| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-small cell lung cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| non-small cell lung cancer |
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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 | 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) |
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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 |
Phase Ib part: To estimate the MTD or RP2D of nazartinib in combination with capmatinib.
Phase II part: To estimate the preliminary anti-tumor activity of nazartinib in combination with capmatinib (Groups 1, 2 and 3) and to characterize the safety and tolerability of nazartinib in combination with capmatinib when taken with food (Group 4).
To estimate the preliminary anti-tumor activity (ORR) of capmatinib monotherapy (Group 5). |
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| E.2.2 | Secondary objectives of the trial |
To characterize the safety and tolerability of nazartinib in combination with capmatinib (Phase Ib/II Groups 1 to 4).
To characterize the PK of nazartinib in combination with capmatinib when given in combination under fasted state or with food (Phase Ib/II Groups 1 to 4).
To evaluate the preliminary anti-tumor activity of nazartinib in combination with capmatinib (Phase Ib/ Phase II Groups 1 to 4).
To estimate the preliminary anti-tumor activity (DOR, DCR, and PFS) of capmatinib monotherapy (Phase II Group 5)
To characterize the safety and tolerability of capmatinib monotherapy as well as capmatinib in combination with nazartinib therapy (Phase II Group 5). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
● Participants (male or female) ≥ 18 years of age.
● Participants in Phase Ib and Phase II Groups 1 to 4 with histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) non-small cell lung cancer.
•Participants in Phase II Group 5 must have stage IIIB/IIIC (not amenable to curative surgery, chemoradiation or radiation) or stage IV NSCLC at the time of study entry according to AJCC version 8.
● Patients must have advanced NSCLC with locally documented EGFR mutation L858R and/or ex19del (or other rare activating mutations that confer sensitivity to first and second generation EGFR inhibitors (e.g. L861Q, G719X, S768I), or a characterized de novo EGFRT790M mutation. Biomarker requirements for participants in Phase II Group 5 are detailed in Inclusion criteria 15.
● Presence of at least one measurable lesion according to RECIST v.1.1
•Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
•Participants must be screened for HBV. Participants who are either HBsAg positive or HBV-DNA positive must be willing and able to take antiviral therapy 1-2 weeks prior to first dose of study treatment (capmatinib+nazartinib) and continue on antiviral therapy for at least 4 weeks after the last dose of study treatment (capmatinib +nazartinib).
Additional management of the participants would be provided by a physician with expertise in management of HBV, if needed.
•Participants must be screened for HCV. Participants must have negative hepatitis C antibody (HCV-Ab) or positive HCV-Ab but with an undetectable level of HCVRNA. Note: participants with detectable HCVRNA are not eligible to enroll into the study.
•For Phase Ib: participants must have either an acceptable local result, detailing their MET and EGFRT790M status in a biopsy collected at or post progression on the previous EGFR TKI therapy or sufficient tumor material available from a biopsy collected at or post progression on the previous EGFR-TKI therapy for central assessment of MET and EGFRT790M. For Phase II, participants must have sufficient material available for results from central assessment of MET and EGFRT790M. The biopsy must be collected at or post progression on last EGFR TKI treatment line for Group 1 and Group 5, at any time for Groups 2, 3 and 4
at any time (if treatment-naïve) or at/or any time after progression on last antineoplastic therapy for advanced setting (if 2/3L participants); if biopsy is not available after last treatment, the most recent available archival biopsy should be collected.
•Phase Ib only: documented progression of disease according to RECIST 1.1 while on continuous treatment with EGFR TKI (e.g. erlotinib, gefitinib or afatinib).
•Phase II Group 1 only: participants with acquired resistance to EGFR TKI treatment defined as documented clinical benefit (CR [any duration], PR [any duration], or SD for at least 6 months) on prior first or second generation EGFR TKI therapy (e.g. erlotinib, gefitinib or afatinib); and subsequently demonstrated progression according to RECIST 1.1.
•Phase II Group 2 only: advanced NSCLC participants who have not been previously treated with any therapy known to inhibit EGFR, who received a maximum of two previous treatment lines of systemic antineoplastic therapies in the advance setting, and harbor de novo T790M mutation as per central assessment.
•Phase II Group 3 only: participants must be naïve for any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV).
•Phase II Group 4 only: participants who are treatment-naïve or have failed (defined as intolerance to treatment or documented disease progression) a maximum of two previous treatment lines of systemic antineoplastic therapies in the advanced setting.
Phase II Group 5 only:
•Histologically or cytologically confirmed diagnosis of NSCLC (excluding squamous cell carcinoma) with all the following:
•EGFR mutations known to be associated with EGFR TKI sensitivity.
•MET gene amplification defined as: Gene copy number (GCN) ≥ 5 per tissue-based result from a CLIA-certified USA laboratory or an accredited local laboratory outside of the USA by a test that is validated according to local regulations with results documented in the participant source documents.
•Histological transformation from NSCLC into small cell lung cancer (SCLC) following previous EGFR TKI treatment are excluded.
•Participants must have progressed on one prior line of therapy either to first/second generation EGFR TKIs, osimertinib or other third generation EGFR TKIs for advanced/metastatic disease (stage IIIB/IIIC [not amenable to curative surgery, chemoradiation or radiation or stage IV NSCLC).
•Participants must have a life expectancy of at least 3 months.
•Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
Please refer to protocol for further details and/or additional inclusion criteria. |
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| E.4 | Principal exclusion criteria |
1.Phase Ib:
•More than one previous treatment line with erlotinib, gefitinib or afatinib
•Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type)
•Participants who have received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting.
2. Phase II:
Group 1:
•More than three prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting.
•More than one previous treatment line with first or second generation EGFR TKI (e.g. erlotinib, gefitinib, afatinib) in the advanced setting.
•Previous treatment with an investigational or marketed third generation EGFR TKI (e.g. osimertinib, CO-1686, nazartinib).
•Previous treatment with other investigational or marketed agent known to inhibit EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).
Group 2 :
•More than two previous treatment lines of systemic antineoplastic therapies in the advance setting.
•Previous treatment with an investigational or marketed agent that inhibits EGFR. EGFR inhibitors include (but not limited to) all generations of EGFR TKI (e.g. erlotinib, gefitinib, afatinib, osimertinib, CO-1686, nazartinib) or other anti-EGFR or EGF monoclonal antibody therapy or dual TKI inhibitors.
Group 3 :
•De novo EGFR T790M mutation identified by central assessment
•Previous treatment with any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV). Participants who received only one cycle of systemic antineoplastic therapy in the advanced setting are allowed.
Group 4
•More than two previous treatment lines of systemic antineoplastic therapies in the advanced setting.
•Previous treatment with an investigational or marketed third generation EGFR TKI (e.g. osimertinib, CO-1686, nazartinib).
•Previous treatment with an investigational or marketed agent that inhibits EGFR
•Previous treatment with a MET inhibitor or HGF-targeting therapy
•Participants with symptomatic brain metastases. However, participants with asymptomatic/controlled brain metastases may participate in the trial.
For Phase II Group 5: Participants with symptomatic CNS metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms. If participants are on corticosteroids for endocrine deficiencies or tumor-associated symptoms other than CNS related, dose must have been stabilized (or decreasing) for at least 5 days before Cycle 1 Day 1.
•Presence or history of another malignancy
For Phase II Group 5: Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years.
•Undergone a bone marrow or solid organ transplant.
•Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory)
For Phase II Group 5: Participants with known history of testing positive for HIV infection, and with a history of AIDS defining opportunistic infections in the last 12 months prior to the first dose of study treatment must be excluded.
•Participants receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry except for control of brain metastases, topical applications, inhaled sprays, eye drops or local injections.
•Participants with clinically significant, uncontrolled cardiovascular disease
•Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis
•Participants have received anti-cancer therapies within time frames defined per protocol prior to the first dose of study treatment.
•Radiation therapy (palliative setting is allowed.): ≤ 4 weeks, for asymptomatic brain metastases ≤ 2 weeks.
•Major surgery: ≤ 2 weeks
For Phase II Group 5: Major surgery within 4 weeks prior (2 weeks for resection of brain metastases) to starting capmatinib or who have not recovered from side effects of such procedure.
•Participants that have not recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE version 5.0).
•Participants in Phase Ib and Phase II Groups 1 to 4 and Participants in Phase II Group 5 have out of range laboratory values (See protocol for details)
•Participants who have impairment of GI function or GI disease that may significantly alter the absorption of study treatment
•For Phase II Group 5: Carcinomatous meningitis
•For Phase II Group 5: Known EGFR T790M positive, Known C797S positive, known druggable molecular alterations (such as ROS1, BRAF, KRAS etc.) who might be candidates for alternative targeted therapies as applicable per local regulations and treatment guidelines
•Participants who received live vaccines within 30 days prior to the first dose of study treatment
•Please refer to protocol for further details
|
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib part: Incidence of DLTs
Phase II part: Objective response rate (ORR) per RECIST v1.1
|
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b part: First 28 days of treatment
Phase II part: up to approximately 3 years
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| E.5.2 | Secondary end point(s) |
Phase Ib/II parts:
•Safety: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs
•Tolerability: Dose interruptions, reductions and dose intensity
Phase Ib part:
•ORR, PFS, time to response (TTR), duration of response (DOR) and disease control rate (DCR), based on investigator's assessment and overall survival (OS)
Phase II part (Groups 1 to 4): PFS, TTR, •DOR, DCR and ORR (Group 4 only) based on investigator's assessment and OS
Phase Ib/II parts (Groups 1 to 4):
•Plasma concentration vs time profiles.
•Plasma PK parameters of nazartinib and capmatinib
Phase II (Group 5):
•DOR, DCR, and PFS based on investigator's assessment for capmatinib monotherapy
•Safety: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs
•Tolerability: Dose interruptions, reductions and dose intensity |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase Ib/II parts - Safety: Incidence and severity of AEs and SAEs,
including changes in hematology and chemistry values, vital signs and
ECGs
Tolerability: Dose interruptions, reductions and dose intensity
Phase Ib part - ORR, PFS, time to response (TTR), duration of
response (DOR) and disease control rate (DCR), overall survival (OS)
Phase II part - PFS, TTR, DOR duration of response,DCR and ORR
(Group 4 only) based on investigator's assessmen DCR and OS
Phase Ib/II parts - Plasma concentration vs time profiles.
Plasma PK parameters of EGF816 and INC280 |
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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 | No |
| 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) | Yes |
| 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 | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| France |
| Germany |
| Hong Kong |
| India |
| Italy |
| Korea, Republic of |
| Norway |
| Singapore |
| Spain |
| Taiwan |
| United States |
|
| 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
|
The end of study is defined as the earliest occurrence of one of the following:
- All participants have died or discontinued from the study
- Futility/Lack of efficacy (only for Group 5 Stage 1)
- Another clinical study becomes available that can continue to provide capmatinib monotherapy or capmatinib in combination with nazartinib in this participant population and all participants ongoing are eligible to be transferred to that clinical study |
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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 | 10 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 26 |
| 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 | 6 |
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