Perioperative Combination Nivolumab and Ipilimumab for the Treatment of Resectable Malignant Peritoneal Mesothelioma
This phase II trial whether perioperative (around the time of surgery) nivolumab and ipilimumab works to shrink tumors in patients with peritoneal mesothelioma (a cancer of the lining of your abdominal wall and organs [the peritoneum]). 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. Giving nivolumab and ipilimumab before and after surgery may help patients with peritoneal mesothelioma get better compared to surgery alone.
Inclusion Criteria
- Have a diagnosis of histologically or cytologically confirmed peritoneal mesothelioma, of epithelial, biphasic, or sarcomatoid subtypes
- Have disease burden amenable to cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC), as determined by a surgeon specializing in mesothelioma
- Have measurable or evaluable disease based on RECIST 1.1 or on laparoscopy
- Have no definitive evidence of visceral metastases by best staging
- Be willing to undergo laparoscopy or mini-laparotomy for peritoneal staging
- Absolute neutrophil count (ANC) >= 1,500 /mL
- Platelets >= 100,000 /mL
- Hemoglobin >= 9 g/dL
- Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or calculated creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN * Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 x ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN. Patients on anticoagulation are expected to hold anticoagulation for at least 5 days prior to surgery
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN. Patients on anticoagulation are expected to hold anticoagulation for at least 5 days prior to surgery
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of < 2
- Be >= 18 years of age on day of signing informed consent
- Be willing and able to provide written informed consent for the trial
Exclusion Criteria
- Is currently participating in a study of an investigational agent and received an investigational agent within 4 weeks of the first dose of treatment on this protocol
- Has received any immunotherapy agents outside of this protocol within 4 weeks of the first dose of treatment on this protocol
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (> 10 mg of prednisone daily or equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study drug
- Has a known history of active TB infection (Bacillus tuberculosis)
- Has active COVID-19 infection
- Has known history of, or any evidence of active, non-infectious pneumonitis that required steroids, or active pneumonitis
- Has a severe hypersensitivity to nivolumab or any of its excipients
- Has a severe hypersensitivity to ipilimumab or any of its excipients
- Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
- Has a known additional malignancy that is progressing or required active treatment within the 3 years prior to enrollment - exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or other tumors that will not affect life expectancy
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment * Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year * Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
- Is on anticoagulation that cannot be discontinued in the perioperative period
- Has received a live vaccine within 30 days of planned start of study therapy
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT05041062.
PRIMARY OBJECTIVE:
I. To determine pathologic response of the tumor to neoadjuvant treatment with nivolumab + ipilimumab via major pathologic response (MPR), defined as =< 10% residual viable tumor (RVT) cells, as well as grade, necrosis, and Ki67.
SECONDARY OBJECTIVES:
I. To determine the safety profile of neoadjuvant nivolumab + ipilimumab, as defined by rate of grade III/IV adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0, occurring up to 30 days post-operatively.
II. To determine feasibility of neoadjuvant nivolumab + ipilimumab, as measured by the number of participants who complete neoadjuvant treatment with nivolumab + ipilimumab and proceed to surgery without extended treatment-related delay (> 6-week delay) or progression precluding surgery.
III. To determine the overall survival (OS) effect from neoadjuvant nivolumab + ipilimumab, defined as time from enrollment on study to death from any cause.
IV. To determine the progression-free survival (PFS) effect from neoadjuvant nivolumab + ipilimumab, defined as time from enrollment on study to disease progression or death.
V. To determine the safety profile of adjuvant nivolumab + ipilimumab after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).
VI. To determine the radiologic response to neoadjuvant nivolumab + ipilimumab utilizing Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 pre- and post-treatment.
VII. To determine the effect of neoadjuvant nivolumab + ipilimumab on peritoneal carcinomatosis index (PCI).
EXPLORATORY OBJECTIVES:
I. To determine immune status/infiltration of the tumor in response to neoadjuvant nivolumab + ipilimumab, including the change in presence of tumor infiltrating lymphocytes (TILs)/macrophages (CD3, CD4, CD8, CD11b, CD68, CD20) and PDL1 status.
II. To determine blood-based changes with nivolumab + ipilimumab treatment, including peripheral blood mononuclear cell (PBMC) inflammation expression profile, serum mesothelin (SMRP), osteopontin, CA-125, and circulating tumor cells.
III. To evaluate health-related quality of life (HRQoL) for patients with peritoneal mesothelioma undergoing perioperative immunotherapy, measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30, which was developed specifically to assess quality of life in patients with cancer.
IV. To correlate radiologic tumor measurements based on RECIST 1.1 and tumor volume with patient survival.
V. To relate pathologic assessment of immune infiltrate with pre-operative image-based tumor signatures.
VI. To assess the response of neoadjuvant immunotherapy in those with BAP1 mutations identified on next-generation sequencing.
OUTLINE:
Patients receive nivolumab intravenously (IV) over 30 minutes on days 1 and 22 and ipilimumab IV for over 30 minutes on day 1 of each cycle. Treatment repeat every 42 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery. Beginning 2-8 weeks after surgery, patients receive nivolumab IV over 30 minutes on days 1 and 22 of each cycle. Cycles repeat every 42 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive ipilimumab IV for over 30 minutes on day 1. Treatment repeats every 42 days for 1 year in the absence of disease progression or unacceptable toxicity.
After completion of the study treatment, patients are followed up at 30 days and then every 12 weeks for 1 year.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorHedy Lee Kindler
- Primary IDIRB21-0672
- Secondary IDsNCI-2022-00616
- ClinicalTrials.gov IDNCT05041062