JSI-1187-01 Monotherapy and in Combination With Dabrafenib for Advanced Solid Tumors With MAPK Pathway Mutations

NCT04418167 | Suspended Phase 1 DMC FDA Drug

• 1 other identifier: JSI-1187-01
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 7

Brief Summary

This is a Phase 1 study of JSI-1187 as monotherapy and in combination with dabrafenib for the treatment of advanced solid tumors with MAPK pathway mutations, including mutations that cause MAPK pathway hyperactivation.

Conditions

Solid Tumors

Keywords

solid tumor; neoplasm; BRAF V600 mutation; MAPK pathway mutation; ERK1/2; JSI-1187; Dabrafenib; KRAS; NRAS; BRAF; melanoma; non-small cell lung cancer; anaplastic thyroid cancer

Outcome Measures

Primary Outcomes (1)

• Incidence of treatment emergent adverse events (safety and tolerability)

  Safety and tolerability assessed by adverse events (AEs) and serious adverse events (SAEs)

  35 months

Secondary Outcomes (6)

• Objective Response Rate

  Assessed at the end of Cycle 2 and every 2 cycles thereafter through 6 months following last dose of study drug (each cycle is 28 days)

• Duration of Response

  Assessed at the end of Cycle 2 and every 2 cycles thereafter through 6 months following the last dose of study drug (each cycle is 28 days)

• Time to Response

  Assessed at the end of Cycle 2 and every 2 cycles thereafter through 6 months following the last dose of study drug (each cycle is 28 days)

• Disease Control Rate

  Assessed at the end of Cycle 2 and every 2 cycles thereafter through 6 months following the last dose of study drug (each cycle is 28 days)

• Progression-Free Survival

  Assessed from the date of the first dose of study drug to the first evidence of disease progression or death, whichever is earlier, assessed up to 35 months

Other Outcomes (3)

• Mean plasma concentrations of JSI-1187 alone and in combination with dabrafenib

  Cycle 1, Day 1; Cycle 1, Day 15; Cycle 2 Day 1; Cycle 4 Day 1; Cycle 6 Day 1 (each cycle is 28 days)

• pRSK/RSK ratio in whole blood (PBMCs) (pharmacodynamic endpoint)

  Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)

• Change in pRSK levels in tumor (pharmacodynamic endpoint)

  At Screening and Week 2 or 3 on study

Study Arms (3)

Part A: JSI-1187 Monotherapy Dose Escalation

EXPERIMENTAL

Locally advanced or metastatic solid tumors with confirmed with MAPK pathway mutation

Drug: JSI-1187

Part B: JSI-1187 Plus Dabrafenib Combination Dose Escalation

EXPERIMENTAL

BRAF V600E/K-mutated unresectable or metastatic melanoma, BRAF V600E-mutated NSCLC, or BRAF V600E-mutated locally advanced or metastatic anaplastic thyroid cancer, or other BRAF V600E-mutated unresectable or metastatic solid tumors

Drug: JSI-1187; Drug: Dabrafenib

Part C: JSI-1187 Plus Dabrafenib Expansion

EXPERIMENTAL

Cohort 1: BRAF V600E/K-mutated unresectable or metastatic melanoma after 1-3 prior therapies for metastatic disease, including anti-PD1 therapy, with or without ipilimumab, and BRAF/MEK inhibitor treatment. Cohort 2: BRAF V600E/K-mutated unresectable or metastatic melanoma after BRAF/MEK inhibitor adjuvant therapy for Stage 3 disease followed by 1-2 prior therapies for metastatic disease, including anti-PD-1 therapy, with or without ipilimumab, and excluding BRAF/MEK inhibitor treatment. Cohort 3: BRAF V600E-mutated metastatic NSCLC after 1-2 prior therapies for metastatic disease.

Drug: JSI-1187; Drug: Dabrafenib

Interventions

JSI-1187 DRUG

JSI-1187 capsules for oral administration

Part A: JSI-1187 Monotherapy Dose Escalation; Part B: JSI-1187 Plus Dabrafenib Combination Dose Escalation; Part C: JSI-1187 Plus Dabrafenib Expansion

Dabrafenib DRUG

Dabrafenib capsules for oral administration

Also known as: TAFINLAR

Part B: JSI-1187 Plus Dabrafenib Combination Dose Escalation; Part C: JSI-1187 Plus Dabrafenib Expansion

Eligibility Criteria

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

You may qualify if:

• Males and females ≥ 18 years of age
• Have locally advanced or metastatic solid tumor malignancy with measurable disease and be an appropriate candidate for experimental therapy
• Part A (JSI-1187 Monotherapy Dose Escalation): Histologically or cytologically confirmed MAPK pathway mutation, including hyperactivating pathway mutations or gene fusions, e.g., BRAF (Class I, II or III), RAS (H/K/N), MEK (MAP2K1), RAS-GAP (NF1 loss, RASA1), RAS-GEF, refractory to or relapsed on prior therapy, and have received all available therapy known to confer clinical benefit
• (On hold, effective 05 July 2023) Part B (JSI-1187 Plus Dabrafenib Combination Dose Escalation): Histologically or cytologically confirmed BRAF V600E/K-mutated unresectable or metastatic melanoma, BRAF V600E-mutated metastatic NSCLC, BRAF V600E-mutated locally advanced or metastatic anaplastic thyroid cancer, or other BRAF V600E-mutated unresectable or metastatic solid tumors, refractory to, or relapsed on, prior therapy, and have received all available therapy known to confer clinical benefit
• (On hold, effective 05 July 2023) Part C (JSI-1187 Plus Dabrafenib Expansion Cohorts): Histologically or cytologically confirmed:
• Cohort 1: BRAF V600E/K-mutated unresectable or metastatic melanoma after 1-3 prior therapies for metastatic disease, including anti-PD1 therapy, with or without ipilimumab, and BRAF/MEK inhibitor treatment
• Cohort 2: BRAF V600E/K-mutated unresectable or metastatic melanoma after BRAF/MEK inhibitor adjuvant therapy for Stage 3 disease followed by 1-2 prior therapies for metastatic disease, including anti-PD-1 therapy, with or without ipilimumab, and excluding BRAF/MEK inhibitor treatment
• Cohort 3: BRAF V600E-mutated metastatic NSCLC after 1 or 2 prior therapies for metastatic disease
• MAPK mutation tumor status will be established prior to entry based on previous MAPK pathway mutation reports from a CLIA qualified laboratory, or, if a report is not available, the mutation analysis will be performed at Screening on archival tissue or newly biopsied tumor tissue.
• Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 2
• Life expectancy of ≥ 3 months
• Subjects with asymptomatic stable, prior or currently treated brain metastases are allowed
• Adequate hematologic parameters without ongoing transfusional support:
• Hemoglobin (Hb) ≥ 9 g/dL
• Absolute neutrophil count (ANC) ≥ 1.0 x 10\^9 cells/L

You may not qualify if:

• Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial infarction, unstable angina or heart disease defined by the New York Heart Association (NYHA) Class III or Class IV
• QT interval corrected for rate (QTc) \> 480 msec on the ECG obtained at Screening using Fridericia method for QTc calculation
• Concomitant medication(s) that may cause QTc prolongation or induce Torsades de Pointes, with the exception of anti-microbials that are used as standard of care to prevent or treat infections and other such drugs that are considered by the Investigator to be essential for patient care.
• Medications that are strong inhibitors of CYP3A4 are prohibited during study and for 14 days prior to the first dose of study drug(s).
• Medications that are strong inducers of CYP3A4 are prohibited during study and for 14 days prior to the first dose of study drug(s).
• Medications that are strong inhibitors of BCRP are prohibited during study and for 14 days prior to the first dose of study drugs(s).
• Subjects on dabrafenib (Parts B and C) also are advised to avoid concurrent administration of strong inhibitors of CYP2C8 as these medications may increase the concentration of dabrafenib
• History of or current evidence/risk of retinal vein occlusion or central serous retinopathy, or has medically relevant abnormalities identified on screening ophthalmologic examination
• Symptomatic central nervous system malignancy or metastasis
• Gastrointestinal conditions that could impair absorption of study drug(s)
• Current hematologic malignancies
• Second, active primary solid tumor malignancy that, in the judgement of the investigator or Sponsor medical monitor, may affect the interpretation of results
• Prior malignancies, with the exception of carcinoma in situ of any origin, non-muscle invasive bladder cancer, Gleason 3+3 prostate cancer and prior malignancies in remission whose likelihood of recurrence is very low, as judged by the Sponsor medical monitor.
• Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment within the last week prior to study treatment
• Other active infection requiring IV antibiotic usage within the last week prior to study treatment

Sponsors & Collaborators

• JS InnoPharm, LLC: lead

Study Sites (7)

Mayo Clinic Cancer Center

Phoenix, Arizona, 85054, United States

Location

University of Arizona Comprehensive Cancer Center

Tucson, Arizona, 85724, United States

Location

University of California Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94158, United States

Location

Mayo Clinic Cancer Center

Jacksonville, Florida, 32224, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic Cancer Center

Rochester, Minnesota, 55905, United States

Location

MeSH Terms

Conditions

Neoplasms; Melanoma; Carcinoma, Non-Small-Cell Lung; Thyroid Carcinoma, Anaplastic

Interventions

dabrafenib

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; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma; Neoplasms, Glandular and Epithelial

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: A total of up to 80 subjects are anticipated in the JSI-1187 monotherapy dose-escalation phase (Part A). A total of up to 36 subjects are anticipated in the JSI-1187 plus dabrafenib dose-escalation phase (Part B). A total of 58 subjects are anticipated in the JSI-1187 plus dabrafenib expansion phase

Study Record Dates

• First Submitted: May 11, 2020
• First Posted: June 5, 2020
• Study Start: June 18, 2020
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: September 3, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)