Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma

  • STATUS
    Recruiting
  • End date
    Aug 20, 2025
  • participants needed
    66
  • sponsor
    National Cancer Institute (NCI)
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Updated on 7 October 2022
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Summary

This phase II trial compares the usual treatment alone to using immunotherapy (atezolizumab) plus the usual treatment in treating patients with peritoneal mesothelioma. The usual treatment consists of surgery or chemotherapy. Chemotherapy drugs, such as carboplatin and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving atezolizumab with usual treatment may work better than usual treatment alone.

Description

PRIMARY OBJECTIVE:

I. To determine whether frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate than carboplatin, pemetrexed and bevacizumab in patients with peritoneal mesothelioma as determined by Response Evaluation Criteria in Solid Tumors (RECIST).

SECONDARY OBJECTIVES:

I. To determine the safety, major pathologic response rates, and completeness of cytoreduction of patients treated with neoadjuvant carboplatin, pemetrexed, bevacizumab and atezolizumab or carboplatin, pemetrexed and bevacizumab.

II. To determine the safety of patients treated with palliative carboplatin, pemetrexed, bevacizumab and atezolizumab or carboplatin, pemetrexed and bevacizumab.

III. To determine whether frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior metabolic response rate than carboplatin, pemetrexed and bevacizumab as determined by Positron Emission Tomography (PET) Response Criteria in Solid Tumors.

IV. Explore the value that analysis of secondary computed tomography (CT) findings and quantitative fludeoxyglucose F-18 (FDG)-PET imaging adds to prognostic information and response assessment in this disease.

V. Determine the number of patients who were deemed to have unresectable disease who are able to undergo surgery following treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab or carboplatin, pemetrexed and bevacizumab due to dramatic response.

VI. To compare the progression-free survival and overall survival between arms. VII. Results of the primary analysis will be examined for consistency, while taking into account the stratification factors and/or covariates of baseline quality of life (QOL) and fatigue.

EXPLORATORY OBJECTIVE:

I. To determine whether blood-based biomarkers including our recently described cell-free chromosomal junctions, soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with clinical outcomes data (i.e. overall survival [OS], progression-free survival [PFS], recurrence, response, etc.).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive atezolizumab intravenously (IV) over 60 minutes, bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients undergo cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Patients not eligible for surgery may receive atezolizumab and bevacizumab in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients undergo cytoreductive surgery and HIPEC. Patients not eligible for surgery may receive bevacizumab with or without atezolizumab at the discretion of the investigator in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3 years.

Details
Condition Peritoneal Malignant Mesothelioma
Treatment carboplatin, bevacizumab, Pemetrexed, cytoreductive surgery, Atezolizumab, Hyperthermic Intraperitoneal Chemotherapy
Clinical Study IdentifierNCT05001880
SponsorNational Cancer Institute (NCI)
Last Modified on7 October 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Histologically or cytologically confirmed malignant peritoneal mesothelioma for which there has been no prior treatment. Given the indolent nature of well-differentiated papillary mesothelioma and multicystic mesothelioma, patients with these variants are not eligible for participation
All slides including performed immunostains from diagnostic tumor tissue together with pathology report for retrospective central pathology review
Must have measurable disease per RECIST version (v) 1.1
Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 28 days prior to registration is required
Age >= 18 years
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Leukocytes >= 2,500/mm^3
Absolute neutrophil count (ANC) >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Total bilirubin =< 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN)
Urine protein:creatinine (UPC) ratio < 1, or urine protein: =< 1+
No prior systemic therapy for peritoneal mesothelioma is allowed. No concurrent radiotherapy is allowed
No active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions
Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
Rash must cover < 10% of body surface area
Disease is well controlled at baseline and requires only low-potency topical corticosteroids
excluded) are eligible for the study provided all of following conditions are
met
No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
No prior allogeneic stem cell or solid organ transplantation
Central nervous system (CNS) metastases must have been treated with local therapy (surgery, radiation, ablation) with systemic steroids tapered to a physiologic dose (10 mg or prednisone equivalent or less)
Patients who have received live attenuated vaccines within 30 days of the first dose of trial treatment are eligible at the discretion of the investigator. All seasonal influenza vaccines and vaccines intended to prevent SARS-CoV-2 and coronavirus disease 2019 (COVID-19) are allowed
No history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
No history of inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg)
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence
No history of hypertensive crisis or hypertensive encephalopathy
of active pneumonitis on screening chest computed tomography (CT) scan
No clinically significant cardiovascular disease, such as cerebrovascular accidents within 12 months prior to randomization, myocardial infarction within 12 months prior to randomization, unstable angina, New York Heart Association (NYHA) grade II or greater CHF, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with study treatment
No significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to randomization
No history of grade >= 4 venous thromboembolism
No history of grade >= 2 hemoptysis (defined as >= 2.5 mL of bright red blood per episode) within 1 month prior to screening
No history or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation)
No major surgical procedure or significant traumatic injury within 28 days prior to initiation of study treatment (diagnostic laparoscopy is allowed as part of diagnosing peritoneal mesothelioma)
No history or evidence upon physical or neurological examination of central nervous system disease (e.g. seizures) unrelated to cancer unless adequately treated with standard medical therapy
No core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of study treatment
Placement of a vascular access device should be at least 2 days prior to initiation of study treatment
No active infection requiring IV antibiotics at the time of initiation of study treatment
No history of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess, or active GI bleeding within 6 months prior to randomization
No serious, non-healing wound, active ulcer, or untreated bone fracture
No other malignancy within 5 years prior to randomization, except for localized cancer in situ, such as basal or squamous cell skin cancer
Patients with a creatinine clearance between 45 and 79 mL/min should not use ibuprofen or other nonsteroidal anti-inflammatory drug (NSAIDs) for 2 days before, the day of, and 2 days following pemetrexed administration
No treatment with immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions
Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) may be eligible for the study
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study

Exclusion Criteria

Physicians should consider whether any of the following may render the patient inappropriate for this protocol
Psychiatric illness which would prevent the patient from giving informed consent
Medical conditions such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
Patients with a "currently active" second malignancy other than non-melanoma skin
cancers or cervical carcinoma in situ. Patients are not considered to have a
currently active" malignancy if they have completed therapy and are free of
disease for >= 3 years
In addition
Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom). A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
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