Clinical Trials /

Phase II MEDI4736 in Combination With Chemotherapy for First-Line Treatment of Unresectable Mesothelioma

NCT02899195

Description:

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).

Related Conditions:
  • Mesothelioma
  • Pleural Mesothelioma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II MEDI4736 in Combination With Chemotherapy for First-Line Treatment of Unresectable Mesothelioma
  • Official Title: Open Label, Phase II Study of Anti - Programmed Death - Ligand 1 Antibody, Durvalumab (MEDI4736), in Combination With Chemotherapy for the First-Line Treatment of Unresectable Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: PrE0505
  • SECONDARY ID: ESR-15-10792
  • NCT ID: NCT02899195

Conditions

  • Mesothelioma
  • Pleural Mesothelioma

Interventions

DrugSynonymsArms
Concurrent DurvalumabMEDI4736Concurrent Durvalumab
Maintenance DurvalumabMEDI4736Maintenance Durvalumab

Purpose

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).

Detailed Description

      Mesothelioma is a malignant tumor of the mesothelial surfaces primarily arising in the
      thoracic pleura and is estimated to cause 43,000 deaths worldwide each year with over 3300
      cases occurring annually in the United States. Approximately 80% of cases of mesothelioma are
      due to inflammation induced by prior asbestos exposure with a lead time from exposure to
      development of cancer of 20-30 years.

      This is a single arm, open label phase II study of the anti-PD-L1 antibody, durvalumab, in
      combination with standard chemotherapy. Pemetrexed and cisplatin will be given for up to six
      3-week cycles with the addition of concurrent durvalumab dosed every 3 weeks. The first 6
      patients who are enrolled and commence treatment will be monitored for safety of the
      combination. Use of carboplatin in place of cisplatin will be permitted for patients who are
      ineligible for cisplatin due to impaired renal function at screening, however these patients
      must otherwise fulfill the eligibility criteria for the study. For patients that receive
      cisplatin, carboplatin may also be substituted after Cycle 1 for cisplatin related toxicity
      (e.g., grade 3 ototoxicity, grade 3 nausea) at the investigator's discretion. After
      completion of Cycle 6 of concurrent therapy, patients with stable or responding disease per
      modified RECIST for malignant mesothelioma will continue on single agent durvalumab every 3
      weeks until progression. Maximum duration of durvalumab treatment is 12 months starting from
      Cycle 1 of concurrent treatment (inclusive of any treatment delays or missed treatments).

      Tumor assessments will be performed approximately every 6 weeks during concurrent therapy and
      every 9 weeks during the maintenance phase.

      Mandatory pre-treatment tumor tissue sample (i.e., obtained during a previous procedure or
      biopsy) and blood samples (prior to Cycle 1, Cycle 2 and Cycle 5) for research will also be
      required.
    

Trial Arms

NameTypeDescriptionInterventions
Concurrent DurvalumabExperimentalPemetrexed/cisplatin will be given for up to six 3-week cycles with the addition of concurrent durvalumab every 3 weeks. The first 6 patients who are enrolled and commence treatment will be monitored for safety of the combination. Use of carboplatin in place of cisplatin will be permitted for patients who are ineligible for cisplatin due to impaired renal function at screening. For patients that receive cisplatin, carboplatin may also be substituted after Cycle 1 for cisplatin related toxicity (e.g., grade 3 ototoxicity, grade 3 nausea) at the investigator's discretion.
  • Concurrent Durvalumab
Maintenance DurvalumabExperimentalAfter completion of Cycle 6 of concurrent therapy, patients with stable or responding disease per modified RECIST for malignant mesothelioma will continue on single agent durvalumab every 3 weeks until progression. Maximum duration of durvalumab treatment is 12 months starting from Cycle 1 of concurrent treatment (inclusive of any treatment delays or missed treatments).
  • Maintenance Durvalumab

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

Primary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:46 months
Safety Issue:
Description:OS assessed in accordance with RECIST 1.1 (modified for malignant mesothelioma).

Secondary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
Time Frame:46 months
Safety Issue:
Description:Number of participants with abnormal laboratory values and/or adverse events related to treatment.
Measure:Progression-Free Survival (PFS)
Time Frame:46 months
Safety Issue:
Description:PFS assessed in accordance with RECIST 1.1 (modified for malignant mesothelioma).
Measure:Time to Progression (TTP) on Durvalumab
Time Frame:46 months
Safety Issue:
Description:TTP measured from the time concurrent treatment with chemotherapy/durvalumab begins until radiologic or clinical progression is noted.
Measure:Objective Response Rate (ORR)
Time Frame:46 months
Safety Issue:
Description:ORR assessed in accordance with RECIST 1.1 (modified for malignant mesothelioma).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:PrECOG, LLC.

Trial Keywords

  • Unresectable Mesothelioma
  • Durvalumab
  • Anti-Programmed Death-Ligand 1 Antibody

Last Updated

January 25, 2018