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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03381274
Recruitment Status : Active, not recruiting
First Posted : December 21, 2017
Results First Posted : July 26, 2022
Last Update Posted : July 26, 2022
Sponsor:
Information provided by (Responsible Party):
MedImmune LLC

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

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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 : December 1, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Osimertinib

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.




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.



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 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

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): NCT03381274


Locations
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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
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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

Additional Information:
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Responsible Party: MedImmune LLC
ClinicalTrials.gov Identifier: NCT03381274    
Other Study ID Numbers: D6070C00004
First Posted: December 21, 2017    Key Record Dates
Results First Posted: July 26, 2022
Last Update Posted: July 26, 2022
Last Verified: July 2022
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

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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 MedImmune LLC:
EGFR mutated
CD73
A2AR
Oleclumab
MEDI9447
AZD4635
Osimertinib
NSCLC
Immunotherapy
Additional relevant MeSH terms:
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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