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Atezolizumab, Pemetrexed Disodium, Cisplatin, and Surgery With or Without Radiation Therapy in Treating Patients With Stage I-III Pleural Malignant Mesothelioma

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ClinicalTrials.gov Identifier: NCT03228537
Recruitment Status : Recruiting
First Posted : July 25, 2017
Last Update Posted : November 5, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I pilot trial studies how well atezolizumab, pemetrexed disodium, cisplatin, and surgery with or without radiation therapy works in treating patients with stage I-III pleural malignant mesothelioma. 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. Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, 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. Giving atezolizumab, pemetrexed disodium, and cisplatin before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving atezolizumab after surgery may kill any remaining tumor cells.

Condition or disease Intervention/treatment Phase
Biphasic Mesothelioma Epithelioid Mesothelioma Stage I Pleural Malignant Mesothelioma AJCC v7 Stage IA Pleural Malignant Mesothelioma AJCC v7 Stage IB Pleural Malignant Mesothelioma AJCC v7 Stage II Pleural Malignant Mesothelioma AJCC v7 Stage III Pleural Malignant Mesothelioma AJCC v7 Drug: Atezolizumab Drug: Cisplatin Procedure: Extrapleural Pneumonectomy Drug: Pemetrexed Disodium Procedure: Pleurectomy Radiation: Radiation Therapy Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate if the regimen of neoadjuvant cisplatin-pemetrexed disodium (pemetrexed)-atezolizumab, surgery +/- radiation, then maintenance atezolizumab is feasible and safe for patients with resectable malignant pleural mesothelioma.

SECONDARY OBJECTIVES:

I. To evaluate progression free survival (both by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 and also using a modified RECIST for pleural tumors) in patients with resectable malignant pleural mesothelioma treated with a regimen of neoadjuvant cisplatin-pemetrexed-atezolizumab, surgery +/- radiation, followed by one year of maintenance atezolizumab.

II. To evaluate overall survival in patients with resectable malignant pleural mesothelioma treated with a regimen of neoadjuvant cisplatin-pemetrexed-atezolizumab, surgery +/- radiation, followed by one year of maintenance atezolizumab.

III. To evaluate response rate (confirmed and unconfirmed, complete and partial, both by RECIST 1.1 and also using a modified RECIST for pleural tumors) in the subset of this patient population with measurable disease.

TRANSLATIONAL MEDICINE OBJECTIVES:

I. To evaluate the association between immunohistochemical (IHC) expression of PD-L1 in tumors and clinical outcomes in mesothelioma patients treated with trimodality/bimodality therapy including atezolizumab (anti-PD-L1).

II. To evaluate the association between expression of immune-related genes identified by Immune Nanostring (depending on ribonucleic acid [RNA] availability) and clinical outcomes in mesothelioma patients treated with trimodality/bimodality therapy including atezolizumab.

III. To evaluate the association between multiplex immunofluorescence (IF) of up to 10 immune markers in two panels and clinical outcomes in mesothelioma patients treated with trimodality/bimodality therapy including atezolizumab.

OUTLINE:

NEOADJUVANT: Patients receive atezolizumab intravenously (IV) over 30-60 minutes, pemetrexed disodium IV over 10 minutes, and cisplatin IV over 2 hours on day 1. Cycles repeats every 21 days for 4 cycles in the absence of disease progression or unexpected toxicity.

SURGERY: Within 21-90 days after completion of neoadjuvant therapy, patients undergo extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD). Patients who undergo EPP will then undergo radiation therapy (RT).

MAINTENANCE: Within 90 days after completion of either PD or radiation (post-EPP), patients receive atezolizumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 1 year in the absence of disease progression or unexpected toxicity.

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Feasibility Trial of Neoadjuvant Cisplatin-Pemetrexed With Atezolizumab in Combination and in Maintenance for Resectable Malignant Pleural Mesothelioma
Actual Study Start Date : November 3, 2017
Estimated Primary Completion Date : June 1, 2020
Estimated Study Completion Date : June 1, 2020


Arm Intervention/treatment
Experimental: Treatment (chemotherapy, surgery, RT)

NEOADJUVANT: Patients receive atezolizumab IV over 30-60 minutes, pemetrexed disodium IV over 10 minutes, and cisplatin IV over 2 hours on day 1. Cycles repeats every 21 days for 4 cycles in the absence of disease progression or unexpected toxicity.

SURGERY: Within 21-90 days after completion of neoadjuvant therapy, patients undergo EPP or PD. Patients who undergo EPP will then undergo RT.

MAINTENANCE: Within 90 days after completion of either PD or radiation (post-EPP), patients receive atezolizumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 1 year in the absence of disease progression or unexpected toxicity.

Drug: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq

Drug: Cisplatin
Given IV
Other Names:
  • Abiplatin
  • Blastolem
  • Briplatin
  • CDDP
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloridoplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cismaplat
  • Cisplatina
  • Cisplatinum
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Neoplatin
  • Peyrone''s Chloride
  • Peyrone''s Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin

Procedure: Extrapleural Pneumonectomy
Undergo EPP

Drug: Pemetrexed Disodium
Given IV
Other Names:
  • Alimta
  • Almita
  • LY231514
  • N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium Salt

Procedure: Pleurectomy
Undergo PD
Other Name: Excision of Pleura

Radiation: Radiation Therapy
Undergo RT
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • irradiated
  • Irradiation
  • Radiation
  • Radiotherapeutics
  • radiotherapy
  • RT
  • Therapy, Radiation




Primary Outcome Measures :
  1. Progression free survival [ Time Frame: From date of registration to step 1 to date of first documentation of progression, symptomatic deterioration, or death due to any cause, assessed up to 3 years ]
    Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method, confidence intervals around landmark time points will use the Greenwood formula for standard errors.

  2. Overall survival [ Time Frame: From date of initial registration to date of death due to any cause, assessed up to 3 years ]
    Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method, confidence intervals around landmark time points will use the Greenwood formula for standard errors.

