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

  • STATUS
    Recruiting
  • End date
    Dec 5, 2022
  • participants needed
    450
  • sponsor
    Turning Point Therapeutics, Inc.
Updated on 5 February 2021
Investigator
TP Therapeutics, Inc.
Primary Contact
Prince of Wales Hospital PHASE 2 (0.0 mi away) Contact
+131 other location
cancer
ROS1
solid tumor

Summary

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.

Description

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

  • EXP-1: ROS1 TKI-nave 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-nave 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.

Details
Condition Lymphoma, Non-Hodgkin's Lymphoma, Locally Advanced Solid Tumors, Metastatic Solid Tumors
Treatment Oral TPX-0005, Oral repotrectinib (TPX-0005)
Clinical Study IdentifierNCT03093116
SponsorTurning Point Therapeutics, Inc.
Last Modified on5 February 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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
ECOG PS 0-1
Age 18 (or age 20 of age as required by local regulation)
Capability to swallow capsules intact (without chewing, crushing, or opening)
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
Prior cytotoxic chemotherapy is allowed
Prior immunotherapy is allowed
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
Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria
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
Life expectancy 3 months
PHASE 2 Key Inclusion Criteria
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
Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either
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
\. 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

Exclusion Criteria

ROS1 TKI-nave 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-nave 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
Concurrent participation in another therapeutic clinical trial
Symptomatic brain metastases or leptomeningeal involvement
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
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
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
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
\. Known active infections (bacterial, fungal, viral including HIV
positivity)
\. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or
short gut syndrome) or other malabsorption syndromes that would impact drug
absorption
\. Peripheral neuropathy of CTCAE grade 2
\. History of extensive, disseminated, bilateral, or presence of CTCAE grade
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
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