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

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ClinicalTrials.gov Identifier: NCT04418167
Recruitment Status : Recruiting
First Posted : June 5, 2020
Last Update Posted : April 19, 2021
Sponsor:
Information provided by (Responsible Party):
JS InnoPharm, LLC

Brief 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.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: JSI-1187 Drug: Dabrafenib Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 124 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: A total of up to 42 subjects are anticipated in the JSI-1187 monotherapy dose-escalation phase (Part A). A total of up to 24 subjects are anticipated in the JSI-1187 plus dabrafenib dose-escalation phase (Part B). A total of 58 subjects are anticipated in the JSI-1187 plus dabrafenib expansion phase
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 18, 2020
Estimated Primary Completion Date : May 17, 2023
Estimated Study Completion Date : November 17, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Dabrafenib

Arm Intervention/treatment
Experimental: Part A: JSI-1187 Monotherapy Dose Escalation
Locally advanced or metastatic solid tumors with confirmed with MAPK pathway mutation, refractory to or relapsed on prior therapy and received all available therapy known to confer clinical benefit
Drug: JSI-1187
JSI-1187 capsules for oral administration

Experimental: Part B: JSI-1187 Plus Dabrafenib Combination Dose Escalation
Locally advanced or metastatic solid tumors with confirmed BRAF V600 mutation, refractory to or relapsed on prior therapy and received all available therapy known to confer clinical benefit
Drug: JSI-1187
JSI-1187 capsules for oral administration

Drug: Dabrafenib
Dabrafenib capsules for oral administration
Other Name: TAFINLAR

Experimental: Part C: JSI-1187 Plus Dabrafenib Expansion

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-muated metastatic solid tumor, after 1 or 2 prior therapies.

Drug: JSI-1187
JSI-1187 capsules for oral administration

Drug: Dabrafenib
Dabrafenib capsules for oral administration
Other Name: TAFINLAR




Primary Outcome Measures :
  1. Incidence of treatment emergent adverse events (safety and tolerability) [ Time Frame: 35 months ]
    Safety and tolerability assessed by adverse events (AEs) and serious adverse events (SAEs)


Secondary Outcome Measures :
  1. Objective Response Rate [ Time Frame: 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) ]
    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.

  2. Duration of Response [ Time Frame: 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) ]
    Length of time from first evidence of objective response (CR, PR) to the first objective evidence of disease progression

  3. Time to Response [ Time Frame: 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) ]
    Length of time from the date of first dose of study drug to the first evidence of objective response (CR, PR)

  4. Disease Control Rate [ Time Frame: 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) ]
    Proportion of subjects with best response of CR, PR or stable disease (SD)

  5. Progression-Free Survival [ Time Frame: 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 months ]
    Length of time from the date of first dose of study drug to the first evidence of disease progression or death, whichever is earlier

  6. Overall Survival [ Time Frame: Assessed from the date of the first dose of study drug to date of death from any cause, assessed up to 35 months ]
    Length of time from the date of first dose of study drug to date of death from any cause


Other Outcome Measures:
  1. Mean plasma concentrations of JSI-1187 alone and in combination with dabrafenib [ Time Frame: 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) ]
    Mean plasma concentrations of JSI-1187 and dabrafenib will be determined and summarized by dose group

  2. pRSK/RSK ratio in whole blood (PBMCs) (pharmacodynamic endpoint) [ Time Frame: Cycle 1 Day 1 and Cycle 1 Day 15 (each cycle is 28 days) ]
    Change from baseline in whole blood (PBMC) pRSK/RSK ratio will be determined and summarized by dose group

  3. Change in pRSK levels in tumor (pharmacodynamic endpoint) [ Time Frame: At Screening and Week 2 or 3 on study ]
    In consenting subjects and when clinically available, tumor biopsies will be taken pre-study and on study to assess change in tumor pRSK.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04418167


Contacts
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Contact: Georgine N Price 301-610-4990 georgineprice@westat.com
Contact: Marsha Johnson 202-669-2954 marshajohnson@westat.com

Locations
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United States, Arizona
University of Arizona Comprehensive Cancer Center Recruiting
Tucson, Arizona, United States, 85724
Contact: Mari Magen    520-626-9526    mpinson@arizona.edu   
Principal Investigator: Jennifer M Segar, MD         
United States, California
University of California Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94158
Contact: Erika Zigman    415-353-7084    erika.zigman@ucsf.edu   
Principal Investigator: Mallika S Dhawan, MD         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Ryan J Sullivan, MD    617-726-4000    rsullivan7@mgh.harvard.edu   
Principal Investigator: Ryan J Sullivan, MD         
Jennifer A Maattala Recruiting
Boston, Massachusetts, United States, 02215
Contact: Jennifer A Maattala, RN       JenniferA_Maattala@DFCI.HARVARD.EDU   
Principal Investigator: Elizabeth I Buchbinder, MD         
United States, Texas
University of Texas M.D. Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Anjali Raina    713-792-3238    araina@mdanderson.org   
Principal Investigator: Filip Janku, MD, PhD         
Sponsors and Collaborators
JS InnoPharm, LLC
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Responsible Party: JS InnoPharm, LLC
ClinicalTrials.gov Identifier: NCT04418167    
Other Study ID Numbers: JSI-1187-01
First Posted: June 5, 2020    Key Record Dates
Last Update Posted: April 19, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by JS InnoPharm, LLC:
solid tumor
neoplasm
BRAF V600 mutation
MAPK pathway mutation
ERK1/2
JSI-1187
Dabrafenib
KRAS
NRAS
BRAF
Additional relevant MeSH terms:
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Neoplasms
Dabrafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action