A Study to Evaluate Chemotherapy Plus Osimertinib Against Chemotherapy Plus Placebo in Patients With Non-small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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The study will evaluate the efficacy and safety of treatment with chemotherapy in combination with osimertinib compared to chemotherapy in combination with placebo in patients whose disease has progressed extracranially following first-line osimertinib treatment.

Detailed Description
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This is a Phase III, randomized, double-blind, placebo-controlled study of platinum plus pemetrexed chemotherapy plus osimertinib versus platinum plus pemetrexed chemotherapy plus placebo in patients with epidermal growth factor receptor mutation-positive (EGFRm), locally advanced or metastatic NSCLC with or wihout stable brain metastases who responded to first-line osimertinib therapy (complete response [CR] or partial response [PR]) or stable disease (SD) for ≥ 6 months during first-line osimertinib treatment, and subsequently experienced radiological, extracranial disease progression. Approximately 204 patients were to be randomized in a 1:1 ratio to treatment with platinum plus pemetrexed chemotherapy plus osimertinib (Treatment Arm A) or platinum plus pemetrexed chemotherapy plus placebo (Treatment Arm B). However, the number of patients has been reduced to approximately 80 patients due to treatment landscape changes which outpaced study recruitment. Patients will be stratified based on the presence of brain metastases (stable brain metastases based on central nervous system (CNS) Response Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST 1.1] assessments versus no brain metastases). The 2 randomized treatment regimens are as follows: Treatment Arm A: Osimertinib 80 mg once daily (QD) with pemetrexed (500 mg/m^2) (with pre-treatment) plus either cisplatin (75 mg/m^2) or carboplatin (area under the concentration-time curve [AUC] 5), both administered on Day 1 of 21-day cycles for 4 cycles, followed by osimertinib 80 mg QD plus pemetrexed maintenance (500 mg/m^2) on Day 1 of 21-day cycles Treatment Arm B: Placebo QD with pemetrexed (500 mg/m^2) (with pre-treatment) plus either cisplatin (75 mg/m^2) or carboplatin (AUC5), both administered on Day 1 of 21-day cycles for 4 cycles, followed by placebo QD plus pemetrexed maintenance (500 mg/m^2) on Day 1 of 21-day cycles.

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Platinum Plus Pemetrexed Chemotherapy Plus Osimertinib Versus Platinum Plus Pemetrexed Chemotherapy Plus Placebo in Patients With EGFRm, Locally Advanced or Metastatic NSCLC Who Have Progressed Extracranially Following First-Line Osimertinib Therapy (COMPEL)

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Osimertinib (AZD9291) pemetrexed cisplatin or carboplatin
* Drug: Placebo for osimertinib (AZD9291) pemetrexed cisplatin or carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol. Pathologically confirmed non-squamous NSCLC. Locally advanced (clinical stage IIIB or IIIC) or metastatic NSCLC (clinical stage IVA or IVB) or recurrent NSCLC, not amenable to curative surgery or radiotherapy. Evidence of radiological extracranial disease progression following (Investigator-assessed) response or SD for ≥ 6 months during first-line osimertinib treatment, but who have not received further, subsequent treatment. Tumor known to harbor 1 of the 2 or both common epidermal growth factor receptor (EGFR) mutations known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations, which may include T790M. World Health Organization performance status of 0 to 1 at screening with no clinically significant deterioration in the previous 2 weeks. Life expectancy >12 weeks at Day 1. At least 1 lesion, not previously irradiated, that can be accurately measured. Females must be using highly effective contraceptive measures, and must have a negative pregnancy test prior to start of dosing if of childbearing potential, or must have evidence of non-childbearing potential by fulfilling criteria at screening. Male patients must be willing to use barrier contraception Exclusion Criteria: Clinical or radiological evidence of CNS progression on first-line osimertinib. Past medical history of interstitial lung disease (ILD)/pneumonitis, drug-induced ILD/pneumonitis, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD/pneumonitis. Any evidence of severe or uncontrolled systemic diseases. Any of the following cardiac criteria: i) Mean resting QTc >470 msec ii) Any clinically important abnormalities in rhythm, conduction, or morphology of resting electrocardiogram iii) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events Any concurrent and/or other active malignancy that has required treatment within 2 years of first dose of investigational product (IP). Any unresolved toxicities from prior therapy. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of osimertinib. More than 4 weeks elapsed since last dose of osimertinib by date of randomization. Unable to tolerate osimertinib 80 mg first-line therapy. Prior treatment with any systemic anti-cancer therapy. Major surgery within 4 weeks of the first dose of IP. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of IP. Current use of medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP) 3A4. Participation in another clinical study with an IP other than first-line osimertinib during the 4 weeks prior to Day 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm A<br>All randomized patients will receive osimertinib 80 mg QD with pemetrexed (500 mg/m^2) (with pre-treatment) plus either cisplatin (75 mg/m^2) or carboplatin ([AUC] 5), both administered on Day 1 of 21-day cycles for 4 cycles, followed by osimertinib 80 mg QD plus pemetrexed maintenance (500 mg/m^2) on Day 1 of 21-day cycles | Drug: Osimertinib (AZD9291) pemetrexed cisplatin or carboplatin<br>* Randomized patients will receive oral dose of osimertinib with intravenous (IV) pemetrexed plus either IV cisplatin or IV carboplatin<br>|
| Placebo Comparator: Treatment Arm B<br>All randomized patients will receive placebo QD with pemetrexed (500 mg/m^2) (with pre-treatment) plus either cisplatin (75 mg/m^2) or carboplatin (AUC5), both administered on Day 1 of 21-day cycles for 4 cycles, followed by placebo QD plus pemetrexed maintenance (500 mg/m^2) on Day 1 of 21-day cycles | Drug: Placebo for osimertinib (AZD9291) pemetrexed cisplatin or carboplatin<br>* Randomized patients will receive oral dose of placebo matching osimertinib with IV pemetrexed plus either IV cisplatin or IV carboplatin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival(PFS):time from randomization until progression(intra- or extracranial whichever occurs first)per RECIST 1.1(for extracranial)and CNS RECIST 1.1(for intracranial progression)as assessed by Investigator or death due to any cause | To compare the efficacy of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo based on PFS | At Screening,every 6 weeks for the first 13 cycles (each cycle is 21 days),then every 12 weeks, relative to randomization,and upto intracranial or extracranial disease progression or end of survival follow-up,whichever comes first (approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intracranial PFS is defined as time from randomization until intracranial progression per CNS RECIST 1.1 as assessed by the Investigator at local site or death due to any cause | To compare the efficacy of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo based on intracranial PFS in patients with baseline brain metastases and patients without baseline brain metastases | At Screening,every 6 weeks for the first 13 cycles (each cycle is 21 days), then every 12 weeks, relative to randomization, and upto intracranial disease progression or end of survival follow-up, whichever comes first (approximately 3 years) | 
| Extracranial PFS is defined as time from randomization until extracranial progression per RECIST 1.1 as assessed by the Investigator at local site or death due to any cause | To compare the efficacy of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo based on extracranial PFS | At Screening,every 6 weeks for the first 13 cycles (each cycle is 21 days), then every 12 weeks, relative to randomization, and upto extracranial disease progression or end of survival follow-up, whichever comes first (approximately 3 years) | 
| OS: the length of time from randomization until the date of death due to any cause | To compare the efficacy of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo based on OS | From randomization through post progression survival follow-up (up to approximately 3 years) | 
| Number of patients with serious and non-serious adverse events | To assess the safety and tolerability of chemotherapy plus osimertinib treatment relative to chemotherapy plus placebo in patients with locally advanced or metastatic EGFRm NSCLC whose disease has progressed extracranially on first-line osimertinib treatment. | From screening through post progression survival follow-up (at least once every 12 weeks relative to randomization) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extracranial progression, Osimertinib, Platinum, Pemetrexed, Epidermal growth factor receptor mutation positive (EGFRm)