Phase 1/2 Open Label solid tumour Safety and Tolerability study in Pediatric and Young Adult subjects.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Turning Point Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Jun 2023 → ongoing

Decision date (initial)

2024-02-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-506464-14-00

EudraCT number

2019-003055-11

ClinicalTrials.gov

NCT04094610

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy, Pharmacodynamic

Phase 2 Study
• Determine the antitumor activity of repotrectinib in pediatric and
young adult subjects with advanced or metastatic malignancies
harboring ROS1 or NTRK1-3 alterations.

Secondary objectives 4

1. Determine the antitumor activity in terms of DOR, overall survival (OS) and progression-free survival (PFS) following treatment with repotrectinib
2. Determine intracranial antitumor activity of repotrectinib
3. Evaluate the safety and tolerability of repotrectinib at the pediatric RP2D
4. Characterize the PK of repotrectinib at the pediatric RP2D

Conditions and MedDRA coding

Advanced solid tumors

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002635-PIP02-21

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. For Phase 2: EU will not enroll subjects in Cohort 1. Cohort 2: Subjects with NTRK+ advanced solid tumors (including primary CNS tumors), TRK TKI-pretreated. Nonresponse, disease progression or intolerability to at least 1 but no more than 2 prior TRK TKIs. Any prior lines are allowed. Subjects must have prospectively confirmed measurable disease by BICR prior to enrollment. Cohort 3: the EU: (1) will only enroll subjects with ROS1 gene fusions. •Documented genetic ROS1 or NTRK1-3 alteration as identified by local testing in a CLIA laboratory in the US or equivalent. •For subjects enrolled per tissue-based test, adequate tumor tissue should be sent prior to enrollment to the central lab. If archived tumor tissue is not available, a fresh biopsy should be obtained. For subjects enrolled by liquid biopsy test; blood samples should be sent prior to enrollment to the central lab.
2. The subject, parent or guardian must voluntarily sign and date an informed consent approved (in addition to pediatric assent, if required) by an IEC, prior to the initiation of any study specific procedures.
3. Age:  Phase 1: Age < 12 years (age at Cycle 1 Day 1)  Phase 2: Up to age 25 years (age at Cycle 1 Day 1). While the Phase 1 dose escalation is ongoing, subjects 12 years of age and above may be enrolled directly in the Phase 2 part of the study. Subjects age < 12 years of age will be enrolled in the Phase 2 part after determination of the pediatric RP2D in Phase 1.
4. Ability to comply with outpatient visits, laboratory testing, and study procedures during study participation.
5. Subjects must have recovered from the acute toxic effects of all previous therapies prior to study enrollment to CTCAE v4.03 criteria ≤ grade 1, with the exception of alopecia. Subjects must not have received the therapies indicated below for the specified time period: •Chemotherapy: Last dose given at least 14 days or 5 half-lives (whichever is shorter) before the start date for repotrectinib. •Monoclonal antibodies (not including IO therapeutic antibodies): Last dose given at least 21 days prior to the start date for repotrectinib. •Immunotherapy (eg, IO therapeutic antibodies or tumor vaccine): Subject is eligible after 28 days of completion prior to first dose of repotrectinib. Steroids are not considered immunotherapy. •Radiation therapy: Subjects must not have received radiation for a minimum of 2 weeks prior to study enrollment. If extensive bone marrow radiation, at least 42 days must have elapsed. •HSCT: Subjects are eligible 12 weeks after infusion following myeloablative therapy (timed from first day of repotrectinib). Subjects who have received an infusion to support nonmyeloablative therapy (such as 131I MIBG) are eligible at any time as long as they meet the other criteria. •131I-MIBG therapy: A minimum of 6 weeks must have elapsed after 131I-MIBG therapy prior to start of repotrectinib. •Growth factors: Subjects are eligible 14 days after last dose of longacting growth factor or 7 days after short-acting growth factor. •Any investigational agent or anticancer therapy other than chemotherapy and not otherwise noted: At least 14 days or 5 half-lives (whichever is shorter) must have elapsed prior to the planned start of repotrectinib treatment. •Any prior treatment with a TKI of ROS1 or NTRK does NOT exclude subject from study.
6. All subjects must have measurable disease by RECIST v1.1 or RANO criteria at time of enrollment. For Phase 2 subjects in Cohort 2 must have prospectively confirmed measurable disease by BICR prior to enrollment. •Exception: Neuroblastoma subjects are permitted to have evaluable disease only.
7. Subjects with Primary CNS Tumors or metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 7 days prior to enrollment.
8. Subjects must have a Lansky (<16 years) or Karnofsky (≥16 years) score ≥50. Subjects who are unable to walk because of paralysis or tumor pain, but who are upright in a wheelchair, will be considered ambulatory for the performance status.
9. Life expectancy ≥12 weeks.
10. Screening Local laboratory values: ANC≥1.5 × 109/L, ≥0.75 × 109L, if known bone marrow involvement PLT ≥100 × 109/L independent of platelets transfusion support for at least 7 days prior to dosing, ≥50 × 109/L, if known bone marrow involvement Hemoglobin≥ 8.0 g/dL independent of red blood cell transfusion support for at least 7 days prior to dosing, unless bone marrow involvement identified at enrollment Serum creatinine or creatinine clearance* Within normal limits per age or creatinine clearance or nuclear GFR>40 mL/min Total serum bilirubin < 1.5 × ULN AST/ALT<2.5 × ULN; <5 × ULN if liver metastases are present 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. •Serum Creatinine by Age Age < 6 years - Maximum Serum Creatinine (mg/dL) – Male: 0,8 - Female: 0,8 / Maximum Serum Creatinine (μmol/L) – Male: 71 Female: 71 Age 6 to < 10 years - Maximum Serum Creatinine (mg/dL) – Male: 1 - Female: 1 / Maximum Serum Creatinine (μmol/L) – Male: 88 - Female: 88 Age 10 to < 13 years - Maximum Serum Creatinine (mg/dL) – Male: 1.2 - Female: 1.2 / Maximum Serum Creatinine (μmol/L) – Male: 106 - Female: 106 Age 13 to < 16 years - Maximum Serum Creatinine (mg/dL) – Male: 1,5 - Female: 1,4 / Maximum Serum Creatinine (μmol/L) – Male: 132 - Female: 124 Age ≥ 16 years - Maximum Serum Creatinine (mg/dL) – Male: 1,7 - Female: 1,4 / Maximum Serum Creatinine (μmol/L) – Male: 150 - Female: 124
11. Reproductive Status: For female and male participants, see Protocol Section 5.1 for the full list of criteria.

Exclusion criteria 11

1. Concurrent participation in another therapeutic clinical trial.
2. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only.
3. Major surgery within 14 days (2 weeks) prior to Cycle 1 Day 1. Central venous access (Broviac, Mediport, etc.) placement does not meet criteria for major surgery.
4. Subjects who are pregnant or breast feeding.
5. Subjects with known active infections requiring ongoing treatment (bacterial, fungal, or viral, including HIV).
6. Subjects with gastrointestinal disease (eg, Crohn's disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
7. Any of the following cardiac criteria: • Mean resting corrected QT interval (electrocardiogram [ECG] interval measured from the onset of the QRS complex to the end of the T wave) for heart rate > 480 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 (eg, 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 (Appendix 5)
8. Subjects with peripheral neuropathy with CTCAE grade ≥ 2.
9. Subjects with other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that, per the judgement of the Investigator or Sponsor, may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of study results, or make the subject inappropriate for entry into the study, or could compromise protocol objectives.
10. Subjects being treated with or anticipating the need for treatment with strong cytochrome P450 (CYP)3A4 inhibitors or inducers as listed in Appendix 4.
11. Any potential allergies to repotrectinib and/or its excipients

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ORR as determined by BICR

Secondary endpoints 6

1. DOR, TTR and CBR
2. Intracranial tumor response
3. Central nervous system (CNS) progression-free survival (CNS-PFS) in subjects with measurable brain metastases
4. PFS and OS
5. PK parameters
6. Type, incidence, severity, timing, seriousness, and relatedness of AEs and laboratory abnormalities

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Turning Point Therapeutics Inc.

Sponsor organisation

Turning Point Therapeutics Inc.

Address

Route 206 And Province Line Road

City

Princeton

Postcode

08543

Country

United States

Scientific contact point

Organisation

Turning Point Therapeutics Inc.

Contact name

GSM-CT

Public contact point

Organisation

Turning Point Therapeutics Inc.

Contact name

GSM-CT

Third parties 2

Locations

4 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 64 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

13 submissions — initial application plus substantial / non-substantial modifications