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

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Recruiting
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JS InnoPharm, LLC

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Updated on 19 February 2024

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cancer

immunomodulator

serum pregnancy test

measurable disease

metastasis

gilbert's syndrome

neutrophil count

lung cancer

solid tumor

liver metastasis

brain metastases

immunomodulators

ipilimumab

adjuvant therapy

solid neoplasm

metastatic malignant solid tumor

alt/ast

mek inhibitor

metastatic melanoma

dabrafenib

investigational treatment

brain metastasis

stage iv nsclc

experimental therapy

braf v600e mutation

gene fusion

adjuvant

melanoma

non-small cell lung cancer

BRAF

small cell lung cancer

metastatic malignant solid neoplasm

ras-gap

ras-gef

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.

Description

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.

Details

Condition	Solid Tumors
Age	18-100 years
Treatment	JSI-1187, Dabrafenib
Clinical Study Identifier	NCT04418167
Sponsor	JS InnoPharm, LLC
Last Modified on	19 February 2024

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Eligibility		Yes	No	Not Sure
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

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