A Phase 1b/2 Safety and Tolerability Study of MEDI6469 in Combination With Therapeutic Immune Agents or Monoclonal Antibodies

Study Overview
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Brief Summary
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The main purpose of this study is to determine the best dose of MEDI6469 that is safe and tolerable when given as monotherapy and in combination with tremelimumab, MEDI4736 (durvalumab), or rituximab in participants with either advanced solid tumors or diffuse large B-cell lymphoma (DLBCL). Tremelimumab and MEDI4736 (durvalumab) will be tested with MEDI6469 in a set of participants with advanced solid tumors while rituximab will be tested with MEDI6469 in participants with DLBCL. MEDI6469 will be tested as monotherapy in participants with advanced solid tumors.

Official Title
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A Phase 1b/2, Open-label Study to Evaluate the Safety and Tolerability of MEDI6469 in Combination With Immune Therapeutic Agents or Therapeutic Monoclonal Antibodies in Subjects With Selected Advanced Solid Tumors or Aggressive B-cell Lymphomas

Conditions
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Advanced Solid Tumors, Aggressive B-cell Lymphomas

Intervention / Treatment
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* Biological: MEDI6469 Monotherapy
* Biological: MEDI6469 Plus Tremelimumab
* Biological: MEDI6469 Plus Durvalumab
* Biological: MEDI6469 plus Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults >/= 18 years old Histologically or cytologically confirmed advanced solid tumors that are refractory to standard therapy or for which no standard therapy exists (Monotherapy and in Cohorts A and B) At least one lesion measurable by RECIST not previously irradiated (Monotherapy and in Cohorts A and B) Histologically confirmed DLBCL(Cohort C) Adequate organ and marrow function ECOG performance status of 0 or 1 Willingness to provide consent for biopsy samples Exclusion Criteria: Prior exposure to immunotherapy (either as a single agent or in combination) including but not limited to CD137 or OX40 agonists, anti-CTLA-4, anti-PD-1, or anti-PD-L1, anti-PD-L2 antibody or pathway-targeting agents History of organ transplant that requires use of immunosuppressives History of primary immunodeficiency or tuberculosis Active or prior documented autoimmune disease within the past 3 years Active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months Major surgical procedure within 30 days prior to the first dose of investigational product or still recovering from prior surgery Women who are pregnant or lactating

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: MEDI6469 6 mg/kg<br>Participants received MEDI6469 6 milligram/kilogram (mg/kg) as a single intravenous (IV) administration on Day 1 | Biological: MEDI6469 Monotherapy<br>* single intravenous (IV) administration of MEDI6469<br>|
| Experimental: MEDI6469 10 mg/kg<br>Participants received MEDI6469 10 mg/kg as a single IV administration on Day 1 | Biological: MEDI6469 Monotherapy<br>* single intravenous (IV) administration of MEDI6469<br>|
| Experimental: MEDI6469 2 mg/kg+Tremelimumab 3 mg/k<br>Participants received MEDI6469 2 mg/kg as a single IV administration on Day 1 plus tremelimumab 3 mg/kg as IV administration on Day 1 then every 4 weeks (Q4W) for 6 doses, after which every 12 weeks (Q12W) for 2 doses or until PD | Biological: MEDI6469 Plus Tremelimumab<br>* MEDI6469 in combination with Tremelimumab<br>|
| Experimental: MEDI6469 2 mg/kg+Tremelimumab 10 mg/kg<br>Participants received MEDI6469 2 mg/kg as a single IV administration on Day 1 plus tremelimumab 10 mg/kg as IV administration on Day 1 then Q4W for 6 doses after which Q12W for 2 doses or until progression of disease (PD) | Biological: MEDI6469 Plus Tremelimumab<br>* MEDI6469 in combination with Tremelimumab<br>|
| Experimental: MEDI6469 2 mg/kg+Durvalumab 3 mg/kg<br>Participants received MEDI6469 2 mg/kg as a single IV administration on Day 1 plus durvalumab 3 mg/kg as IV administration on Day 1 then every 2 weeks (Q2W) for 12 months or until PD | Biological: MEDI6469 Plus Durvalumab<br>* MEDI6469 in combination with Durvalumab<br>|
| Experimental: MEDI6469 2 mg/kg+Durvalumab 10 mg/kg<br>Participants received MEDI6469 2 mg/kg as a single IV administration on Day 1 plus durvalumab 10 mg/kg as IV administration on Day 1, then Q2W for 12 months or until PD | Biological: MEDI6469 Plus Durvalumab<br>* MEDI6469 in combination with Durvalumab<br>|
| Experimental: MEDI6469 10 mg/kg+Durvalumab 10 mg/kg<br>Participants received MEDI6469 10 mg/kg as a single IV administration on Day 1 plus durvalumab 10 mg/kg as IV administration on Day 1, then Q2W for 12 months or until PD | Biological: MEDI6469 Plus Durvalumab<br>* MEDI6469 in combination with Durvalumab<br>|
| Experimental: MEDI6469 2 mg/kg+Rituximab 375 mg/m^2<br>Participants received MEDI6469 2 mg/kg as a repeat IV administration on Day 3 then Q4W for 11 doses, or until confirmed complete response (CR) plus 1 cycle, or PD plus rituximab 375 mg/m^2 as IV administration on Days 1, 8, and 29; then Q4W for 10 doses, or until confirmed CR plus 1 cycle, or PD | Biological: MEDI6469 plus Rituximab<br>* MEDI6469 in combination with Rituximab<br>|
| Experimental: MEDI6469 10 mg/kg+Rituximab 375 mg/m^2<br>Participants received MEDI6469 10 mg/kg as a repeat IV administration on Day 3 then Q4W for 11 doses, or until confirmed CR plus 1 cycle, or PD plus rituximab 375 mg/m2 as IV administration on Days 1, 8, and 29; then Q4W for 10 doses, or until confirmed CR plus 1 cycle, or PD | Biological: MEDI6469 plus Rituximab<br>* MEDI6469 in combination with Rituximab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of MEDI6469 | The MTD was the highest dose within a cohort where no more than 1 out of 6 participants experienced dose-limiting toxicities (DLTs) or the highest protocol-defined dose for each agent in the absence of exceeding the MTD. | From the first dose of study treatment through 28 days after the first dose (up to 28 days) | 
| Number of Participants With DLTs | The DLT was any Grade 3 or higher treatment-related toxicity (including liver transaminase elevation higher than 8×upper limit of normal [ULN] or total bilirubin higher than 5×ULN; any >=Grade 2 pneumonitis that did not resolve to <=Grade 1 within 3 days) that occurred during the DLT time frame, and excluded the following: Grade 3 fatigue for less than or equal to (<=) 7 days; Grade 3 endocrinopathy that was managed and the participant was asymptomatic; Grade 3 inflammatory reaction attributed to a local antitumor response that resolved to <=Grade 1 within 30 days; concurrent vitiligo or alopecia of any grade; Grade 3 infusion-related reaction that resolved within 6 hours; and any more than or equal to (>=) Grade 3 lymphopenia (unless clinically significant). | From the first dose of study treatment through 28 days after the first dose (up to 28 days) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. TEAEs were events present at baseline that worsened in intensity after administration of study treatment or events absent at baseline that emerged after administration of study treatment. | From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year) | 
| Number of Participants With Treatment-emergent Serious Adverse Events | A serious adverse event (SAE) was any AE that resulted in death, immediately life threatening, required (or prolonged) inpatient (or existing) hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly or birth defect in offspring of the participant, or an important medical event that could jeopardize the participant or required medical intervention to prevent one of the outcomes listed above. Treatment-emergent SAEs were defined as SAEs present at baseline that worsened in intensity after administration of study treatment or SAEs absent at baseline that emerged after administration of study treatment. | From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year) | 
| Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs | Laboratory evaluations of blood and urine samples were performed, including hematology (white blood cell [WBC] count with differential, red blood cell [RBC] count, hematocrit, hemoglobin, platelet count, mean corpuscular volume [MCV], and mean corpuscular hemoglobin concentration [MCHC]); serum chemistry (calcium, chloride, magnesium, creatinine, sodium, blood urea nitrogen [BUN], bicarbonate, glucose, aspartate transaminase [AST], total bilirubin, C-reactive protein, gamma-glutamyl transpeptidase [GGT], lactate dehydrogenase, uric acid, potassium, alanine transaminase [ALT], alkaline phosphatase, albumin, total protein, triglycerides, and cholesterol); urinalysis; and coagulation parameters. | From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year) | 
| Number of Participants With Vital Signs and Physical Examination Abnormalities Reported as TEAEs | Vital signs examination included assessment of temperature, blood pressure, pulse rate, and respiratory rate. Physical examination included assessments of head, eyes, ears, nose, throat, respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, neurological, psychiatric, dermatological, hematologic/lymphatic, and endocrine systems. The TEAEs related to these vital sign and physical examination abnormalities were reported. | From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year) | 
| Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as TEAEs | Electrocardiogram (ECG) parameters included atrial rate, PR interval, QRS duration, QTC interval, QT interval, and ventricular rate. All 12-lead ECGs performed during the study were obtained in triplicate. The TEAEs related to these ECG evaluation abnormalities were reported. | From study treatment administration (Day 1) to 90 days after the last dose of study treatment or early termination of study (up to 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) | Best overall response: Percentage (%) of participants with CR, partial response (PR), stable disease (SD), progressive disease (PD), or non-evaluable disease based on revised Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1) for monotherapy and combination tremelimumab and durvalumab arms, and Cheson criteria for combination rituximuab arms. Per RECIST v1.1: CR-disappearance of all target/non-target lesions; PR at least a 30% decrease in sum of diameters of target lesions; SD-neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; PD-at least a 20% increase in sum of diameters of target lesions, or a substantial worsening in a non-target lesion, or the appearance of new lesions. Per Cheson criteria: CR-disappearance of all evidence of disease; PR-regression of measurable disease and no new sites; SD-failure to attain CR/PR or PD; PD-any new lesion or increase by at least 50% of previously involved sites from nadir. | From study entry until early termination (up to 1 year) | 
| Objective Response Rate (ORR) | Objective response rate was defined as the percentage of participants with confirmed CR or confirmed PR according to revised RECIST v1.1 for monotherapy and combination tremelimumab and durvalumab arms, and Cheson criteria for combination rituximuab arms. Confirmed CR and PR were those that persisted on repeat consecutive assessment >= 4 weeks after the initial documentation of response. Tumor assessments according to revised RECIST v1.1 were defined as follows: CR - disappearance of all target/non-target lesions; PR - at least a 30% decrease in the sum of the diameters of target lesions. Tumor assessments according to Cheson criteria were defined as follows: CR - disappearance of all evidence of disease; PR- regression of measurable disease and no new sites. | From study entry until early termination (up to 1 year) | 
| Disease Control Rate | Disease control rate: Percentage of participants with CR, PR, or SD (if they maintained SD for >= 8 weeks) according to revised RECIST v1.1 for monotherapy and combination tremelimumab and durvalumab arms, and Cheson criteria for combination rituximuab arms. Tumor assessments according to revised RECIST v1.1 were defined as follows: CR -disappearance of all target/non-target lesions; PR - at least a 30% decrease in sum of diameters of target lesions; SD - neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; PD - at least a 20% increase in sum of diameters of target lesions, or a substantial worsening in a non-target lesion, or the appearance of new lesions. Tumor assessments according to Cheson criteria were defined as follows: CR- disappearance of all evidence of disease; PR - regression of measurable disease and no new sites; SD- failure to attain CR/PR or PD; PD- any new lesion or increase by at least 50% of previously involved sites from nadir. | From study entry until early termination (up to 1 year) | 
| Duration of Response (DOR) | Duration of response was the duration from the first documented objective response to the first documented PD or death due to any cause, whichever occurred first. Progression was based on revised RECIST v1.1 criteria for monotherapy and combination tremelimumab and durvalumab arms, and Cheson criteria for combination rituximuab arms. PD according to revised RECIST v1.1 was defined as: at least a 20% increase in the sum of diameters of target lesions, or a substantial worsening in a non-target lesion, or the appearance of new lesions. PD per Cheson criteria was defined as: any new lesion or increase by at least 50% of previously involved sites from nadir. | From Study entry until early termination (up to 1 year) | 
| Progression-free Survival (PFS) | Progression-free survival was the duration measured from the start of study treatment until the first documentation of PD or death due to any cause, whichever occurred first. Progression was based on revised RECIST v1.1 criteria for monotherapy and combination tremelimumab and durvalumab arms, and Cheson criteria for combination rituximuab arms. PD according to revised RECIST v1.1 was defined as: at least a 20% increase in the sum of diameters of target lesions, or a substantial worsening in a non-target lesion, or the appearance of new lesions. PD per Cheson criteria was defined as: any new lesion or increase by at least 50% of previously involved sites from nadir. | From Study entry until early termination (up to 1 year) | 
| Overall Survival (OS) | The OS was the duration from the start of study treatment until death due to any cause. | From Study entry until early termination (up to 1 year) | 
| Maximum Observed Serum Concentration (Cmax) | The pharmacokinetics (PK) parameter was estimated using the non-compartmental analysis methods, based on the participant serum concentration-time data. The concentration-time curve was the result of blood sampling at specified time points and its measured concentration of MEDI6469 | MEDI6469 monotherapy: Days 1, 2, 3, 8, 15, and 29; MEDI6469 + tremelimumab or durvalumab: Days 1, 2, 3, 4, 8, 15, 29, and end of treatment (up to 1 year); MEDI6469 + rituximab: Days 3, 4, 8, 15, 29, 31, 59, every 28 days thereafter, and end of treatment | 
| Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUC0-inf) | The PK parameter was estimated using the non-compartmental analysis methods, based on the participant serum concentration-time data. The concentration-time curve was the result of blood sampling at specified time points and its measured concentration of MEDI6469 | MEDI6469 monotherapy: Days 1, 2, 3, 8, 15, and 29; MEDI6469 + tremelimumab or durvalumab: Days 1, 2, 3, 4, 8, 15, 29, and end of treatment (up to 1 year); MEDI6469 + rituximab: Days 3, 4, 8, 15, 29, 31, 59, every 28 days thereafter, and end of treatment. | 
| Systemic Clearance (CL) | The PK parameter was estimated using the non-compartmental analysis methods, based on the participant serum concentration-time data. The concentration-time curve was the result of blood sampling at specified time points and its measured concentration of MEDI6469 | MEDI6469 monotherapy: Days 1, 2, 3, 8, 15, and 29; MEDI6469 + tremelimumab or durvalumab: Days 1, 2, 3, 4, 8, 15, 29, and end of treatment (up to 1 year); MEDI6469 + rituximab: Days 3, 4, 8, 15, 29, 31, 59, every 28 days thereafter, and end of treatment. | 
| Terminal Phase Elimination Half-Life (T1/2) | The PK parameter was estimated using the non-compartmental analysis methods, based on the participant serum concentration-time data. The concentration-time curve was the result of blood sampling at specified time points and its measured concentration of MEDI6469 | MEDI6469 monotherapy: Days 1, 2, 3, 8, 15, and 29; MEDI6469 + tremelimumab or durvalumab: Days 1, 2, 3, 4, 8, 15, 29, and end of treatment (up to 1 year); MEDI6469 + rituximab: Days 3, 4, 8, 15, 29, 31, 59, every 28 days thereafter, and end of treatment. | 
| Number of Participants Positive for Human Anti-mouse Antibodies (HAMA) | The number of participants who developed detectable HAMA are presented. ImmuSTRIP® HAMA IgG ELISA Test System was used for detection, confirmation, and titration of HAMA in human serum with a HAMA positivity cut-off level of 74 nanogram per millilitre (ng/mL). | All treatment arms: Days 8, 15, 29, and end of treatment (up to 1 year). Additionally for MEDI6469 + rituximab arm: Days 3, 31, 59, and every 28 days thereafter until end of treatment (up to 1 year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Solid tumors, Diffuse Large B-cell Lymphoma, programmed death 1, programmed dealth ligand 1, cytotoxic T-lymphocyte-associated antigen-4, OX40 ligand