Selected subjects will include males and females age 18 years; histologically confirmed locally advanced or metastatic solid tumors with archived tumor sample from the primary, recurrent or metastatic disease with documented MAPK pathway mutation or pathway hyperactivating mutations; advanced or recovered from all acute toxicities ( Grade 1) due to prior therapy; adequate renal and hepatic function; and no known history of significant cardiac or retinal disease.

Part A (Monotherapy Dose Escalation): Following screening, a total of up to 42 subjects are anticipated to establish the MTD of JSI-1187 monotherapy in subjects with locally advanced or metastatic solid tumors with MAPK pathway mutations, including hyperactivating pathway mutations or gene fusions, refractory to or relapsed on prior therapy. JSI-1187 will be administered orally twice daily (BID) at doses of 2, 4, 8, 16, 24 and 32 mg (total daily doses of 4, 8, 16, 32, 48 and 64 mg), repeated every 28 days (=1 cycle). Subjects will take their BID doses in a fasted state, 1 hour before or 2 hours after a meal. If 2 of 3 subjects at a given dose level experience a Grade 2 adverse event, or a single subject experiences a Grade 3 adverse event, further JSI-1187 dose increases will not exceed 50%. A total of 6 subjects will be treatment at the MTD before starting Part B.

Part B (Combination Dose Escalation): Following screening, a total of up to 24 subjects are anticipated to establish the MTD of JSI-1187 plus dabrafenib in BRAF V600-mutated locally advanced or metastatic solid tumors. Twice daily doses of both drugs will be taken in the fasted state. A 3+3 dose escalation schema will be followed to establish the MTD of the JSI-1187 plus dabrafenib combination. A total of 6 subjects will be treated at the JSI-1187 plus dabrafenib combined MTD before beginning Part C.

Part C (Expansion Cohorts): Following screening, a total of 58 subjects in 3 cohorts are anticipated to expand the disease treatment settings of JSI-1187 in combination with dabrafenib in BRAF V600-mutated advanced solid tumor malignancies.

Cohort 1: JSI-1187 plus dabrafenib in 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. (n=21).

Cohort 2: JSI-1187 plus dabrafenib in BRAF V600-mutated metastatic melanoma after adjuvant therapy for Stage 3 disease followed by therapy for metastatic disease, including anti-PD-1 therapy, with or without ipilimumab or BRAF/MEK inhibitor treatment. (n=21).

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. (n=16).

JSI-1187 plus dabrafenib will be administered at the MTDs established for both drugs in Part B, repeated every 28 days (=1 cycle).

Subjects who demonstrate clinical benefit (CR, PR or SD) will be allowed to continue therapy with JSI-1187 until progression of disease, observation of unacceptable adverse events, intercurrent illness or changes in the subject's condition that prevents further study participation.

Disease response will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1).

Blood for hematology, coagulation parameters and serum chemistry determinations will be collected, ECGs will be taken and ophthalmologic exams will be conducted during the study.

Blood will be taken for PK assessment of JSI-1187 and dabrafenib and PD assessment of pRSK/RSK ratio determinations.

Tumor biopsies will be taken from consenting subjects at Screening and on-study for pRSK determination. Results will be correlated with clinical outcome.