"A study to learn how well the drug larotrectinib works in adults with different solid cancers with a change in the genes called NTRK fusion"

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Bayer Consumer Care AG, Bayer AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Jun 2016 → 30 Sep 2025

Decision date (initial)

2024-01-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Bayer Consumer Care AG, Peter-MerianStrasse 84, 4052 Basel, Switzerland · Bayer HealthCare Pharmaceuticals Inc.,100 Bayer Boulevard, P.O. Box 915,Whippany, NJ 07981-0915,USA

External identifiers

EU CT number

2022-502667-38-00

EudraCT number

2015-003582-28

ClinicalTrials.gov

NCT02576431

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Pharmacogenetic, Pharmacogenomic, Efficacy, Therapy

To determine the overall response rate (ORR) as determined by an independent radiology review committee and measured by the proportion of subjects with best overall confirmed response of complete response (CR) or partial response (PR) by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) or Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate, following treatment with larotrectinib in subjects with an advanced cancer harboring a fusion involving NTRK1, NTRK2, or NTRK3 (collective referred to as NTRK fusions).

Secondary objectives 9

1. To determine the ORR based on the treating Investigator’s response assessment using RECIST v1.1 or RANO criteria, as appropriate to tumor type.
2. To evaluate the DOR in subjects with best overall response of CR or PR as determined by 1) an independent radiology review committee and 2) the treating Investigator.
3. To estimate the proportion of subjects that has any tumor regression as a best response.
4. To evaluate the duration of progression-free survival (PFS) following initiation of larotrectinib.
5. To evaluate the duration of overall survival (OS) following initiation of larotrectinib.
6. To assess the safety profile and tolerability of larotrectinib.
7. To compare the duration of PFS following initiation of larotrectinib to that following the line of therapy immediately preceding larotrectinib in subjects who have received prior therapy.
8. To evaluate the clinical benefit rate (CBR) based on the proportion of subjects with best overall response of CR, PR, or stable disease lasting 16 or more weeks following initiation of larotrectinib.
9. To evaluate the concordance of prior molecular profiling that detected an NTRK fusion within the subject’s tumor with the diagnostic test being evaluated by the Sponsor.

Conditions and MedDRA coding

Solid tumors harboring NTRK fusion

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, National Agency For The Safety Of Medicine And Health Products, Swedish Medical Products Agency

EMA paediatric investigation plan (PIP)

EMEA-001971-PIP03-18, EMEA-001971-PIP02-16

Plan to share IPD

No

IPD plan description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion, identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) or other similarly-certified laboratories. Subjects who have an NTRK gene fusion identified in a lab where CLIA or equivalent certification cannot be confirmed by the Sponsor at the time of consent may have been enrolled in Cohort 9 as per protocol versions 1.0 - 8.0. From protocol version 9.0: CLIA or similar certification of the lab performing the fusion assay is required. However, patients may be included after discussion with the sponsor if the lab performing the fusion assay is not CLIA or similar certified.
2. Subjects who have received prior standard therapy appropriate for their tumor type and stage of disease, or who have no satisfactory alternative treatments and in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.
3. "Subjects must have at least one measurable lesion as defined by RECIST v1.1 (Eisenhauer et al. 2009). Subjects with solid tumors without RECIST v1.1 measurable disease (e.g., evaluable disease only) had been eligible for enrollment to Cohort 8 as per protocol versions 1.0 - 8.0, regardless of tumor type. Subjects with primary central nervous system (CNS) tumors should meet the following criteria: a. Have received prior treatment including radiation and/or chemotherapy, with radiation completed > 12 weeks prior to C1D1 of therapy, as recommended or appropriate for that CNS tumor type. b. Have ≥ 1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions ≥ 1 cm in each dimension and noted on more than one imaging slice. c. Imaging study performed within 28 days before enrollment. If on steroid therapy, the dose must be stable for at least 7 days immediately before and during the imaging study. d. Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment. For subjects eligible for enrollment to bone health cohort, inclusion criterion 3 is modified as the following: e. Subjects must have at least one lesion at baseline (measurable or non-measurable as defined by RECIST v1.1 or RANO criteria, as appropriate to tumor type). f. Subjects with primary CNS tumors must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment."
4. At least 18 years of age
5. Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 3. If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky Performance Score (KPS) ≥ 50%.
6. Tumor tissue before treatment (mandatory). If neither fresh tissue can be obtained nor archival tissue is available patients might be enrolled after consultation with the sponsor.
7. "Adequate organ function as defined by the following criteria: a. Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN), or AST and ALT < 5 x ULN if liver function abnormalities are due to underlying malignancy b. Total bilirubin < 2.5 x ULN, except in the setting of biliary obstruction. Subjects with a known history of Gilberts Disease and an isolated elevation of indirect bilirubin are eligible c. Serum creatinine < 2.0 x ULN OR an estimated glomerular filtration rate ≥ 30 mL/minute using the Cockcroft-Gault formula: (140- age) x body weight (kg) x 0.85 (if female)/serum creatinine (mg/dL) x 72 with either result acceptable for enrollment."
8. Ability to comply (or for guardian to ensure compliance) with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
9. Willingness of men and women of reproductive potential to use double effective birth control methods, defined as one used by the subject and another by his/her partner, for the duration of treatment and for 1 month following study completion.
10. Capable of giving signed informed consent as described in protocol which includes compliance with the requirements, restrictions listed in the informed consent form (ICF), and in this protocol.
11. " For subjects eligible for enrollment to bone health cohort only: life expectancy of at least 6 months, based on investigator assessment."

Exclusion criteria 10

1. Investigational agent or anticancer therapy within 2 weeks prior to the planned start of larotrectinib or 5 half-lives, whichever is shorter, and without recovery of acute and/or clinically significant toxicities from that therapy.
2. Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting tropomyosin receptor kinase (TRK). Subjects who received less than 28 days of treatment and discontinued because of intolerance or toxicity are eligible.
3. Symptomatic or unstable brain metastases. (Note: Subjects with asymptomatic brain metastases are eligible to participate in the study.) Subjects with primary CNS tumors are eligible.
4. Uncontrolled concurrent malignancy that would limit assessment of efficacy of larotrectinib. Allowed conditions may include, but are not limited to in situ cancers of cervix, breast, or skin, superficial bladder cancer, limited-stage prostate cancer, and basal or squamous cancers of the skin.
5. "Active uncontrolled systemic bacterial, viral, or fungal infection Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2; unstable cardiovascular disease, or other systemic disease that would limit compliance with study procedures. Unstable cardiovascular disease is defined as: a. In adults, persistently uncontrolled hypertension defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic BP > 100 mmHg despite antihypertensive therapy. b. Myocardial infarction within 3 months of screening. c. Stroke within 3 months of screening."
6. Inability to discontinue treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducer
7. Currently recovering from AEs/ ADRs due to previous treatments (excluding alopecia). Inclusion is only advised once the AE/ADR resolves or recovers to baseline or at least to CTCAE grade 1.
8. Known or suspected hypersensitivity against the active substance or any of the ingredients of the Investigational Medicinal Product (IMP).
9. Known history of Human immunodeficiency virus (HIV) infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.
10. Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Best overall response of confirmed complete response (CR) or partial response (PR) as determined by an independent radiology review committee using RECIST v1.1 or RANO criteria, as appropriate to tumor type.

Secondary endpoints 10

1. Best overall response of confirmed CR or PR as determined by the treating Investigator using RECIST v1.1 or RANO criteria, as appropriate to tumor type
2. Duration of response (DOR): determined for subjects with best overall response of confirmed CR or PR by 1) an independent radiology review committee and 2) the treating Investigator
3. Clinical benefit rate (CBR): best overall response of confirmed CR, PR, or stable disease lasting 16 or more weeks following the initiation of Larotrectinib
4. Rate of subjects that have any tumor regression as a best response, measured as shrinkage of target lesions
5. Progression-free survival (PFS)
6. Overall survival (OS)
7. Comparison of PFS following initiation of Larotrectinib to that following the line of therapy immediately preceding Larotrectinib in each subject who has received prior therapy
8. Number of subjects with AEs categorized by severity. (including all, serious, and those considered treatment related.)
9. Changes from baseline in clinical safety laboratory values and vital signs
10. The concordance of prior molecular profiling that detected NTRK fusion within the subject’s tumor with the diagnostic test being evaluated by the sponsor

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Bayer Consumer Care AG

Sponsor organisation

Bayer Consumer Care AG

Address

Peter Merian-Strasse 84

City

Basel

Postcode

4052

Country

Switzerland

Scientific contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Public contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Third parties 15

Bayer AG

Sponsor organisation

Bayer AG

Address

Kaiser-Wilhelm-Allee 1, Wiesdorf Wiesdorf

City

Leverkusen

Postcode

51373

Country

Germany

Scientific contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Public contact point

Organisation

Bayer AG

Contact name

Therapeutic Area Head

Sponsor responsibilities

Article 77 compliance

Bayer Consumer Care AG

Article 77 implementation

Bayer Consumer Care AG

Locations

6 EU/EEA countries · 14 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 34 files

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

Application history

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