MEDI9447 Alone and in Combination With MEDI4736 in Adult Participants With Select Advanced Solid Tumors.

Study Overview
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Brief Summary
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The purpose of this study is to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of MEDI9447 Alone and in Combination with MEDI4736 in Adult Participants with Select Advanced Solid Tumors

Official Title
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A Phase 1 Multicenter, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of MEDI9447 Alone and in Combination With MEDI4736 in Adult Subjects With Select Advanced Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: Oleclumab
* Drug: Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants; age ≥ 18 Written and signed informed consent must be obtained Have histologic or cytologic documentation of solid tumor including EGFRm NSCLC Participants must have at least 1 lesion that is measurable using RECIST guidelines Participants must consent to provide archived tumor specimens or tumor biopsies for correlative biomarker studies. Eastern Cooperative Oncology Group performance score of 0 or 1 Adequate organ function Exclusion Criteria: Prior treatment with tumor necrosis factor receptor superfamily agonists including OX40, CD27, CD137 (4-1BB), CD357 (GITR). One cohort also excludes anti CTLA-4, PD-L1, and anti PD-L1. Participants who have received prior therapy with regimens containing CTLA-4, PD-L1, or PD-1 antagonists may be permitted to enroll under certain conditions Cardiac or peripheral vascular disease meeting any of the following criteria: Past history of myocardial infarction in the prior 12 months Past history of stroke or transient ischemic attack requiring medical therapy Congestive heart failure ≥ Class 3 based on New York Heart Association Functional Classification Grade 3 or greater edema (eg, peripheral, pulmonary) History of Grade 3 or greater thromboembolic events in the prior 12 months Participants with active tuberculosis are ineligible. In settings where there is clinical or radiographic evidence of tuberculosis, active disease must be ruled out Active or prior documented autoimmune or inflammatory disorders Untreated central nervous system (CNS) metastatic disease Known positive for human immunodeficiency virus (HIV), chronic or active hepatitis B or active hepatitis A or C Other invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, ductal carcinoma in situ of the breast that has been surgically cured Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active peptic ulcer disease or gastritis, uncontrolled hypertension, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirement

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: Dose-escalation: Oleclumab Dose 1<br>Participants will receive oleclumab Dose 1 intravenously (IV) every two weeks (Q2W) until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>|
| Experimental: Dose-escalation: Oleclumab Dose 2<br>Participants will receive oleclumab Dose 2 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>|
| Experimental: Dose-escalation: Oleclumab Dose 3<br>Participants will receive oleclumab Dose 3 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>|
| Experimental: Dose-escalation: Oleclumab Dose 4<br>Participants will receive oleclumab Dose 4 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>|
| Experimental: Dose-escalation: Oleclumab Dose 1 + Durvalumab Dose 1<br>Participants will receive oleclumab Dose 1 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>Drug: Durvalumab<br>* Participants will receive IV infusion of durvalumab as stated in arms' description.<br>|
| Experimental: Dose-escalation: Oleclumab Dose 2 + Durvalumab Dose 1<br>Participants will receive oleclumab Dose 2 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>Drug: Durvalumab<br>* Participants will receive IV infusion of durvalumab as stated in arms' description.<br>|
| Experimental: Dose-escalation: OleclumabDose 3 + Durvalumab Dose 1<br>Participants will receive oleclumab Dose 3 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>Drug: Durvalumab<br>* Participants will receive IV infusion of durvalumab as stated in arms' description.<br>|
| Experimental: Dose-escalation: OleclumabDose 4 + Durvalumab Dose 1<br>Participants will receive oleclumab Dose 4 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>Drug: Durvalumab<br>* Participants will receive IV infusion of durvalumab as stated in arms' description.<br>|
| Experimental: Dose-expansion (CRC): Oleclumab Dose 4 + Durvalumab Dose 1<br>Participants with previously treated microsatellite stable-colorectal cancer (MSS-CRC) will receive oleclumab Dose 4 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>Drug: Durvalumab<br>* Participants will receive IV infusion of durvalumab as stated in arms' description.<br>|
