Neoplasms

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Gland and Hormone Related Diseases

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Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

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Cystadenocarcinoma, Serous

Adenocarcinoma, Clear Cell

Cystadenocarcinoma

Carcinoma, Endometrioid

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

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Female Urogenital Diseases

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Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Cystic, Mucinous, and Serous

Endometrial Neoplasms

Uterine Neoplasms

Ovarian Cancer

Ovarian Epithelial Cancer

Fallopian Tube Cancer

Adenocarcinoma of the Appendix

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Bevacizumab

Pembrolizumab

Immunoglobulins

Immunoglobulin G

Endothelial Growth Factors

Mitogens

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Immunologic Factors

Immune Checkpoint Inhibitors

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

Bone Density Conservation Agents

Anticoagulants

Anti-Infective Agents

Other Dietary Supplements

Paclitaxel

Albumin-Bound Paclitaxel

Tamoxifen

Doxorubicin

Liposomal doxorubicin

Letrozole

Topotecan

Citric Acid

Sodium Citrate

Trametinib

Dimethyl Sulfoxide

Tubulin Modulators

Antimitotic Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Aromatase Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Topoisomerase I Inhibitors

Antineoplastic Agents, Hormonal

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Protein Kinase Inhibitors

Protective Agents

Antioxidants

Citrate

Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.

Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Pegylated Liposomal Doxorubicin Hydrochloride

Tamoxifen Citrate

Trametinib Dimethyl Sulfoxide

David M Gershenson

This phase II/III trial studies how well trametinib works and compares it to standard treatment with either letrozole, tamoxifen, paclitaxel, pegylated liposomal doxorubicin, or topotecan in treating patients with low-grade ovarian cancer or peritoneal cavity cancer that has come back (recurrent), become worse (progressive), or spread to other parts of the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib is more effective than standard therapy in treating patients with ovarian or peritoneal cavity cancer.

PRIMARY OBJECTIVE:

I. To estimate the progression-free survival (PFS) hazard ratio of trametinib compared to that of "commercially available therapies" consisting of one of five commercially available agents in women with recurrent low-grade serous carcinoma of the ovary or peritoneum previously treated with platinum-based chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the nature, frequency and maximum degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4 for each treatment arm.

II. To determine the quality of life, as assessed by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O).

IIa. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) quality of life as measured by the FACT-O-Trial Outcome Index (TOI).

IIb. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) neurotoxicity as measured by the FACT-Gynecologic Oncology Group (GOG)-Neurotoxicity (NTX).

III. To estimate the objective response rate (RR) of patients in each treatment arm.

IV. To test whether high expression of pERK, as quantified by immunohistochemistry (IHC), is associated with better prognosis (RR or PFS) among patients receiving the randomized treatment.

V. To test whether genetic changes associated with MAPK pathway activation (KRAS, NRAS, HRAS, BRAF, MEK, ERBB2 or NF1) are associated with improved prognosis (RR or PFS) among patients receiving the randomized treatment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive clinician's choice of either letrozole orally (PO) once daily (QD) on days 1-28, tamoxifen citrate PO twice daily (BID) on days 1-28, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride (PLD) IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.

ARM B: Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer

A Randomized Phase II/III Study to Assess the Efficacy of Trametinib (GSK 1120212) in Patients With Recurrent or Progressive Low-Grade Serous Ovarian Cancer or Peritoneal Cancer

Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the PFS endpoint definition.

Number of treated patients with Adverse Events (grade 3 or higher) observed while receiving randomized therapy. Excludes AEs observed among control patients treated with trametinib after crossover.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the AE endpoint definition.

Overall survival (OS) was defined as the number of months between study enrollment and death from any cause. Patients still alive at the last follow-up were censored on the date of last contact. Patients with disease progression on the Control arm were allowed to cross over to the trametinib arm. Per the protocol, the intent-to-treat OS analysis was not adjusted for crossover.

The Response Rates were estimated as the binomial proportion of patients with Best Overall Response of Complete or Partial response according to RECIST 1.1 criteria.

Patient reported quality of life was measured with the Treatment Outcome Index (TOI) of the Functional Assessment of Cancer Therapy for ovarian cancer (FACT-O TOI). The FACT-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). . The FACT-O TOI score is calculated as the sum of the subscale scores if more than 80% of the FACT-O TOI items provide valid answers and all of the component subscales have valid scores. The FACT-O TOI score ranges 0-100 with a large score suggesting better QOL. Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the quality of life endpoint definition

Patient reported peripheral neuropathy symptoms was measured with the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - neurotoxicity subscale (short version) (FACT/GOG-Ntx subscale). The FACT/GOG-Ntx subscale contains 4 items. Each item was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). According to the FACIT measurement system, the Ntx score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the scale. The Ntx score ranges 0-16 with a large score suggesting less peripheral neuropathy symptoms

Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan. RECIST v1.1 defines progression as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Will be quantified using the H-score derived from the immunohistochemistry analysis of patient tumor tissue and is expected to present as a continuous measure. will consider the prognostic and predictive abilities of pERK relative to objective response rate (ORR) or PFS. Analysis of the dichotomous markers will be supported by Kaplan Meier plots, and forest plots of the odds-ratio and hazard ratio estimates. Duration of response will be depicted using swimmer plots, with median duration estimated using Kaplan Meier methods. The multivariable models will include covariate adjustment for geographic region, performance status and number of prior regimens, presented using effect coding. The adjusted hazard- and odds- ratio estimates from the multivariable models will be supported by nominal p-values and 2-sided, 95% confidence intervals. Confidence intervals will be interpreted as the plausible range of values for the true (unobserved) ratio that is supported by the data.

NRG Oncology

Investigators choice of Letrozole 2.5 mg po qd continuously, tamoxifen 20mg po bid continuously, paclitaxel 80mg/m2 IV over 1 hr on day 1q 7d, 3 wks on, 1 wk off, Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV over 1 hr on day 1 q. 28d, Topotecan 4.0mg/m2 over 30 min on day 1,8 and 15 of a 28 day cycle. For each arm, 1 cycle - 28 days

Arm A - Control Arm

Trametinib 2 mg po daily continuous treatment, For each arm, 1 cycle = 28 days

Arm B - Experimental Arm

Patients randomized to the control arm who crossed over to the experimental arm after disease progression.

Crossover From Control to Experimental Arm

Total

Age, Continuous

20-29 years

30-39 years

40-49 years

50-59 years

60-69 years

>= 70 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

United Kingdom

Region of Enrollment

1 Prior Treatment Regimens

2 Prior Treatment Regimens

3 or More Prior Treatment Regimens

Number of Prior Treatment Regimens

The pERK expression analysis is still under development, and will not be available for approximately 2 - 3 years.

Linda Gedeon for Austin Miller, PhD

Progression-free Survival (PFS)

Abdominal pain

Anemia

Diarrhea

Fatigue

Hypertension

Nausea

Neutrophil count decreased

Rash maculo-papular

Small Intestinal Obstruction

Vomiting

Incidence of Adverse Events (AEs)

Overall Survival

Objective Tumor Response Rate (Complete Response and Partial Response)

Baseline

12 Weeks

24 Weeks

36 Weeks

52 Weeks

Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.

Letrozole: Given PO

Paclitaxel: Given IV

Pegylated Liposomal Doxorubicin Hydrochloride: Given IV

Quality-of-Life Assessment: Ancillary studies

Tamoxifen: Given PO

Tamoxifen Citrate: Given PO

Topotecan: Given IV

Topotecan Hydrochloride: Given IV

Arm A (Letrozole, Tamoxifen, Paclitaxel, PLD, Topotecan)

Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Quality-of-Life Assessment: Ancillary studies

Trametinib: Given PO

Trametinib Dimethyl Sulfoxide: Given PO

Arm B (Trametinib)

Patients who provided baseline and ≥ 1 follow-up assessment

Patients Reported Acute Quality of Life

Patients that provided baseline and ≥ 1 follow-up assessment

Patient Reported Acute Peripheral Neuropathy Symptoms

Prognostic effect of the mutation status among patients in the SOC arm.

KRAS/BRAF/NRAS mutant group (MAPK pathway) (Trametinib treatment) - Whole Exome Sequencing

KRAS/BRAF/NRAS Mutant Group (MAPK Pathway) (Trametinib)

KRAS/BRAF/NRAS mutant group (MAPK pathway) (Standard of Care treatment) - Whole Exome Sequencing

KRAS/BRAF/NRAS Mutant Group (MAPK Pathway) (SOC)

KRAS/BRAF/NRAS wild-type (MAPK pathway) (Trametinib treatment) - Whole Exome Sequencing

KRAS/BRAF/NRAS Wild-type (MAPK Pathway) (Trametinib)

KRAS/BRAF/NRAS wild-type (MAPK pathway) (Standard of Care treatment) - Whole Exome Sequencing

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
Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer	NCT02101788	Borderline Ovar... Micropapillary ... Ovarian Serous ... Primary Periton... Recurrent Ovari... Recurrent Prima...	Letrozole Paclitaxel Pegylated Lipos... Quality-of-Life... Questionnaire A... Tamoxifen Citra... Topotecan Trametinib Dime...	18 Years -	National Cancer Institute (NCI)
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 primary peritoneal serous adenocarcinoma