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 |
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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 | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
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: To determine MTD and/or RP2D of INC280 in combination with erlotinib
Phase II: To compare the antitumor activity of INC280 alone, and INC280 in combination with erlotinib, vs platinum with pemetrexed, as measured by Progression Free Survival (PFS) per investigator’s assessment |
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E.2.2 | Secondary objectives of the trial |
Phase Ib:
● To assess the antitumor activity of INC280 in combination with erlotinib, as measured by overall response rate (ORR), disease control rate (DCR), duration of response (DOR) and PFS per investigator’s assessment
● To evaluate overall survival (OS)
● To determine safety and tolerability of INC280 in combination with erlotinib
● To characterize the PK of INC280 in the presence of erlotinib
● To characterize the PK of erlotinib in the presence of INC280
Phase II:
● To assess the antitumor activity of INC280 alone, and INC280 in combination with erlotinib, vs. platinum with pemetrexed, as measured by ORR, DCR, and DOR per Investigator’s assessment
● To evaluate OS
● To determine safety and tolerability of the combination of INC280 and erlotinib and of INC280 single agent
● To characterize the PK of INC280 in the presence of erlotinib
● To characterize the PK of INC280 single agent
● To characterize the PK of erlotinib in the presence of INC280 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Specific for Phase Ib:
● Patients must have received at least one line of systemic therapy, including one prior 1st generation (e.g., erlotinib, gefitinib) or 2nd generation (e.g., afatinib) EGFR TKI; any line of prior systemic chemotherapy is allowed
● Molecular pre-screening assessment:
● cMET-amplification (GCN ≥ 6) by FISH assessed from a biopsy or an archival tumor sample collected at or any time after the progression on prior 1st or 2nd generation EGFR TKI, determined locally or by a Novartis-designated central laboratory
● Patients with known EGFRT-790M mutation are not eligible
● Patients must have at the screening visit: Platelet count ≥ 75 x 109/L
Specific for Phase II:
● Patients must have received one and only one prior line of 1st generation (e.g., erlotinib, gefitinib) or 2nd generation (e.g., afatinib) EGFR TKI for the treatment of locally advanced or metastatic NSCLC
● No prior chemotherapy is allowed, except:
● Patients, who switched from platinum-based chemotherapy to EGFR TKI during first line treatment within 28 days since the start date of chemotherapy, will be allowed to enter the study, in the absence of disease progression
● Prior neoadjuvant/adjuvant cytotoxic chemotherapy is not allowed, unless the relapse occurred more than 12 months after the last administration of neoadjuvant/adjuvant chemotherapy
● Molecular pre-screening assessment:
● cMET-amplification (GCN ≥ 6) by FISH determined by a Novartis-designated central laboratory on a newly obtained tumor biopsy (preferred) or an archival tumor sample obtained at or any time after the progression on prior 1st or 2nd generation EGFR TKI
● EGFR-T790M negative status assessed from a biopsy or an archival tumor sample collected at or any time after the progression on prior 1st or 2nd generation EGFR TKI, determined locally by either Roche Cobas or Qiagen therascreen test or by a Novartis designated central laboratory
● Presence of at least one measurable lesion according to RECIST v1.1. A previously irradiated site lesion may only be counted as a target lesion if there is clear sign of progression since the irradiation.
● Patients must have at the screening visit:
● White blood cell count ≥ 4 x 109/L
● Platelet count ≥ 100 x 109/L
Common for Phase Ib and Phase II:
● ≥ 18 years of age at the time of informed consent.
● Locally advanced or metastatic NSCLC (stage IIIB and is not a candidate for definitive multimodality therapy or IV) other than predominantly squamous cell histology harboring EGFR mutation known to be associated with EGFR TKI drug sensitivity (exon 19 deletion or L858R).
● Patients must meet the criteria for acquired resistance to EGFR TKI (either 1st generation (e.g., erlotinib, gefitinib) or 2nd generation (e.g., afatinib)) defined as: Documented clinical benefit (CR, PR, or SD (≥ 6 months) as per RECIST) or Demonstrated progression, while on continuous treatment, or within 30 days since the date of last administration of EGFR TKI, per RECIST
● Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia are allowed to enter the study.
● Life expectancy ≥ 3 months.
● ECOG performance status (PS) ≤ 1.
● Patients must have at the screening visit:
● Hemoglobin ≥ 9 g/dL
● Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
● Calculated creatinine clearance (using Cockcroft-Gault formula) > 45 mL/min
● Total bilirubin ≤ 1.5 x ULN, except for patients with Gilbert’s syndrome, who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
● Aspartate transaminase (AST) ≤ 3 x ULN, except for patients with liver metastasis, who are only included if AST ≤ 5 x ULN
● Alanine transaminase (ALT) ≤ 3 x ULN, except for patients with liver metastasis, who are only included if ALT ≤ 5 x ULN
● Fasting plasma glucose ≤ 175 mg/dL (≤ 9.8 mmol/L)
● Alkaline phosphatase (ALP) ≤ 5.0 x ULN
● Asymptomatic serum amylase ≤ grade 2. Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
● Serum lipase ≤ ULN
● Patients enrolled must have the following laboratory values within the laboratory normal limits or corrected to within normal limits with supplements during screening:
● Potassium
● Magnesium
● Phosphorus
● Total calcium (corrected for serum albumin)
● Written informed consent must be obtained prior to any screening procedures
● Willing and able to comply with scheduled visits, treatment plan and laboratory tests |
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E.4 | Principal exclusion criteria |
Specific Phase II:
● Patients with history of severe hypersensitivity reaction to platinum containing drugs, pemetrexed or any known excipients of these drugs.
● Prior treatment with any of the following agents
● Crizotinib, or any other cMET inhibitor or HGF-targeting inhibitor.
● Concomitant EGFR TKI and platinum based chemotherapy as first line regimen.
● Platinum-based chemotherapy as first line treatment.
Common for Phase Ib and Phase II:
● Prior treatment with any 3rd generation EGFR TKI (e.g., CO1686, AZD9192).
● Symptomatic central nervous system (CNS) metastases
● Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
● Presence of clinically significant ophthalmologic abnormalities
● Strong inhibitors or moderate inducers of CYP3A4; strong inducers of CYP3A4; strong inhibitors or strong inducers of CYP1A2; proton pump inhibitors, within 1 week prior to start of treatment with INC280 and for the duration of the study
● Pregnant or nursing women |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase Ib: Frequency and characteristics of DLTs to the INC280 and erlotinib combination
Phase II: PFS, defined as time from randomization to progression or death due to any cause, by investigator’s assessment according to RECIST v1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Phase Ib:
● ORR, DCR, DOR, PFS by investigator’s assessment according to
RECIST v1.1
● OS
● Incidence of adverse events and serious adverse events, change in vital signs, laboratory results and ECG
● Plasma concentration-time profiles and pharmacokinetic parameters of INC280 and of erlotinib
Phase II:
● ORR, DCR, DOR by investigator’s assessment according to RECIST v1.1
● OS
● Incidence of adverse events and serious adverse events, change in vital signs, laboratory results and ECG
● Plasma concentrations of INC280
● Plasma concentrations of erlotinib |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) dose escalation |
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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 |
MTD or RP2D dose escalation |
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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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 3 |
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 | 74 |
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 |
Belgium |
Brazil |
Canada |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Portugal |
Russian Federation |
Singapore |
Spain |
Sweden |
Turkey |
United States |
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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
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The end of study defined as the earliest occurrence of the following:
• All patients have died or discontinued from the study
• Another clinical study becomes available that can continue to provide INC280 in this patient population and all patients ongoing are eligible to be transferred to that clinical study
• INC280 is commercially available and ongoing patients are able to obtain reimbursement of commercial supply
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
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 | 8 |