| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Solid tumors harboring NTRK fusion |
|
| E.1.1.1 | Medical condition in easily understood language |
Solid cancers harboring an NTRK gene fusion, rare cancers caused by
specific changes in the genes |
|
| 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 | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10081769 |
| E.1.2 | Term | NTRK gene fusion overexpression |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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). |
|
| 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 |
|
| 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 Clinical Laboratory Improvement Amendments (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 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. Subjects with solid tumors without Response Evaluation
Criteria in Solid Tumors, version 1.1 (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 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 central nervous system
(CNS) tumor type
b. Have ≥ 1 site of bi-dimensionally measurable disease (confirmed by
magnetic resonance imaging [MRI] and evaluable by Response
Assessment in Neuro-Oncology (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 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. Ability to understand and willingness to sign written informed
consent
11. For subjects eligible for enrollment to bone health cohort only: life
expectancy of at least 6 months, based on investigator assessment |
|
| 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. Patients positive for anti-HCV antibody
will be eligible if they are negative for HCV-RNA. |
|
| 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.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 2-3 months from baseline until disease progression up to 120 months. |
|
| E.5.2 | Secondary end point(s) |
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 treatment-related adverse events
9. Number of subjects with treatment-related adverse events,
categorized by severity
10. Number of subjects with serious adverse events
11. Number of subjects with serious adverse events, categorized by
severity
12. Incidence and severity serious adverse events
13. Incidence and severity treatment-related adverse events
14. Changes from baseline in clinical safety laboratory values and vital
signs
15. The concordance of prior molecular profiling that detected NTRK
fusion within the subject's tumor with the diagnostic test being
evaluated by the sponsor |
|
| 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 up to 120 months. |
|
| 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 |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Colombia |
| India |
| Japan |
| Singapore |
| United States |
| Russian Federation |
| Turkey |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Norway |
| Poland |
| Portugal |
| Slovakia |
| Spain |
| Sweden |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
Print
