This phase Ib trial studies the side effects and best dose of nivolumab with or without ipilimumab in treating patients with female reproductive cancer that has come back (recurrent) or is high grade and has spread extensively throughout the peritoneal cavity (metastatic). Immunotherapy with 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.
Recruiting
Phase 1
| Drug | Synonyms | Arms |
|---|---|---|
| Ipilimumab | Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, Yervoy | Group II (nivolumab and ipilimumab) |
| Nivolumab | BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo | Group I (nivolumab) |
PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose (RP2D) of intraperitoneal (i.p.) nivolumab in
combination with ipilimumab.
SECONDARY OBJECTIVES:
I. To describe the pharmacokinetics (PK), toxicities, and immune-related adverse events
associated with i.p. checkpoint inhibitor therapy.
II. To estimate the clinical benefit rate (rate of partial response [PR], complete response
[CR], and stable disease [SD] using Response Evaluation Criteria in Solid Tumors [RECIST]
version 1.1 modified to include immune-related response criteria) for the expansion cohort.
EXPLORATORY OBJECTIVES:
I. To determine blood based transcriptional changes associated with pharmacokinetics (PK)
time points and determine their correlation with serum drug concentrations, clinical
response, and immune related adverse events.
II. To determine baseline and on-treatment molecular alteration (ribonucleic acid [RNA] and
protein) associated with i.p. and nivolumab (Nivo) (for the expansion cohort).
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 groups.
GROUP I: Patients receive nivolumab i.p. over 90 minutes on days 1, 15, and 29. Cycles repeat
every 6 weeks in the absence of disease progression or unacceptable toxicity.
GROUP II: Patients receive nivolumab as in group I and ipilimumab i.p. on day 1. Cycles
repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.
After completion of the study treatment, patients are followed up every 6 weeks for at least
100 days.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Group I (nivolumab) | Experimental | Patients receive nivolumab i.p. over 90 minutes on days 1, 15, and 29. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. |
|
| Group II (nivolumab and ipilimumab) | Experimental | Patients receive nivolumab as in group I and ipilimumab i.p. on day 1. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. |
|
Inclusion Criteria:
- Patients must have biopsy-confirmed ovarian or other gynecologic cancers (fallopian
tube, peritoneal, endometrial, or cervical cancer) who have recurred after or
progressed on frontline and one or more second-line standard treatments; patients with
ovarian/fallopian tube/peritoneal cancers must have platinum refractory or resistant
disease (defined as progression on a platinum containing regimen or recurrence within
180 days of prior dose of platinum-containing regimen) to be eligible for the
dose-finding phase; enrollment for the expansion cohort will be limited to subjects
with high grade epithelial ovarian, fallopian tube, or peritoneal carcinomas who have
recurred after or progressed on frontline and one or more second-line standard
treatments; however, for the dose expansion phase, potential subjects are not required
to have platinum refractory or resistant disease
- Measurable metastatic disease (by RECIST version [v] 1.1) in the peritoneal cavity or
retroperitoneal lymph nodes; disease outside of the peritoneal cavity is allowed as
long as metastatic sites are also present within the peritoneum/retroperitoneum
- Absolute neutrophil count >= 1500/mL
- Platelets >= 100,000/mL
- Hemoglobin >= 9 g/dL (transfusion to meet this criterion is allowed)
- Serum creatinine clearance (CL) >= 40 mL/min by the Cockcroft-Gault formula (Cockcroft
and Gault 1976) or by 24-hour urine collection for determination of creatinine
clearance
- Total bilirubin =< 1.5 X upper limit of normal (ULN)
- Aspartate aminotransferase (AST/serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X
ULN (=< 5 X ULN in subjects with bone or liver metastases)
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
- Subjects must be >= 4 weeks beyond treatment with any chemotherapy or other
investigational therapy to include hormonal, biological, or targeted agents (>= 8
weeks from previous bevacizumab treatment) at the time of first dose of study drug(s)
- Women of child-bearing potential MUST have a negative serum human chorionic
gonadotropin (HCG) test unless prior hysterectomy or menopause (defined as 12
consecutive months of amenorrhea); subjects are considered not to be of child-bearing
potential if they are surgically sterilized or post-menopausal (>= 50 years of age and
has not had menses for greater than 1 year or with serum follicle stimulating hormone
(FSH) in the menopausal range will be considered postmenopausal); subjects should not
become pregnant or breastfeed while on this study; sexually active subjects of child
bearing potential must agree to use contraception for the duration of study
participation and for 5 months after the last dose of ipilimumab or nivolumab
- Ability to understand and willingness to sign informed consent form prior to
initiation of the study and any study procedures
- Subjects in expansion cohort only: Willing to undergo pre- and on-treatment biopsies
Exclusion Criteria:
- Patients who are pregnant or breastfeeding
- Patients with low grade ovarian/fallopian tube/peritoneal cancers
- Prior immune checkpoint inhibitor therapy
- History of inflammatory bowel disease (including ulcerative colitis and Crohn's
disease), or any other known autoimmune diseases including rheumatoid arthritis,
scleroderma, systemic lupus erythematosus, and autoimmune vasculitis
- History of previous malignancy that in the principal investigator (PI)'s opinion has a
reasonable chance of recurrence during the study period or otherwise confounding this
clinical trial
- Active peritonitis or diverticulitis
- Patients requiring corticosteroids use at doses greater than prednisone 10 mg daily
equivalent (use of inhaled steroids, and short-term steroid for radiologic contrast
allergy, or treatment of immune-related adverse events are allowed)
- Medical or surgical history that in the treating physician's opinion would make the
subject not a suitable candidate for i.p. therapy; examples would include surgically
documented extensive intraperitoneal adhesions or large volume ascites
- History of chronic obstructive pulmonary disease (COPD) or other chronic pulmonary
disease requiring systemic steroid therapy, oxygen, or hospitalization
- Chronic hepatitis B or C virus infection, or known human immunodeficiency virus (HIV)
positive, that might affect host immunity
- Any other illness or condition that in the investigator's opinion would adversely
affect the safety of checkpoint inhibitor therapy
- Active infection requiring intravenous (IV) antibiotics or other uncontrolled
intercurrent illness requiring hospitalization
- Inability to comply with the study and follow-up procedures
- History of cerebrovascular accident, myocardial infarction or unstable angina within
the previous 6 months before starting therapy
- Prolongation of QT interval (QT)/corrected QT interval (QTc) (QTc interval > 470 ms)
using the Fridericia method of QTc analysis
- Known active central nervous system metastases and/or carcinomatous meningitis
- History of severe hypersensitivity reaction with biologics therapy (monoclonal
antibodies)
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
| Measure: | Maximum tolerated dose (MTD)/recommended phase II dose (RP2D) of intraperitoneal (i.p.) nivolumab in combination with ipilimumab |
| Time Frame: | 12 weeks |
| Safety Issue: | |
| Description: | The RP2D or the MTD is defined as the combination of ipilimumab + nivolumab with the dose limiting toxicity (DLT) rate =< 30%. Dose-finding for the combination of ipilimumab plus nivolumab will be done using the time-to-event Bayesian optimal interval (TITE-BOIN) design". |
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | M.D. Anderson Cancer Center |
July 13, 2020
