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

PHASE1PHASE2RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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.

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. 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.

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

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

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.

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.

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.

Subjects 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 > 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.

Exclusion criteria

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 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.

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Eligibility

Age eligible for study : 12 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2017-03-07

Primary completion: 2028-02-29

Study completion finish: 2028-02-29

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT03093116

Intervention or treatment

DRUG: Oral repotrectinib (TPX-0005)

Conditions

• Locally Advanced Solid Tumors
• Metastatic Solid Tumors

Image related to Locally Advanced Solid Tumors

Condition: Locally Advanced Solid Tumors, Metastatic Solid Tumors
DRUG: Oral repotrectinib (TPX-0005)
Camperdown, New South Wales, Australia and more
Sponsor: Turning Point Therapeutics, Inc.

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Find a site

Closest Location:

Local Institution - 6102

Research sites nearby

Select from list below to view details:

Local Institution - 6102
Camperdown, New South Wales, Australia
Local Institution - 6103
Adelaide, South Australia, Australia
Local Institution - 6101
Melbourne, Victoria, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
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 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	DRUG: Oral repotrectinib (TPX-0005) Oral repotrectinib (TPX-0005) capsules.

Participant Group/Arm

Intervention/Treatment

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 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

DRUG: Oral repotrectinib (TPX-0005)

Oral repotrectinib (TPX-0005) capsules.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Dose limiting toxicities (DLTs) (Phase 1)	Define the dose limiting toxicities (DLTs) (Phase 1)	Within 28 days of the first repotrectinib dose
Recommended Phase 2 Dose (RP2D) (Phase 1)	To determine the RP2D (Phase 1)	Within 28 days of the last patient dosed in escalation
Overall Response Rate (ORR) Phase 2	To determine the confirmed ORR of repotrectinib (TPX-0005) as assessed by Blinded Independent Central Review (Phase 2)	Two to three years after first dose of repotrectinib dose

Secondary outcome

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

Frequently Asked Questions

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References

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