Phase II MEDI4736 in Combination With Chemotherapy for First-Line Treatment of Unresectable Mesothelioma
Condition: Mesothelioma; Pleural Mesothelioma
MeSH terms: Mesothelioma; Mesothelioma, Malignant
Intervention: Durvalumab
Intervention description: On Day 1 of each 21 day cycle: Durvalumab 1120 mg IV will be administered before pemetrexed and cisplatin chemotherapy over approximately 60 minutes. Approximately 30 minutes after the durvalumab infusion is complete, pemetrexed 500 mg/m² IV will be administered over 10 minutes. Cisplatin 75 mg/m² IV over 2 hours will begin approximately 30 minutes after the end of pemetrexed administration. If carboplatin is substituted for cisplatin, carboplatin Area Under the Concentration-Time Curve (AUC) 5 will be infused over 30 minutes beginning approximately 15-30 minutes after the end of the pemetrexed administration. Maintenance: On Day 1 of each 21 day cycle: Durvalumab 1120 mg IV over approximately 60 minutes.
Intervention MeSH terms: Durvalumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Concurrent therapy with Durvalumab, Pemetrexed and Cisplatin (or Carboplatin) for up to 6 cycles followed by Maintenance Therapy with Durvalumab
Masking: None (Open Label)
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Unresectable Mesothelioma; Durvalumab; Anti-Programmed Death-Ligand 1 Antibody

Summary:

      Patients with pleural mesothelioma that can not be surgically removed will receive
      durvalumab, in combination with standard chemotherapy of pemetrexed and cisplatin as
      first-line treatment.

      Durvalumab is a type of drug called a monoclonal antibody (a type of protein). Laboratory
      tests show that it works by allowing the immune system to detect your cancer and reactivates
      the immune response. This may help to slow down the growth of cancer or may cause cancer
      cells to die.

      The purpose of this study is to see whether adding durvalumab to standard chemotherapy will
      improve overall survival (OS).
    

Eligibility criteria:

        Criteria:

          -  Histologically and/or cytologically confirmed malignant pleural mesothelioma.

          -  Unresectable disease (defined as the participant not being a candidate for curative
             surgery).

          -  Measurable disease, defined as at least 1 lesion (measurable) that can be accurately
             assessed at baseline by computed tomography (CT) or magnetic resonance imaging (MRI)
             and is suitable for repeated assessment (modified RECIST for pleural mesothelioma).

          -  Available unstained archived tumor tissue sample in sufficient quantity to allow for
             analyses. At least fifteen unstained slides or a tumor block (preferred). NOTE: A fine
             needle aspiration sample is not sufficient to make the patient eligible for
             enrollment. Given the complexity of mesothelioma pathological diagnosis and that these
             will be newly diagnosed patients it is expected that they will have a core needle
             biopsy or surgical tumor biopsy as part of their initial diagnostic work up.

          -  Age ≥ 18 years.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          -  Ability to understand and willingness to sign Institutional Review Board
             (IRB)-approved informed consent.

          -  Willing to provide archived tumor tissue and blood samples for research.

          -  Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks
             prior to registration:

               -  Absolute Neutrophil Count (ANC) ≥ 1500/mm³

               -  Hemoglobin ˃9.0 g/dL

               -  Platelets ˃100,000/mm³

               -  Serum creatinine clearance (CL)>60 mL/min by the Cockcroft-Gault formula or by
                  24-hour urine collection for determination of creatinine clearance. NOTE:
                  Patients with a creatinine Cl ≥ 45 mL/min however ≤ 60 mL/min may be considered
                  for enrollment provided they fulfill all other eligibility criteria, these
                  subjects will receive pemetrexed carboplatin concurrent with durvalumab during
                  the combination phase of treatment. Patients with a creatinine CL<45 mL/min
                  should not be enrolled.

               -  Albumin ≥ 2.8 g/dL

               -  Total Bilirubin ≤ 1.5x Upper Limit of Normal (ULN)

               -  Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) ≤ 2.5x ULN (≤ 5x
                  ULN in patients with liver metastases)

          -  Women must either be of non-reproductive potential or must have a negative serum
             pregnancy test upon study entry.

          -  Women must not be pregnant or breastfeeding.

          -  Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including
             follow-up.

          -  Patient must not have involvement in the planning and/or conduct of the study. No
             previous enrollment in the present study.

          -  Patients may not have participated in another clinical study with an investigational
             product during the last 4 weeks.

          -  Patients must not have any prior systemic therapy (chemotherapy, immunotherapy,
             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies, and other investigational agent) for mesothelioma.

          -  No previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or any other
             agent targeting immune checkpoints.

          -  Patients must not have non-pleural mesothelioma e.g. mesothelioma arising in
             peritoneum, tunica vaginalis or any serosal surface other than the pleura.

          -  Patients must not have an active second malignancy other than non-melanoma skin cancer
             or cervical carcinoma in situ.

          -  Patients must not have mean QT interval corrected for heart rate (QTc) ≥470 ms
             calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction.

          -  Patients must not have symptomatic or uncontrolled brain metastases requiring
             concurrent treatment, inclusive of but not limited to surgery, radiation and/or
             corticosteroids (prednisone >10 mg or equivalent). Surgery, radiation and/or
             corticosteroids (any dose >10 mg prednisone equivalent) must have been completed ≥ 2
             weeks prior to registration.

          -  Patients must not have uncontrolled seizures.

          -  Patients must not have current or prior use of immunosuppressive medication within 28
             days before the first dose of durvalumab, with the exceptions of intranasal and
             inhaled corticosteroids or systemic corticosteroids at physiological doses, which are
             not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Standard
             steroid premedication given prior to chemotherapy or as prophylaxis for imaging
             contrast allergy should not be counted for this criterion.

          -  No active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease, diverticulitis with the exception of diverticulosis,
             celiac disease, irritable bowel disease; Wegner syndrome) within the past 2 years.
             Subjects with vitiligo, alopecia, Grave's disease, or psoriasis not requiring systemic
             treatment (within the past 3 years) are not excluded.

          -  No history of primary immunodeficiency.

          -  No history of allogeneic organ transplant.

          -  No history of hypersensitivity to durvalumab, cisplatin, carboplatin, pemetrexed or
             any of their excipients.

          -  No uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
             bleeding diatheses including any subject known to have psychiatric illness/social
             situations that would limit compliance with study requirements or compromise the
             ability of the subject to give written informed consent.

          -  No active infection including tuberculosis (clinical evaluation including: physical
             examination findings, radiographic findings, positive PPD test, etc.), hepatitis B
             (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human
             immunodeficiency virus (positive HIV 1/2 antibodies as defined by a positive ELISA
             test). Patients with a past or resolved HBV infection (defined as the presence of
             hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients
             positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction
             is negative for HCV RNA. HIV testing is not required in absence of clinical suspicion.

          -  No known history of leptomeningeal carcinomatosis.

          -  Patients must not have received live attenuated vaccination within 30 days prior to
             study entry or within 30 days of receiving durvalumab.

          -  Patients must not have any condition that, in the opinion of the investigator, would
             interfere with evaluation of study treatment or interpretation of patient safety or
             study results.