| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Locally Advanced or Metastatic Solid Tumors that Harbor NTRK1/2/3, ROS1,
or ALK Gene Rearrangements |
|
| E.1.1.1 | Medical condition in easily understood language |
Cancer that arises from organs and solid tissues which has spread to
other organs |
|
| 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 | 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 |
|
| 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 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 |
|
| E.2.2 | Secondary objectives of the trial |
benefit rate of entrectinib, in each patient population basket of solid
tumors
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
•To estimate the progression-free survival and overall survival of
patients with solid tumors treated with entrectinib
•To evaluate the safety and tolerability of entrectinib when administered
at the RP2D
•To assess the population pharmacokinetics (PK) of Entrectinib and to
explore correlations between PK, response, and/or safety findings
•To evaluate the effect of entrectinib on ventricular repolarization
•To assess treatment-related symptoms and general health status using
validated instruments of patient reported outcomes
See protocol for the full list of secondary objectives |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 acidbased 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 enrollment.
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
|
|
| E.4 | Principal exclusion criteria |
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.
Note: The ALK-rearranged NSCLC basket for patients previously treated with crizotinib and presenting with CNS-only progression is closed for further enrollment.
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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Objective Response Rate (ORR), defined as the proportion of
patients with complete response (CR) or partial response (PR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor assessments will be performed at Screening, at the end of Cycle 1 (Cycle 2 Day 1 +/- 2 days), every 8 weeks (+/- 7 days) thereafter, regardless of treatment delays resulting from toxicity, and at the End of Treatment (if more than 4 weeks have passed since the last imaging assessment). |
|
| E.5.2 | Secondary end point(s) |
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
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumor assessments will be performed at Screening, at the end of Cycle 1 (Cycle 2 Day 1 +/- 2 days), every 8 weeks (+/- 7 days) thereafter, regardless of treatment delays resulting from toxicity, and at the End of Treatment (if more than 4 weeks have passed since the last imaging assessment).
Clinical Benefit Rate - 6 months after the first dose of entrectinib
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 |
| Basket study of entrectinib for the treatment of patients with solid tumors |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 72 |
| 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 |
| Singapore |
| Switzerland |
| Hong Kong |
| Taiwan |
| Australia |
| Japan |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of trial in all participating countries will be defined as the time at which the secondary endpoint of OS has been met, if the study is not terminated beforehand per recommendation of DMC |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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