Clinical Trial - NCT03093116

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

Recruiting

Sponsor: Turning Point Therapeutics, Inc.

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03093116

Protocol Info

Short Description: Phase 1/2 TPX-0005 in Solid Tumors with ALK, ROS1, OR NTRK1-3
Long Description: 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)
MGH Status: Open
Sponsor: TP Therapeutics
Disease Program: Thoracic

Next Steps


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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 an ALK, 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 an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Condition Title Intervention Phase
Locally Advanced Solid Tumors Metastatic Solid Tumors Oral repotrectinib (TPX-0005) Phase 1/Phase 2
Study Type Interventional
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)

Primary Outcome Measures

Dose limiting toxicities (DLTs) (Phase 1) [Time Frame: Within 28 days of the first repotrectinib dose] [Designated as safety issue: ]

Recommended Phase 2 Dose (RP2D) (Phase 1) [Time Frame: Within 28 days of the last patient dosed in escalation] [Designated as safety issue: ]

Overall Response Rate (ORR) Phase 2 [Time Frame: Two to three years after first dose of repotrectinib dose] [Designated as safety issue: ]


Secondary Outcome Measures

Maximum plasma concentration (CMAX) of repotrectinib (TPX-0005) (Phase 1) [Time Frame: Up to 72 hours post dose] [Designated as safety issue: ]

Area under the plasma concentration time curve (AUC) of repotrectinib (TPX-0005) (Phase 1) [Time Frame: Up to 72 hours post dose] [Designated as safety issue: ]

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] [Designated as safety issue: ]

Maximum plasma concentration (CMAX) of repotrectinib under different food intake conditions(TPX-0005) (Phase 1) [Time Frame: Up to 72 hours post dose] [Designated as safety issue: ]

Area under the plasma concentration time curve (AUC) of midazolam(TPX-0005) (Phase 1) [Time Frame: Up to 24 hours post dose] [Designated as safety issue: ]

Maximum plasma concentration (CMAX) of midazolam(TPX-0005) (Phase 1) [Time Frame: Up to 24 hours post dose] [Designated as safety issue: ]

Plasma concentration of repotrectinib following administration at RP2D (Phase 2) [Time Frame: Pre dose and 4 hours post dose] [Designated as safety issue: ]

Preliminary objective response rate (ORR) (Phase 1) [Time Frame: Approximately three years] [Designated as safety issue: ]

Duration of response (DOR) (Phase 2) [Time Frame: Approximately three years] [Designated as safety issue: ]

Clinical benefit rate (CBR) (Phase 2) [Time Frame: Approximately three years] [Designated as safety issue: ]

Progression free survival (PFS) (Phase 2) [Time Frame: Approximately three years] [Designated as safety issue: ]

Overall survival (OS) (Phase 2) [Time Frame: Approximately three years] [Designated as safety issue: ]

Intracranial objective response rate (Phase 2) [Time Frame: Approximately three years] [Designated as safety issue: ]

Estimated Enrollment: 450
Study Start Date: February 2017
Estimated Study Completion Date: December 2022
Estimated Primary Completion Date: March 2021
Arms Assigned Interventions

Experimental:Repotrectinib (TPX-0005)

Phase 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 ROS1+ NSCLC EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC EXP-4: ROS1 or ALK TKI-naïve ROS1+ or ALK+ solid tumors (non-NSCLC) EXP-5: TRK TKI-naïve NTRK+ solid tumors EXP-6: TRK TKI-pretreated NTRK+ solid tumors
Drug:Oral repotrectinib (TPX-0005)
Oral repotrectinib (TPX-0005) capsules.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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, ALK or NTRK1-3 gene fusion.

2. Subjects must have a documented ROS1, ALK or NTRK1-3 gene fusion that has been identified by local testing AND that has been prospectively confirmed by a central diagnostic laboratory selected by the Sponsor to determine molecular eligibility 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 ALK, 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 ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC iv. EXP-4: ROS1 or ALK TKI-naïve ROS1+ or ALK+ solid tumors (non-NSCLC) 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 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

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03093116

Locations

  • United States, California
    • Adventist Health Glendale PHASE 2 Glendale, California, United States, 91206
    • Pacific Shores Oncology PHASE 2 Long Beach, California, United States, 90813
    • UC Irvine Health, Chao Family Comprehensive Cancer Center PHASE 1 (recruiting) & PHASE 2 (not yet recruiting) Orange, California, United States, 92868
    • UC San Diego Moores Cancer Center PHASE 2 San Diego, California, United States, 92093
  • United States, Colorado
    • University of Colorado Denver PHASE 1 (recruiting) & PHASE 2 (not yet recruiting) Aurora, Colorado, United States, 80045
  • United States, District of Columbia
    • Georgetown Lombardi Comprehensive Cancer Center PHASE 2 Washington, District of Columbia, United States, 20007
    • Johns Hopkins Kimmel Cancer Center PHASE 2 Washington, District of Columbia, United States, 20016
  • United States, Florida
    • Moffit Cancer Center PHASE 2 Tampa, Florida, United States, 33612
  • United States, Louisiana
    • Ochsner Medical Center PHASE2 New Orleans, Louisiana, United States, 70121
  • United States, Massachusetts
    • Massachusetts General Hospital PHASE 1 (recruiting) & PHASE 2 (not yet recruiting) Boston, Massachusetts, United States, 02114
  • United States, Michigan
    • University of Michigan Rogel Cancer Center PHASE 2 Ann Arbor, Michigan, United States, 48109
    • Karmanos Cancer Institute PHASE 2 Detroit, Michigan, United States, 48201
  • United States, Missouri
    • Washington University Siteman Cancer Center PHASE 2 Saint Louis, Missouri, United States, 63110
  • United States, New York
    • NYU Langone Health PHASE 2 New York, New York, United States, 10016
    • Memorial Sloan Kettering Cancer Center PHASE 1 (recruiting) & PHASE 2 (Recruiting) New York, New York, United States, 10065
  • United States, Ohio
    • Gabrail Cancer Center PHASE 2 Canton, Ohio, United States, 44718
    • Cleveland Clinic PHASE 2 Cleveland, Ohio, United States, 44195
    • University of Toledo PHASE 2 Toledo, Ohio, United States, 22031
  • United States, Pennsylvania
    • Fox Chase Cancer Center PHASE 2 Philadelphia, Pennsylvania, United States, 19111
  • United States, Washington
    • UW Seattle Cancer Care Alliance PHASE 2 Seattle, Washington, United States, 98109
  • Korea, Republic of,
    • Seoul National University Hospital PHASE 1 (recruiting) and PHASE 2 (not yet recruiting) Seoul, , Korea, Republic of, 110-744
    • Yonsei Cancer Center, Severance Hospital PHASE 1 (recruiting) & PHASE 2 (not yet recruiting) Seoul, , Korea, Republic of, 120-752
    • Samsung Medical Center PHASE 1 (recruiting) & PHASE 2 (not yet recruiting) Seoul, , Korea, Republic of, 135-710

Sponsors and Collaborators

Turning Point Therapeutics, Inc.

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03093116
Other Study ID Numbers:
Study First Received:
Last Updated:
Health Authority:

Keywords provided by Turning Point Therapeutics, Inc.:

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

Additional relevant MeSH terms:

Neoplasms

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on August 15, 2019