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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02335944




Registration number
NCT02335944
Ethics application status
Date submitted
9/10/2014
Date registered
12/01/2015
Date last updated
14/10/2020

Titles & IDs
Public title
Study of Safety and Efficacy of EGFR-TKI EGF816 in Combination With cMET Inhibitor INC280 in Non-small Cell Lung Cancer Patients With EGFR Mutation.
Scientific title
A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.
Secondary ID [1] 0 0
2014-000726-37
Secondary ID [2] 0 0
CINC280X2105C
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non Small Cell Lung Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lung - Mesothelioma
Cancer 0 0 0 0
Lung - Non small cell
Cancer 0 0 0 0
Lung - Small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - INC280
Treatment: Drugs - EGF816

Experimental: INC280 plus EGF816 - Recruitment in Phase I dose escalation part is completed. Recruitment in Phase II dose expansion is ongoing.


Treatment: Drugs: INC280
cMET inhibitor

Treatment: Drugs: EGF816
EGFR-TKI

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase Ib: Incidence of dose limiting toxicities (DLTs) and Estimation of the Maximum tolerated dose (MTD) or Recommended Phase II dose (RP2D)
Timepoint [1] 0 0
First 28 days of treatment
Primary outcome [2] 0 0
Phase II Groups 1, 2 and 3: Overall Response Rate per RECIST 1.1 - ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Timepoint [2] 0 0
At least 24 weeks
Primary outcome [3] 0 0
Phase II Group 4 Incidence and severity of AEs/SAEs, dose interruptions, reductions and dose intensity - Frequency of treatment-emergent adverse events
Timepoint [3] 0 0
At least 24 weeks
Secondary outcome [1] 0 0
Safety of INC280 and EGF816: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs (Phase I/II) - Assessment of the safety of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment
Timepoint [1] 0 0
At least 24 weeks
Secondary outcome [2] 0 0
Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II) - Assessment of the tolerability of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment
Timepoint [2] 0 0
At least 24 weeks
Secondary outcome [3] 0 0
Overall Response Rate (Phase Ib and Phase II Group 4) - ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Timepoint [3] 0 0
At least 24 weeks
Secondary outcome [4] 0 0
Disease Control Rate (Phase I/II) - DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Timepoint [4] 0 0
At least 24 weeks
Secondary outcome [5] 0 0
Progression Free Survival (Phase I/II) - Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
Timepoint [5] 0 0
At least 24 weeks
Secondary outcome [6] 0 0
Duration of Response (Phase I/II) - DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1
Timepoint [6] 0 0
At least 24 weeks
Secondary outcome [7] 0 0
Overall Survival (Phase I/II) - OS is defined as the time from first dose of the study treatment to the date of death due to any cause.
Timepoint [7] 0 0
At least 24 weeks
Secondary outcome [8] 0 0
Plasma concentration versus time profiles
Timepoint [8] 0 0
Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1
Secondary outcome [9] 0 0
Area under the plasma concentration versus time curve (AUC) of EGF816
Timepoint [9] 0 0
Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1
Secondary outcome [10] 0 0
Area under the plasma concentration versus time curve (AUC) of INC280
Timepoint [10] 0 0
Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1
Secondary outcome [11] 0 0
Peak plasma concentration (Cmax) of INC280
Timepoint [11] 0 0
Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1
Secondary outcome [12] 0 0
Peak plasma concentration (Cmax) of EGF816
Timepoint [12] 0 0
Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1
Secondary outcome [13] 0 0
Elimination half life (t1/2) of INC280
Timepoint [13] 0 0
Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1
Secondary outcome [14] 0 0
Elimination half life (t1/2) of EGF816
Timepoint [14] 0 0
Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1
Secondary outcome [15] 0 0
Time to Response (Phase I/II) - TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Timepoint [15] 0 0
At least 24 weeks

Eligibility
Key inclusion criteria
Inclusion criteria:

- Histologically documented, locally advanced or recurrent (stage IIIB who are not
eligible for combined modality treatment) or metastatic (Stage IV) NSCLC

- Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR
T790M mutation (or other rare activating mutations that confer sensitivity to 1st and
2nd generation EGFR inhibitors (e.g. L861Q, G719X, S768I)

- Presence of at least one measurable lesion according to RECIST v.1.1

- ECOG performance status =1

- Patients must be screened for HBV. Patients who are either HBsAg positive or HBV-DNA
positive must be willing and able to take antiviral therapy 1-2 weeks prior to 1st
dose of EGF816 treatment and continue on antiviral therapy for at least 4 weeks after
the last dose of EGF816.

- Patients must be screened for HCV. Patients must have negative hepatitis C antibody
(HCV Ab) or are HCV Ab positive but with an undetectable level of HCV-RNA. Note:
patients with detectable HCV-RNA are not eligible for the study.

- Phase Ib only: documented progression of disease according to RECIST v1.1 while on
continuous treatment with EGFR TKI (e.g.: erlotinib, gefitinib or afatinib).

- Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI
resistant) only: Patients demonstrated a documented clinical benefit (CR (any
duration), PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g.
erlotinib, gefitinib or afatinib, and subsequently demonstrated progression according
to RECIST v1.1.

- Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI
naïve) only: Advanced NSCLC patients who have not been previously treated with any
therapy known to inhibit EGFR and harbor de novo T790M mutation .

- Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic) only:
patients must harbor an EGFR activating mutation and must be naïve from any line of
systemic antineoplastic therapy in the advanced setting.

- Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1L (treatment-naïve), 2//3L
antineoplastic): All patients must harbor an EGFR activating mutation and 2/3L
patients must have failed (defined as intolerance to treatment or documented disease
progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced
setting
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- 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)

- Patients who have received more than three prior lines of antineoplastic
therapies (including EGFR TKI) in advanced setting.

- Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI
resistant):

- More than 3 prior lines of systemic antineoplastic therapies (including EGFR TKI)
in the advanced setting

- More than 1 previous treatment line with 1st or 2nd generation EGFR TKI (e.g.
erlotinib, gefitinib, afatinib) in the advanced setting

- Previous treatment with an investigational or marketed 3rd generation EGFR TKI
(e.g. AZD9291, CO-1686, ASP8273, EGF816)

- Previous treatment with an investigational or marketed agent known to inhibit
EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).

- Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI
naïve):

- More than two previous treatment lines of systemic antineoplastic therapies in
the advanced 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, AZD9291, CO-1686, ASP8273, EGF816) or other
anti-EGFR or EGFR monoclonal antibody therapy or dual TKI inhibitors.

- Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic):

- 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. Patients who received only one cycle of
antineoplastic therapy in the advanced setting are allowed).

- Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1/3L antineoplastic):

- More than 2 prior lines of systemic antineoplastic therapies in the advanced
setting

- Previous treatment with an investigational or marketed 3rd generation EGFR TKI
(e.g. AZD9291, CO-1686, ASP8273, EGF816)

- Previous treatment with an investigational or marketed agent known to inhibit
EGFR (e.g. EGF monoclonal antibody therapy, dual TKI inhibitor).

- Previous treatment with a c-MET inhibitor or HGF-targeting therapy.

- Patients with symptomatic brain metastases.

- Presence or History of another malignancy. Exception: Patients who have been
disease-free for 3 years, or patients with a history of adequately treated in-situ
carcinoma of the uterine cervix, completely resected basal or squamous cell carcinoma,
non-melanomatous cancer of skin, history of stage IA melanoma that has been cured, are
eligible.

- Undergone a bone marrow or solid organ transplant.

- Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not
mandatory)

- Patients 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

- Patients with clinically significant, uncontrolled cardiovascular disease

- Presence or history of interstitial lung disease or interstitial pneumonitis

- Patients have not recovered from all toxicities related to prior anticancer therapies
to grade =1 (CTCAE v 4.03)

- Patients have out of range laboratory values defined as

1. Absolute Neutrophil Count (ANC) <1.5 x 109/L (1.5x103/µL)

2. Hemoglobin (Hb) <9 g/dL (90g/L)

3. Platelets (PLT) <75 x 109/L (75x103/µL)

4. Total bilirubin >1.5 x upper limit of normal (ULN).

5. AST and/or ALT >3 x ULN

6. Patients with liver metastasis may not be included if AST and/or ALT >5 xULN

7. Alkaline phosphatase (ALP) >5 xULN

8. Calculated creatinine clearance < 45mL/min (0.75 mL/sec)using Cockroft-Gault
formula

9. Asymptomatic serum amylase or lipase > Grade 2

10. Serum amylase or serum lipase CTCAE grade = 1 with signs and/or symptoms
suggesting pancreatitis or pancreatic injury (e.g. elevated P-amylase, abnormal
imaging findings of pancreas, etc)

- Patients have the following laboratory values outside of the laboratory normal limits
or cannot be corrected to within normal limits with supplements during screening:
Potassium, Magnesium, Phosphorus, Total calcium (corrected for serum albumin)

Other protocol-defined inclusion/exclusion criteria may apply.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Melbourne
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Massachusetts
Country [2] 0 0
Canada
State/province [2] 0 0
Alberta
Country [3] 0 0
France
State/province [3] 0 0
Marseille cedex 05
Country [4] 0 0
Germany
State/province [4] 0 0
Baden-Württemberg
Country [5] 0 0
Germany
State/province [5] 0 0
Nordrhein-Westfalen
Country [6] 0 0
Italy
State/province [6] 0 0
BO
Country [7] 0 0
Italy
State/province [7] 0 0
MO
Country [8] 0 0
Italy
State/province [8] 0 0
PG
Country [9] 0 0
Korea, Republic of
State/province [9] 0 0
Korea
Country [10] 0 0
Norway
State/province [10] 0 0
Oslo
Country [11] 0 0
Singapore
State/province [11] 0 0
Singapore
Country [12] 0 0
Spain
State/province [12] 0 0
Catalunya
Country [13] 0 0
Spain
State/province [13] 0 0
Galicia
Country [14] 0 0
Spain
State/province [14] 0 0
Las Palmas De Gran Canaria
Country [15] 0 0
Spain
State/province [15] 0 0
Madrid
Country [16] 0 0
Taiwan
State/province [16] 0 0
Taiwan ROC

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2
dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor
activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung
cancer (NSCLC) with documented EGFR mutation.
Trial website
https://clinicaltrials.gov/show/NCT02335944
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications