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Testing Nivolumab With or Without Ipilimumab in Deficient Mismatch Repair System (dMMR) Recurrent Endometrial Carcinoma

ConditionsEndometrial AdenocarcinomaEndometrial Clear Cell AdenocarcinomaEndometrial Dedifferentiated CarcinomaEndometrial Endometrioid AdenocarcinomaEndometrial Mixed Cell AdenocarcinomaEndometrial Mucinous AdenocarcinomaEndometrial Undifferentiated CarcinomaEndometrioid AdenocarcinomaRecurrent Endometrial Carcinoma
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexFemale
Age18+
SponsorNational Cancer Institute (NCI)

About this trial

This phase II trial tests whether the combination of nivolumab and ipilimumab is better than nivolumab alone to shrink tumors in patients with deficient mismatch repair system (dMMR) endometrial carcinoma that has come back after a period of time during which the cancer could not be detected (recurrent). Deoxyribonucleic acid (DNA) mismatch repair (MMR) is a system for recognizing and repairing damaged DNA. In 2-3% of endometrial cancers this may be due to a hereditary condition resulted from gene mutation called Lynch Syndrome (previously called hereditary nonpolyposis colorectal cancer or HNPCC). MMR deficient cells usually have many DNA mutations. Tumors that have evidence of mismatch repair deficiency tend to be more sensitive to immunotherapy. There is some evidence that nivolumab with ipilimumab can shrink or stabilize cancers with deficient mismatch repair system. However, it is not known whether this will happen in endometrial cancer; therefore, this study is designed to answer that question. Monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with ipilimumab may be better than nivolumab alone in treating dMMR recurrent endometrial carcinoma.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Patients with measurable or non-measurable (detectable) recurrent endometrial cancer

Measurable disease will be defined and monitored by RECIST v 1.1. Measurable disease is defined per RECIST 1.1 criteria as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be >= 10 mm when measured by computed tomography (CT) or magnetic resonance imaging (MRI). Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI

All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with >= 10 to < 15 mm short axis), are considered non-measurable disease

Ascites and/or pleural effusion attributed to tumor

Disqualifiers

Patients with a diagnosis of endometrial serous carcinoma or carcinosarcoma

Patients who received prior anti-PD1/PD-L1 therapy and had grade 3-4 or recurring grade 2 immune-related toxicities that led to dose delay or discontinuation of immunotherapy due to those toxicities

Patients who received anti-CTLA-4 therapy or other immunotherapeutic agents

Patients on chronic steroid therapy except those on replacement therapy at a daily dose of 10mg or less prednisone or equivalent

Trial design

Design model

Parallel

Treatments tested in this trial

  • Biospecimen Collection

    Procedure/Surgery

    Undergo collection of tissue and/or blood samples

  • Computed Tomography

    Procedure/Surgery

    Undergo CT

  • Ipilimumab

    Biological/Vaccine

    Given IV

  • Magnetic Resonance Imaging

    Procedure/Surgery

    Undergo MRI

  • Nivolumab

    Biological/Vaccine

    Given IV

Treatment groups

81 Participants
are divided into 2 treatment groups
Group A: Arm I (nivolumab and ipilimumab)Experimental treatment 5 interventions
Group B: Arm II (nivolumab)Active comparator 4 interventions

Trial outcomes

Primary outcomes

1

Progression-free survival (PFS)

The statistical test used for decision making is the stratified, standardized log-rank test (Z) based on PFS. For the safety lead-in analysis, the primary endpoint is the observation of at least one dose-limiting toxicity (DLT) in the first 3 cycles of treatment. Patients are classified as having a DLT in 3 cycles or receiving adequate treatment.

Time frame
From study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed up to 5 years after randomization

Secondary outcomes

1

Overall survival (OS)

Will be assessed when the PFS data are mature. The null hypothesis will be that the hazard of death in regimen 1 is equal to the hazard of death in regimen 2. That is, Ho: HR = 1.00. The alternative will be that Ha: HR \< 1.00 (regimen 1 to 2). The number of deaths is unknown.

Time frame
Up to 5 years after randomization
2

Objective tumor response (ORR)

Defined as the frequency of patients who have either a partial or complete response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The number of patients with responses will be tabulated by the treatment they were randomized to. Fisher's Exact Test will be used to test the hypothesis that the probabilities of response in each arm is the same. ORR will be evaluated only in patients who had measurable disease per RECIST 1.1 before starting treatment.

Time frame
Up to 5 years after randomization
3

Progression-free survival (PFS) at 6 months

A patient who survives at least 6 months progression-free will be considered to have had a successful outcome. Those who progress or die within 6 months are considered treatment failures, and those who survive progression-free for less than 6 months will be considered to have an unknown outcome or indeterminate. If the patient's status cannot be determined, she will be moved to the "failure" status for analysis. Like tumor response, the hypothesis of equivalent probabilities will be assessed with Fisher's Exact Test.

Time frame
From study entry to time of progression or death, whichever occurs first, or date of last contact if neither progression nor death has occurred, assessed at 6 months after randomization
4

Incidence of adverse events

Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE). Will be tabulated by frequency and severity by treatment regimen. The treatment regimens will be compared by classifying the toxicities as severe or not and tested for equivalent probabilities by Fisher's Exact Test or whether the estimated probabilities of severe toxicities diverge by more than 10%.

Time frame
Up to 5 years after randomization

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

National Cancer Institute (NCI)

Lead sponsor

NRG Oncology

Collaborator

Source ClinicalTrials.gov
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