A Study to Evaluate MEDI5752 in 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 MEDI5752 and carboplatin and pemetrexed or paclitaxel or nab-paclitaxel in adult subjects with advanced solid tumors, when administered as a single agent or combined with chemotherapy.

Detailed Description
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This is a phase 1, first-time-in-human, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety and tolerability, and efficacy, pharmacokinetics and Immunogenicity of MEDI5752 and carboplatin and pemetrexed or paclitaxel or nab-paclitaxel in adult subjects with advanced solid tumors, when administered as a single agent or combined with chemotherapy.

Official Title
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A Phase 1, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability Pharmacokinetics Immunogenicity, and Antitumor Activity of MEDI5752 in Subjects With Advanced Solid Tumors.

Conditions
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Selected Advanced Solid Tumors

Intervention / Treatment
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* Biological: MEDI5752
* Drug: Pemetrexed
* Drug: Carboplatin
* Biological: Pembrolizumab
* Drug: Paclitaxel or Nab-Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age ≥ 18 years at the time of screening World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment Life expectancy ≥ 12 weeks Histologically or cytologically-confirmed advanced solid tumors Subjects who have received prior anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy or any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment may be eligible to enter the study following a washout period as applicable Females of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective method of contraception Nonsterilized males who are sexually active with a female partner of childbearing potential must use a male condom with spermicide where locally available from Day 1 and for 90 days after the final dose of investigational product. Males receiving pemetrexed or carboplatin must use contraception during study treatment and up to 6 months thereafter. Subjects must have at least one measurable lesion Adequate organ and marrow function Written informed consent and any locally required authorization Subjects must provide tumor material as applicable Exclusion Criteria Involvement in the planning and/or conduct of the study (applies to both MedImmune staff and/or staff at the study site) Concurrent enrollment in another clinical study, unless it is an observational clinical study or the follow-up period of an interventional study For subjects who have received prior anti-PD-1, anti-PD-L1, or anti-CTLA-4: Subjects must not have received anti-PD-1, anti-PD-L1, anti-CTLA-4 or any other immunotherapy or immune-oncology (IO) agent within 21 days of commencing treatment with investigational product. Subject must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. All AEs while receiving prior immunotherapy must have completely resolved or resolved to Grade 1 prior to screening for this study. Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product is excluded. Receipt of live attenuated vaccine within 30 days prior to the first dose of investigational product. Active or prior documented autoimmune or inflammatory disorders History of active primary immunodeficiency: History of organ transplant Known allergy or reaction to any component of the planned study treatment. Untreated CNS metastatic disease, leptomeningeal disease, or cord compression Unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v4.03 Grade 0 or 1, or to levels dictated in the inclusion/exclusion criteria Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of Investigational Product or still recovering from prior surgery Female subjects who are pregnant or breastfeeding, as well as male or female subjects of reproductive potential who are not willing to employ one highly effective method of birth control Uncontrolled intercurrent illness, that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent. Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of the subject's safety or study results Judgment by the investigator that the subject is unsuitable to participate in the study and the subject is unlikely to comply with study procedures, restrictions, and requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: MEDI5752<br>MEDI5752 | Biological: MEDI5752<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease, or development of other reason for treatment discontinuation.<br>|
| Experimental: Arm B: MEDI5752 and chemotherapy<br>MEDI5752, pemetrexed, carboplatin and paclitaxel. | Biological: MEDI5752<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease, or development of other reason for treatment discontinuation.<br>Drug: Pemetrexed<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease, or development of other reason for treatment discontinuation<br>Drug: Carboplatin<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease, or development of other reason for treatment discontinuation<br>Drug: Paclitaxel or Nab-Paclitaxel<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease, or development of other reason for treatment discontinuation<br>|
| Active Comparator: Arm C: Pembrolizumab and chemotherapy<br>pembrolizumab, pemetrexed, and carboplatin | Drug: Pemetrexed<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease, or development of other reason for treatment discontinuation<br>Drug: Carboplatin<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease, or development of other reason for treatment discontinuation<br>Biological: Pembrolizumab<br>* Subjects will remain on treatment until unacceptable toxicity, documentation of progressive disease, 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 |
| --- | --- | --- |
| The number of subjects experiencing treatment related adverse events (AEs) (Dose-escalation phase) | The primary endpoint is as assessed by the number of subjects experiencing adverse events (AEs) graded per NCI CTCAE v4.03 | From the time of informed consent through 114 days following termination of treatment with investigational product | 
| Preliminary anti-tumor activitiy of MEDI5752 (versus pembrolizumab, where applicable) using Objective Response based on RECIST v1.1 (Dose-expansion phase) | The primary endpoint of antitumor activity include Objective Response and will be based on all post baseline disease assessments that occur prior to initiation of subsequent anticancer therapy. | From the first dose of study drug through the date of first documented progression, end of study, date of death, or two years after the last patient starts treatment, whichever should occur first | 
| The number of subjects experiencing dose-limiting toxicities (DLTs) (Dose-escalation phase) | The primary endpoint is as assessed by the number of subjects experiencing dose limiting toxicities (DLTs) as defined by the protocol. | Up to 21 days following the first dose | 
| The number of subjects experiencing abnormal laboratory evaluations (Dose-escalation phase) | The primary endpoint is as assessed as the number of subjects experiencing changes in laboratory parameters from baseline. | From the time of informed consent through 114 days following termination of treatment with investigational product | 
| The number of subjects experiencing changes from baseline in vital signs reported as adverse events (Dose-escalation phase) | The primary endpoint is as assessed by the number of subjects experiencing clinically significant changes in vital signs from baseline. | From the time of informed consent through 114 days following termination of treatment with investigational product | 
| The number of subjects experiencing abnormal electrocardiograms (ECG) reported as Adverse Events (Dose-escalation phase) | The primary endpoint is as assessed by the the number of subjects experiencing clinically significant changes in ECG parameters from baseline. | From the time of informed consent through 114 days following termination of treatment with investigational product | 
| The number of subjects experiencing treatment related serious adverse events (SAEs) (Dose-escalation phase) | The primary endpoint is as assessed by the number of subjects with serious adverse events (SAEs) graded per NCI CTCAE v4.03. | From the time of informed consent through 114 days following termination of treatment with investigational product | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of MEDI5752: Cmax | The endpoints for the assessment of PK of MEDI5752 include individual MEDI5752 concentrations at different time points after administration. PK parameters that may be modeled on this data include maximum observed concentration (Cmax) | To be assessed at Day 1, 2, 3, 8, 15, 22, 29, 43, 64, 85, and 106 over the first 4 months of treatment and up to 114 days following end of treatment | 
| Pharmacokinetics of MEDI5752: AUC | The endpoints for the assessment of PK of MEDI5752 include individual MEDI5752 concentrations at different time points after administration. PK parameters that may be modeled on this data include area under the concentration-time curve (AUC) | To be assessed at Day 1, 2, 3, 8, 15, 22, 29, 43, 64, 85, and 106 over the first 4 months of treatment and up to 114 days following end of treatment | 
| Pharmacokinetics of MEDI5752: Clearance | The endpoints for the assessment of PK of MEDI5752 include individual MEDI5752 concentrations at different time points after administration. PK parameters that may be modeled on this data include clearance (CL) | To be assessed at Day 1, 2, 3, 8, 15, 22, 29, 43, 64, 85, and 106 over the first 4 months of treatment and up to 114 days following end of treatment | 
| Pharmacokinetics of MEDI5752: t 1/2 | The endpoints for the assessment of PK of MEDI5752 include individual MEDI5752 concentrations at different time points after administration. PK parameters that may be modeled on this data include terminal phase half life (t 1/2) | To be assessed at Day 1, 2, 3, 8, 15, 22, 29, 43, 64, 85, and 106 over the first 4 months of treatment and up to 114 days following end of treatment. | 
| Ability of MEDI5752 to generate immune response in subjects with advanced solid tumors | The endpoints for the immunogenicity of MEDI5752 include the number of subjects who develop detectable anti-drug antibodies (ADAs) | To be assessed at Day 1, 8, 15, 22, 29, 43, 64, 85, and 106 over the first 4 months of treatment and up to 114 days following end of treatment. | 
| PD-L1 Expression in subjects with advanced solid tumors | The endpoint for the PD-L1 expression will be determined by Immunohistochemistry characterization. | To be assessed at baseline | 
| 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 documentation of OR to the first documentation of disease progression or death due to any cause. | From the date of response through the date of first documented progression, end of study, date of death, or two years after last subject starts treatment whichever should occur first | 
| Preliminary Antitumor Activity: Disease Control | The endpoints for assessment of antitumor activity include disease control (DC) and is defined as CR, PR, or SD according to RECIST v1.1. | From the first dose of study drug through the date of first documented progression, end of study, date of death, or two years after last subject starts treatment whichever should occur first | 
| 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. | From the first dose of study drug through the date of first documented progression, end of study, date of death, or two years after last subject starts treatment whichever should occur first | 
| Preliminary Antitumor Activity: Overall Survival | The endpoints for assessment of antitumor activity include overall survival (OS) and is defined as the duration measured from the start of treatment with investigational product until death due to any cause. | From the first dose of study drug through the end of study, or date of death, or two years after last subject starts treatment whichever should occur first | 
| The number of subjects experiencing treatment related adverse events (AEs) (Dose-expansion phase) | The secondary endpoint is as assessed by the number of subjects experiencing adverse events (AEs) graded per NCI CTCAE v4.03 | From the time of informed consent through 114 days following termination of treatment with investigational product | 
| The number of subjects experiencing abnormal laboratory evaluations (Dose-expansion phase) | The secondary endpoint is as assessed by the number of subjects experiencing changes in laboratory parameters from baseline. | From the time of informed consent through 114 days following termination of treatment with investigational product | 
| The number of subjects experiencing Changes from baseline in vital signs reported as adverse events (Dose-expansion phase) | The secondary endpoint is as assessed by the number of subjects experiencing clinically significant changes in vital signs from baseline. | From the time of informed consent through 114 days following termination of treatment with investigational product | 
| The number of subjects experiencing abnormal ECGs reported as adverse events (Dose-expansion phase) | The secondary endpoint is as assessed by the number of subjects experiencing clinically significant changes in ECG parameters from baseline. | From the time of informed consent through 14 days following termination of treatment with investigational product | 
| The number of subjects experiencing treatment related serious adverse events (SAEs) (Dose-expansion phase) | The secondary endpoint is as assessed by the number of subjects with serious adverse events (SAEs) graded per NCI CTCAE v4.03 | From the time of informed consent through 114 days following termination of treatment with investigational product | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumors, MEDI5752, immuno-oncology, Cancer, PD-1/CTLA-4 Bispecific, PD-1, CTLA-4, Bispecific, Chemotherapy, Pemetrexed, Carboplatin, Pembrolizumab