Clinical trial NCT05001880: Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma
Official title: Phase 2 Randomized Trial of Neoadjuvant or Palliative Chemotherapy With or Without Immunotherapy for Peritoneal Mesothelioma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Peritoneal Malignant Mesothelioma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2021-08-12
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase II trial compares the usual treatment alone (carboplatin, pemetrexed, and bevacizumab) to using immunotherapy (atezolizumab) plus the usual treatment in treating patients with peritoneal mesothelioma. The usual treatment consists of surgery or chemotherapy. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by stopping cells from using folic acid to make deoxyribonucleic acid and may kill cancer cells. 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.

Detailed 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 30-60 minutes, bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients then undergo cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Patients not eligible for surgery may receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1 of each maintenance therapy cycle. Treatment repeats every 21 days 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 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients then undergo cytoreductive surgery and HIPEC. Patients not eligible for surgery may receive bevacizumab IV over 30-90 minutes with or without atezolizumab IV over 30-60 minutes on day 1 of each maintenance therapy cycle at the discretion of the investigator. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Patients also undergo CT scan, PET scan, and collection of blood and tissue samples throughout the study.

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

Eligibility criteria: Inclusion 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)
* 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
* 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 excluded) are eligible for the study provided all of following conditions are met:

  * Rash must cover \< 10% of body surface area
  * Disease is well controlled at baseline and requires only low-potency topical corticosteroids
  * 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 history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
* 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 inadequately controlled hypertension (defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg)
* No history of hypertensive crisis or hypertensive encephalopathy
* 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 congestive heart failure (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 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 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 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

Primary outcomes:
measure: Response rate
timeFrame: Up to 4 years after study activation
Secondary outcomes:
measure: Major pathologic response rate
timeFrame: Up to 3 years
measure: Completeness of cytoreduction
timeFrame: Up to 3 years
measure: Conversion rate to surgical resection among those not deemed to be surgical candidates
timeFrame: Up to 3 years
measure: Progression-free survival (PFS)
timeFrame: From study entry to the first of either disease progression or death from any cause, where disease progression will be determined based on Response Evaluation Criteria in Solid Tumors 1.1 criteria, assessed up to 3 years
measure: Overall survival
timeFrame: From study entry to death from any cause, assessed up to 3 years
measure: Incidence of adverse events
timeFrame: Up to 3 years
Other outcomes:
measure: Soluble mesothelin-related peptides and megakaryocyte potentiating factor
timeFrame: Up to 3 years
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital in Arizona
state: Arizona
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Danville
country: United States
facility: Carle at The Riverfront
state: Illinois
city: Effingham
country: United States
facility: Carle Physician Group-Effingham
state: Illinois
city: Mattoon
country: United States
facility: Carle Physician Group-Mattoon/Charleston
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Urbana
country: United States
facility: The Carle Foundation Hospital
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: Boston
country: United States
facility: Alliance for Clinical Trials in Oncology
state: Massachusetts
city: Bemidji
country: United States
facility: Sanford Joe Lueken Cancer Center
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Fridley
country: United States
facility: Unity Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Abbott-Northwestern Hospital
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Clinic - Saint Louis Park
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Worthington
country: United States
facility: Sanford Cancer Center Worthington
state: Minnesota
city: Bismarck
country: United States
facility: Sanford Bismarck Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Sanford Broadway Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Sanford Roger Maris Cancer Center
state: North Dakota
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Cancer Center Oncology Clinic
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford USD Medical Center - Sioux Falls
state: South Dakota
city: Conroe
country: United States
facility: MD Anderson in The Woodlands
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson West Houston
state: Texas
city: League City
country: United States
facility: MD Anderson League City
state: Texas
city: Sugar Land
country: United States
facility: MD Anderson in Sugar Land
state: Texas
city: Appleton
country: United States
facility: ThedaCare Regional Cancer Center
state: Wisconsin
city: Eau Claire
country: United States
facility: Marshfield Medical Center-EC Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Medical Center-Marshfield
state: Wisconsin
city: Minocqua
country: United States
facility: Marshfield Medical Center - Minocqua
state: Wisconsin
city: Rice Lake
country: United States
facility: Marshfield Medical Center-Rice Lake
state: Wisconsin
city: Stevens Point
country: United States
facility: Marshfield Medical Center-River Region at Stevens Point
state: Wisconsin
city: Weston
country: United States
facility: Marshfield Medical Center - Weston
state: Wisconsin
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Aaron S Mansfield
role: PRINCIPAL_INVESTIGATOR
References: