Clinical Trials /

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

NCT04418167

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: JSI-1187-01
  • NCT ID: NCT04418167

Conditions

  • Solid Tumors

Interventions

DrugSynonymsArms
JSI-1187Part A: JSI-1187 Monotherapy Dose Escalation
DabrafenibTAFINLARPart B: JSI-1187 Plus Dabrafenib Combination Dose Escalation

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Part A: JSI-1187 Monotherapy Dose EscalationExperimentalLocally 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
  • JSI-1187
Part B: JSI-1187 Plus Dabrafenib Combination Dose EscalationExperimentalLocally 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
  • JSI-1187
  • Dabrafenib
Part C: JSI-1187 Plus Dabrafenib ExpansionExperimentalCohort 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.
  • JSI-1187
  • Dabrafenib

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of treatment emergent adverse events (safety and tolerability)
Time Frame:35 months
Safety Issue:
Description:Safety and tolerability assessed by adverse events (AEs) and serious adverse events (SAEs)

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description:Length of time from first evidence of objective response (CR, PR) to the first objective evidence of disease progression
Measure: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)
Safety Issue:
Description:Length of time from the date of first dose of study drug to the first evidence of objective response (CR, PR)
Measure: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)
Safety Issue:
Description:Proportion of subjects with best response of CR, PR or stable disease (SD)
Measure: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
Safety Issue:
Description:Length of time from the date of first dose of study drug to the first evidence of disease progression or death, whichever is earlier
Measure: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
Safety Issue:
Description:Length of time from the date of first dose of study drug to date of death from any cause

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:JS InnoPharm, LLC

Trial Keywords

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

Last Updated

July 20, 2020