  3. Modified Response Evaluation Criteria in Solid Tumors (RECIST) progression free survival [ Time Frame: From date of registration to step 1 to date of first documentation of progression, symptomatic deterioration, or death due to any cause, assessed up to 3 years ]
    Will be assessed by modified RECIST 1.1. Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method, confidence intervals around landmark time points will use the Greenwood formula for standard errors.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • STEP 1: NEOADJUVANT
  • Patient must have stage I-III malignant pleural mesothelioma that is deemed resectable and must be planning to undergo pleurectomy decortication (P/D) or extrapleural pneumonectomy (EPP)
  • Patient must have epithelioid or biphasic histology (sarcomatoid histology is excluded); histologic diagnosis and typing of mesothelioma requires at least a core needle biopsy or surgical biopsy of the pleura via thoracoscopy and small thoracotomy; cytology only will not be regarded as sufficient for the diagnosis
  • Patient must have computed tomography (CT) chest/abdomen/pelvis with contrast or fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/CT scan performed within 28 days prior to step 1 registration
  • Patients must have non-measurable or measurable disease documented by CT or magnetic resonance imaging (MRI); the CT from a combined PET/CT may be used to document only non-measurable disease unless it is of diagnostic quality; measurable disease must be assessed within 28 days prior to step 1 registration; non-measurable disease must be assessed within 42 days prior to step 1 registration; all disease must be assessed and documented on the RECIST 1.1 and modified RECIST baseline tumor assessment form
  • Patient must have undergone extended surgical staging including mediastinoscopy or endobronchial ultrasound; at minimum, samples must be obtained from the mediastinal stations 4R, 7 (subcarinal), and 4L; this surgical staging must be performed within 42 days prior to step 1 registration; patient must be T1-3 and N0-N2 (single station)
  • Patient must undergo video-assisted thoracoscopic surgery and diagnostic laparoscopy within 28 days prior to step 1 registration to rule out peritoneal disease spread
  • Patient must have consultation with a surgeon within 21 days prior to step 1 registration; the surgeon must confirm that the patient's disease is resectable by pleurectomy decortication (P/D) or extrapleural pneumonectomy (EPP) and that the patient is an appropriate candidate for the surgical procedures
  • Patient must not have had prior immunotherapy or chemotherapy for malignant pleural mesothelioma
  • Patient must have Zubrod performance status 0 or 1 documented within 28 days prior to step 1 registration
  • Patients requiring hearing aids or reporting hearing loss must have audiogram performed within 28 days prior to step 1 registration
  • Patient must have not had any major surgery or radiation within 28 days prior to step 1 registration; diagnostic thoracotomies and laparoscopies are not considered major surgeries
  • Patients must not have any anticancer therapy or investigational agent within 28 days prior to step 1 registration
  • Absolute neutrophil count (ANC) >= 1,500/mcl (documented within 28 days prior to step 1 registration)
  • Hemoglobin >= 9 g/dl (documented within 28 days prior to step 1 registration)
  • Platelets >= 100,000/mcl (documented within 28 days prior to step 1 registration)
  • Creatinine =< 1.5 x upper limit of normal (ULN) (documented within 28 days prior to step 1 registration)
  • Creatinine clearance >= 45 ml/min (documented within 28 days prior to step 1 registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days prior to step 1 registration)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 28 days prior to step 1 registration)
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years
  • Patients must not be pregnant or nursing due to the potential teratogenic side effects of the protocol treatment; women of reproductive potential and men must have agreed to use an effective contraceptive method for the duration of study treatment and for 5 months (150 days) after the last dose of atezolizumab; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
  • Patient must NOT have a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Patient must NOT have a known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
  • Patients must not have severe infections within 28 days prior to step 1 registration, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Patients must not have active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; autoimmune diseases include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis; this protocol includes an immunotherapy agent which can precipitate known autoimmune diseases
  • Patients must not have undergone prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • Patient must not have active tuberculosis
  • Patient must not have history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis; this protocol includes an immunotherapy agent which can precipitate known pneumonitis
  • Patient must not have active (chronic or acute) hepatitis B virus (HBV) infection as evidenced by testing performed within 28 days prior to registration; patients with past or resolved HBV infection are eligible; active HBV is defined as having a positive hepatitis B surface antigen (HBsAg) test; past or resolved HBV is defined as having a negative HBsAG test and a positive total hepatitis B core antibody (HBcAb) test; patient must not have active hepatitis C virus (HCV) infection as evidenced by testing performed within 28 days prior to registration; active HCV is defined as having a positive HCV antibody test followed by a positive HCV RNA test
  • Patient must NOT have a known positive test for human immunodeficiency virus (HIV); patients do not need to be screened for HIV; patients with HIV are excluded due to a potential incompetent immune system and need for medications that could interfere with the treatment and immunotherapy
  • Patient must not have significant cardiovascular disease, such as New York Heart Association cardiac disease (class II or greater), myocardial infarction within 3 months prior to initiation of treatment, unstable arrhythmias, or unstable angina given the higher risks associated with surgical resection
  • Patient must not receive live, attenuated influenza vaccine within 4 weeks prior to registration or at any time during the study and until 5 months after the last dose of atezolizumab
  • Patient must be willing to have tissue specimens submitted for translational medicine studies
  • Patient must be offered the opportunity to participate in tissue and blood banking for future studies
  • Patient must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the Oncology Patient Enrollment Network (OPEN) registration process, the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
  • STEP 2: SURGERY
  • Patient must have a CT of chest/abdomen with contrast or FDG-PET/CT scan within 28 days prior to step 2 registration; patients must not have evidence of progression per RECIST 1.1 or modified RECIST for pleural tumors
  • Patients planning to receive EPP must also be evaluated for appropriateness of radiation therapy (RT) by a radiation oncologist within 14 days prior to step 2 registration
  • Patients must have a Zubrod performance status of 0-1 documented within 28 days prior to step 2 registration
  • Patients must have postoperative predicted forced expiratory volume in 1 second (FEV1) > 35% prior to surgery obtained within 28 days prior to step 2 registration; pulmonary function tests to ascertain these values must be obtained within 28 days prior to Step 2 registration
  • Patients must have postoperative predicted carbon monoxide diffusing capability (DLCO) > 35% prior to surgery obtained within 28 days prior to step 2 registration; pulmonary function tests to ascertain these values must be obtained within 28 days prior to Step 2 registration
  • Patient must have received at least two cycles of triplet neoadjuvant therapy (all three drugs) during step 1
  • Patient must be registered to step 2 no less than 21 days and no more than 90 days after the end of their final cycle of neoadjuvant therapy
  • STEP 3: MAINTENANCE
  • Patient must have received either P/D or EPP and must have recovered from all effects of surgery with adequate wound healing; patients who received radiation therapy (RT) must be registered to step 3 within 90 days after discontinuing RT; patients who did not receive RT must be registered to step 3 within 90 days after surgery
  • Patient must have a CT of chest/abdomen/pelvis with contrast or FDG-PET/CT scan within 28 days prior to step 3 registration; patient must not have evidence of progression per RECIST 1.1 or modified RECIST for pleural tumors
  • Patient may have discontinued RT early due to toxicity or other reasons
  • Patients must have a Zubrod performance status of 0-1 documented within 28 days prior to step 3 registration
  • ANC > 1,500/mcl (documented within 28 days prior to step 3 registration)
  • Hemoglobin > 9 g/dl (documented within 28 days prior to step 3 registration)
  • Platelets > 100,000/mcl (documented within 28 days prior to step 3 registration)
  • Creatinine < 1.5 x ULN (documented within 28 days prior to step 3 registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days prior to step 3 registration)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 28 days prior to step 3 registration)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03228537


  Show 176 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anne S Tsao Southwest Oncology Group

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03228537     History of Changes
Other Study ID Numbers: NCI-2017-01230
NCI-2017-01230 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1619 ( Other Identifier: SWOG )
S1619 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: July 25, 2017    Key Record Dates
Last Update Posted: November 5, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Mesothelioma
Lung Neoplasms
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Mesothelial
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Cisplatin
Pemetrexed
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors
Immunologic Factors
Physiological Effects of Drugs