Clinical Trials /

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

NCT03228537

Description:

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.

Related Conditions:
  • Malignant Pleural Mesothelioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Atezolizumab, Pemetrexed Disodium, Cisplatin, and Surgery With or Without Radiation Therapy in Treating Patients With Stage I-III Pleural Malignant Mesothelioma
  • Official Title: A Feasibility Trial of Neoadjuvant Cisplatin-Pemetrexed With Atezolizumab in Combination and in Maintenance for Resectable Malignant Pleural Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01230
  • SECONDARY ID: NCI-2017-01230
  • SECONDARY ID: S1619
  • SECONDARY ID: S1619
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT03228537

Conditions

  • 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

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqTreatment (chemotherapy, surgery, RT)
CisplatinAbiplatin, 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, PlatosinTreatment (chemotherapy, surgery, RT)
Pemetrexed DisodiumAlimta, 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 SaltTreatment (chemotherapy, surgery, RT)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, surgery, RT)ExperimentalNEOADJUVANT: 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.
  • Atezolizumab
  • Cisplatin
  • Pemetrexed Disodium

Eligibility 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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