Clinical Trials /

Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations

NCT04161391

Description:

A phase 1/2, first-in-human, open-label study to determine the safety, tolerability, PK, and preliminary efficacy of the novel RET/SRC inhibitor TPX-0046 in adult subjects with advanced or metastatic solid tumors harboring RET mutations or alterations. The study consists of two portions: 1) Phase 1 Dose Escalation and Food Effect Sub-study, and 2) Phase 2 efficacy evaluation.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations
  • Official Title: A Phase 1/2 Study of TPX-0046, A Novel Oral RET/SRC Inhibitor in Adult Subjects With Advanced/Metastatic Solid Tumors Harboring Oncogenic RET Fusions or Mutations

Clinical Trial IDs

  • ORG STUDY ID: TPX-0046-01
  • NCT ID: NCT04161391

Conditions

  • Non Small Cell Lung Cancer
  • Medullary Thyroid Cancer
  • RET Gene Mutation
  • Metastatic Solid Tumor
  • Advanced Solid Tumor

Interventions

DrugSynonymsArms
TPX-0046TPX-0046

Purpose

A phase 1/2, first-in-human, open-label study to determine the safety, tolerability, PK, and preliminary efficacy of the novel RET/SRC inhibitor TPX-0046 in adult subjects with advanced or metastatic solid tumors harboring RET mutations or alterations. The study consists of two portions: 1) Phase 1 Dose Escalation and Food Effect Sub-study, and 2) Phase 2 efficacy evaluation.

Detailed Description

      Phase 1 Dose Escalation: To evaluate the overall safety profile, characterize the PK profiles
      and assess the preliminary efficacy of TPX-0046 in adults subjects with advanced solid tumors
      harboring oncogenic RET fusions or mutations.

      Food Effect Sub-Study: To determine the effect of food on PK of TPX-0046 in adult subjects
      with advanced or metastatic solid tumors harboring oncogenic RET fusions or mutations.

      Phase 2 Efficacy Evaluation: To determine the overall safety and anti-tumor efficacy of
      TPX-0046 in defined cohorts of subjects with advanced/metastatic solid tumors harboring
      oncogenic RET fusions or mutations.
    

Trial Arms

NameTypeDescriptionInterventions
TPX-0046ExperimentalThe Phase 1 part of the study will determine the safety, tolerability, PK, MTD, and RP2D of TPX-0046. A food-effect sub-study will be conducted once the RP2D has been determined. The Phase 2 part of the study will determine the safety, tolerability, PK, and preliminary efficacy in specific cohorts. Phase 2 Cohorts: Cohort I (NSCLC + RET fusion, RET TKI Therapy Naive) Cohort II (NSCLC + RET fusion, RET TKI Therapy Pre-treated) Cohort III (MTC + RET mutation, RET TKI Therapy Naive) Cohort IV (MTC + RET mutation, RET TKI Therapy Pre-treated) Cohort V (advanced/metastatic tumor with RET fusion or mutation, RET TKI Therapy Naive) Cohort VI (advanced/metastatic tumor with RET fusion or mutation, RET TKI Therapy Pre-Treated)
  • TPX-0046

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≥ 18 (or age ≥ 20 as required by local regulation).

          2. Histological or cytological confirmation of advanced/metastatic solid tumors harboring
             oncogenic RET fusions or mutations, who either have disease progression on, or are
             intolerant to standard therapy; OR are ineligible for standard therapy or for whom no
             standard therapy exists; OR are unlikely to tolerate or derive clinical benefit from
             standard therapy in the opinion of the Investigator OR have declined standard therapy.

          3. ECOG performance status ≤ 1.

          4. Existence of measurable or evaluable disease (according to Response evaluation
             criteria in solid tumors [RECIST v1.1] criteria).

          5. Subjects with asymptomatic primary CNS tumors or brain metastases are eligible for the
             study if they meet protocol specified criteria.

          6. Adequate organ function.

          7. Life expectancy ≥ 12 weeks.

        Exclusion Criteria:

          1. Locally advanced solid tumor that is a candidate for curative treatment through
             radical surgery and/or radiotherapy, or chemotherapy.

          2. Presence or history of any other primary malignancy within 5 years other than a
             history of adequately treated basal or squamous cell carcinoma of the skin, or any
             adequately treated in situ carcinoma.

          3. Major surgery within four weeks of the start of therapy.

          4. Clinically significant cardiovascular disease (either active or within six months
             before enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
             bypass graft, symptomatic congestive heart failure (New York Heart Association
             Classification Class ≥ II), cerebrovascular accident or transient ischemic attack,
             symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
             dysrhythmias of CTCAE version 5.0 grade ≥ 2.

          5. Any of the following cardiac criteria:

               -  Mean resting corrected QT interval (ECG interval measured from the onset of the
                  QRS complex to the end of the T wave) for heart rate (QTc) > 470 msec obtained
                  from three ECGs, using the screening clinic ECG machine-derived QTc value

               -  Any clinically important abnormalities in rhythm, conduction, or morphology of
                  resting ECG (e.g., complete left bundle branch block, third degree heart block,
                  second degree heart block, PR interval > 250 msec)

               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, congenital long QT syndrome, family history of long
                  QT syndrome, or any concomitant medication known to prolong the QT interval

          6. Known clinically significant active infections not controlled with systemic treatment
             (bacterial, fungal, viral including HIV positivity).

          7. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
             syndrome) or other malabsorption syndromes that would impact drug absorption.

          8. Subjects being treated with or anticipating the need for treatment with strong CYP3A4
             inhibitors or inducers.

          9. Subjects with current or anticipated need for drugs that are sensitive CYP2C9
             substrates with narrow therapeutic indices.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of first cycle dose-limiting toxicities (DLTs) of TPX-0046
Time Frame:Within 28 days of the first TPX-0046 dose for each patient
Safety Issue:
Description:Evaluate the safety and tolerability of TPX-0046

Secondary Outcome Measures

Measure:Adverse events (AEs)
Time Frame:Approximately 48 months
Safety Issue:
Description:Evaluate the overall safety profile of TPX-0046
Measure:Cmax (maximum plasma concentration) of TPX-0046
Time Frame:Up to 96 hours post-dose
Safety Issue:
Description:Evaluate the maximum plasma concentration of TPX-0046
Measure:AUC (area under plasma concentration time curve) of TPX-0046
Time Frame:Up to 96 hours post-dose
Safety Issue:
Description:Determine the AUC of TPX-0046
Measure:Cmax (maximum plasma concentration) of TPX-0046 under different food intake conditions
Time Frame:Up to 96 hours post-dose
Safety Issue:
Description:Determine the effect of food (specifically, a high-fat, high-calorie meal) on the single-dose PK (Cmax) of TPX-0046 at the RP2D
Measure:AUC (area under plasma concentration time curve) of TPX-0046 under different food intake conditions
Time Frame:Up to 96 hours post-dose
Safety Issue:
Description:Determine the effect of food (specifically, a high-fat, high-calorie meal) on the single-dose PK (AUC) of TPX-0046 at the RP2D
Measure:Preliminary Objective Response Rate (ORR)
Time Frame:Approximately 48 months
Safety Issue:
Description:Determine the preliminary objective response rate (ORR) by Blinded Independent Central Review (BICR) of TPX-0046
Measure:Clinical benefit rate (CBR)
Time Frame:Approximately 48 months
Safety Issue:
Description:Determine the CBR of TPX-0046
Measure:Time to response (TTR)
Time Frame:Approximately 48 months
Safety Issue:
Description:Determine the TTR of TPX-0046
Measure:Duration of Response (DOR)
Time Frame:Approximately 48 months
Safety Issue:
Description:Determine the DOR of TPX-0046
Measure:Progression free survival (PFS)
Time Frame:Approximately 48 months
Safety Issue:
Description:Determine the PFS of TPX-0046
Measure:Intracranial tumor response
Time Frame:Approximately 48 months
Safety Issue:
Description:Determine the intracranial tumor response in subjects with measurable brain metastases, as determined by BICR
Measure:Overall survival (OS)
Time Frame:Approximately 48 months
Safety Issue:
Description:Determine efficacy and safety of TPX-0046

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Turning Point Therapeutics, Inc.

Trial Keywords

  • Non small cell lung cancer
  • Non-small cell lung cancer
  • NSCLC
  • Medullary Thyroid Cancer
  • MTC
  • RET gene mutation
  • RET gene alteration
  • Advanced non small cell lung cancer
  • Advanced/metastatic disease
  • lung cancer
  • lung adenocarcinoma
  • Metastatic solid tumor
  • Advanced Solid Tumors
  • RET gene fusion
  • RET inhibitor
  • SRC
  • TPX-0046
  • Thyroid cancer

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