Clinical trial NCT02335944: Study of Safety and Efficacy of EGFR-TKI EGF816 in Combination With cMET Inhibitor INC280 in Adult Patients With EGFR Mutated Non Small Cell Lung Cancer.
Official 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Non Small Cell Lung Cancer
Keywords: non small cell lung cancer
NSCLC
EGF816
INC280
tyrosine kinase inhibitor
c-MET
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-01-12
Enrollment: 177
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to determine the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) of nazartinib (EGF816) in combination with capmatinib (INC280) and to estimate the preliminary anti-tumor activity of nazartinib in combination with capmatinib in participants with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.

Detailed description: This study was designed as a Phase Ib/II, multi-center, open-label study starting with a Phase Ib dose escalation part followed by a Phase II expansion part. Oral nazartinib (once daily) and capmatinib (twice daily) was administered on a continuous schedule until participant experienced unacceptable toxicity, progressive disease (PD) and/or treatment was discontinued at the discretion of the investigator or withdrawal of consent/opposition to use data/biological samples. Study treatment could be continued beyond Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) defined PD, in the judgment of the investigator, when there was evidence of clinical benefit and the subject wished to continue with the study treatment.

In Phase Ib part, participants with NSCLC harboring EGFR activating mutations were enrolled. At the end of the Phase Ib part, once the MTD or RP2D of nazartinib in combination with capmatinib was declared, additional participants with NSCLC were enrolled in the Phase II part in order to assess the preliminary anti-tumor activity of nazartinib in combination with capmatinib. Participants with locally advanced or metastatic NSCLC were assigned into different groups according to their resistance mechanisms.

As per the Protocol amendment 7, an additional group (Group 5) was included into study CINC280X2105C, which was intended to support study CINC280L12301. After thorough and careful assessment of study CINC280L12301 enrollment status, projected study completion timelines, and the changing clinical landscape, Novartis made the decision to discontinue the study. Importantly, this decision was not driven by safety concerns; no new safety signals were observed in the study participants or in the ongoing capmatinib program. As such, Group 5 data was no longer needed and the new arm in study CINC280X2105C was not opened as planned.

Eligibility criteria: Key Inclusion criteria:

- Participants in Phase Ib and Phase II Groups 1 to 4: histologically documented, locally advanced or recurrent (stage IIIB who were not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC.

Participants in Phase II Group 5: stage IIIB/IIIC (not amenable to curative surgery, chemoradiation or radiation) or stage IV NSCLC

* Participants in Phase Ib and Phase II Groups 1 to 4: 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), or a characterized de novo EGFRT790M mutation.
* Presence of at least one measurable lesion according to RECIST v.1.1
* ECOG performance status ≤1
* Participants had to be screened for HBV. Participants who were either HBsAg positive or HBV-DNA positive had to 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.
* Participants had to be screened for HCV. Participants had to have negative hepatitis C antibody (HCV Ab) or were HCV Ab positive but with an undetectable level of HCV-RNA. Note: participants with detectable HCV-RNA were 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: Participants 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 participants who were not 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: participants had to harbor an EGFR activating mutation and had to 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 participants had to harbor an EGFR activating mutation and 2/3L participants had to have failed (defined as intolerance to treatment or documented disease progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting
* Phase II Group 5 only: Histologically or cytologically confirmed diagnosis of NSCLC (excluding squamous cell carcinoma) with all the following:

  1. EGFR mutations known to be associated with EGFR TKI sensitivity. This had to be assessed as part of the participant standard of care by a validated test for EGFR mutations, as per local regulations. Exon 19 del, L858R, either alone or in combination with other EGFR sensitivity mutation assessed by a Clinical Laboratory Improvement Amendments (CLIA) certified USA laboratory or an accredited local laboratory outside the USA had to be documented in the participant source documents before the participant consented for pre-screening for MET amplification status.
  2. EGFR T790M negative status for participants who had progressed on first or second generation EGFR TKI, or third generation EGFR TKI other than osimertinib, as per tissue-based result from a CLIA-certified USA laboratory or an accredited local laboratory outside of the USA, by a validated test according to local regulations.
  3. 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.
  4. Histological transformation from NSCLC into small cell lung cancer (SCLC) following previous EGFR TKI treatment were excluded.
* Participants had to 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 had to have a life expectancy of at least 3 months.

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)
  * Participants who had 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. Participants who received only one cycle of antineoplastic therapy in the advanced setting were 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.
  * Participants with symptomatic brain metastases.
* Phase II Group 5: Participants with symptomatic central nervous system (CNS) metastases who were neurologically unstable or had required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
* Presence or history of another malignancy. Exception: Participants who had been disease-free for 3 years, or participants 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 had been cured, were eligible.

For Phase II Group 5: Presence or history of a malignant disease other than NSCLC that had been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.

* Undergone a bone marrow or solid organ transplant.
* Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory).

For Group 5: Participants with known history of testing positive for human immunodeficiency virus (HIV) infection, and with a history of Acquired ImmunoDeficiency Syndrome (AIDS) defining opportunistic infections in the last 12 months prior to the first dose of study treatment had to be excluded

* Participants receiving concomitant immunosuppressive agents or chronic corticosteroids used 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
* Participants who had not recovered from all toxicities related to prior anticancer therapies to grade ≤1 (CTCAE v 4.03)
* Participants who had out of range laboratory values
* Participants who received live vaccines

Primary outcomes:
measure: Phase Ib: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to first 28 days of treatment
measure: Phase II Group 1, 2 and 3: Overall Response Rate (ORR) by Investigator's Assessment Per RECIST 1.1
timeFrame: Up to approximately 4 years
measure: Phase II Group 4: Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
timeFrame: From start of treatment up to 30 days after last dose of study treatment, assessed up to 3.7 years
measure: Phase II Group 4: Number of Participants With Dose Reductions and Dose Interruptions of INC280 and EGF618
timeFrame: From start of treatment until end of treatment, assessed up to 3.6 years
measure: Phase II Group 4: Dose Intensity
timeFrame: From start of treatment until end of treatment, assessed up to 3.6 years
measure: Phase II Group 5: ORR Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy
timeFrame: Up to approximately 3 years (while on INC280 monotherapy)
Secondary outcomes:
measure: Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of INC280 and EGF618
timeFrame: From start of treatment until end of treatment, assessed up to approximately 5 years
measure: Phase II Group 1, 2 and 3: Number of Participants With Dose Reductions and Dose Interruptions of INC280 and EGF618
timeFrame: From start of treatment until end of treatment, assessed up to approximately 4 years
measure: Phase Ib: Dose Intensity
timeFrame: From start of treatment until end of treatment, assessed up to approximately 5 years
measure: Phase II Group 1, 2 and 3: Dose Intensity
timeFrame: From start of treatment until end of treatment, assessed up to approximately 4 years
measure: Phase Ib: Overall Response Rate (ORR) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: Up to approximately 5 years
measure: Phase II Group 4: Overall Response Rate (ORR) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: Up to approximately 4 years
measure: Phase Ib: Progression Free Survival (PFS) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: From date of first dose to first documented disease progression or death, assessed up to approximately 5 years
measure: Phase II Groups 1, 2, 3 and 4: Progression Free Survival (PFS) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: From date of first dose to first documented disease progression or death, assessed up to approximately 4 years
measure: Phase Ib: Time to Response (TTR) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: From the date of the first dose to the date of first documented response, up to approximately 5 years
measure: Phase II Groups 1, 2, 3 and 4: Time to Response (TTR) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: From the date of the first dose to the date of first documented response, up to approximately 4 years
measure: Phase Ib: Duration of Response (DOR) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: From date of first documented response to first documented disease progression or death, assessed up to approximately 5 years
measure: Phase II Groups 1, 2, 3 and 4: Duration of Response (DOR) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: From date of first documented response to first documented disease progression or deaths, assessed up to approximately 4 years
measure: Phase Ib: Disease Control Rate (DCR) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: Up to approximately 5 years
measure: Phase II Group 1, 2 3 and 4: Disease Control Rate (DCR) Per RECIST 1.1 Based on Investigator's Assessment
timeFrame: Up to approximately 4 years
measure: Phase Ib: Overall Survival (OS)
timeFrame: From date of first dose to death, assessed up to approximately 5 years
measure: Phase II Groups 1, 2, 3 and 4: Overall Survival (OS)
timeFrame: From date of first dose to death, assessed up to approximately 4 years
measure: Phase Ib: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 12 Hours (AUC0-12) of INC280
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase Ib: Peak Plasma Concentration (Cmax) of INC280
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase Ib: Time to Reach Maximum Concentration (Tmax) of INC280
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase II Groups 3 and 4: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 12 Hours (AUC0-12) of INC280
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase II Groups 3 and 4: Peak Plasma Concentration (Cmax) of INC280
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase II Groups 3 and 4: Time to Reach Maximum Concentration (Tmax) of INC280
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase Ib: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) of EGF816
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase Ib: Peak Plasma Concentration (Cmax) of EGF816
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase Ib: Time to Reach Maximum Concentration (Tmax) of EGF816
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase II Groups 3 and 4: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) of EGF816
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase II Groups 3 and 4: Peak Plasma Concentration (Cmax) of EGF816
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase II Groups 3 and 4: Time to Reach Maximum Concentration (Tmax) of EGF816
timeFrame: Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)
measure: Phase II Group 5: Duration of Response (DOR) Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy
timeFrame: From date of first documented response to the date of first documented disease progression or death, assessed up to approximately 3 years (while on INC280 monotherapy)
measure: Phase II Group 5: Disease Control Rate (DCR) Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy
timeFrame: Up to approximately 3 years (while on INC280 monotherapy)
measure: Phase II Group 5: Progression Free Survival (PFS) Per RECIST 1.1 Based on Investigator's Assessment for INC280 Monotherapy
timeFrame: Up to approximately 3 years (while on INC280 monotherapy)
measure: Phase II Group 5: Number of Participants With Dose Modifications for INC280 Monotherapy as Well as INC280 in Combination With EGF816 Therapy
timeFrame: From start of treatment until end of treatment, up to approximately 3 years
measure: Phase II Group 5: Dose Intensity for INC280 Monotherapy as Well as INC280 in Combination With EGF816 Therapy
timeFrame: From start of treatment until end of treatment, up to approximately 3 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital Mass General
state: Massachusetts
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Marseille Cedex 05
country: France
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
state: Baden-Württemberg
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Perugia
country: Italy
facility: Novartis Investigative Site
state: PG
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: La Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Las Palmas De Gran Canarias
country: Spain
facility: Novartis Investigative Site
state: Las Palmas De Gran Canaria
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan ROC
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Jia Y, Juarez J, Li J, Manuia M, Niederst MJ, Tompkins C, Timple N, Vaillancourt MT, Pferdekamper AC, Lockerman EL, Li C, Anderson J, Costa C, Liao D, Murphy E, DiDonato M, Bursulaya B, Lelais G, Barretina J, McNeill M, Epple R, Marsilje TH, Pathan N, Engelman JA, Michellys PY, McNamara P, Harris J, Bender S, Kasibhatla S. EGF816 Exerts Anticancer Effects in Non-Small Cell Lung Cancer by Irreversibly and Selectively Targeting Primary and Acquired Activating Mutations in the EGF Receptor. Cancer Res. 2016 Mar 15;76(6):1591-602. doi: 10.1158/0008-5472.CAN-15-2581. Epub 2016 Jan 29.