A Study to Evaluate MEDI0562 in Combination With Immune Therapeutic Agents in Adult Subjects With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate MEDI0562 in combination with immune therapeutic agents in adult subjects with select advanced solid tumors.

Detailed Description
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This is a Phase 1 multicenter, open-label study to evaluate the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity of MEDI0562 in combination with immune therapeutic agents in adult subjects with select advanced solid tumors.

Official Title
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A Phase 1 Multicenter, Open-label, Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Antitumor Activity of MEDI0562 in Combination With Immune Therapeutic Agents in Adult Subjects With Advanced Solid Tumors

Conditions
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Select Advanced Solid Tumors

Intervention / Treatment
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* Biological: MEDI0562
* Biological: Tremelimumab
* Biological: Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following criteria: Written and signed informed consent. Age ≥ 18 years at the time of study entry. Subjects must have received and have progressed, are refractory, or are intolerant to standard therapy appropriate for the specific tumor type. Subjects should not have received more than 3 prior lines of systemic therapy for recurrent or metastatic. Subjects in the dose-escalation phase, must have histologic documentation of advanced solid tumors, excluding primary CNS tumors and hematologic malignancies. Subjects in the dose-expansion phase, must have recurrent or metastatic disease solid tumors according to treatment arm as specified in the protocol. Subjects who have received prior therapy with regimens containing CTLA 4, PD L1, or PD 1 antagonists are permitted to enroll if additional protocol criteria are met. Subjects must have at least 1 lesion that is measurable using RECIST guidelines. Subjects must consent to provide archived tumor specimens for correlative biomarker studies. In the setting where archival material is unavailable or unsuitable for use, subjects must consent and undergo fresh tumor biopsy. All subjects are encouraged to consent to and provide both pretreatment and on treatment tumor biopsies. ECOG Performance score of 0 or 1, unless protocol exceptions are met. In the opinion of the investigator likely to complete ≥ 8 weeks of treatment. Adequate hematologic, renal and hepatic function as determined by blood laboratory values. At the time of Day 1 of the study, subjects with CNS metastases must have been treated and must be asymptomatic and meet the following: No concurrent treatment, inclusive of, but not limited to surgery, radiation, and/or corticosteroids At least 42 days without progression of CNS metastases as evidenced by magnetic resonance imaging (MRI) or computed tomography (CT) after last day of treatment At least 14 days since last dose of corticosteroids Note: Subjects with leptomeningeal disease or cord compression are excluded from the study. Female subjects of childbearing potential who are sexually active with a non-sterilized male partner must use at least 1 highly effective method of contraception from screening, and must agree to continue using such precautions for 180 days after the final dose of investigational product. Non-sterilized male subjects who are sexually active with a female partner of childbearing potential must use male condom plus, if locally available, spermicide from Day 1 and for 180 days after receipt of the final dose of investigational product. Exclusion Criteria: Any of the following would exclude the subject from participation in the study: Prior treatment with TNFRSF agonists Prior treatment with IMT for certain disease types may be restricted per protocol. History of severe allergic reactions to any unknown allergens or any components of the study drug formulations Active or prior documented autoimmune disease within the past 2 years. Concurrent enrollment in another clinical study, unless it is an observational clinical study or the follow up period of an interventional study Receipt of any conventional or investigational anticancer therapy not otherwise specified above within 28 days prior to the first dose Any concurrent chemotherapy, IMT, or biologic or hormonal therapy for cancer treatment. Unresolved toxicities from prior anticancer therapy. Systemic therapeutic anticoagulation or daily aspirin dose exceeding 325 mg/per day. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of MEDI0562 with exceptions as per protocol. History of primary immunodeficiency, solid organ transplantation, or tuberculosis Test results indicating active infection with human immunodeficiency virus (HIV) or hepatitis B or C defined by positive serologic testing and confirmatory viral nucleic acid testing Pregnant or breastfeeding women Major surgery within 4 weeks prior to first dose of MEDI0562 or still recovering from prior surgery. Other invasive malignancy within 2 years with the exception of protocol specified criteria Any uncontrolled intercurent illness or condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Arm A: MEDI0562 and durvalumab<br>MEDI0562 and durvalumab | Biological: MEDI0562<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease (PD), or development of other reason for treatment discontinuation.<br>Biological: Durvalumab<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease (PD), or development of other reason for treatment discontinuation.<br>|
| Experimental: Arm B: MEDI0562 and tremelimumab<br>MEDI0562 and tremelimumab | Biological: MEDI0562<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease (PD), or development of other reason for treatment discontinuation.<br>Biological: Tremelimumab<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease (PD), or development of other reason for treatment discontinuation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as defined by the presence of adverse events (AE), serious adverse events (SAE), and dose limiting toxicities (DLT). | The primary endpoint is safety as assessed by presence of adverse event (AE), serious adverse event (SAE), and dose limiting toxicity (DLT). | From time of informed consent through 12 weeks after ending treatment with investigational product | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary Antitumor Activity:Best Overall Response | The endpoints for assessment of antitumor activity include Best Overall Response (BOR) and will be based on all post-baseline disease assessments that occur prior to the initiation of subsequent anticancer therapy | At approximately 3 time points through Day 113. | 
| Pharmacokinetics of MEDI0562/durvalumab or MEDI0562/tremelimumab: Cmax | The endpoints for assessment of PK of MEDI0562 and durvalumab or tremelimumab include individual MEDI0562, durvalumab, and tremelimumab concentrations at different time points after administration. PK parameters that may be modeled on these data include, but are not limited to, maximum observed concentration (Cmax). | To be assessed at approximately 12 clinic visits through Day 113 | 
| Immunogenicity | The endpoints for assessment of immunogenicity of MEDI0562, durvalumab, and tremelimumab include the number and percentage of subjects who develop detectable anti drug antibodies (ADAs). | At approximately 8 time points through Day 113. | 
| Pharmacodynamic Activity | The endpoints for assessment of pharmacodynamic activity include induction of proliferation markers in various lymphocyte populations and assessment of tumor-infiltrating lymphocytes (TILs) in tumor biopsy specimens. | At approximately 12 time points through Day 113. | 
| Preliminary Antitumor Activity: Disease Control | The endpoints for assessment of antitumor activity include disease control and is defined as CR, PR, or SD according to RECIST v1.1 | At approximately 3 time points through Day 113. | 
| Preliminary Antitumor Activity: Duration of Response | The endpoints for assessment of antitumor activity include duration of response (DoR) and is defined as the duration from the first documentation of OR to the first documentation of disease progression or death due to any cause. | At approximately 3 time points through Day 113. | 
| Preliminary Antitumor Activity: Progression-free Survival | The endpoints for assessment of antitumor activity include progression-free survival (PFS) and is defined as the duration measured from the start of treatment with investigational product to the first documentation of disease progression or death due to any cause | At approximately 3 time points through Day 113. | 
| Preliminary Antitumor Activity: Overall Survival | The endpoints for assessment of antitumor activity include overall survival (OS) and is defined as the time from the start of treatment with Investigational Product until death due to any cause. | At approximately 3 time points through Day 113. | 
| Pharmacokinetics of MEDI0562/durvalumab or MEDI0562/tremelimumab: AUC | The endpoints for assessment of PK of MEDI0562 and durvalumab or tremelimumab include individual MEDI0562, durvalumab, and tremelimumab concentrations at different time points after administration. PK parameters that may be modeled on these data include area under the concentration-time curve (AUC). | To be assessed at approximately 12 clinic visits through Day 113 | 
| Pharmacokinetics of MEDI0562/durvalumab or MEDI0562/tremelimumab: Clearance | The endpoints for assessment of PK of MEDI0562 and durvalumab or tremelimumab include individual MEDI0562, durvalumab, and tremelimumab concentrations at different time points after administration. PK parameters that may be modeled on these data include clearance (CL). | To be assessed at approximately 12 clinic visits through Day 113 | 
| Pharmacokinetics of MEDI0562/durvalumab or MEDI0562/tremelimumab: t½ | The endpoints for assessment of PK of MEDI0562 and durvalumab or tremelimumab include individual MEDI0562, durvalumab, and tremelimumab concentrations at different time points after administration. PK parameters that may be modeled on these data include terminal phase half-life (t½). | To be assessed at approximately 12 clinic visits through Day 113 | 
| Preliminary Antitumor Activity: Objective Response | The endpoints for assessment of antitumor activity include objective response (OR) and is defined as confirmed CR or confirmed PR based on RECIST v1.1 | At approximately 3 time points through Day 113. | 
| Preliminary Antitumor Activity: Time to Response | The endpoints for assessment of Time to Response TTR and is defined as the time of first treatment to a subsequently confirmed CR or confirmed PR based on RECIST v1.1 | At approximately 3 time points through Day 113. | 
| Preliminary Antitumor Activity: Percent Change from Baseline | The endpoints for assessment percent change from baseline in target lesion sum of diameters will be calculated at each adequate post baseline disease assessment with recorded measurement for all target lesions defined at baseline. | At approximately 3 time points through Day 113. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumors, MEDI0562, durvalumab, tremelimumab, OX40, PD-L1, CTLA-4, immuno-oncology, Cancer