Study of Tumor Alterations Responsive to Targeting Receptor Kinases-2

Overview

Sponsor-declared trial summary

Key facts

Sponsor

F. Hoffmann-La Roche AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Aug 2016 → ongoing

Decision date (initial)

2024-06-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

F. Hoffmann-La Roche Ltd

External identifiers

EU CT number

2023-505034-10-00

EudraCT number

2015-003385-84

ClinicalTrials.gov

NCT02568267

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Pharmacokinetic

To determine the objective response rate of entrectinib, as assessed by BICR, in each patient population basket of solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement

Secondary objectives 7

1. To determine the duration of response, time to response, and clinical benefit rate of entrectinib, in each patient population basket of solid tumors
2. To determine the intracranial tumor response of entrectinib and CNS progression-free survival (CNS-PFS) in patients presenting with measurable CNS disease at baseline, as assessed by BICR using RECIST v1.1 or RANO for primary CNS tumors as applicable
3. To estimate the progression-free survival and overall survival of patients with solid tumors treated with entrectinib
4. To evaluate the safety and tolerability of entrectinib when administered at the RP2D
5. To assess the population pharmacokinetics (PK) of Entrectinib and to explore correlations between PK, response, and/or safety findings
6. To evaluate the effect of entrectinib on ventricular repolarization
7. To assess treatment-related symptoms and general health status using validated instruments of patient reported outcomes.

Conditions and MedDRA coding

Locally Advanced or Metastatic Solid Tumors that Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement that is predicted to translate into a fusion protein with a functional TrkA/B/C, ROS1, or ALK kinase domain, respectively, without a concomitant second oncodriver (e.g., EGFR, KRAS), as determined by Foundation Medicine, Inc. or by any nucleic acid-based diagnostic testing method (please refer to Section 5.1) performed at a local CLIA-certified or equivalently-accredited diagnostic laboratory. These are patients for whom no alternative effective standard therapy is available or for whom standard therapy is considered unsuitable or intolerable. Note: Patients diagnosed with anaplastic large cell lymphoma (ALCL) harboring a gene rearrangement of interest are no longer eligible.
2. For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Foundation Medicine, Inc. 1. or to the alternative, approved central laboratory for that region.
3. Measurable disease as assessed locally using RECIST v1.1. Note: Patients with non-measurable disease (evaluable disease only) will be eligible for enrollment in the "non-evaluable for the primary endpoint" basket and will mainly contribute to assessment of safety, PK, and other secondary endpoints.
4. Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previouslytreated and controlled, are allowed. The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme-inducing anti-epileptic drugs (non-EIAEDs).
5. Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK (non-NSCLC patients only) inhibitors in patients who have tumors that harbor those respective gene rearrangements). Note: The ALK basket is closed to enrolment.
6. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy, respectively, at the time of the start of entrectinib treatment. Note: For targeted therapies, there must be no signs of disease flare or accelerated disease progression after treatment discontinuation.
7. At least 4 weeks must have elapsed since completion of antibody-directed therapy at the time of the start of Entrectinib treatment.
8. Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment.
9. Age ≥ 18 years
10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and minimum life expectancy of at least 4 weeks.
11. Adequate liver function as defined by the following criteria: -Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase (SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase (SGPT)) ≤ 3.0 × upper limit of normal (ULN); ≤ 5.0 × ULN if liver metastases are present -Total serum bilirubin ≤ 2.0 × ULN; patients with a known history of Gilbert's syndrome and/or isolated elevations of indirect bilirubin are eligible
12. Women patients of childbearing potential: • Must have a negative serum pregnancy test during screening and must not be breastfeeding or intending to become pregnant during the study • Must agree to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year prior to entering into the study and for 5 weeks following the last dose of study drug • Allowance for locally recognized adequate methods of contraception • Must agree to refrain from donating eggs during the same period -Oral contraceptives and intrauterine hormone releasing systems (IUSs) used by female patients must be combined with a barrier method. Male patients with female partners of childbearing potential: • Must agree to use highly effective contraception during the study and for 3 months following the last dose of study drug. • Requirement for male patients to abstain from donating sperm during the study and for 3 months after study.
13. Ability to swallow entrectinib intact without chewing, crushing, or opening the capsules. Please refer to the Section 5.2.2 of the Protocol for the complete list of the Inclusion criteria

