Clinical Trials /

A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements

NCT03093116

Description:

Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction. Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements
  • Official Title: A Phase 1/2, Open-Label, Multi-Center, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of TPX-0005 in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)

Clinical Trial IDs

  • ORG STUDY ID: TPX-0005-01
  • NCT ID: NCT03093116

Conditions

  • Locally Advanced Solid Tumors
  • Metastatic Solid Tumors

Interventions

DrugSynonymsArms
Oral repotrectinib (TPX-0005)repotrectinibRepotrectinib (TPX-0005)

Purpose

Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose (RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction. Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR) of repotrectinib in each subject population expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement. The secondary objective will include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.

Detailed Description

      In Phase 2, study subjects will be enrolled into 6 distinct expansion (EXP) cohorts:

        -  EXP-1: ROS1 TKI-naïve ROS1+ NSCLC. Up to one prior line of chemotherapy OR immunotherapy
           is allowed

        -  EXP-2: 1 Prior ROS1 TKI AND 1 Platinum-based Chemotherapy ROS1+ NSCLC. Disease
           progression, or intolerant to one prior line of a ROS1 TKI. Must have received one prior
           line of platinum based chemotherapy OR one prior line of platinum based chemotherapy in
           combination with immunotherapy before or after a ROS1 TKI

        -  EXP-3: 2 Prior ROS1 TKIs AND NO Chemotherapy ROS1+ NSCLC. Disease progression, or
           intolerant to 2 prior lines of a ROS1 TKI treatment. No prior lines of chemotherapy or
           immunotherapy are allowed.

        -  EXP-4: 1 Prior ROS1 TKI and NO Chemotherapy or Immunotherapy. Disease progression or
           intolerant to one prior line of a ROS1 TKI. No prior lines of chemotherapy or
           immunotherapy are allowed.

        -  EXP-5: TRK TKI-naïve NTRK+ solid tumors. Any number of prior lines of chemo or
           immunotherapy is allowed.

        -  EXP-6: TRK TKI-pretreated NTRK+ solid tumors. Disease progression, or intolerant to 1 or
           2 prior TRK TKIs. Any number of prior lines of chemo- or immunotherapy are allowed.
    

Trial Arms

NameTypeDescriptionInterventions
Repotrectinib (TPX-0005)ExperimentalPhase 1 Oral repotrectinib (TPX-0005): Phase 1a dose escalation, Phase 1b food-effect sub-study, and Phase 1c dose escalation with food, and Midazolam drug-drug interaction sub-study. Phase 2 Oral repotrectinib (TPX-0005): 6 distinct expansion cohorts EXP-1: ROS1 TKI-naïve ROS1+ NSCLC EXP-2: 1 Prior ROS1 TKI and 1 Platinum based chemo ROS1+ NSCLC EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) EXP-5: TRK TKI-naïve NTRK+ solid tumors EXP-6: TRK TKI-pretreated NTRK+ solid tumors
  • Oral repotrectinib (TPX-0005)

Eligibility Criteria

        PHASE 1

        Key Inclusion Criteria:

          1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
             solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on
             Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by
             protocol specified tests.

          2. ECOG PS 0-1.

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

          4. Capability to swallow capsules intact (without chewing, crushing, or opening).

          5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only
             measurable disease as defined by RECIST version 1.1 is allowed.

          6. Prior cytotoxic chemotherapy is allowed.

          7. Prior immunotherapy is allowed.

          8. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
             therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
             (NCI CTCAE) Version 4.03 Grade less than or equal to 1.

          9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
             leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
             specified criteria.

         10. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
             count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
             Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
             clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN;
             Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present
             Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are
             present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or
             without supplementation

         11. Life expectancy ≥ 3 months.

        PHASE 2 Key Inclusion Criteria

          1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
             solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene
             fusion.

          2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based
             local testing using either:

               1. a next-generation sequencing (NGS) or quantitative polymerase chain reaction
                  (qPCR) test will be accepted to determine molecular eligibility.

                  • Adequate tumor tissue needs to be sent to the Sponsor designated central
                  diagnostic laboratory for retrospective confirmation by a central diagnostic
                  laboratory test selected by the Sponsor.

                  OR

               2. a fluorescence in situ hybridization (FISH) test AND prospective confirmation of
                  fusion status by a central diagnostic laboratory test selected by the Sponsor
                  PRIOR to enrollment will be accepted to determine molecular eligibility.

                    -  Adequate tumor tissue must be sent to the Sponsor designated central
                       diagnostic laboratory for prospective confirmation by a central diagnostic
                       laboratory test selected by the Sponsor PRIOR to enrollment.

          3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.

          4. Age ≥12 (or age ≥ 20 as required by local regulation).

          5. Willing and able to provide written institutional review board (IRB)/institutional
             ethics committee-approved Informed Consent or an Assent signed by a parent or legal
             guardian for subjects age 12 to 17.

          6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed
             by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to
             enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST
             (v1.1) are eligible.

          7. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3
             rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all
             inclusion and exclusion criteria are met.

             i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based
             chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv.
             EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+
             solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors

          8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
             leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
             specified criteria.

