Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study

Study Overview
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Brief Summary
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The objective of this study is to investigate the safety, tolerability, and antitumor activity of novel combination therapies administered in participants with advanced EGFRm NSCLC.

Official Title
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A Multiarm, Open-label, Multicenter, Phase 1b/2 Study to Evaluate Novel Combination Therapies in Subjects With Previously Treated Advanced EGFRm NSCLC

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Biological: Oleclumab
* Drug: Osimertinib
* Drug: AZD4635


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Weight ≥ 35 kg Diagnosed with histologically or cytologically confirmed locally advanced/metastatic NSCLC with EGFRm For Arm A (Oleclumab + Osimertinib arms): must have received 1 prior line of therapy with an EGFR tyrosine kinase inhibitor (TKI) and confirmed T790M negative For Arm B (Oleclumab + AZD4635 arms): must have received at least 2 but not more than 4 prior lines of therapy. Exclusion Criteria: Receipt of an EGFR TKI within 14 days of the first dose of study treatment Receipt of any conventional or investigational anticancer therapy not otherwise specified within 21 days of the planned first dose Prior receipt of any investigational immunotherapy. Participants may have received agents that have local health authority approval for the disease indication Concurrent enrollment in another therapeutic clinical study. Enrollment in observational studies will be allowed. Participants with a history of venous thrombosis within the past 3 months Participants with prior history of myocardial infarction, transient ischemic attack, or stroke in the last 6 months Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment Other invasive malignancy within 2 years Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression Current or prior use of immunosuppressive medication within 14 days prior to the first dose Additional Exclusion Criteria for Arm A Concurrent treatment (or inability to stop therapy) with medications or herbal supplements known to be potent inducers of cytochrome P (CYP) 3A4 Participants has a history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD Participants requires continuous supplemental oxygen for any reason Additional Exclusion Criteria for Arm B Herbal preparations/medications are not allowed throughout the study History of seizures excluding those that occurred due to previously untreated CNS metastasis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 101 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oleclumab Dose 1 + Osimertinib Dose 1<br>In Part 1 (dose-escalation), participants will receive intravenous oleclumab (MEDI9447) Dose 1 every 2 weeks (Q2W) and oral osimertinib Dose 1 once daily (QD). | Biological: Oleclumab<br>* Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.<br>* Other names: MEDI9447;Drug: Osimertinib<br>* Participants will receive osimertinib in combination with oleclumab as stated in the arms' description.<br>* Other names: Tagrisso®;|
| Experimental: Oleclumab Dose 2 + Osimertinib Dose 1<br>In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD. In Part 2 (dose-expansion), participants (including participants dosed at the RP2D in Part 1) will receive IV oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD until documentation of disease progression, intolerable toxicity, or development of other reason for treatment discontinuation, whichever occurs first. | Biological: Oleclumab<br>* Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.<br>* Other names: MEDI9447;Drug: Osimertinib<br>* Participants will receive osimertinib in combination with oleclumab as stated in the arms' description.<br>* Other names: Tagrisso®;|
| Experimental: Oleclumab Dose 1 + AZD4635 Dose 1<br>In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 1 QD. | Biological: Oleclumab<br>* Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.<br>* Other names: MEDI9447;Drug: AZD4635<br>* Participants will receive AZD4635 in combination with oleclumab as stated in the arms' description.<br>|
| Experimental: Oleclumab Dose 1 + AZD4635 Dose 2<br>In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 2 QD. | Biological: Oleclumab<br>* Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.<br>* Other names: MEDI9447;Drug: AZD4635<br>* Participants will receive AZD4635 in combination with oleclumab as stated in the arms' description.<br>|
| Experimental: Oleclumab Dose 2 + AZD4635 Dose 2<br>In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral AZD4635 Dose 2 QD. | Biological: Oleclumab<br>* Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.<br>* Other names: MEDI9447;Drug: AZD4635<br>* Participants will receive AZD4635 in combination with oleclumab as stated in the arms' description.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs) in Part 1 | A DLT was defined as >= Grade 3 toxicity or adverse events (AE) occurred during DLT evaluation period which included any Grade 4 immune-mediated (immune nature) AE, anemia, thrombocytopenia (present > 4 days), or neutropenia (present > 4 days); >= Grade 3 colitis or pneumonitis or interstitial lung disease (ILD); >= Grade 3 nausea, vomiting, or diarrhea (not resolved to <= Grade 2 in 3 days); Grade 2 pneumonitis or ILD (not resolved to <= Grade 1 in 3 days); Grade 3 thrombocytopenia with bleeding, any grade febrile neutropenia; convulsions, seizures, or stroke; protocol defined elevations of isolated liver transaminase, isolated total bilirubin (TBL), or Hy's Law; confirmed QT interval corrected for heart rate by Fridericia's formula prolongation (>= 501 msec) on triplicate electrocardiograms within a short period of time; or any other toxicity greater than that at baseline, was clinically significant and/or unacceptable, and was judged to be a DLT by the Dose Escalation Committee. | From Day 1 to Day 28 after first dose of study drug | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Parts 1 and 2 | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. | From Day 1 through 90 days of the last dose of study drug (approximately 37 months) | 
| Number of Participants With Abnormal Laboratory Parameters Reported as TEAEs in Parts 1 and 2 | Participants with abnormal laboratory parameters reported as TEAEs are reported. Laboratory analysis included hematology, clinical chemistry, thyroid function tests, and urinalysis. | From Day 1 through 90 days of the last dose of study drug (approximately 37 months) | 
| Number of Participants With Abnormal Vital Signs and Physical Examination Reported as TEAEs in Parts 1 and 2 | Participants with abnormal vital signs (heart rate, blood pressure, temperature, and respiratory rate) and physical examination reported as TEAEs are reported. | From Day 1 through 90 days of the last dose of study drug (approximately 37 months) | 
| Number of Participants With Notable QTc Interval in Parts 1 and 2 | Notable QTc intervals included single beat changes from baseline (Day 1) values (> 30, > 60, and > 90 milliseconds). Participants who had notable QTc interval are reported. | From Day 1 through 90 days of the last dose of study drug (approximately 37 months) | 
| Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 in Part 2 | The OR is defined as confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The PR is defined as >= 30% decrease in the sum of the diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. | From Day 1 through 90 days of the last dose of study drug (approximately 37 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DoR) Per RECIST v 1.1 for Parts 1 and 2 | The DoR is defined as duration from the first documentation of OR (confirmed CR or PR) to the first documented disease progression based on RECIST v1.1 guidelines or death due to any cause, whichever occurs first. A CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. A PR is defined as >= 30% decrease in the sum of the diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. The progressive disease is defined at least a 20% increase in sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started, the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. The DoR was analyzed using Kaplan-Meier method. | From Day 1 through 90 days of the last dose of study drug (approximately 37 months) | 
| Percentage of Participants With Disease Control (DC) in Parts 1 and 2 | The DC is defined as percentage of participants with CR, PR, or stable disease (SD, which was maintained by >= 8 week) based on RECIST v1.1 guidelines. A CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. A PR is defined as >= 30% decrease in the sum of the diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum longest diameter since the study treatment started, and non-progressive disease and not evaluable or no non-target lesion. | From Day 1 through 90 days of the last dose of study drug (approximately 37 months) | 
| Progression Free Survival (PFS) for Parts 1 and 2 | The PFS is defined as the time from the start of study treatment until the documentation of disease progression based on RECIST version 1.1 or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer treatment prior to progression. The progressive disease is defined at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. Participants who were alive and progression-free at the time of data cut-off for analysis had PFS censored at the last tumor assessment date. The PFS was estimated using Kaplan-Meier method. | From Day 1 through 90 days of the last dose of study drug (approximately 37 months) | 
| Overall Survival (OS) for Parts 1 and 2 | The OS is defined as the time from the start of study treatment until death due to any cause. Participants who are alive at the time of data cut-off had OS censored at the last known to be alive date. The OS was estimated using Kaplan-Meier method. | From Day 1 through 90 days of the last dose of study drug (approximately 37 months) | 
| Percentage of Participants With OR by T790M Status at Baseline (Determined by a Central Laboratory) for Parts 1 and 2 | The T790M status was determined by plasma testing in a central laboratory at Baseline (Days -28 to -1). The OR is defined as confirmed CR or confirmed PR based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The PR is defined as >= 30% decrease in the sum of the diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. Cell-free circulating tumor deoxyribonucleic acid (ctDNA) from liquid biopsy was used as a surrogate marker for T790M status in tumor tissue. | From Baseline (Days -28 to -1) through 90 days of the last dose of study drug (approximately 37 months) | 
| Percentage of Participants With DC by T790M Status at Baseline (Determined by a Central Laboratory) for Parts 1 and 2 | The T790M status was determined by plasma testing in a central laboratory at Baseline (Days -28 to -1). The DC is defined as percentage of participants with CR, PR, or SD (maintained by >= 8 week) based on RECIST v1.1 guidelines. A CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. A PR is defined as >= 30% decrease in the sum of longest diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum longest diameter since the study treatment started, and persistence of one or more non-target lesion(s). Cell-free circulating tumor deoxyribonucleic acid (ctDNA) from liquid biopsy was used as a surrogate marker for T790M status in tumor tissue. | From Baseline (Days -28 to -1) through 90 days of the last dose of study drug (approximately 37 months) | 
| Observed Serum Concentration at the Time of End of Infusion (CEOI) of Oleclumab (MEDI9447) Over Time | The CEOI of oleclumab is reported. | Predose (within 90 minutes prior to start of infusion) and postdose (10 minutes after the end of infusion) on Days 1 and 57 | 
| Observed Lowest Serum Concentration (Ctrough) of MEDI9447 Over Time | The Ctrough of oleclumab is reported. | Predose (within 90 minutes prior to start of infusion) on Day 57 | 
| Maximum Plasma Concentration (Cmax) of Osimertinib and Its Metabolite (AZ5104) | The Cmax of osimertinib and AZ5104 are reported. | Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, and 4 hours) on Days 1 and 29 | 
| Cmax of AZD4635 and Its Metabolites (SSP-005173X and SSP-005174X) | The Cmax of AZD4635, SSP-005173X, and SSP-005174X are reported. | Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, 4, 6, and 24 hours) on Days 1 and 57 | 
| Tmax of AZD4635 and Its Metabolites (SSP-005173X and SSP-005174X) | The Tmax of AZD4635, SSP-005173X, and SSP-005174X are reported. | Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, 4, 6, and 24 hours) on Days 1 and 57 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of AZD4635 and Its Metabolites (SSP-005173X and SSP-005174X) | The AUC0-24 of AZD4635, SSP-005173X, and SSP-005174X are reported. | Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, 4, 6, and 24 hours) on Days 1 and 57 | 
| Number of Participants With Positive Post-baseline for Anti-oleclumab Antibodies | Number of participants with positive post-baseline for anti-oleclumab antibodies are reported. | Predose on Days 1 (Baseline), 29, and 57, and later every 12 weeks through the 12 months and 90 days after the last dose of study drug (approximately 37 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD73, EGFR mutated, A2AR, Oleclumab, MEDI9447, AZD4635, Osimertinib, NSCLC, Immunotherapy