Summary

Eligibility
for people ages 18 years and up (full criteria)
Location
at UCSF
Dates
study started
estimated completion
Principal Investigator
Mallika S Dhawan, MD (ucsf)
Photo of Mallika S Dhawan
Mallika S Dhawan

Description

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.

Official Title

A Phase 1 Study of ERK1/2 Inhibitor JSI-1187 Administered as Monotherapy and in Combination With Dabrafenib for the Treatment of Advanced Solid Tumors With MAPK Pathway Mutations

Details

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.

Keywords

Solid Tumors solid tumor neoplasm BRAF V600 mutation MAPK pathway mutation ERK1/2 JSI-1187 Dabrafenib KRAS NRAS BRAF Neoplasms

Eligibility

You can join if…

Open to people ages 18 years and up

  • 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

You CAN'T join 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
  • 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

Locations

  • University of California Helen Diller Family Comprehensive Cancer Center not yet accepting patients
    San Francisco California 94158 United States
  • University of Arizona Comprehensive Cancer Center not yet accepting patients
    Tucson Arizona 85724 United States

Lead Scientist at UC Health

  • Mallika S Dhawan, MD (ucsf)
    Dr. Dhawan is an assistant professor in Medical Oncology and specializes in the prevention and treatment of hereditary cancer syndromes in the Center for BRCA Research as well as the development of Phase 1 clinical trials for patient with advanced cancers through the Experimental Therapeutics program. She joined UCSF for fellowship in 2014 and remains on as a faculty member.

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
JS InnoPharm, LLC
ID
NCT04418167
Phase
Phase 1
Study Type
Interventional
Last Updated