| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable Metastatic Non-small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
The primary objectives are:
For Phase 1 Combination Dose Selection:
- To identify the RP2CD(s) of the amivantamab and capmatinib combination therapy in with NSCLC.
For Phase 2 Expansion:
-To evaluate the antitumor effect of the amivantamab and capmatinib combination therapy in MET exon 14 skipping mutation and MET amplified NSCLC, when administered at the selected RP2CD(s)
Refer to Section 3 of Master protocol PLATFORMPANSC2001 for other primary objectives / endpoints.
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
For Phase 1 Combination Dose Selection:
- To further evaluate safety and tolerability of the amivantamab and capmatinib combination therapy
For Phase 2 Expansion (Cohorts 1A, 1B, and 1C):
- To further assess the clinical benefit achieved by the amivantamab and capmatinib combination therapy
- To assess Health-related Quality of Life (Cohort 1A)
Refer to Section 3 of Master protocol PLATFORMPANSC2001 for other secondary objectives / endpoints. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Master protocol PLATFORMPANSC2001 - ISA 61186372PANSC2001
inclusion criteria
Age
1. ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of informed consent.
Disease Characteristics
2. Previously diagnosed with histologically or cytologically confirmed unresectable Stage IV (metastatic) NSCLC (any histology).
3. Criterion modified per Amendment 1
3.1. For Phase 1 – Combination Dose Selection:
Metastatic NSCLC progressed on or after standard of care systemic anti-cancer therapy and is declining other systemic treatment options, if any:
- Participants must have had disease progression on or have intolerance to prior platinumbased chemotherapy and an anti-PD-(L)1 antibody given concurrently or sequentially OR
- Participants with targetable genomic aberrations must have had prior disease progression on or have intolerance to appropriate targeted therapies as per local standard of care Participants who may have received prior therapy with amivantamab and/or capmatinib as long as discontinuation was not due to toxicity.
4. Criterion modified per Amendment 1
4.1. For Phase 2 – Expansion:
- Cohort 1A: MET exon 14 skipping mutation (without prior therapy for metastatic disease)
- Metastatic NSCLC previously characterized as MET exon 14 skipping mutation positive AND lacking EGFR and ALK mutation, by a local test using a CLIA certified laboratory or an accredited laboratory
- Participant must not have received systemic anti-cancer therapy for metastatic NSCLC. Neo-adjuvant and adjuvant therapies for earlier stage disease are allowed if relapse occurred >12 months from end of neoadjuvant or adjuvant systemic therapy
- Adequate tumor tissue sample must be submitted to the sponsor.
- Cohort 1B: MET exon 14 skipping mutation (prior therapy)
- Metastatic NSCLC previously characterized as MET exon 14 skipping mutation positive AND lacking EGFR and ALK mutation, by a local test using a CLIA certified laboratory or an accredited laboratory
- Progression of metastatic disease on at least 1 but no more than 3 lines of prior systemic anti-cancer therapy, which may include MET TKI or chemotherapy as per local standard of care, but may not include prior amivantamab
- Participants who have received prior amivantamab will be excluded
- Adequate tumor tissue sample must be submitted to the sponsor.
- Cohort 1C: MET amplification (prior therapy)
- Metastatic NSCLC previously characterized as having MET amplification (≥5 copy number of MET) AND lacking EGFR and ALK mutation, by a local test using a CLIA certified laboratory or an accredited laboratory
- Progression of metastatic disease on at least 1 but no more than 3 prior lines of standard of care therapy for metastatic disease
- Participants who have received prior amivantamab will be excluded
- Submission of adequate archival or fresh tumor tissue, obtained following metastatic NSCLC diagnosis and after disease progression on the last systemic therapy is required.
5. At least 1 measurable lesion, according to RECIST v1.1. Must not have been previously irradiated. May be used for the screening biopsy provided baseline tumor assessment scans are performed ≥7 days after the biopsy.
Brain and Central Nervous System Metastases
6. May have: definitively, locally treated brain metastases that are clinically stable and asymptomatic for >2 weeks and who are off or receiving low-dose corticosteroid treatment (≤10 mg prednisone or equivalent) for at least 2 weeks prior to start of study treatment.
Prior Malignancies
7. May have a prior malignancy (other than the disease under study) the natural history or treatment of which is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s). Must be reviewed and agreed to with medical monitor.
Performance Status
8. Have an ECOG performance status of 0 or 1.
Renal Function
9. Have an estimated glomerular filtration rate (eGFR) >30 mL/min as measured or calculated by Modification of Diet in Renal Disease (MDRD) 4-variable formula.
