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

• ClinicalTrials.gov Identifier: NCT03381274
• Recruitment Status: Active, not recruiting
• First Posted: December 21, 2017
• Results First Posted: July 26, 2022
• Last Update Posted: March 10, 2023
• Sponsor: MedImmune LLC
• Information provided by (Responsible Party): MedImmune LLC

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Non-Small-Cell Lung	Biological: Oleclumab; Drug: Osimertinib; Drug: AZD4635	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 43 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multiarm, Open-label, Multicenter, Phase 1b/2 Study to Evaluate Novel Combination Therapies in Subjects With Previously Treated Advanced EGFRm NSCLC
• Actual Study Start Date: May 8, 2018
• Actual Primary Completion Date: May 24, 2021
• Estimated Study Completion Date: January 3, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Oleclumab Dose 1 + Osimertinib Dose 1; 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; Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.; Other Name: MEDI9447; Drug: Osimertinib; Participants will receive osimertinib in combination with oleclumab as stated in the arms' description.; Other Name: Tagrisso®
Experimental: Oleclumab Dose 2 + Osimertinib Dose 1; 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; Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.; Other Name: MEDI9447; Drug: Osimertinib; Participants will receive osimertinib in combination with oleclumab as stated in the arms' description.; Other Name: Tagrisso®
Experimental: Oleclumab Dose 1 + AZD4635 Dose 1; In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 1 QD.	Biological: Oleclumab; Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.; Other Name: MEDI9447; Drug: AZD4635; Participants will receive AZD4635 in combination with oleclumab as stated in the arms' description.
Experimental: Oleclumab Dose 1 + AZD4635 Dose 2; In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 2 QD.	Biological: Oleclumab; Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.; Other Name: MEDI9447; Drug: AZD4635; Participants will receive AZD4635 in combination with oleclumab as stated in the arms' description.
Experimental: Oleclumab Dose 2 + AZD4635 Dose 2; In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral AZD4635 Dose 2 QD.	Biological: Oleclumab; Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.; Other Name: MEDI9447; Drug: AZD4635; Participants will receive AZD4635 in combination with oleclumab as stated in the arms' description.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Dose-limiting Toxicities (DLTs) in Part 1 [ Time Frame: From Day 1 to Day 28 after first dose of study drug ]
   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.
2. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Parts 1 and 2 [ Time Frame: From Day 1 through 90 days of the last dose of study drug (approximately 37 months) ]
   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.
3. Number of Participants With Abnormal Laboratory Parameters Reported as TEAEs in Parts 1 and 2 [ Time Frame: From Day 1 through 90 days of the last dose of study drug (approximately 37 months) ]
   Participants with abnormal laboratory parameters reported as TEAEs are reported. Laboratory analysis included hematology, clinical chemistry, thyroid function tests, and urinalysis.
4. Number of Participants With Abnormal Vital Signs and Physical Examination Reported as TEAEs in Parts 1 and 2 [ Time Frame: From Day 1 through 90 days of the last dose of study drug (approximately 37 months) ]
   Participants with abnormal vital signs (heart rate, blood pressure, temperature, and respiratory rate) and physical examination reported as TEAEs are reported.
5. Number of Participants With Notable QTc Interval in Parts 1 and 2 [ Time Frame: From Day 1 through 90 days of the last dose of study drug (approximately 37 months) ]
   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.
6. Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 in Part 2 [ Time Frame: From Day 1 through 90 days of the last dose of study drug (approximately 37 months) ]
   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.

Secondary Outcome Measures :

1. Duration of Response (DoR) Per RECIST v 1.1 for Parts 1 and 2 [ Time Frame: From Day 1 through 90 days of the last dose of study drug (approximately 37 months) ]
   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.
2. Percentage of Participants With Disease Control (DC) in Parts 1 and 2 [ Time Frame: From Day 1 through 90 days of the last dose of study drug (approximately 37 months) ]
   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.
3. Progression Free Survival (PFS) for Parts 1 and 2 [ Time Frame: From Day 1 through 90 days of the last dose of study drug (approximately 37 months) ]
   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.
4. Overall Survival (OS) for Parts 1 and 2 [ Time Frame: From Day 1 through 90 days of the last dose of study drug (approximately 37 months) ]
   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.
5. Percentage of Participants With OR by T790M Status at Baseline (Determined by a Central Laboratory) for Parts 1 and 2 [ Time Frame: From Baseline (Days -28 to -1) through 90 days of the last dose of study drug (approximately 37 months) ]
   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.
6. Percentage of Participants With DC by T790M Status at Baseline (Determined by a Central Laboratory) for Parts 1 and 2 [ Time Frame: From Baseline (Days -28 to -1) through 90 days of the last dose of study drug (approximately 37 months) ]
   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.
7. Observed Serum Concentration at the Time of End of Infusion (CEOI) of Oleclumab (MEDI9447) Over Time [ Time Frame: Predose (within 90 minutes prior to start of infusion) and postdose (10 minutes after the end of infusion) on Days 1 and 57 ]
   The CEOI of oleclumab is reported.
8. Observed Lowest Serum Concentration (Ctrough) of MEDI9447 Over Time [ Time Frame: Predose (within 90 minutes prior to start of infusion) on Day 57 ]
   The Ctrough of oleclumab is reported.
9. Maximum Plasma Concentration (Cmax) of Osimertinib and Its Metabolite (AZ5104) [ Time Frame: Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, and 4 hours) on Days 1 and 29 ]
   The Cmax of osimertinib and AZ5104 are reported.
10. Cmax of AZD4635 and Its Metabolites (SSP-005173X and SSP-005174X) [ Time Frame: Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, 4, 6, and 24 hours) on Days 1 and 57 ]
    The Cmax of AZD4635, SSP-005173X, and SSP-005174X are reported.
11. Tmax of AZD4635 and Its Metabolites (SSP-005173X and SSP-005174X) [ Time Frame: Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, 4, 6, and 24 hours) on Days 1 and 57 ]
    The Tmax of AZD4635, SSP-005173X, and SSP-005174X are reported.
12. 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) [ Time Frame: Predose (within 90 minutes prior to start of infusion) and postdose (1, 2, 4, 6, and 24 hours) on Days 1 and 57 ]
    The AUC0-24 of AZD4635, SSP-005173X, and SSP-005174X are reported.
13. Number of Participants With Positive Post-baseline for Anti-oleclumab Antibodies [ Time Frame: 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) ]
    Number of participants with positive post-baseline for anti-oleclumab antibodies are reported.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 101 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥ 18
2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
3. Weight ≥ 35 kg

4. 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:

1. Receipt of an EGFR TKI within 14 days of the first dose of study treatment
2. Receipt of any conventional or investigational anticancer therapy not otherwise specified within 21 days of the planned first dose
3. Prior receipt of any investigational immunotherapy. Participants may have received agents that have local health authority approval for the disease indication
4. Concurrent enrollment in another therapeutic clinical study. Enrollment in observational studies will be allowed.
5. Participants with a history of venous thrombosis within the past 3 months
6. Participants with prior history of myocardial infarction, transient ischemic attack, or stroke in the last 6 months
7. Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment
8. Other invasive malignancy within 2 years
9. Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression
10. Current or prior use of immunosuppressive medication within 14 days prior to the first dose

Additional Exclusion Criteria for Arm A

1. Concurrent treatment (or inability to stop therapy) with medications or herbal supplements known to be potent inducers of cytochrome P (CYP) 3A4
2. 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
3. Participants requires continuous supplemental oxygen for any reason

Additional Exclusion Criteria for Arm B

1. Herbal preparations/medications are not allowed throughout the study
2. History of seizures excluding those that occurred due to previously untreated CNS metastasis

Contacts and Locations

Locations

United States, California

Research Site

La Jolla, California, United States, 92093

Research Site

San Francisco, California, United States, 94143

United States, Colorado

Research Site

Aurora, Colorado, United States, 80045

United States, Connecticut

Research Site

New Haven, Connecticut, United States, 06510

United States, Georgia

Research Site

Atlanta, Georgia, United States, 30322

United States, Illinois

Research Site

Chicago, Illinois, United States, 60611

United States, Maryland

Research Site

Baltimore, Maryland, United States, 21224

United States, New York

Research Site

New York, New York, United States, 10032

United States, Texas

Research Site

Houston, Texas, United States, 77030

Korea, Republic of

Research Site

Seoul, Korea, Republic of, 03080

Research Site

Seoul, Korea, Republic of, 05505

Research Site

Seoul, Korea, Republic of, 06351

Taiwan

Research Site

Taichung, Taiwan, 40705

Sponsors and Collaborators

MedImmune LLC

Investigators

• Study Director: MedImmune LLC; MedImmune LLC

  Study Documents (Full-Text)

Documents provided by MedImmune LLC:

Study Protocol  [PDF] February 1, 2021

Statistical Analysis Plan  [PDF] June 18, 2018

More Information

Additional Information:

D6070C00004 redacted protocol 

D6070C00004 SAP redacted 

D6070C00004 CSR Synopsis redacted 

• Responsible Party: MedImmune LLC
• ClinicalTrials.gov Identifier: NCT03381274
• Other Study ID Numbers: D6070C00004
• First Posted: December 21, 2017
• Results First Posted: July 26, 2022
• Last Update Posted: March 10, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by MedImmune LLC:

EGFR mutated; CD73; A2AR; Oleclumab; MEDI9447; AZD4635; Osimertinib; NSCLC; Immunotherapy

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Osimertinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action