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Patients receive pembrolizumab IV over 30 minutes and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 3 weeks until disease progression or development of unacceptable toxicity.

Patients receive pembrolizumab IV over 30 minutes, bevacizumab IV over 30-90 minutes, and CDX-1140 IV over 90 minutes on day 1. Cycles repeat every 3 weeks until disease progression or development of unacceptable toxicity.

Anti-CD40 Agonist Monoclonal Antibody CDX-1140

Quality-of-Life Assessment

Questionnaire Administration

Emese Zsiros

Amir A. Jazaeri

This phase II trial tests whether pembrolizumab combined with bevacizumab with or without agonist anti-CD40 CDX-1140 works to shrink tumors in patients with ovarian cancer that has come back (recurrent). Anti-CD40 CDX-1140 works by stimulating certain immune cells within the tumor and, when combined with other immunotherapy treatments, may increase antitumor antibody production. Immunotherapy with monoclonal antibodies, such as pembrolizumab and bevacizumab, may help the body's immune system, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab and bevacizumab with anti-CD40 CDX-1140 may decrease symptoms, prolonged survival, and improve quality of life in patients with ovarian cancer.

PRIMARY OBJECTIVES:

I. Determine the safety of anti-CD40 agonist monoclonal antibody CDX-1140 (CDX-1140) combined with pembrolizumab and bevacizumab in patients with recurrent ovarian cancer (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0).

II. Determine the objective response rate (ORR) per immune related response criteria (immune-modified Response Evaluation Criteria in Solid Tumors \[iRECIST\]).

SECONDARY OBJECTIVES:

I. Determine progression free survival (PFS), disease control rate (DCR) and overall survival (OS).

II. Changes in quality of life measures during the clinical trial (European Organization for Research and Treatment of Cancer \[EORTC\] Quality of Life Questionnaire-Core 30 \[QLQ-C30\], EORTC QLQ-Ovarian Cancer Module \[OV28\] and Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF)\].

EXPLORATORY OBJECTIVES:

I. Pharmacokinetic (PK)/anti-drug antibody (ADA) analysis for CDX-1140. II. Evaluate the immunologic and phenotypic changes in blood samples. III. To obtain data on changes in tumor microenvironment prior to and subsequent to therapy and, to screen for potential biomarkers to predict clinical benefit.

IV. Microbiome analysis from stool, tumor tissue.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive pembrolizumab intravenously (IV) over 30 minutes and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 3 weeks until disease progression or development of unacceptable toxicity.

ARM II: Patients receive pembrolizumab IV over 30 minutes, bevacizumab IV over 30-90 minutes, and CDX-1140 IV over 90 minutes on day 1. Cycles repeat every 3 weeks until disease progression or development of unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6 months for 2 years.

Pembrolizumab Combined With Bevacizumab With or Without Agonist Anti-CD40 CDX-1140 for the Treatment of Patients With Recurrent Ovarian Cancer

Randomized Phase 2 Clinical Trial of Pembrolizumab Combined With Bevacizumab With or Without Agonist Anti-CD40 CDX-1140 in Patients With Recurrent Ovarian Cancer

Evaluated according to National Cancer Institute Common Terminology Criteria for adverse events (NCI CTCAE) version (v)5.0. Will be summarized by cohort and grade using frequencies and relative frequencies.

Will be summarized by cohort (with or without CDX 1140) using frequencies and relative frequencies, with the ORR estimated using 90% confidence intervals obtained by Jeffrey's prior method. The final analysis will be performed on all n=80 (40 in each cohort) evaluable patients; and if the p-value is less than or equal to 0.10, then the triplet regimen will be considered superior with respect to response.

Will be summarized by cohort using standard Kaplan-Meier methods, with estimates of the median obtained with 90% confidence intervals. PFS will be compared between cohorts using a one-sided log-rank test.

Will be summarized by cohort using standard Kaplan-Meier methods, with estimates of the median obtained with 90% confidence intervals. OS will be compared between cohorts using a one-sided log-rank test.

Will be summarized by cohort using frequencies and relative frequencies, with the DCR estimated by cohort using 90% confidence intervals obtained by Jeffrey's prior method. The DCR will be compared between cohorts using a one-sided Cohran-Mantel-Haenszel test.

European Organization for Research and Treatment of Cancer (EORTC) QLQ-30 consists of 28 questions with answers that range from 1 (Not At All) to 4 (Very Much) and 2 questions that range from 1 (Very Poor) to 7 (Excellent)

National Cancer Institute (NCI)

Merck Sharp & Dohme LLC

Celldex Therapeutics

Roswell Park Cancer Institute

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pembrolizumab Combined With Bevacizumab With or Without Agonist Anti-CD40 CDX-1140 for the Treatment of Patients With Recurrent Ovarian Cancer	NCT05231122	Ovarian Clear C... Platinum-Sensit... Recurrent Endom... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Plati... Recurrent Prima... Recurrent Prima... Recurrent Prima... Recurrent Prima...	Anti-CD40 Agoni... Bevacizumab Pembrolizumab Quality-of-Life... Questionnaire A...	18 Years -	Roswell Park Cancer Institute
Pembrolizumab Combined With Bevacizumab With or Without Agonist Anti-CD40 CDX-1140 for the Treatment of Patients With Recurrent Ovarian Cancer	NCT05231122	Ovarian Clear C... Platinum-Sensit... Recurrent Endom... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Plati... Recurrent Prima... Recurrent Prima... Recurrent Prima... Recurrent Prima...	Anti-CD40 Agoni... Bevacizumab Pembrolizumab Quality-of-Life... Questionnaire A...	18 Years -	Roswell Park Cancer Institute
Pembrolizumab Combined With Bevacizumab With or Without Agonist Anti-CD40 CDX-1140 for the Treatment of Patients With Recurrent Ovarian Cancer	NCT05231122	Ovarian Clear C... Platinum-Sensit... Recurrent Endom... Recurrent Fallo... Recurrent Fallo... Recurrent Fallo... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Ovari... Recurrent Plati... Recurrent Prima... Recurrent Prima... Recurrent Prima... Recurrent Prima...	Anti-CD40 Agoni... Bevacizumab Pembrolizumab Quality-of-Life... Questionnaire A...	18 Years -	Roswell Park Cancer Institute

Spots Global Cancer Trial Database for recurrent fallopian tube serous adenocarcinoma