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.
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.
- Have discontinued previous treatments for cancer and have resolution, except where
otherwise stated in the inclusion criteria, of all clinically significant toxic
effects of prior chemotherapy, surgery, or radiotherapy to Grade ≤ 1
- 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 109 cells/L
- Platelets ≥ 75 x 109 cells/L
- Adequate renal and hepatic function:
- Creatinine ≤ 1.5 times the upper limit of normal (ULN), or calculated creatinine
clearance ≥ 50 mL/minute x 1.73 m2 per the Cockcroft-Gault formula
- Total bilirubin ≤ 2 times the (ULN) unless due to Gilbert's disease
- ALT/AST ≤ 2.5 times the ULN, or < 5 times the ULN for subjects with liver
metastases
- Negative serum pregnancy test within 14 days prior to the first dose of study therapy
for women of child-bearing potential (WCBP). Sexually active WCBP and male subjects
must agree to use adequate methods to avoid pregnancy throughout the study and for 28
days after the completion of study treatment.
- Ability to provide written informed consent
Exclusion Criteria:
- 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
- Any other medical intervention or other condition which, in the opinion of the
Principal Investigator, could compromise adherence to study requirements or confound
the interpretation of study results
- Participation within the last 28 days in a clinical trial, or currently enrolled in a
clinical trial, involving an investigational product or any other type of medical
research judged not to be scientifically or medically compatible with this study
- Previously completed or withdrawn from this study or any other study investigating an
ERK1/2 inhibitor.
- If female, pregnant, breast-feeding, or planning to become pregnant
