Nivolumab with or without Ipilimumab before Surgery for the Treatment of Resectable Stage I-III Malignant Pleural Mesothelioma
This phase II trial studies the side effects of nivolumab with or without ipilimumab before surgery in treating patients with stage I-III malignant pleural mesothelioma that can be removed by surgery (resectable). 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.
- Primary tumor amenable to safe research biopsy. A tumor biopsy is required for study entry
- Histology proven epithelial or biphasic MPM * Diagnostic core biopsy specimens must be reviewed by faculty pathologist at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (SKCC), MD Anderson Cancer Center (MDACC), or University of Maryland Greenebaum Cancer Center (UMGCCC) * Either a formalin fixed paraffin block that has been confirmed by a pathologist to contain tumor or a minimum of twenty 5‐micron tissue sections (slides) of tumor biopsy sample must be available for biomarker evaluation (study pathologist must review for adequacy of sampling). This can be obtained from archived tissues if adequate, or from a new biopsy as needed
- Stage I‐III and deemed to be potentially surgically resectable as assessed by faculty surgeon at SKCC, MDACC, or UMGCCC
- Eastern Cooperative Oncology Group (ECOG) performance status 0‐1
- Leukocytes >= 2,000/mm^3
- Absolute neutrophil count (ANC) >= 1000/mm^3
- Platelet count >= 100,000/mm^3
- Hemoglobin >= 9 g/dl
- Creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 40 mL/min
- Total bilirubin =< 1.5 x institutional ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 times the institutional upper limit of normal
- Alkaline phosphatase =< 3 times the institutional upper limit of normal
- Subjects must have adequate lung function to permit surgical resection determined by pre‐enrollment pulmonary function tests to include diffusion capacity of the lung for carbon monoxide (DLCO)
- The effects of nivolumab on the developing human fetus are unknown. For this reason, women of child‐bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for up to 23 weeks after the last dose of nivolumab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Sexually active fertile men must use effective barrier birth control if their partners are WOCBP for up to 31 weeks after the last dose of nivolumab. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within two weeks of registration. Women must not be breastfeeding
- Patient understands the study regimen, its requirements, risks and discomforts and is able and willing to sign the informed consent form. Voluntary signed and dated Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines must be obtained before the performance of any protocol related procedures that are not part of normal patient care. Subjects must be competent to report adverse events (AEs), understand the drug dosing schedule and use of medications to control AEs
- Stage I‐III disease but deemed to be unresectable, a poor surgical candidate, or unfit for study therapy as assessed by study investigators
- Pure sarcomatoid histology
- Subjects are excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
- Subjects are excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab‐containing regimen
- Administration of chemotherapy or any other cancer therapy in the pre‐operative period
- Subjects with active concurrent malignancies are excluded i.e. cancers other than MPM (except non‐melanoma skin cancers, cervical dysplasia, and in situ cancers of bladder, stomach, breast, colon and cervix)
- Subjects with a history of symptomatic interstitial lung disease
- Active systemic infection requiring therapy, as well as positive tests for hepatitis B surface antigen or hepatitis C antibody
- Known positive history or positive test for human immunodeficiency virus or acquired immunodeficiency syndrome (AIDS)
- History of allergy to study drug components
- Women who are pregnant or nursing
- Men with female partners (WOCBP) that are unwilling to use contraception
- Prior therapy with an anti‐PD1, anti‐PD‐L1, anti‐PD‐L2, or anti‐CTLA‐4 antibody (or any other antibody targeting T‐cell co‐regulatory pathways)
- History of any other condition that may require the initiation of anti‐tumor necrosis factor alpha (TNFalpha) therapies or other immunosuppressant medications during the study
- Underlying medical conditions that, in the investigator’s opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events
- Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness
Locations & Contacts
Contact: Patrick M. Forde
Contact: Christian Diego Rolfo
Contact: Boris Sepesi
Trial Objectives and Outline
I. To investigate the safety & feasibility of neoadjuvant nivolumab +/‐ ipilimumab in patients with resectable malignant pleural mesothelioma (MPM).
I. To assess pathologic response to neoadjuvant nivolumab +/‐ ipilimumab in resected tumor and lymph nodes in patients with resectable MPM in terms of percent tumor regression.
II. To assess radiographic response to neoadjuvant nivolumab +/‐ ipilimumab, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST for pleural tumors.
III. To assess toxicity profile of adjuvant nivolumab treatment.
IV. To evaluate baseline and serial markers of immunogenicity in preoperative immunotherapy‐ treated MPM tumors, normal tissue and peripheral blood and compare with tumor, normal tissue and peripheral blood samples from a group of patients who do not receive preoperative immunotherapy prior to surgery on a parallel tissue collection protocol.
V. To explore biologic features of the gut microbiome(s) of MPM patients receiving neoadjuvant nivolumab +/‐ ipilimumab and correlate these with clinical response.
I. To determine changes in the genomic landscape, global expression and expression of selected immune markers compared to baseline, in the blood, primary tumor tissue and draining lymph nodes from patients receiving neoadjuvant nivolumab +/‐ ipilimumab therapy; to determine changes in the quality and quantity of tumor infiltrating lymphocytes; and to compare findings in tumor and draining lymph nodes from treated patients, to findings in a parallel stage‐matched cohort of untreated patients on a companion tissue collection protocol.
II. To evaluate the potential effects of neoadjuvant therapy on normal pleural tissues, by comparing tissues obtained on this study to those obtained from untreated patients undergoing resection on a parallel tissue collection protocol.
III. To explore the association between nivolumab +/‐ ipilimumab exposure and selected pharmaco‐dynamic markers in the peripheral blood and in the tumor microenvironment, including measurement of PD‐1 receptor occupancy on tumor infiltrating lymphocytes.
IV. To assess progression free survival in patients receiving neoadjuvant nivolumab +/‐ ipilimumab in this study.
V. To assess overall survival in patients receiving neoadjuvant nivolumab +/‐ ipilimumab in this study.
VI. To assess response rates (confirmed and unconfirmed complete and partial responses) in patients receiving neoadjuvant nivolumab +/‐ ipilimumab.
OUTLINE: Patients are sequentially assigned to 1 of 2 arms.
ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes on days -42, -28, and -14 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery on day 0. After surgery, patients may receive standard of care cisplatin and pemetrexed for 4 cycles and may also undergo standard of care radiation therapy. Following completion of cisplatin, pemetrexed, and radiation therapy, patients receive nivolumab IV over 30 minutes once every 4 weeks (Q4W) for up to 1 year in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive nivolumab IV over 30 minutes on days -42, -28, and -14 and ipilimumab IV over 30 minutes on day -42 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgery on day 0. After surgery, patients may receive standard of care cisplatin and pemetrexed for 4 cycles and may also undergo standard of care radiation therapy. Following completion of cisplatin, pemetrexed, and radiation therapy, patients receive nivolumab IV over 30 minutes Q4W for up to 1 year in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3‐6 months for 2 years and then every 6‐12 months up to 5 years.
Trial Phase & Type
Johns Hopkins University / Sidney Kimmel Cancer Center
Patrick M. Forde
Secondary IDs NCI-2019-06933, CRMS-71507, IRB00203283
Clinicaltrials.gov ID NCT03918252