| Experimental: Dose-expansion (Pancreatic adenocarcinoma): Oleclumab Dose 4+ Durvalumab Dose 1<br>Participants with previously treated pancreatic adenocarcinoma will receive oleclumab Dose 4 IV Q2W followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>Drug: Durvalumab<br>* Participants will receive IV infusion of durvalumab as stated in arms' description.<br>|
| Experimental: Dose-expansion (NSCLC): Oleclumab Dose 4 + Durvalumab Dose 1<br>Participants with previously treated EGFRm NSCLC will receive oleclumab Dose 4 IV followed by durvalumab Dose 1 IV Q2W until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or development of other reason for treatment discontinuation, whichever occurs first. | Drug: Oleclumab<br>* Participants will receive IV infusion of oleclumab as stated in arms' description.<br>Drug: Durvalumab<br>* Participants will receive IV infusion of durvalumab as stated in 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 Dose-escalation Phase | A DLT was defined as any Grade 3 or higher treatment-related toxicity that occurred during the DLT-evaluation period, which included any Grade 4 immune-mediated adverse event (imAE), any >= Grade 3 colitis, any Grade 3 or 4 non-infectious pneumonitis irrespective of duration, any Grade 3 imAE (excluding colitis or pneumonitis, did not downgrade to <= Grade 2 within 3 days after onset of the event despite maximal medical supportive care including systemic corticosteroids or did not downgrade to <= Grade 1 or baseline within 14 days), liver transaminase elevation >= 5 × but <= 8 × upper limit of normal (ULN) that did not downgrade to Grade 2 within 5 days after onset with optimal medical management (including systemic corticosteroids), transaminase elevation > 8 × ULN or total bilirubin (TBL) > 5 × ULN regardless of duration or reversibility, or any increase in aspartate aminotransferase or alanine aminotransferase > 3 × ULN and concurrent increase in TBL > 2 × ULN (Hy's Law). | 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) | 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 200.1 weeks (corresponding to maximum observed duration) | 
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs | Participants with abnormal laboratory parameters reported as TEAEs are reported. Laboratory analysis included hematology, clinical chemistry, thyroid function tests, coagulation, and urinalysis. | From Day 1 through 200.1 weeks (corresponding to maximum observed duration) | 
| Number of Participants With Abnormal Vital Signs Reported as TEAEs | Participants with abnormal vital signs (temperature, blood pressure, pulse rate, and respiratory rate) reported as TEAEs are reported. | From Day 1 through 188.1 weeks (corresponding to maximum observed duration) | 
| Number of Participants With Change From Baseline in QTcF | Number of participants with change from Baseline in QTcF (> 60 msec and > 90 msec) is reported. | Baseline (prior to Day 1 dose) through 188.1 weeks (corresponding to maximum observed duration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 | 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, and no new lesions. The PR is defined as >= 30% decrease in the sum of the diameters of target lesions compared to baseline, and the non-target lesion at least stable with no evidence of new lesions. 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. Percentage of participants with OR are reported. | Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration) | 
| Percentage pf Participants With Disease Control (DC) per RECIST v1.1 | The DC is defined as CR, PR, or stable disease (SD) which was maintained by >= 8 weeks from the start of treatment. The SD is defined as neither sufficient shrinkage of target lesion to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study and non-progressive disease and not evaluable or no non-target lesion. The CR is defined as disappearance of all target and non-target lesions, and no new lesions. The PR is defined as >= 30% decrease in the sum of the diameters of target lesions compared to baseline, and the non-target lesion at least stable with no evidence of new lesions. Percentage of participants with DC at >= 8 weeks, >= 16 weeks, and >= 24 weeks are reported. | Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration) | 
| Duration of Response (DoR) per RECIST v1.1 | The DoR is defined as the duration from the first documentation of OR (confirmed CR or PR) to the first documented PD or death due to any cause, whichever occurred first. The CR is defined as disappearance of all target and non-target lesions, and no new lesions. The PR is defined as >= 30% decrease in the sum of the diameters of target lesions compared to baseline, and the non-target lesion at least stable with no evidence of new lesions. 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 or not evaluable response in-between. The PD 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. The DoR was estimated using Kaplan-Meier method. | Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration) | 
| Progression-Free Survival (PFS) | The PFS is defined as the time from the start of study treatment until the documentation of PD based on RECIST version 1.1 or death due to any cause, whichever occurred first. The PD is defined at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of longest diameter recorded since the treatment started, the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. The PFS was estimated using Kaplan-Meier method. | Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration) | 
| Overall Survival (OS) | The OS is defined as the time from the start of treatment with study drug until death due to any cause. The OS was estimated using Kaplan-Meier method. | Baseline (Days -28 to -1) through 53 months (corresponding to maximum observed duration) | 
| Maximum Observed Serum Concentration (Cmax) of MEDI9447 | The Cmax of MEDI9447 (oleclumab) for Cycle 1 and at steady state (Day 57) are reported. | Day 1 (pre-dose, and 10 minutes and 2 hours post end of infusion), Day 57 (pre-dose and 10 minutes post end of infusion) | 
| Area Under the Serum Concentration Time Curve From 0 To 14 Days Post First Dose [AUC(0-14)] of MEDI9447 | The AUC(0-14) of MEDI9447 is reported. | Day 1 (pre-dose; 10 minutes and 2 hours post end of infusion) | 
| Time To Maximum Observed Serum Concentration (Tmax) of MEDI9447 | The Tmax of MEDI9447 for Cycle 1 and at steady state (Day 57) of MEDI9447 are reported. | Day 1 (pre-dose; 10 minutes, 2 hours post end of infusion); Day 57 (pre-dose; 10 minutes post end of infusion) | 
| Observed Lowest Serum Concentration Reached Before the Next Dose (Ctrough) of MEDI9447 | The Ctrough of MEDI9447 for Cycle 1 and at steady state (Day 57) of MEDI9447 are reported. | Day 1 (pre-dose; 10 minutes, 2 hours post end of infusion); Day 57 (pre-dose; 10 minutes post end of infusion) | 
| Accumulation Ratio for Cmax (Rac Cmax) of MEDI9447 | The Rac Cmax of MEDI9447 for Cycle 1 and at steady state (Day 57) of MEDI9447 is reported. | Day 57 (pre-dose; 10 minutes post end of infusion) | 
| Accumulation Ratio for Ctrough (Rac Ctrough) of MEDI9447 | The Rac Ctrough of MEDI9447 is reported. | Day 57 (pre-dose; 10 minutes post end of infusion) | 
| Cmax of MEDI4736 | The Cmax of MEDI4736 (durvalumab) is reported. | Day 1 (prior to start of MEDI9447 infusion and 10 minutes post end of MEDI4736 infusion) | 
| Tmax of MEDI4736 | The Tmax of MEDI4736 is reported. | Day 1 (prior to start of MEDI9447 infusion and 10 minutes post end of MEDI4736 infusion) | 
| Ctrough of MEDI4736 | The Ctrough of MEDI4736 for Cycle 1 and at steady state (Day 57) are reported. | Day 1 (prior to start of MEDI9447 infusion and 10 minutes post end of MEDI4736 infusion), Day 57 (prior to start of MEDI9447 infusion) | 
| Rac Ctrough of MEDI4736 | The Rac Ctrough of MEDI4736 is reported. | Day 57 (prior to start of MEDI4736 infusion) | 
| Number of Participants With Positive Anti-Drug Antibody Response (ADA) to MEDI9447 | Number of participants with positive ADA to MEDI9447 is reported. Persistent positive was defined as positive at >= 2 post-baseline assessments (with >= 16 weeks between first and last positive) or positive at last post-baseline assessment. Transient positive was defined as negative at last post-baseline assessment and positive at only one post-baseline assessment or at >= 2 post-baseline assessments (with < 16 weeks between first and last positive). | Day 1 through 192.3 weeks (Days 1 , 29, and 57, EOT, and 30 days post end of treatment) | 
| Number of Participants With Positive ADA to MEDI4736 | Number of participants with positive ADA to MEDI4736 is reported. Persistent positive was defined as positive at >= 2 post-baseline assessments (with >= 16 weeks between first and last positive) or positive at last post-baseline assessment. Transient positive was defined as negative at last post-baseline assessment and positive at only one post-baseline assessment or at >= 2 post-baseline assessments (with < 16 weeks between first and last positive). | Day 1 through 200.1 weeks (Day 1 through 192.3 weeks (Days 1 , 29, and 57, EOT, and 30 days post end of treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumors,, MEDI9447,, oleclumab,, MEDI4736,, durvalumab,, CD73,, programmed death ligand-1 (PD-L1),, epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC),, immunotherapy,, pancreatic,, colorectal