral binimetinib 45mg BID, for the first 4 weeks of the study. Starting week 5, monotherapy pembrolizumab 400 mg Q6W.

Drug: Pembrolizumab; Drug: Encorafenib; Drug: Binimetinib

Interventions

Pembrolizumab DRUG

Solution for IV

Also known as: Keytruda, MK3475

Single Arm MK3475, encorafenib and binimetinib

Encorafenib DRUG

Oral QD

Also known as: Braftovi

Single Arm MK3475, encorafenib and binimetinib

Binimetinib DRUG

Oral BID

Also known as: Mektovi

Single Arm MK3475, encorafenib and binimetinib

Eligibility Criteria

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

You may qualify if:

• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of metastatic melanoma with BRAF V600E/K mutation will be enrolled in this study.
• Male participants:
• A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 125 days (5 terminal half-lives for pembrolizumab) after the last dose of study treatment and refrain from donating sperm during this period.
• Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
• A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days after the last dose of study treatment.
• Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
• Has received at least 2 doses of an approved anti-PD-1/L1 mAb. Note: participants who have received prior anti-PD-1+ CTLA4 may be included in the study.
• Has demonstrated clinical PD after anti-PD-1/L1 The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented PD, in the absence of rapid clinical progression.
• Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb.
• This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression.
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have not been previously treated with BRAF inhibitors and/or MEK inhibitors.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of treatment initiation.

You may not qualify if:

• A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment initiation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks prior to treatment initiation.
• Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
• Note: If the participant had major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
• Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
• Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
• Note: This time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in-situ cancers
• Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

Sponsors & Collaborators

• Dr. Ronnie Shapira: lead

Study Sites (1)

Sheba Medical Center

Ramat Gan, Israel, 522651, Israel

Location

MeSH Terms

Conditions

Melanoma; Neoplasms

Interventions

pembrolizumab; encorafenib; binimetinib

Condition Hierarchy (Ancestors)

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

Study Officials

• Ronnie Shapira-Frommer, Dr

  Ella Lemelbaum Institute for Immuno-Oncology & Melanoma, Sheba Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of the Ella Lemelbaum Institute for Immuno-Oncology

Study Record Dates

• First Submitted: March 16, 2022
• First Posted: March 31, 2022
• Study Start: September 5, 2023
• Primary Completion: July 17, 2025
• Study Completion: July 17, 2025
• Last Updated: July 22, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)