          9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
             count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
             Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
             clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases
             (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline
             phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present;
             Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without
             supplementation

         10. Life expectancy ≥ 3 months.

        Key Exclusion Criteria PHASE 1 and PHASE 2

          1. Concurrent participation in another therapeutic clinical trial.

          2. Symptomatic brain metastases or leptomeningeal involvement.

          3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the
             skin, or any in situ carcinoma that has been completely resected, requiring therapy
             within the previous 2 years.

          4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy
             (except palliative to relieve bone pain) within 2 weeks of study entry. Palliative
             radiation (≤10 fractions) must have been completed at least 48 hours prior to study
             entry

          5. Clinically significant cardiovascular disease (either active or within 6 months prior
             to 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 NCI CTCAE grade ≥2

          6. 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 (QTcF) > 470 msec obtained from 3
             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, hypokalemia, congenital long QT
             syndrome, family history of long QT syndrome, or any concomitant medication known to
             prolong the QT interval.

          7. Known active infections (bacterial, fungal, viral including HIV positivity).

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

          9. Peripheral neuropathy of CTCAE ≥grade 2.

         10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4
             interstitial fibrosis or interstitial lung disease including a history of pneumonitis,
             hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
             obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior
             radiation pneumonitis are not excluded.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLTs) (Phase 1)
Time Frame:Within 28 days of the first repotrectinib dose
Safety Issue:
Description:Define the dose limiting toxicities (DLTs) (Phase 1)

Secondary Outcome Measures

Measure:Maximum plasma concentration (CMAX) of repotrectinib (TPX-0005) (Phase 1)
Time Frame:Up to 72 hours post dose
Safety Issue:
Description:To determine the maximum plasma concentration (CMAX) of repotrectinib (TPX-0005)
Measure:Area under the plasma concentration time curve (AUC) of repotrectinib (TPX-0005) (Phase 1)
Time Frame:Up to 72 hours post dose
Safety Issue:
Description:To determine the area under the plasma concentration time curve (AUC) of repotrectinib
Measure:Area under the plasma concentration time curve (AUC) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
Time Frame:Up to 72 hours post dose
Safety Issue:
Description:To determine the area under the plasma concentration time curve (AUC) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
Measure:Maximum plasma concentration (CMAX) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
Time Frame:Up to 72 hours post dose
Safety Issue:
Description:To determine the maximum plasma concentration (CMAX) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1)
Measure:Area under the plasma concentration time curve (AUC) of midazolam(TPX-0005) (Phase 1)
Time Frame:Up to 24 hours post dose
Safety Issue:
Description:To determine the area under the plasma concentration time curve (AUC) of midazolam(TPX-0005) (Phase 1)
Measure:Maximum plasma concentration (CMAX) of midazolam(TPX-0005) (Phase 1)
Time Frame:Up to 24 hours post dose
Safety Issue:
Description:To determine the maximum plasma concentration (CMAX) of midazolam(TPX-0005) (Phase 1)
Measure:Plasma concentration of repotrectinib following administration at RP2D (Phase 2)
Time Frame:Pre dose and 4 hours post dose
Safety Issue:
Description:To evaluate the plasma concentration of repotrectinib following administration at RP2D (Phase 2)
Measure:Preliminary objective response rate (ORR) (Phase 1)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the preliminary objective response rate (ORR) by Blinded Independent Central Review (BICR) (Phase 1)
Measure:Duration of response (DOR) (Phase 2)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the DOR of repotrectinib (TPX-0005) (Phase 2)
Measure:Clinical benefit rate (CBR) (Phase 2)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the CBR of repotrectinib (TPX-0005) (Phase 2)
Measure:Progression free survival (PFS) (Phase 2)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the PFS (Phase 2)
Measure:Overall survival (OS) (Phase 2)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the OS (Phase 2)
Measure:Intracranial objective response rate (Phase 2)
Time Frame:Approximately three years
Safety Issue:
Description:To determine the intracranial objective response rate (Phase 2)

Details

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

Trial Keywords

  • ALK
  • ROS1
  • NTRK
  • Sarcoma
  • Lung Neoplasms
  • Carcinoma, NSCL
  • NSCLC
  • Non Small Cell Lung
  • Thyroid Disease
  • Colonic Neoplasms
  • Thyroid Neoplasms
  • Carcinoma, Neuroendocrine
  • Respiratory Tract Neoplasms
  • Thoracic Neoplasms
  • Neoplasms by Site
  • Neoplasms
  • Lung Disease
  • Respiratory Tract Disease
  • Carcinoma, Bronchogenic
  • Bronchial Neoplasms
  • Endocrine System Disease
  • Colorectol Neoplasms
  • Intestinal Neoplasms
  • Gastrointestinal Neoplasms
  • Digestive System Neoplasms
  • Gastrointestinal Disease
  • Colonic Disease
  • Intestinal Disease
  • Endocrine Gland Neoplasms
  • Head and Neck Neoplasms
  • Neuroendocrine Tumors
  • Neuroectodermal Tumors
  • Neoplasms, Germ Cell and Embryonal
  • Neoplasms by Histologic Type
  • Adenocarcinoma
  • Non Small Cell Lung Cancer
  • Solid Tumors
  • Rearrangements
  • TRIDENT-1
  • TKI
  • TKI naive
  • TKI pretreated
  • Anti-tumor activity
  • Repotrectinib
  • Advanced Solid Malignancies

Last Updated

February 1, 2021