| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RET fusion-positive, Metastatic Non-Small Cell Lung Cancer |
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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 | 10029514 |
| E.1.2 | Term | Non-small cell lung cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025044 |
| E.1.2 | Term | Lung cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| - To assess whether pralsetinib improves progression-free survival (PFS) as compared to Investigator’s choice platinum-containing chemotherapy regimens for patients with RET fusion-positive metastatic NSCLC |
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| E.2.2 | Secondary objectives of the trial |
The key secondary objectives are:
•To evaluate objective response rate (ORR) determined by central radiology assessment according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1
•To evaluate overall survival (OS)
To control study-wide Type I error, the key secondary objectives will be tested in the order presented, as part of the sequential testing scheme for the study if the primary analysis is significant.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient must be ≥18 years of age inclusive, at the time of signing the informed consent.
2. Patient has pathologically confirmed, definitively diagnosed, advanced (not able to be treated with surgery or radiotherapy) or metastatic NSCLC and has not been treated with systemic anticancer therapy for metastatic disease.
3. Patient must meet 1 of the following 2 criteria:
a. Have a documented RET fusion using either tissue or plasma as determined by a local test. Refer to laboratory manual for details on acceptable local RET fusion testing methods and tissue requirements. Patient agrees to provide adequate tumor tissue (archived, if available, or a fresh biopsy) for central confirmation of RET fusion using a next generation sequencing (NGS) based assay. If no adequate tumor tissue is available and a new biopsy is not feasible, the patient will not be eligible for enrolment.
b. Have documentation of a RET fusion by a positive result from tumor tissue testing performed at a Sponsor designated central laboratory using an NGS-based assay.
4. Patient has measurable disease based on RECIST 1.1 as determined by the local site Investigator/radiology assessment. Lesions located in a previously irradiated area are considered measurable if progression has been demonstrated after irradiation.
5. Patient has an ECOG PS of 0-1.
6. Patient cannot have received any prior anticancer therapy for metastatic disease.
a. Patients can have received previous anticancer therapy (except a selective RET inhibitor) in the neoadjuvant or adjuvant setting but must have experienced an interval of at least ≥ 6 months from completion of therapy to recurrence.
b. Patients that received previous immune checkpoint inhibitors in the adjuvant or consolidation following chemoradiation are not allowed to receive pembrolizumab if randomized in Arm B
7. Patient is an appropriate candidate for and agrees to receive 1 of the Investigator choice platinum-based chemotherapy regimens if randomized to Arm B.
8. Patient agrees to use contraception consistent with local regulations, as outlined in Contraception Requirements.
9. Patient provides signed informed consent to participate in the study.
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| E.4 | Principal exclusion criteria |
1. Patient’s tumor has any additional known primary driver alterations other than RET, such as targetable mutations of EGFR, ALK, ROS1, MET, and BRAF. Investigators should discuss enrollment with Sponsor designee regarding co-mutations.
2. Patient previously received treatment with a selective RET inhibitor.
3. Patient received radiotherapy or radiosurgery to any site within 14 days before randomization or more than 30 Gy of radiotherapy to the lung in the 6 months before randomization.
4. Patient has a presence of Grade 2 or worse interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis within 28 days before randomization.
5. Patients with autoimmune disease that requires systemic therapy (excluding thyroid, vitiligo) within 2 years of treatment are not eligible for the pembrolizumab-containing regimen.
6. Patients with a medical condition that requires immunosuppression
7. Patient has CNS metastases or a primary CNS tumor that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks before C1D1.
8. Patient has a QT interval corrected using Fridericia’s formula (QTcF) >480 msec. Patient has a history of prolonged QT syndrome or torsades de pointes. Patient has a familial history of prolonged QT syndrome.
9. Patient has clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association (NYHA) classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension, or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (eg, Type II second degree heart block or third-degree heart block).
10. Patient requires treatment with a prohibited medication or herbal remedy that cannot be discontinued at least 2 weeks before the start of study drug administration. BLU-667 may be started within 14 days of stopping a prohibited medication if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
11. Patient received hematopoietic growth factor support within 14 days of the first dose of study drug.
12. Patient has had a major surgical procedure within 14 days of the first dose of study drug (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
13. Patient has a history of another primary malignancy that has been diagnosed or required therapy within the past 3 years before randomization. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, curatively treated localized thyroid cancer, and completely resected carcinoma in situ of any site.
14. Patient has any of the following within 14 days before the first dose of study drug:
a. Platelet count <75×109/L.
b. Absolute neutrophil count (ANC) <1.0×109/L.
c. Hemoglobin <9.0 g/dL (red blood cell transfusion and erythropoietin may be used to reach at least 9.0 g/dL, but must have been administered at least 2 weeks before the first dose of study drug.
d. Aspartate aminotransferase (AST) or ALT >3× the upper limit of normal (ULN) if no hepatic metastases are present; >5× ULN if hepatic metastases are present.
e. Total bilirubin >1.5×ULN; >3×ULN in presence of Gilbert’s disease
f. Estimated (Cockroft-Gault formula) or measured creatinine clearance <45 mL/min.
g. Total serum phosphorous >5.5 mg/dL
15. Patient has a known sensitivity to cisplatin, carboplatin, pemetrexed (non-squamous histology only), or gemcitabine (squamous histology only).
16. Patient an active infection requiring systemic antibiotic therapy.
17. Patient is unwilling or unable to comply with scheduled visits, study drug administration plan (including the inability or unwillingness to swallow capsules), laboratory tests, or other study procedures and study restrictions.
18. Women who are unwilling, if not post menopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 30 days after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 90 days after the last dose of study drug.
19. Patient is pregnant,
20. Patient is breastfeeding
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| - PFS, defined as the number of weeks from randomization date to the earlier of documented progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 central imaging review or death due to any cause |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Imaging will be performed at the following timepoints, regardless of treatment delays: Screening, at 6 and 12 weeks, then every 9 weeks for the first 48 weeks, and every 12 weeks thereafter. |
|
| E.5.2 | Secondary end point(s) |
ORR / DOR / Intracranial Progression or Response Rate - "Imaging will be performed at the following timepoints, regardless of treatment delays: Screening, at 6 and 12 weeks, then every 9 weeks for the first 48 weeks, and every 12 weeks thereafter."
OS - "Patients who have confirmed progressive disease at EOT or during follow-up for PFS or those who initiate another antineoplastic therapy will be followed for overall survival by telephone contact that will include questions regarding subsequent antineoplastic therapy and survival status approximately every 3 months from the EOT visit until death, withdrawal of consent, or closure of the study by the Sponsor."
PROs: EORTC-QLQ-LC13, EORTC-QLQ-C30 symptom scores, and EQ-5D-5L assessments will be evaluated as mean change from baseline to Week 12. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR / DOR / Intracranial Progression or Response Rate - "Imaging will be performed at the following timepoints, regardless of treatment delays: Screening, at 6 and 12 weeks, then every 9 weeks for the first 48 weeks, and every 12 weeks thereafter."
OS - "Patients who have confirmed progressive disease at EOT or during follow-up for PFS or those who initiate another antineoplastic therapy will be followed for overall survival by telephone contact that will include questions regarding subsequent antineoplastic therapy and survival status approximately every 3 months from the EOT visit until death, withdrawal of consent, or closure of the study by the Sponsor."
Please refer to protocol for more details. |
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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 | 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| 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 | No |
| 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
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 |
| Belarus |
| Belgium |
| Canada |
| China |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hong Kong |
| Ireland |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Turkey |
| United Kingdom |
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| 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 is defined as the last patient's telephone contact follow up. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 6 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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