Please refer to Master Protocol PLATFORMPANSC2001 and protocol ISA 61186372PANSC2001 for additional inclusion criteria |
|
| E.4 | Principal exclusion criteria |
Master protocol PLATFORMPANSC2001 - ISA 61186372PANSC2001
exclusion criteria
Medical Conditions
1. History of uncontrolled illness, including but not limited to:
a. Uncontrolled diabetes
b. Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics 1 week prior to starting study treatment] or diagnosed or suspected viral infection).
c. Active bleeding diathesis
d. Impaired oxygenation requiring continuous oxygen supplementation
e. Psychiatric illness or any other circumstances (including social circumstances) that would limit compliance with study requirements
2. Medical history of (non-infectious) ILD/pneumonitis, or has current ILD/ pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
3. Known allergies, hypersensitivity, or intolerance to
a. amivantamab excipients.
b. capmatinib or its excipients.
4. Participant has, or will have, any of the following:
a. An invasive operative procedure with entry into a body cavity, within 4 weeks or without complete recovery before administration of the first study treatment. Thoracentesis, if needed, and percutaneous biopsy for baseline tumor tissue sample may be done less than 4 weeks prior to administration of the first study treatment, as long as the participant has adequately recovered from the procedure prior to the first dose of study treatment in the clinical judgement of the investigator.
b. Significant traumatic injury within 3 weeks before the start of administration of the first study treatment (all wounds must be fully healed prior to Day 1). Expected major surgery while the investigational agent is being administered or within 6 months after the last dose of study treatment
5. The participant has impairment of the gastrointestinal function that could affect absorption of capmatinib or is unable or unwilling to swallow tablets.
6. Participant has a history of clinically significant cardiovascular disease including, but not limited to the following:
a. Diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to administration of the first dose of study treatment, or any of the following within 6 months prior to administration of the first dose of study treatment: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots, are not exclusionary.
b. Prolonged QTc interval >480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate).
c. Note: Participants with cardiac pacemakers who are clinically stable are eligible
d. Uncontrolled (persistent) hypertension: systolic blood pressure >160 mmHg; diastolic blood pressure >100 mmHg.
e. Congestive heart failure (CHF) defined as New York Heart Association (NYHA) class III-IV or hospitalization for CHF (any NYHA class) within
6 months of administration of the first study treatment.
f. Pericarditis/clinically significant pericardial effusion within 1 month prior to administration of the first dose of study treatment.
g. Myocarditis.
Disease Characteristics
7. Participant received thoracic radiotherapy to lung fields ≤4 weeks prior to Cycle 1 Day 1 or patients who have not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤2 weeks prior to Cycle 1 Day 1 or patients who have not recovered from radiotherapy-related toxicities.
8. Participant has:
a. (or has a history of) leptomeningeal disease (carcinomatous meningitis).
b. spinal cord compression not definitively treated with surgery or radiation.
9. Participant has symptomatic central nervous system (CNS) metastases which are neurologically unstable or have required increasing doses of steroids >10 mg prednisone or equivalent within the 2 weeks prior to study entry to manage CNS symptoms.
10. Participant has uncontrolled tumor-related pain: Symptomatic lesions amenable to palliative radiotherapy (eg, bone metastases, or metastases causing nerve impingement) should be treated more than 7 days prior to the administration of the first study treatment.
Please refer to Master Protocol PLATFORMPANSC2001 and protocol ISA 61186372PANSC2001 for additional exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The Primary end points are:
For Phase 1 Combination Dose Selection:
- Incidence and Severity of AEs, including Dose Limiting Toxicities (DLTs)
For Phase 2 Expansion:
- Objective response rate (ORR) according to RECIST v1.1 by investigator review; confirmatory analysis may be performed using blinded independent central review (BICR)
Refer to Section 3 of Master protocol PLATFORMPANSC2001 for other
primary endpoints. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The Secondary end points are:
For Phase 1 Combination Dose Selection:
- Incidence and Severity of AEs and Clinical Laboratory Abnormalities
For Phase 2 Expansion (Cohorts 1A, 1B, and 1C):
- Duration of response (DoR) confirmatory analysis may be performed using BICR
- Disease control rate (DCR)
- Progression free survival (PFS) according to RECIST v1.1 by investigator review
- Overall Survival (OS)
- Time to subsequent therapy (TTST)
- EORTC-QLQ-C30 change from baseline
- NSCLC-SAQ
- EQ-5D-5L
- PROMIS-PF
Refer to Section 3 of Master protocol PLATFORMPANSC2001 for other
secondary endpoints. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Biomarkers and Immunogenicity Assessments |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Recommended Phase 2 combination Dose Study (RP2CD) |
|
| 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Brazil |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| United States |
| France |
| Poland |
| Spain |
| Germany |
| Italy |
| Turkey |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 11 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| 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 | 11 |
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