Etigilimab and Nivolumab for the Treatment of Platinum-Resistant Recurrent Clear Cell Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

EON: A Single-Arm Phase II Study of Etigilimab (OMP-313M32) in Combination With Checkpoint Inhibition (Nivolumab) in Patients With Platinum-Resistant, Recurrent Epithelial Ovarian Cancer

This phase II trial the side effects and possible benefits of etigilimab and nivolumab in treating patients with platinum-resistant clear cell ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent). Immunotherapy with monoclonal antibodies, such as etigilimab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The goal of this clinical trial is to learn if adding etigilimab to nivolumab therapy can help to control clear cell ovarian, fallopian tube, and primary peritoneal cancers that are resistant to platinum-based therapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Recurrent Platinum-Resistant Ovarian Carcinoma; Recurrent Fallopian Tube Clear Cell Adenocarcinoma; Recurrent Ovarian Clear Cell Adenocarcinoma; Recurrent Platinum-Resistant Fallopian Tube Carcinoma; Recurrent Platinum-Resistant Primary Peritoneal Carcinoma; Recurrent Primary Peritoneal Clear Cell Adenocarcinoma
• Intervention / Treatment: Biological: Nivolumab; Biological: Etigilimab

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the objective response rate of the combination of etigilimab and nivolumab in patients with platinum resistant clear cell ovarian cancer.

II. To evaluate the toxicity of the combination of etigilimab and nivolumab in patients with platinum resistant clear cell ovarian cancer.

SECONDARY OBJECTIVES:

1. To determine progression free survival (PFS) of the combination of etigilimab and nivolumab in patients with platinum resistant clear cell ovarian cancer.

II. To estimate the disease control rate of the combination of etigilimab and nivolumab in patients with platinum resistant clear cell ovarian cancer.

III. To investigate molecular and immunological changes associated with the combination of TIGIT and PD-1 inhibition; specifically to describe changes in T cell populations (including but not limited to CD3, CD8, CD4, FOXP3) and cell proliferation, as well as report changes in the proportion of macrophage phenotypes M1 and M2 (with phenotypic markers potentially including arginase1, CD11b, PDL-1, and CD206).

OUTLINE:

Patients receive etigilimab intravenously (IV) over 30-90 minutes on days 1 and 15 and nivolumab IV over 30 minutes on days 2 and 15 of cycle 1 and days 1 and 15 of subsequent cycles. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ability to provide signed informed consent
• Age >= 18 years at time of study entry
• Willingness and ability to comply with the protocol for the duration of the study including undergoing treatment, biopsy, and scheduled visits and examinations including follow up
• Histology showing recurrent clear cell ovarian, peritoneal, or fallopian tube cancer
• Platinum resistant or refractory disease as defined by progression of disease on a platinum-containing regimen or recurrence of disease within 180 days of previous platinum treatment
• Have measurable disease based on modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. For the purposes of this study measurable disease is defined at least one "target lesion" that can be accurately measured in at least one dimension (longest dimension to be recorded). Each target lesion must be > 20 mm when measured by conventional techniques, including palpation, plain x-ray, computed tomography (CT), and magnetic resonance imaging (MRI), or >10 mm when measured by spiral CT. The target lesion must be distinct from other tumor areas selected for pre-treatment biopsies. Pretreatment imaging must be performed within 4 weeks of starting therapy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Hemoglobin >= 9.0 g/dL (within 28 days of starting study treatment)
• Absolute neutrophil count (ANC) > 1500/mm^3 (within 28 days of starting study treatment)
• Platelet count >=100 x 10^9/L (> 75,000/mm^3) (within 28 days of starting study treatment)
• Serum bilirubin =< 1.5 x upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician (within 28 days of starting study treatment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN unless liver metastases are present, in which case it must be =< 5 x ULN (within 28 days of starting study treatment)
• Measured creatinine clearance (CL) >40 mL/min or calculated creatinine CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (within 28 days of starting study treatment)

• Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
  • Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)

Exclusion Criteria:

• Participation in another clinical study with an investigational product during the last 28 days
• Prior treatment with CD137 agonists, anti-TIGIT antibody, anti-CTLA-4 or anti-PDL1/PD1 antibodies
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) =< 28 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or pharmacokinetic (PK) properties of an agent, a longer wash-out period will be required, as agreed by study sponsors and the investigator

• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria

  • Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the primary investigator
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with investigational therapy may be included only after consultation with the primary investigator
• Any concurrent chemotherapy, investigational produce (IP), biologic, or hormonal therapy for cancer treatment

• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP

  • Note: Local surgery of isolated lesions for palliative intent is acceptable
• History of allogenic organ transplantation

• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion

  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients without active disease in the last 5 years may be included but only after consultation with the primary investigator
  • Patients with celiac disease controlled by diet alone
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events (AEs) or compromise the ability of the patient to give written informed consent
• Any medical, social, or psychological condition that would interfere with evaluation of study treatment or interpretation of patient safety or study results
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)

• History of another primary malignancy except for the following histories.

  • Malignancy treated with curative intent and with no known active disease >= 5 years before the first dose of IP and of low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease
• History of leptomeningeal carcinomatosis
• Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a MRI (preferred) or CT each preferably with intravenous (IV) contrast of the brain prior to study entry
• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 470 ms

• Current or prior use of immunosuppressive medication within 14 days before the first dose of trial therapies. The following are exceptions to this criterion:

  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)

• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP

  • Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 90 days after the last dose of IP
• Female patients who are pregnant or breastfeeding or of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of nivolumab/etigilimab combination therapy
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Unresolved partial or complete small or large bowel obstruction
• Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (etigilimab, nivolumab); Patients receive etigilimab IV over 30-90 minutes on days 1 and 15 and nivolumab IV over 30 minutes on days 2 and 15 of cycle 1 and days 1 and 15 of subsequent cycles. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.	Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; CMAB819; Nivolumab Biosimilar CMAB819; Biological: Etigilimab; Given IV; Other Names: Anti-TIGIT OMP-313M32; OMP 313M32; OMP-313M32; WHO 10742

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	Will estimate the ORR along with a 90% confidence interval.	Up to 90 days
Incidence of adverse events	Will tabulate adverse events by grade, and by relationship to study drug. Will estimate the proportion of subjects that discontinue treatment due to adverse events with 90% confidence intervals. Will estimate the unacceptable toxicity rate with a 90% confidence interval.	Up to 90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median immune-related progression free survival (irPFS)	Will estimate the median irPFS after treatment with combination etigilimab and nivolumab using the product-limit estimator of Kaplan and Meier. When appropriate, will model irPFS using Cox proportional hazards regression as an exploratory analysis because of the small sample size.	From the date of dual therapy treatment initiation to the date of initial radiologic evidence of progressive disease or death, assessed up to 90 days after completion of treatment
Disease control rate (DCR)	Will estimate the DCR along with a 90% confidence interval.	Up to 90 days
Molecular changes	Will be summarized with standard descriptive statistics. Changes in T cell populations and proliferation will be calculated along with 95% confidence intervals and compared between pre- and post-treatment biopsies using paired t-test. Similar summaries will be used to compare proportions of macrophage phenotypes. Logistic regression and Cox proportional hazards model will be used to assess the relationship between clinical responses and the molecular and immunological changes.	through study completion, an average of 1 year
Immunological changes	Will be summarized with standard descriptive statistics. Changes in T cell populations and proliferation will be calculated along with 95% confidence intervals and compared between pre- and post-treatment biopsies using paired t-test. Similar summaries will be used to compare proportions of macrophage phenotypes. Logistic regression and Cox proportional hazards model will be used to assess the relationship between clinical responses and the molecular and immunological changes.	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2021
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: August 9, 2021
• First Submitted That Met QC Criteria: August 23, 2021
• First Posted (Actual): August 30, 2021

Study Record Updates

• Last Update Posted (Estimate): May 5, 2023
• Last Update Submitted That Met QC Criteria: May 4, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Carcinoma; Recurrence; Adenocarcinoma; Adenocarcinoma, Clear Cell; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: 2021-0511 (Registry Identifier: Clinical Trials Gov); NCI-2021-08531 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No