| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the overall response rate (ORR) as determined by an independant 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). |
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| E.2.2 | Secondary objectives of the trial |
• To determine the ORR using RECIST1.1 or RANO criteria
• To evaluate the DOR in subjects with best overall response of CR or PR
• To estimate the proportion of subjects that has any tumor regression as a best response
• To evaluate the duration of progression-free survival (PFS) following initiation of Larotrectinib
• To evaluate the duration of OS following initiation of Larotrectinib
• To assess the safety profile and tolerability of Larotrectinib
• 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
• To evaluate the 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
• 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 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Locally-advanced or metastatic malignancy with an NTRK1, NTRK2 or NTRK3 gene fusion, identified through molecular assays as routinely performed at CLIA or other similarly-certified laboratories. Subjects who have an NTRK gene fusion identified in a lab where certification of the lab 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 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 2009). Subjects with solid tumors without RECIST 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 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.
4. At least 18 years of age.
5. Performance Status: Eastern Cooperative Oncology Group (ECOG) score of ≤ 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 transaminase (AST) and serum alanine transaminase (ALT) < 2.5 × upper limit of normal (ULN), or AST and ALT < 5 × ULN if liver function abnormalities are due to underlying malignancy.
b. Total bilirubin < 2.5 × 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 × ULN OR an estimated glomerular filtration rate ≥ 30 mL/minute using the Cockroft-Gault formula:
(140 – age) x body weight (kg) × 0.85 (if female) / serum creatinine (mg/dL) × 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 Appendix 1 (Section 10.1.3) which includes compliance with the requirements,
restrictions listed in the informed consent form (ICF), and in this protocol. |
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| E.4 | Principal exclusion criteria |
1. Investigational agent or anticancer therapy within 2 weeks prior to 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 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, basal or squamous cancers of the skin.
5.Active uncontrolled systemic bacterial, viral, or fungal infection, 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 CYP3A4 inhibitor or inducer (refer to Appendix C in section 12.3) prior to start of treatment initiation.
7. Pregnancy or lactation.
8. Currently recovering from adverse events (AEs) or adverse drug reactions (ADRs) due to previous treatments. Inclusion is only advised once the pre-existing AE/ADR resolves or recovers to baseline or at least to CTCAE grade 1.
9. Known or suspected hypersensitivity against the active substance or any of the ingredients of the investigational medicinal product (IMP).
10. 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.
11. Hepatitis B (HBV) or C (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 hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy as per rituximab label. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Best overall response of confirmed complete response (CR) or partial response (PR) as determined by an independant radiology review committee using RECIST v1.1 or RANO criteria, as appropriate to tumor type. Confirmed CR or PR will be defined as a repeat assessment performed no less than 28 days after the criteria for response is first met.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 2-3 months from baseline until disease progression |
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| E.5.2 | Secondary end point(s) |
• 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.
• 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; DOR is defined as the number of months from the start of CR or PR (whichever response is recorded first) and subsequently confirmed to the first date that recurrent or progressive disease is documented or death.
• Clinical benefit rate (CBR): best overall response of confirmed CR, PR, or stable disease lasting 16 or more weeks following the initiation of Larotrectinib.
• Progression-free survival (PFS): number of months from initiation of Larotrectinib to the earlier of disease progression or death due to any cause.
• Overall survival (OS): number of months from the initiation of Larotrectinib to the date of death due to any cause.
• 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.
• Incidence, severity, and duration of adverse events, including all, serious, and those considered treatment-related.
• Changes from baseline in clinical safety laboratory values and vital signs.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Every 2-3 months from baseline until disease progression or toxicity onset or death |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| China |
| Colombia |
| India |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Singapore |
| Taiwan |
| United States |
| Greece |
| Norway |
| European Union |
| Argentina |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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