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Study Evaluating Efficacy and Safety of Capmatinib in Combination With Osimertinib in Adult Subjects With Non-small Cell Lung Cancers as Second Line Therapy (GEOMETRY-E)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04816214
Recruitment Status : Recruiting
First Posted : March 25, 2021
Last Update Posted : May 10, 2022
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This phase III study is designed to evaluate the anticancer activity of capmatinib in combination with osimertinib compared to platinum-pemetrexed based doublet chemotherapy as second line treatment in patients with advanced or metastatic non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation, T790M negative, mesenchymal-to-epithelial transition factor (MET) amplified who progressed following EGFR tyrosine kinase inhibitors (TKIs). The randomized part will be preceded by a safety run-in part in which the recommended dose of the combination of capmatinib and osimertinib will be confirmed.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: capmatinib Drug: pemetrexed Drug: cisplatin Drug: carboplatin Drug: osimertinib Phase 3

Detailed Description:

This is a multicenter, open-label, randomized, active-controlled, global phase III study that will enroll adult participants with locally advanced or metastatic NSCLC with EGFR activating mutation, T790M negative, MET amplified who have progressed following EGFR TKIs.

The study will consist of an initial safety run-in part to evaluate the safety and tolerability of capmatinib in combination with osimertinib and to confirm the recommended dose for the randomized part, and a randomized part that will evaluate the efficacy and safety of capmatinib in combination with osimertinib compared to platinum (cisplatin or carboplatin) - pemetrexed doublet based chemotherapy as second line treatment.

Participant's respective treatment (either with capmatinib in combination with osimertinib, or with platinum (cisplatin or carboplatin) - pemetrexed based doublet chemotherapy) will be continued until participant experiences any of the following: documented disease progression by Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) (as assessed by the investigator in the run-in part, and as assessed by the investigator confirmed by blinded independent review committee (BIRC) in the randomization part), withdrawal of consent, pregnancy, lost to follow-up, or death. Participants who progressed in the platinum-pemetrexed arm will be allowed to crossover to capmatinib in combination with osimertinib therapy after BIRC confirmed, RECIST 1.1-defined progressive disease. Study treatment may be continued beyond initial disease progression as per RECIST 1.1 if, in the judgement of the investigator, there is evidence of clinical benefit, and the participant wishes to continue on the study treatment.

After treatment discontinuation, all participants will be followed for safety evaluations during the safety follow-up period.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 245 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants randomized to platinum-pemetrexed based doublet chemotherapy arm will be allowed to crossover to receive capmatinib in combination with osimertinib
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Randomized, Controlled, Open-label, Multicenter, Global Study of Capmatinib in Combination With Osimertinib Versus Platinum - Pemetrexed Based Doublet Chemotherapy in Patients With Locally Advanced or Metastatic NSCLC Harboring EGFR Activating Mutations Who Have Progressed on Prior Generation EGFR-TKI Therapy and Whose Tumors Are T790M Mutation Negative and Harbor MET Amplification (GEOMETRY-E)
Actual Study Start Date : September 22, 2021
Estimated Primary Completion Date : October 28, 2025
Estimated Study Completion Date : April 15, 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Combination of capmatinib + osimertinib (run-in part)
For run-in part: Up to 2 dose levels of capmatinib in combination with osimertinib may be investigated. The starting dose of combination is capmatinib 400 mg orally twice daily (b.i.d) and osimertinib 80 mg orally once per day (q.d). If a dose de-escalation is required, a lower dose level is defined as capmatinib 400 mg orally twice a day (b.i.d) and osimertinib 40 mg orally once per day (q.d.)
Drug: capmatinib
film-coated tablet for oral use
Other Name: INC280

Drug: osimertinib
tablet for oral use
Other Names:
  • Tagrisso
  • Tagrix

Experimental: Combination of capmatinib + osimertinib (randomized part)
For randomized part: capmatinib in combination with osimertinib administered at the recommended Phase III regimen (defined in the safety run-in part).
Drug: capmatinib
film-coated tablet for oral use
Other Name: INC280

Drug: osimertinib
tablet for oral use
Other Names:
  • Tagrisso
  • Tagrix

Active Comparator: Platinum + pemetrexed based doublet chemotherapy (randomized part)
For randomized part: following local guidelines as per standard of care and products labels Participants randomized to platinum-pemetrexed based doublet chemotherapy arm will be allowed to crossover to receive capmatinib in combination with osimertinib
Drug: pemetrexed
concentrate for solution for intravenous use
Other Names:
  • Alimta
  • Pleumet
  • Pemecad
  • Pemfexy

Drug: cisplatin
concentrate for solution for intravenous use

Drug: carboplatin
concentrate for solution for intravenous use




Primary Outcome Measures :
  1. Run-in part: Incidence of dose limiting toxicities (DLTs) [ Time Frame: 3 weeks ]
    Incidence of Dose Limiting Toxicities (DLT) during the first 21 days (3 weeks) of treatment for each dose level associated with administration of capmatinib in combination with osimertinib

  2. Randomized part: Progression free survival (PFS) [ Time Frame: 37 months ]
    Progression free survival (PFS) per Blinded Independent Review Committee (BIRC) according to Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1)


Secondary Outcome Measures :
  1. Run-in part: Percentage of participants with dose adjustments (reductions, interruptions or permanent discontinuation) [ Time Frame: 6 months ]
    To define the percentage of participants with dose adjustments (reductions, interruption, or permanent discontinuation) and the reasons by treatment arm

  2. Run-in part: Dose intensity of each study drug [ Time Frame: 6 months ]
    Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure

  3. Run-in part: Median Duration of exposure to each study drug [ Time Frame: 6 months ]
    Median duration of exposure to capmatinib and osimertinib where duration of exposure is defined as the time between the first and last dose of treatment

  4. Run-in part: Maximum plasma concentration (Cmax) of capmatinib [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days) ]
    The Cmax values are based on the plasma concentration-time profile of capmatinib. To characterize the pharmacokinetics of capmatinib

  5. Run-in part: Maximum plasma concentration (Cmax) of osimertinib and its metabolites [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days), and also 24 hours post-dose on Cycle 1 Day 1. ]
    The Cmax values are based on the plasma concentration-time profile of osimertinib and its metabolites. To characterize the pharmacokinetics of osimertinib and its metabolites in combination setting

  6. Run-in part: Time to maximum plasma concentration (Tmax) of capmatinib [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days) ]
    The Tmax values are based on the plasma concentration-time profile of capmatinib. To characterize the pharmacokinetics of capmatinib

  7. Run-in part: Time to maximum plasma concentration (Tmax) of osimertinib and its metabolites [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days), and also 24 hours post-dose on Cycle 1 Day 1. ]
    The Tmax values are based on the plasma concentration-time profile of osimertinib and its metabolites. To characterize the pharmacokinetics of osimertinib and its metabolites in combination setting

  8. Run-in part: Area Under the Curve (AUC) of capmatinib [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days) ]
    The AUC values are based on the plasma concentration-time profile of capmatinib. To characterize the pharmacokinetics of capmatinib

  9. Run-in part: Area Under the Curve (AUC) of osimertinib and its metabolites [ Time Frame: pre-dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post-dose on Cycle 1 Day 1 and Day 15 (one cycle is 21 days), and also 24 hours post-dose on Cycle 1 Day 1. ]
    The AUC values are based on the plasma concentration-time profile of osimertinib and its metabolites. To characterize the pharmacokinetics of osimertinib and its metabolites

  10. Run-in part: Duration of response (DOR) [ Time Frame: 6 months ]
    Duration of response is defined as the time from first documented response of complete response (CR) or partial response (PR) to date of first documented progression or death as per investigator judgment according to RECIST 1.1

  11. Run-in part: Overall Response Rate (ORR) [ Time Frame: 6 months ]
    ORR is defined as the proportion of subjects with confirmed best overall response of CR or PR, as per investigator judgment according to RECIST 1.1

  12. Run-in part only: Time to Response (TTR) [ Time Frame: 6 months ]
    Time to response (TTR) is defined as duration of time between the date of randomization and the date of first documented response of either CR or PR as per investigator judgment according to RECIST 1.1 criteria

  13. Run-in part: Disease control rate (DCR) [ Time Frame: 6 months ]
    Disease control rate is defined as the proportion of subjects with CR or PR or subjects with stable disease (SD) as per investigator judgment according to RECIST 1.1

  14. Run-in part: Progression-Free Survival (PFS) [ Time Frame: 6 months ]
    Progression-free survival is defined as the time from randomization to the date of the first documented radiological progression as per investigator judgment according to RECIST 1.1 response criteria or death due to any cause

  15. Randomized part: Overall Response Rate (ORR) [ Time Frame: 37 months ]
    ORR is defined as the proportion of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per BIRC by RECIST 1.1

  16. Randomized part: overall intracranial response rate (OIRR) [ Time Frame: 37 months ]
    OIRR is defined as the proportion of participants with a confirmed best overall intracranial response (BOIR) of CR or PR as per BIRC according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria

  17. Randomized part: Duration of response (DOR) [ Time Frame: 37 months ]
    Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death as per BIRC according to RECIST 1.1 criteria

  18. Randomized part: Time to Response (TTR) [ Time Frame: 37 months ]
    Time to response (TTR) is defined as duration of time between the date of randomization and the date of first documented response of either CR or PR as per BIRC according to RECIST 1.1 criteria

  19. Randomized part: Disease control rate (DCR) [ Time Frame: 37 months ]
    Disease control rate is defined as the proportion of patients with CR or PR or subjects with SD as per BIRC according to RECIST 1.1 criteria

  20. Randomized part: Progression-Free Survival after next line of treatment (PFS2) [ Time Frame: 37 months ]
    PFS2 is defined as the documented radiological progression after next-line of treatment as per investigator judgment according to RECIST 1.1 response criteria or death due to any cause

  21. Randomized part: plasma concentration of capmatinib [ Time Frame: Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and 6 (one cycle is 21 days) ]
    Plasma concentration to characterize the pharmacokinetics of capmatinib

  22. Randomized part: plasma concentration of osimertinib and its metabolites [ Time Frame: Pre-dose on Day 1 of Cycles 1, 2, 3, 4 and 6 (one cycle is 21 days) ]
    Plasma concentration to characterize the pharmacokinetics of osimertinib and its metabolites in combination setting

  23. Randomized part: Overall Survival (OS) [ Time Frame: 37 months ]
    OS is defined as the time from date of randomization/start of treatment to date of death due to any cause

  24. Randomized part: change from baseline in the EORTC QLQ-C30 score [ Time Frame: Baseline, 37 months ]
    The European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (EORTC QLQ-C30) is a questionnaire developed to assess the quality of life of cancer patients. It contains 30 items and is composed of both multi-item scales and single-item measures based on the patients experience over the past week. These include five scales (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/quality of life scale (QoL) scale. All of the scales and single-item measures range in score from 0 to 100. A high score for a functional scale represents a high /healthy level of functioning; a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology/problems.

  25. Randomized part: change from baseline in the EORTC QLQ-LC13 score [ Time Frame: Baseline, 37 months ]
    The Lung Cancer module of the EORTC's quality of life questionnaire (EORTC QLQ-LC13) is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The five domains of the LC13 include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from "not at all" to "very much". Pain score is based on its presence, hence yes or no. A higher score indicates a higher presence of symptoms.

  26. Randomized part: change from baseline in the EQ-5D-5L score [ Time Frame: Baseline, 37 months ]
    The EuroQoL-5 Dimension-5 Level (EQ-5D-5L) is a standardized measure of health status developed by the EuroQol (EQ) Group in order to provide a simple, generic measure of health for clinical and economic appraisal The EQ-5D-5L consists of 2 pages - the descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The participant is asked to indicate his/her health state by ticking in the box against the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number expressing the level selected for that dimension. The EQ VAS records the participant's self-rated health on a 20 cm vertical VAS with endpoints labeled 'the best health you can imagine' at the top and 'the worst health you can imagine' at the bottom.

  27. Randomized part: change from baseline in the NCCN FACT-Brain Symptom Index [ Time Frame: Baseline, 37 months ]
    The National Comprehensive Cancer Network (NCCN) Functional Assessment of Cancer Therapy (FACT)-Brain Symptom Index version 2.0 (FBrSI) will be used to explore changes in symptoms associated with potential BM in this study. The FBrSI was adapted from the previously developed FACT-Brain module. The symptoms module contains 12 items with a recall period of the past 7 days. The participant responds to 12 statements and indicates to what extent it applies to them on a 5-point Likert response scale from "not at all" to "very much."

  28. Randomized part: Time to symptom deterioration for EORTC QLQ-C30 questionnaire [ Time Frame: 37 months ]
    Time to symptom deterioration from baseline category to one more severe category of the EORTC QLQ-C30 questionnaire

  29. Randomized part: Time to symptom deterioration for EORTC QLQ-LC13 questionnaire [ Time Frame: 37 months ]
    Time to symptom deterioration from baseline category to one more severe category of the EORTC QLQ-LC13 questionnaire

  30. Randomized part: Time to symptom deterioration for NCCN FBrSl questionnaire [ Time Frame: 37 months ]
    Time to symptom deterioration from baseline category to one more severe category of the NCCN FBrSl questionnaire

  31. Randomized part: Duration of intracranial response (DOIR) [ Time Frame: 37 months ]
    Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death as per BIRC according to RANO-BM criteria

  32. Randomized part: Time to intracranial response (TTIR) [ Time Frame: 37 months ]
    TTIR is defined as the time from the date of randomization/start of the treatment to the date of the first documented intracranial response of either CR or PR as per BIRC according to RANO-BM criteria

  33. Randomized part: Intracranial Disease control rate (IDCR) [ Time Frame: 37 months ]
    Intracranial Disease control rate is defined as the proportion of patients with CR or PR or subjects with SD as per BIRC according to RANO-BM criteria



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Histologically or cytologically confirmed diagnosis of NSCLC with EGFR mutations known to be associated with EGFR TKI sensitivity, EGFR T790M negative and MET gene amplification
  • Stage IIIB/IIIC or IV NSCLC
  • Patients must have progressed on one prior line of therapy (1st/2nd generation EGFR TKIs, osimertinib or other third generation EGFR TKIs) for advanced/metastatic disease (stage IIIB/IIIC and must be candidates for platinum (cisplatin or carboplatin) - pemetrexed doublet based chemotherapy
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
  • Participants must have recovered from all toxicities related to prior systemic therapy to grade ≤ 1 Common Terminology Criteria Adverse Event 5.0 (CTCAE v 5.0)
  • At least one measurable lesion as defined by RECIST 1.1

Key Exclusion Criteria:

  • Prior treatment with any MET inhibitor or HGF-targeting therapy
  • Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms
  • Carcinomatous meningitis
  • Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years
  • Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis
  • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome
  • Clinically significant, uncontrolled heart diseases
  • known druggable molecular alterations that may render participants eligible for alternative targeted therapies

Other protocol-defined inclusion/exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04816214


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, California
UCLA Santa Monica Hematology / Oncology Recruiting
Santa Monica, California, United States, 90404
Contact: Joanna Gutierrez    310-453-2213    JGGutierrez@mednet.ucla.edu   
Principal Investigator: Edward B Garon         
University of California at Los Angeles Recruiting
Torrance, California, United States, 90502
Contact: Andy Amaya    310-222-2345    andy.amaya@lundquist.org   
Principal Investigator: Mykola Onyshchenko         
United States, Colorado
Rocky Mountain Cancer Centers RMCC - Longmont Recruiting
Denver, Colorado, United States, 80501
Contact    303-385-2000      
Principal Investigator: Hossein Maymani         
United States, Texas
Baylor Health Care System/Sammons Cancer Center Baylor Texas Oncology Recruiting
Dallas, Texas, United States, 75246
Contact: Sarah Shipley    214-370-1279    sarah.shipley@usoncology.com   
Principal Investigator: Kartik Konduri         
United States, Washington
Tacoma General Hospital Recruiting
Tacoma, Washington, United States, 98405
Principal Investigator: Nehal Masood         
France
Novartis Investigative Site Recruiting
Villejuif Cedex, France, 94800
Israel
Novartis Investigative Site Recruiting
Haifa, Israel, 3109601
Novartis Investigative Site Recruiting
Kfar Saba, Israel, 4428164
Novartis Investigative Site Recruiting
Petach Tikva, Israel, 4941492
Japan
Novartis Investigative Site Recruiting
Kashiwa, Chiba, Japan, 277 8577
Novartis Investigative Site Recruiting
Sunto Gun, Shizuoka, Japan, 411 8777
Korea, Republic of
Novartis Investigative Site Recruiting
Seoul, Korea, Republic of, 05505
Poland
Novartis Investigative Site Recruiting
Warszawa, Poland, 02 781
Singapore
Novartis Investigative Site Recruiting
Singapore, Singapore, 169610
Spain
Novartis Investigative Site Recruiting
Santander, Cantabria, Spain, 39008
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Madrid, Spain, 28009
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04816214    
Other Study ID Numbers: CINC280L12301
2020-003677-21 ( EudraCT Number )
First Posted: March 25, 2021    Key Record Dates
Last Update Posted: May 10, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
INC280
capmatinib
osimertinib
pemetrexed
platinum-based chemotherapy
NSCLC
Non-Small Cell Lung Cancer
Carcinoma
EGFR Mutation
T790M negative
MET amplification
second line therapy
GEOMETRY
GEOMETRY-E
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carboplatin
Pemetrexed
Osimertinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Protein Kinase Inhibitors