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.
Name: JSI-1187
Name: Dabrafenib
Description: Safety and tolerability assessed by adverse events (AEs) and serious adverse events (SAEs)
Measure: Incidence of treatment emergent adverse events (safety and tolerability) Time: 35 monthsDescription: Proportion of subjects with objective responses (complete response [CR] + partial response [PR]) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
Measure: Objective Response Rate Time: 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)Description: Length of time from first evidence of objective response (CR, PR) to the first objective evidence of disease progression
Measure: Duration of Response Time: 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)Description: Length of time from the date of first dose of study drug to the first evidence of objective response (CR, PR)
Measure: Time to Response Time: 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)Description: Proportion of subjects with best response of CR, PR or stable disease (SD)
Measure: Disease Control Rate Time: 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)Description: Length of time from the date of first dose of study drug to the first evidence of disease progression or death, whichever is earlier
Measure: Progression-Free Survival Time: 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 monthsDescription: Length of time from the date of first dose of study drug to date of death from any cause
Measure: Overall Survival Time: Assessed from the date of the first dose of study drug to date of death from any cause, assessed up to 35 monthsDescription: Mean plasma concentrations of JSI-1187 and dabrafenib will be determined and summarized by dose group
Measure: Mean plasma concentrations of JSI-1187 alone and in combination with dabrafenib Time: 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)Description: Change from baseline in whole blood (PBMC) pRSK/RSK ratio will be determined and summarized by dose group
Measure: pRSK/RSK ratio in whole blood (PBMCs) (pharmacodynamic endpoint) Time: Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days)Description: In consenting subjects and when clinically available, tumor biopsies will be taken pre-study and on study to assess change in tumor pRSK.
Measure: Change in pRSK levels in tumor (pharmacodynamic endpoint) Time: At Screening and Week 2 or 3 on studyAllocation: Non-Randomized
Sequential Assignment
There is one SNP
In consenting subjects and when clinically available, tumor biopsies will be taken pre-study and on study to assess change in tumor pRSK.. Inclusion Criteria: - 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 - Part B (JSI-1187 Plus Dabrafenib Combination Dose Escalation): Histologically or cytologically confirmed BRAF V600-mutated locally advanced or metastatic solid tumor, refractory to, or relapsed on, prior therapy, and have received all available therapy known to confer clinical benefit - Part C (JSI-1187 Plus Dabrafenib Expansion Cohorts): Histologically or cytologically confirmed: - Cohort 1: BRAF V600-mutated metastatic melanoma after two prior therapies for metastatic disease, including anti-PD1 therapy, with or without ipilimumab, and BRAF/MEK inhibitor treatment - Cohort 2: BRAF V600-mutated metastatic melanoma after adjuvant therapy for Stage 3 disease followed by one prior therapy for metastatic disease, including anti-PD-1 therapy, with or without ipilimumab or BRAF/MEK inhibitor treatment - Cohort 3: Either BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC), or BRAF V600-mutated metastatic solid tumor, after 1 or 2 prior therapies - 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. --- V600E ---
- If female, pregnant, breast-feeding, or planning to become pregnant Inclusion Criteria: - 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 - Part B (JSI-1187 Plus Dabrafenib Combination Dose Escalation): Histologically or cytologically confirmed BRAF V600-mutated locally advanced or metastatic solid tumor, refractory to, or relapsed on, prior therapy, and have received all available therapy known to confer clinical benefit - Part C (JSI-1187 Plus Dabrafenib Expansion Cohorts): Histologically or cytologically confirmed: - Cohort 1: BRAF V600-mutated metastatic melanoma after two prior therapies for metastatic disease, including anti-PD1 therapy, with or without ipilimumab, and BRAF/MEK inhibitor treatment - Cohort 2: BRAF V600-mutated metastatic melanoma after adjuvant therapy for Stage 3 disease followed by one prior therapy for metastatic disease, including anti-PD-1 therapy, with or without ipilimumab or BRAF/MEK inhibitor treatment - Cohort 3: Either BRAF V600E-mutated metastatic non-small cell lung cancer (NSCLC), or BRAF V600-mutated metastatic solid tumor, after 1 or 2 prior therapies - 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. --- V600E ---
Cohort 3: JSI-1187 plus dabrafenib in either BRAF V600E-mutated non-small cell lung cancer (NSCLC) or BRAF V600-mutated solid tumors after 1 or 2 prior therapies. --- V600E ---