Exclusion criteria 14

1. Current participation in another therapeutic clinical trial.
2. Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements. Note: In cases where the patient was intolerant to prior Trk, ROS1, or ALK inhibitors, please discuss with the Sponsor. In addition, prior treatment with crizotinib is permitted ONLY in ALK- or ROS1-rearranged NSCLC patients presenting with CNS-only progression. Other ALK or ROS1 inhibitors are prohibited in that scenario.
3. History of other previous cancer that would interfere with the determination of safety or efficacy of entrectinib with respect to the qualifying solid tumor malignancy. Note: Patients presenting with dual primary cancers may enroll in the "non-evaluable for the primary endpoint" basket if at least one of the cancers harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement as per Inclusion Criterion 1.
4. Familial or personal history of congenital bone disorders or bone metabolism alterations
5. Incomplete recovery from any surgery prior to the start of entrectinib treatment that would interfere with the determination of safety or efficacy of entrectinib.
6. Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of entrectinib: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication.
7. History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction 50% observed during screening for the study
8. History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 450 milliseconds from ECGs performed at least 24 hours apart).
9. History of additional risk factors for torsades de pointes (e.g., family history of long QT syndrome).
10. Peripheral sensory neuropathy Grade ≥ 2.
11. Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral) with the exceptions of human Immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections, as noted below: – HIV positivity, only if patients meet any of the following criteria: Patients with a CD4+ T-cell count of <350 cells/μL Patients with a detectable HIV viral load Patients with a history of an opportunistic infection within the past 12 months Patients who are on stable antiretroviral therapy for < 4 weeks – Active HBV infection (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test), with the following exception: Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) if they are negative for HBV DNA – HCV antibody (HCV Ab) positivity, with the following exceptions: Patients who are HCV Ab-positive but HCV RNA-negative due to prior treatment or natural resolution are eligible Patients with untreated HCV if the HCV is stable, the patient is not at risk for hepatic decompensation, and the intended treatment is not expected to exacerbate the HCV infection Patients on concurrent HCV treatment if they have HCV below the limit of quantification
12. Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.
13. Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis. Note: Radiation-induced lung disorders are not included in this exclusion criterion.
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Objective Response Rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR)

Secondary endpoints 12

1. Duration of Response (DOR)
2. Time to Response (TTR)
3. Clinical Benefit Rate (CBR)
4. Intracranial tumor response in patients with measurable brain metastases, as determined by BICR using RANO or RANO-BM as applicable
5. CNS Progression-Free Survival (CNS-PFS) in patients with measurable CNS disease,
6. Progression-Free Survival (PFS)
7. Overall Survival (OS)
8. Type, incidence, severity, timing, seriousness, and relatedness of adverse events and laboratory abnormalities
9. Population PK
10. Ventricular repolarization
11. Quality-of-life and health status to examine biological markers of bone formation and resorption and markers of calcium metabolism
12. Assessment of bone mineral density (BMD) via dual X-ray absorptiometry (DXA) scans

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

F. Hoffmann-La Roche AG

Sponsor organisation

F. Hoffmann-La Roche AG

Address

Grenzacherstrasse 124

City

Basel

Postcode

4058

Country

Switzerland

Scientific contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information Support Line-TISL

Public contact point

Organisation

F. Hoffmann-La Roche AG

Contact name

Trial Information Support Line-TISL

Third parties 3

Locations

6 EU/EEA countries · 26 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 52 files

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

Application history

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