Study of safety and efficacy of INC280 alone, and in combination with erlotinib, compared to chemotherapy, in advanced/metastatic non-small cell lung cancer patients with EGFR mutation and cMET amplification

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2015-001241-84-NL
• Date of registration: 29/09/2015
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: Study of safety and efficacy of INC280 alone, and in combination with erlotinib, compared to chemotherapy, in advanced/metastatic non-small cell lung cancer patients with EGFR mutation and cMET amplification
• Scientific title: A phase Ib/II, open-label, multicenter trial with oral cMET inhibitor INC280 alone and in combination with erlotinib versus platinum/pemetrexed in adult patients with EGFR mutated, cMET-amplified, locally advanced/metastatic nonsmall cell lung cancer (NSCLC) with acquired resistance to prior EGFR tyrosine kinase inhibitor (EGFR TKI) - Study of INC280 alone and in combination with erlotinib vs. chemotherapy in EGFR+/cMET amp NSCLC
• Date of first enrolment: 01/12/2015
• Target sample size: 135
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001241-84
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Phase Ib/Phase II; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Brazil, Canada, China, France, Germany, Hungary, India, Israel, Italy, Japan, Korea, Republic of, Luxembourg, Netherlands, Portugal, Russian Federation, Singapore, Spain, Sweden, Taiwan, Turkey, United Kingdom, United States

Contacts

• Name: Trial Manager
• Affiliation: Novartis Pharma BV

• Name: Trial Manager
• Affiliation: Novartis Pharma BV

Key inclusion & exclusion criteria

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
? Aspartat
Exclusion criteria:
Specific Phase II:
? 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:
? Known hypersensitivity to any of the excipients of INC280
? Prior treatment with any 3rd generation EGFR TKI (e.g., CO1686,
AZD9192, EGF816).
? Symptomatic central nervous system (CNS) metastases
? Presence or history of carcinomatous meningitis
? 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)
? Thoracic radiotherapy to lung fields = 4 weeks prior to study
enrollment or patients who have not recovered from radiotherapyrelated
toxicities
? Presence or history of a malignant disease other than NSCLC that has
been diagnosed and/or required therapy within the past 3 years
? Presence of clinically significant ophthalmologic abnormalities
?Bullous and exfoliative skin disorders at baseline of any grade
?Presence or history of microangiopathic hemolytic anemia with
thrombocytopenia
?Clinically significant, uncontrolled heart diseases and/or recent cardiac
event (within 6 months prior to screening)
?Presence of acute or chronic pancreatitis, surgery of the pancreas,
history of cystic fibrosis or any other factors that may increase the risk
of pancreatitis
?Impairment of GI function or GI disease that may significantly alter the
absorption of INC280 or erlotinib
?Previous anti-cancer and investigational agents within 4 weeks or = 5 x
half-life of the agent (whichever is longer) before Cycle 1 Day 1. If
previous treatment is a monoclonal antibody, then the treatment must
be discontinued at least 4 weeks before Cycle 1 Day 1. If previous
treatment is gefitinib, then the treatment must be discontinued at least 8
days before C1D1. If previous treatment is erlotinib or afatinib, the
treatment must be discontinued at least 7 days prior to C1D1.
?Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic)
within 4 weeks prior (2 weeks for resection of brain metastases) to
study enrollment or who have not recovered from side effects of such
procedure
?Patients receiving treatment with any enzyme-inducing anticonvulsant
that cannot be discontinued at least 1 week before first dose of study
treatment, and for the duration of the study. Patients on non-enzymeinducing
anticonvulsants are eligible
? 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 (lactating) women

Please refer to protocol for further details and any additional exclusion criteria


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Non-small cell lung cancer
MedDRA version: 19.0 Level: PT Classification code 10059515 Term: Non-small cell lung cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 19.0 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Code: INC280
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: capmatinib
CAS Number: 1197376-85-4
Current Sponsor code: INC280
Other descriptive name: INC280
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
INN or Proposed INN: capmatinib
CAS Number: 1197376-85-4
Current Sponsor code: INC280
Other descriptive name: INC280
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: Tarceva
Product Name: erlotinib
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ERLOTINIB HYDROCHLORIDE
CAS Number: 183319-69-9
Other descriptive name: erlotinib
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 25-150

Trade Name: Alimta
Product Name: pemetrexed
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: pemetrexed
CAS Number: 150399-23-8
Other descriptive name: PEMETREXED DISODIUM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Cisplatin
Product Name: cisplatin
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: cisplatin
Other descriptive name: CISPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Trade Name: Carboplatin
Product Name: carboplatin
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: carboplatin
Other descriptive name: CARBOPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Main Objective: 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

Secondary Objective: Phase Ib:
? To assess the antitumor activity of INC280 in combination with erlotinib, as measured by ORR, DCR, 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 and its metabolite CMN288 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 and its metabolite CMN288 in the presence of erlotinib
? To characterize the PK of INC280 single agent and its metabolite CMN288
? To characterize the PK of erlotinib in the presence of INC280

Timepoint(s) of evaluation of this end point: As defined per protocol

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

Secondary Outcome(s)

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 its metabolite CMN288
? Plasma concentration-time profiles and pharmacokinetic parameters 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 and its metabolite CMN288
? Plasma concentrations of erlotinib

Timepoint(s) of evaluation of this end point: As defined per protocol

Secondary ID(s)

2015-001241-84-ES

CINC280B2201

Source(s) of Monetary Support

Novartis Pharma Services AG

Ethics review

Status: Approved
Approval date:
Contact: