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A Safety and Efficacy Study of INC280 and Gefitinib in Patients With EGFR Mutated, c-MET-amplified NSCLC Who Have Progressed After EGFRi Treatment

Primary Purpose

Non-small Cell Lung Cancer

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

INC280

Gefitinib

About this trial

This is an interventional treatment trial for Non-small Cell Lung Cancer focused on measuring EGFR, c-MET, Lung cancer, Gefitinib, Erlotinib, Non-small cell lung cancer (NSCLC), lung adenocarcinoma, large-cell lung carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Documented EGFR mutation
Documented c-MET dysregulation
Prior clinical benefit on EGFR inhibitors and then subsequent progression
-≥ 18 year old
Life expectancy of ≥ 3 months
ECOG performance status ≤ 2

Exclusion Criteria:

Unable to swallow tables once or twice daily
Previous treatment with c-MET inhibitor
Any unresolved toxicity from previous anticancer therapy greater than grade 1
History of cystic fibrosis
History of acute or chronic pancreatitis
Unable to undergo MRI or CT scans
Known history of HIV
Undergone a bone marrow or solid organ transplant
Clinically significant wound or lung tumor lesions with increased likelihood of bleeding
Pregnant or nursing

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm Type

Experimental

Arm Label

INC280 100 mg Cap QD Phase Ib

INC280 200 mg Cap QD Phase Ib

INC280 400 mg Cap QD Phase Ib

INC280 800 mg Cap QD Phase Ib

INC280 200 mg Cap BID Phase Ib

INC280 400 mg Cap BID Phase Ib

INC280 600 mg Cap BID Phase Ib

INC280 200 mg Tab BID Phase Ib

INC280 400 mg Tab BID Phase Ib

INC280 400 mg Cap BID Phase II

INC280 400 mg Tab BID Phase II

Arm Description

cap=capsule; QD=once daily

cap=capsule; BID=twice daily

tab=tablet; BID=twice daily

cap=capsule; BID=twice daily

tab=tablet; BID=twice daily

Outcomes

Primary Outcome Measures

Phase Ib: Frequency of Dose Limiting Toxicities (DLTs)

A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.

Phase II : Overall Response Rate (ORR)

Overall response rate is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), as per RECIST 1.1 (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

Secondary Outcome Measures

Phase Ib and II: Number of Participants With Adverse Events (AEs)

Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs)

Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level

Number of patients with dose reductions of INC280 by dose level as a measure of tolerability.

Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level

Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability

Phase II: Overall Survival (OS)

Overall survival is defined as the time from the start of treatment date to the date of death, due to any cause

Phase II: Progression Free Survival (PFS)

Progression-free survivalis the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.

Phase II: Duration of Response (DoR)

Duration of overall response (DOR) is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression or death due to underlying cancer.

Phase I: PK Parameters AUCtau of INC280 and Gefitinib

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Area under the plasma concentration-time curve (AUC) from time zero to the end of dosing interval at steady state (tau), where tau=24 hours for once daily dosing and tau=12 hours for twice daily dosing

Phase I: PK Parameters Cmax of INC280 and Gefitinib

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Cmax is the maximum observed plasma concentration of INC280 and gefitinib

Phase I: PK Parameters Tmax of INC280 and Gefitinib

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Tmax is the time to reach maximum plasma concentration of INC280 and gefitinib

Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Apparent systemic plasma clearance rate of INC280 and gefitinib

Phase I: PK Parameters Half-life of INC280 and Gefitinib

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. The elimination half-life of INC280 and gefitinib associated with the terminal slope (Lamda_z) of a semi-logarithmic plasma concentration-time curve

Full Information

NCT ID

NCT01610336

First Posted

April 3, 2012

Last Updated

March 12, 2021

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT01610336

Brief Title

A Safety and Efficacy Study of INC280 and Gefitinib in Patients With EGFR Mutated, c-MET-amplified NSCLC Who Have Progressed After EGFRi Treatment

Official Title

A Phase IB/II, Open Label, Multicenter Study of INC280 Administered Orally in Combination With Gefitinib in Adult Patients With EGFR Mutated, c-MET-amplified Non-small Cell Lung Cancer Who Have Progressed After EGFR Inhibitor Treatment

Study Type

Interventional

2. Study Status

Record Verification Date

March 2021

Overall Recruitment Status

Completed

Study Start Date

April 5, 2012 (Actual)

Primary Completion Date

June 10, 2016 (Actual)

Study Completion Date

May 27, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

This study assessed the safety and efficacy of escalating doses INC280 when added to gefitinib in patients with lung cancer that were known to have dysregulation of the c-MET pathway and who had failed after benefiting on a prior treatment with either gefitinib or erlotinib.

Detailed Description

The Phase Ib dose escalation part was aimed at the determination of the MTD/RP2D of capmatinib in combination with 250 mg gefitinib in patients with NSCLC patients with epidermal growth factor receptor (EGFR) mutation and cMET dysregulation and showing disease progression following EGFR tyrosine-kinase inhibitor (EGFR TKI) therapy. Dose escalation started with a dose of 100 mg/day to a maximum of 1200 mg/day, as capsule or tablet formulation. Successive cohorts of patients were to receive increasing doses of capmatinib in combination with a 250 mg once daily (qd) dose of gefitinib until the MTD/RP2D of capmatinib had been determined. The Phase II dose expansion part consisted of 400 mg capmatinib twice daily (bid), as either capsules or tablets, in combination with 250 mg gefitinib.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Non-small Cell Lung Cancer

Keywords

EGFR, c-MET, Lung cancer, Gefitinib, Erlotinib, Non-small cell lung cancer (NSCLC), lung adenocarcinoma, large-cell lung carcinoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

161 (Actual)

8. Arms, Groups, and Interventions

Arm Title

INC280 100 mg Cap QD Phase Ib

Arm Type

Experimental

Arm Description

cap=capsule; QD=once daily

Arm Title

INC280 200 mg Cap QD Phase Ib

Arm Type

Experimental

Arm Description

cap=capsule; QD=once daily

Arm Title

INC280 400 mg Cap QD Phase Ib

Arm Type

Experimental

Arm Description

cap=capsule; QD=once daily

Arm Title

INC280 800 mg Cap QD Phase Ib

Arm Type

Experimental

Arm Description

cap=capsule; QD=once daily

Arm Title

INC280 200 mg Cap BID Phase Ib

Arm Type

Experimental

Arm Description

cap=capsule; BID=twice daily

Arm Title

INC280 400 mg Cap BID Phase Ib

Arm Type

Experimental

Arm Description

cap=capsule; BID=twice daily

Arm Title

INC280 600 mg Cap BID Phase Ib

Arm Type

Experimental

Arm Description

cap=capsule; BID=twice daily

Arm Title

INC280 200 mg Tab BID Phase Ib

Arm Type

Experimental

Arm Description

tab=tablet; BID=twice daily

Arm Title

INC280 400 mg Tab BID Phase Ib

Arm Type

Experimental

Arm Description

tab=tablet; BID=twice daily

Arm Title

INC280 400 mg Cap BID Phase II

Arm Type

Experimental

Arm Description

cap=capsule; BID=twice daily

Arm Title

INC280 400 mg Tab BID Phase II

Arm Type

Experimental

Arm Description

tab=tablet; BID=twice daily

Intervention Type

Drug

Intervention Name(s)

INC280

Other Intervention Name(s)

Capmatinib

Intervention Description

During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.

Intervention Type

Drug

Intervention Name(s)

Gefitinib

Intervention Description

Gefitinib 250 mg taken once daily

Primary Outcome Measure Information:

Title

Phase Ib: Frequency of Dose Limiting Toxicities (DLTs)

Description

Time Frame

Up to 215 weeks

Title

Phase II : Overall Response Rate (ORR)

Description

Time Frame

Until disease progression, up to 60.8 weeks

Secondary Outcome Measure Information:

Title

Phase Ib and II: Number of Participants With Adverse Events (AEs)

Description

Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Time Frame

Up to 421 weeks

Title

Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs)

Description

Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Time Frame

Up to 421 weeks

Title

Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level

Description

Number of patients with dose reductions of INC280 by dose level as a measure of tolerability.

Time Frame

Up to 417 weeks

Title

Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level

Description

Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability

Time Frame

Up to 417 weeks

Title

Phase II: Overall Survival (OS)

Description

Overall survival is defined as the time from the start of treatment date to the date of death, due to any cause

Time Frame

From date of treatment until death due to any cause, up to 70.2 months

Title

Phase II: Progression Free Survival (PFS)

Description

Progression-free survivalis the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.

Time Frame

Up to 60.8 months

Title

Phase II: Duration of Response (DoR)

Description

Time Frame

Up to 23.2 months

Title

Phase I: PK Parameters AUCtau of INC280 and Gefitinib

Description

Time Frame

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

Title

Phase I: PK Parameters Cmax of INC280 and Gefitinib

Description

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Cmax is the maximum observed plasma concentration of INC280 and gefitinib

Time Frame

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

Title

Phase I: PK Parameters Tmax of INC280 and Gefitinib

Description

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Tmax is the time to reach maximum plasma concentration of INC280 and gefitinib

Time Frame

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

Title

Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib

Description

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Apparent systemic plasma clearance rate of INC280 and gefitinib

Time Frame

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

Title

Phase I: PK Parameters Half-life of INC280 and Gefitinib

Description

Time Frame

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(Cycle=28 days)

Other Pre-specified Outcome Measures:

Title

Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15

Description

Inhibition of c-MET signaling by pre- and post- treatment immunohistochemistry of p-c-MET

Time Frame

Baseline, Day 15 of cycle 1 (Cycle=28days)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Documented EGFR mutation Documented c-MET dysregulation Prior clinical benefit on EGFR inhibitors and then subsequent progression -≥ 18 year old Life expectancy of ≥ 3 months ECOG performance status ≤ 2 Exclusion Criteria: Unable to swallow tables once or twice daily Previous treatment with c-MET inhibitor Any unresolved toxicity from previous anticancer therapy greater than grade 1 History of cystic fibrosis History of acute or chronic pancreatitis Unable to undergo MRI or CT scans Known history of HIV Undergone a bone marrow or solid organ transplant Clinically significant wound or lung tumor lesions with increased likelihood of bleeding Pregnant or nursing

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Woolloongabba

State/Province

Queensland

ZIP/Postal Code

4102

Country

Australia

Facility Name

Novartis Investigative Site

City

East Bentleigh

State/Province

Victoria

ZIP/Postal Code

3165

Country

Australia

Facility Name

Novartis Investigative Site

City

Auckland

Country

Australia

Facility Name

Novartis Investigative Site

City

Leuven

ZIP/Postal Code

3000

Country

Belgium

Facility Name

Novartis Investigative Site

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

51000

Country

China

Facility Name

Novartis Investigative Site

City

Shanghai

State/Province

Shanghai

ZIP/Postal Code

200433

Country

China

Facility Name

Novartis Investigative Site

City

Beijing

ZIP/Postal Code

100039

Country

China

Facility Name

Novartis Investigative Site

City

Guangzhou

ZIP/Postal Code

510060

Country

China

Facility Name

Novartis Investigative Site

City

Strasbourg Cedex

ZIP/Postal Code

67091

Country

France

Facility Name

Novartis Investigative Site

City

Toulouse Cedex 9

ZIP/Postal Code

31059

Country

France

Facility Name

Novartis Investigative Site

City

Frankfurt

ZIP/Postal Code

60590

Country

Germany

Facility Name

Novartis Investigative Site

City

Freiburg

ZIP/Postal Code

79106

Country

Germany

Facility Name

Novartis Investigative Site

City

Ramat Gan

ZIP/Postal Code

52621

Country

Israel

Facility Name

Novartis Investigative Site

City

Milano

State/Province

ZIP/Postal Code

20133

Country

Italy

Facility Name

Novartis Investigative Site

City

Milano

State/Province

ZIP/Postal Code

20141

Country

Italy

Facility Name

Novartis Investigative Site

City

Modena

State/Province

ZIP/Postal Code

41124

Country

Italy

Facility Name

Novartis Investigative Site

City

Koto ku

State/Province

Tokyo

ZIP/Postal Code

135 8550

Country

Japan

Facility Name

Novartis Investigative Site

City

Gyeonggi do

State/Province

Korea

ZIP/Postal Code

10408

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Seoul

State/Province

Korea

ZIP/Postal Code

05505

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Seoul

State/Province

Seocho Gu

ZIP/Postal Code

06591

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Seoul

ZIP/Postal Code

03080

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Seoul

ZIP/Postal Code

06351

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Maastricht

State/Province

ZIP/Postal Code

5800

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Amsterdam

ZIP/Postal Code

1066 CX

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Rotterdam

ZIP/Postal Code

3015 GD

Country

Netherlands

Facility Name

Novartis Investigative Site

City

Singapore

ZIP/Postal Code

169610

Country

Singapore

Facility Name

Novartis Investigative Site

City

Barcelona

State/Province

Catalunya

ZIP/Postal Code

08035

Country

Spain

Facility Name

Novartis Investigative Site

City

Madrid

ZIP/Postal Code

28034

Country

Spain

Facility Name

Novartis Investigative Site

City

Tainan

ZIP/Postal Code

70403

Country

Taiwan

Facility Name

Novartis Investigative Site

City

Taipei

ZIP/Postal Code

10002

Country

Taiwan

Facility Name

Novartis Investigative Site

City

Bangkok

ZIP/Postal Code

10400

Country

Thailand

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Citations:

PubMed Identifier

30156984

Citation

Wu YL, Zhang L, Kim DW, Liu X, Lee DH, Yang JC, Ahn MJ, Vansteenkiste JF, Su WC, Felip E, Chia V, Glaser S, Pultar P, Zhao S, Peng B, Akimov M, Tan DSW. Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR-Mutated, MET Factor-Dysregulated Non-Small-Cell Lung Cancer. J Clin Oncol. 2018 Nov 1;36(31):3101-3109. doi: 10.1200/JCO.2018.77.7326. Epub 2018 Aug 29. Erratum In: J Clin Oncol. 2019 Jan 20;37(3):261.

Results Reference

derived

Learn more about this trial

A Safety and Efficacy Study of INC280 and Gefitinib in Patients With EGFR Mutated, c-MET-amplified NSCLC Who Have Progressed After EGFRi Treatment

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A Safety and Efficacy Study of INC280 and Gefitinib in Patients With EGFR Mutated, c-MET-amplified NSCLC Who Have Progressed After EGFRi Treatment

Non-small Cell Lung Cancer

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial