Study of Inupadenant (EOS100850) With Chemotherapy as Second Line Treatment for Nonsquamous Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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Part 1 of the study determines the optimal dose of inupadenant to be given in combination with carboplatin and pemetrexed to patients that progressed after receiving specific first line treatments for Stage 3 or metastatic non-small cell lung cancer. Part 2 compares the efficacy of inupadenant to placebo when both are combined with carboplatin and pemetrexed for patients that progressed after receiving the same first line treatments for Stage 3 or metastatic non-small cell lung cancer.

Detailed Description
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In both Part 1 and Part 2, there are two nonsquamous NSCLC patient populations eligible for the study treatment: 1)patients with Stage III, non-resectable cancer that have received chemoradiotherapy, followed by durvalumab, and then have progressed; 2)patients who have received only first-line immunotherapy with anti-PD-L1 therapy, but no chemotherapy, in the metastatic setting, then progressed. In Part 1, all participants receive open-label inupadenant with standard of care doses of carboplatin and pemetrexed. Carboplatin is given at q3week intervals for no more than 4 cycles; pemetrexed continues at q3week as prescribed by the Investigator. Inupadenant is given orally BID. Dose-limiting toxicities are monitored during the first 21 days of treatment and a modified 3+3 escalation method is utilized to determine the recommended phase 2 dose (RP2D). Imaging and safety and PRO assessments are performed during the treatment and follow-up phase. Treatment continues until progression, withdrawal of consent, start of new anti-cancer treatment, end of study, or death. Part 2 is double-blinded, with subjects randomized 1:1 to receive the RP2D of inupadenant or matched placebo. All subjects receive the carboplatin and pemetrexed per standard of care. Imaging, safety and PRO assessments are performed during the treatment and follow-up phase. Treatment continues until progression, withdrawal of consent, start of new anti-cancer treatment, end of study, or death. In both Parts 1 and 2, blood samples are drawn to further define the pharmacokinetic profile of inupadenant and biosamples are collected for additional exploratory analyses.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Phase 2 Study Evaluating Efficacy and Safety of Inupadenant in Combination With Carboplatin and Pemetrexed in Adults With Nonsquamous Non-small Cell Lung Cancer Who Have Progressed on Immunotherapy

Conditions
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Metastatic NSCLC, Stage III NSCLC

Intervention / Treatment
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* Drug: inupadenant
* Drug: Placebo
* Drug: Carboplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of metastatic (Stage IV) or locally advanced, unresectable (Stage III) NSCLC of nonsquamous pathology that has relapsed or progressed Measurable disease as defined by RECIST v1.1 criteria PD-L1 expression status available at or after the time of diagnosis of advanced or metastatic NSCLC disease Can provide existing biopsy taken within 2 years prior to entering trial or provide fresh biopsy Have relapsed or progressed after prior anti- PD-(L)1 therapy as follows: At least 12 weeks of treatment with only 1 line of anti-PD-(L)1 therapy (mono or combo) in the metastatic setting, without concomitant chemotherapy OR At least 12 weeks of single-agent durvalumab Adequate organ function ECOG performance status of 0 to 1. Exclusion Criteria: Symptomatic and/or untreated central nervous system (CNS) metastases or leptomeningeal disease. Presence of active second malignancy EGFR or ALK mutation. Participants with presence of other driver mutations are allowed if targeted therapy is not available as per local standard of care. Preexisting gastrointestinal disorders/conditions that may interfere with ingestion or absorption of oral medications. History of or active (non-infectious) pneumonitis/ interstitial disease or lung fibrosis, except for Grade 1 pneumonitis from prior chemoradiation therapy (Stage III patients). History of or active autoimmune disease requiring systemic treatment in the last 6 months or persistent immune-mediated toxicity caused by checkpoint inhibitor therapy > Grade 2 Known active or chronic hepatitis B or C infection unless adequately treated for at least 4 weeks with no detectable viral load; known infection with human immunodeficiency virus (HIV) unless receiving antiretroviral therapy with well-controlled disease. History of life-threatening toxicity related to prior immune therapy or any toxicity resulting in permanent discontinuation from prior therapy. Diagnosis of immunodeficiency or any condition requiring concurrent use of systemic immunosuppressants or corticosteroids. Active infection requiring systemic therapy ≤ 7 days prior to first dose of study treatment. Any other oncologic treatments administered ≤14 days (<28 days in case of checkpoint inhibitor therapy) prior to first dose of study treatment. Also, ongoing adverse effects from such treatment > Grade 1 with the exception for alopecia and Grade 2 peripheral neuropathy. Non-study related minor surgical procedure ≤7 days, or major surgical procedure of ≤ 5 weeks prior to first dose of study treatment. Uncontrolled or significant cardiovascular disease History of allergy or hypersensitivity to any of the study treatments. Treatment with a live or live attenuated vaccine. Treatment with moderate or strong inducers or inhibitor of CYP 3A4, inhibitors of P-glycoprotein, or substrates of breast cancer resistance protein Pregnant or breast-feeding Male and Female participants: Lack of agreement to use highly effective method of contraception during treatment and for 6 months after the last administration of chemotherapy

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Single Group Assignment Part 1 sequential dose escalation. Part 2 randomized double-blind.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1, open label<br>Inupadenant will be given at one or more dose levels to determine the recommended Phase 2 dose (RP2D). | Drug: inupadenant<br>* Adenosine 2a receptor antagonist<br>* Other names: EOS100850;Drug: Carboplatin<br>* standard of care chemotherapeutic, alkylating agent<br>Drug: Pemetrexed<br>* standard of care chemotherapeutic, anti-metabolite<br>* Other names: Alimta;|
| Experimental: Part 2, active treatment<br>Treatment with inupadenant combined with carboplatin and pemetrexed | Drug: inupadenant<br>* Adenosine 2a receptor antagonist<br>* Other names: EOS100850;Drug: Carboplatin<br>* standard of care chemotherapeutic, alkylating agent<br>Drug: Pemetrexed<br>* standard of care chemotherapeutic, anti-metabolite<br>* Other names: Alimta;|
| Placebo Comparator: Part 2, placebo<br>Treatment with matched placebo combined with carboplatin and pemetrexed | Drug: Placebo<br>* matched placebo capsule to inupadenant<br>Drug: Carboplatin<br>* standard of care chemotherapeutic, alkylating agent<br>Drug: Pemetrexed<br>* standard of care chemotherapeutic, anti-metabolite<br>* Other names: Alimta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-finding to determine recommended Phase 2 dose | Incidence of dose-limiting toxicities | At the end of Cycle 1 (each cycle is 21 days) | 
| Incidence of treatment-emergent adverse events [Safety and Tolerability] | Incidence of adverse events (AEs), serious adverse events, AEs leading to discontinuation, deaths, and clinically significant laboratory abnormalities. | Duration of intervention (up to 24 months) plus 30 days follow-up | 
| Progression-free survival [Efficacy] | Time from first dose to the date of first documented radiologic progression per RECIST v1.1 or time of death, which ever comes first | From randomization to first-documented radiological progression or date of death from any cause, whichever comes first, assessed up to 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate [Efficacy] | Proportion of participants with a best overall response of complete (CR) or partial (PR) response as assessed by RECIST v1.1 | From randomization to first-documented radiological improvement, if applicable, assessed up to 24 months. | 
| Duration of Response [Efficacy] | Time from first CR or PR to first documented progression or death from any cause, per RECIST v1.1 | From first-documented CR or PR to first radiological progression or date of death, whichever comes first, assessed up to 24 months. | 
| Percent Change in Tumor Size [Efficacy] | Change in sum of size of target tumors from baseline, per RECIST v1.1 | From randomization to the documented radiological assessment with the smallest tumor size sum, assessed up to 24 months. | 
| Disease Control Rate [Efficacy] | Proportion of participants with CR, PR, or stable disease (SD) sustained over at least 2 consecutive tumor assessments, per RECIST v1.1 | From randomization to second-documented radiological CR, PR or SD, if applicable, assessed up to 24 months. | 
| Overall Survival [Efficacy] | Time from randomization to date of death due to any cause. | From randomization to death due to any cause, assessed up to 24 months. | 
| Efficacy (Patient Reported Outcomes) | Time to definitive deterioration in global health status/quality of life | Duration of intervention (up to 24 months) plus 30 days follow-up | 
| Peak plasma concentration (Cmax) | Cmax for inupadenant and its primary metabolite as observed by assessment of concentration-time profile | From first dose of inupadenant through 24 hours | 
| Time to peak plasma concentration (Tmax) | Tmax for inupadenant and its primary metabolite as observed by assessment of concentration-time profile | From first dose of inupadenant through 24 hours | 
| Plasma half-life (T-1/2) | T-1/2 for inupadenant and its primary metabolite | At the end of Cycle 12 (each cycle is 3 weeks) | 
| Area under the concentration-time curve (AUCinf) | AUC from Time 0 extrapolated to infinity for inupadenant and its primary metabolite | At the end of Cycle 12 (each cycle is 3 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-squamous NSCLC