Clinical Trials /

DuRvalumab With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma

NCT04334759

Description:

Patients with malignant pleural mesothelioma (MPM) that cannot be surgically removed will receive first-line treatment with standard chemotherapy of pemetrexed and cisplatin. Two-thirds of the participants in the study will be randomly assigned to also receive a new treatment called durvalumab. Durvalumab is an antibody (a type of human protein) that works by blocking a body substance called Programmed Death-Ligand 1 (PD-L1). Blocking PD-L1 helps the body's immune system attack cancer cells. Research has shown that durvalumab can slow tumor growth and shrink tumors in some people with cancer. Previous studies of combining durvalumab and chemotherapy showed that this combination is active in advanced mesothelioma. The purpose of this study is to see whether adding durvalumab to standard chemotherapy will improve overall survival (OS) in patients with MPM.

Related Conditions:
  • Malignant Pleural Mesothelioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: DuRvalumab With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma
  • Official Title: DREAM3R: DuRvalumab (MEDI4736) With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma - A Phase 3 Randomised Trial

Clinical Trial IDs

  • ORG STUDY ID: DREAM3R
  • SECONDARY ID: PrE0506
  • SECONDARY ID: ALTG 18/001
  • SECONDARY ID: CTC 0231
  • NCT ID: NCT04334759

Conditions

  • Mesothelioma
  • Pleural Mesothelioma
  • Malignant Pleural Mesothelioma

Interventions

DrugSynonymsArms
DurvalumabMEDI4736, ImfinziArm A: Durvalumab + Chemotherapy, then Durvalumab Maintenance
Standard ChemotherapyCisplatin and PemetrexedArm B: Chemotherapy, then Observation

Purpose

Patients with malignant pleural mesothelioma (MPM) that cannot be surgically removed will receive first-line treatment with standard chemotherapy of pemetrexed and cisplatin. Two-thirds of the participants in the study will be randomly assigned to also receive a new treatment called durvalumab. Durvalumab is an antibody (a type of human protein) that works by blocking a body substance called Programmed Death-Ligand 1 (PD-L1). Blocking PD-L1 helps the body's immune system attack cancer cells. Research has shown that durvalumab can slow tumor growth and shrink tumors in some people with cancer. Previous studies of combining durvalumab and chemotherapy showed that this combination is active in advanced mesothelioma. The purpose of this study is to see whether adding durvalumab to standard chemotherapy will improve overall survival (OS) in patients with MPM.

Detailed Description

      Mesothelioma is a malignant tumor of the mesothelial surfaces primarily arising in the
      thoracic pleura. In the United Kingdom and USA the expected number of cases in the next few
      decades are 65,000 and 85,000, respectively. Once diagnosed, this disease is rarely cured
      with a median survival of less than a year.

      This is an International, Open-Label, Multi-center, Phase III study. Patients will be
      randomized 2:1 to receive durvalumab with standard chemotherapy or to receive standard
      chemotherapy alone.

      Arm A: Durvalumab every 3 weeks + standard chemotherapy (Cisplatin every 3 weeks + Pemetrexed
      every 3 weeks) for 4 to 6 cycles, followed by Durvalumab every 4 weeks.

      Arm B: Standard chemotherapy (Cisplatin every 3 weeks + Pemetrexed every 3 weeks) for 4 to 6
      cycles followed by observation.

      Treatment with durvalumab in Arm A will continued until disease progression, unacceptable
      toxicity or patient withdrawal.

      Tumor assessments and Quality of Life forms will be performed at baseline, then at weeks 6,
      12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression.

      Mandatory pre-treatment tumor tissue sample (i.e., obtained during a previous procedure or
      biopsy) for research will also be required. Blood samples for research at baseline, day 1 of
      cycle 2, and day 1 of cycle 3 will be done.

      The study is being led jointly by PrECOG as the US sponsor and University of Sydney as the
      international sponsor
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: Durvalumab + Chemotherapy, then Durvalumab MaintenanceExperimentalDurvalumab + Standard Chemotherapy for 4 to 6 cycles, followed by Maintenance with Durvalumab
  • Durvalumab
Arm B: Chemotherapy, then ObservationActive ComparatorStandard Chemotherapy for 4 to 6 cycles, followed by Observation
  • Standard Chemotherapy

Eligibility Criteria

        Inclusion Criteria:

          -  Adults (18 years or over) with a histological diagnosis of malignant pleural
             mesothelioma that is not amenable to curative surgical resection.

          -  Measurable disease as per modified RECIST 1.1 (mRECIST 1.1) criteria for assessment of
             response in malignant pleural mesothelioma, without prior radiotherapy to these sites.

          -  Body weight >30 kg,

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  Tumour tissue (Formalin-Fixed Paraffin-Embedded [FFPE]) available from diagnostic
             biopsy for PD-L1 testing and other correlative biomarker testing at a central
             laboratory.

          -  Life expectancy of at least 12 weeks.

          -  Adequate blood tests (done within 14 days prior to randomisation) and with values
             within the ranges specified below. Blood transfusions are permissible if completed at
             least 7 days prior to treatment start.

               -  Haemoglobin ≥ 9.0 g/L

               -  Absolute neutrophil count ≥ 1.5 x 10^9/L

               -  Platelets ≥ 100 x 10^9/L

               -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except participants with
                  Gilbert's Syndrome, who are eligible with bilirubin ≤ 2.5 ULN)

               -  Alanine transaminase ≤ 2.5 x upper limit of normal (ULN), unless liver metastases
                  or invasion are present, in which case it must be ≤ 5 x ULN

               -  Aspartate aminotransferase ≤ 2.5 x ULN, unless liver metastases or invasion are
                  present, in which case it must be ≤ 5 x ULN

               -  Creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-Gault formula)

          -  Patient consent must be appropriately obtained in accordance with applicable local and
             regulatory requirements. Each patient must sign a consent form prior to enrolment in
             the trial to document their willingness to participate.

          -  Willing and able to comply with all study requirements, including treatment, timing
             and/or nature of required assessments.

          -  Women of childbearing potential must use a reliable means of contraception during
             treatment and for at least 90 days thereafter. Breastfeeding is not permissible during
             or for at least 90 days after the final study treatment. Men must have been surgically
             sterilised or use a barrier method of contraception if they are sexually active with a
             woman of child bearing potential.

          -  Evidence of post-menopausal status or negative serum pregnancy test for female
             pre-menopausal patients. Women will be considered post-menopausal if they have been
             amenorrheic for 12 months without an alternative medical cause.

        Exclusion Criteria:

          -  Prior chemotherapy or other systemic anti-cancer or immunotherapy for MPM.

          -  Diagnosis on cytology or fine needle aspiration biopsy only.

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the
             exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
             Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
             criterion:

               1. Patients with vitiligo or alopecia

               2. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on
                  hormone replacement

               3. Any chronic skin condition that does not require systemic therapy

               4. Patients without active disease in the last 5 years may be included

               5. Patients with celiac disease controlled by diet alone

          -  Any condition requiring systemic treatment with either corticosteroids (>10 mg daily
             prednisone or equivalent dose of an alternative corticosteroid) or other
             immunosuppressive medications within 28 days of durvalumab administration. Intranasal,
             inhaled or topical steroids or local steroid injections (e.g. intra-articular
             injection) are permitted in the absence of active autoimmune disease. Standard steroid
             premedication given prior to chemotherapy or as prophylaxis for imaging contrast
             allergy should not be counted for this criterion.

          -  Participants with symptomatic or uncontrolled brain metastases or leptomeningeal
             disease are excluded.

          -  Prior therapy with an anti-PD-1, anti-PD-L1 (including durvalumab), anti-PD-L2,
             anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell
             co-stimulation or immune checkpoint pathways.

          -  Current treatment or treatment within the last 12 months with any investigational
             anti-cancer products.

          -  Concurrent enrolment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study.

          -  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 msec
             in screening ECG measured using standard institutional method or history of familial
             long QT syndrome.

          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of durvalumab. Note: Local surgery of isolated lesions for palliative
             intent is acceptable.

          -  No other malignancy that requires active treatment. Participants with a past history
             of adequately treated carcinoma in situ, non-melanoma skin cancer or lentigo maligna
             without evidence of disease or superficial transitional cell carcinoma of the bladder
             are eligible.

          -  Hearing loss or peripheral neuropathy considered by the investigators to
             contraindicate cisplatin administration.

          -  History of allergy or hypersensitivity to investigational product, cisplatin,
             pemetrexed or any excipient.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive cardiac failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, active peptic ulcer
             disease or gastritis, serious chronic gastrointestinal conditions associated with
             diarrhoea, active bleeding diatheses.

          -  Hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Exceptions include
             past or resolved Hepatitis B (defined as the presence of hepatitis B core antibody
             [anti-HBc] and absence of HBsAg) and patients positive for hepatitis C (HCV) antibody
             if polymerase chain reaction is negative for HCV RNA. HIV testing is not required in
             absence of clinical suspicion of HIV.

          -  Known history of primary immunodeficiency, allogeneic organ transplant, pneumonitis or
             active tuberculosis.

          -  Receipt of live attenuated vaccination within 30 days prior to enrolment or within 30
             days of receiving durvalumab.

          -  Specific comorbidities or conditions or concomitant medications which may interact
             with the investigational product(s).

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results.

          -  Serious medical or psychiatric conditions or social situation that might limit
             compliance with study requirements, substantially increase risk of incurring adverse
             events or compromise the ability of the patient to give written informed consent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival
Time Frame:Minimum follow-up is 24 months after randomisation.
Safety Issue:
Description:Defined as the time from randomisation to the date of death due to any cause.

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS)
Time Frame:Performed at baseline, then at weeks 6, 12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression (minimum follow-up is 24 months after randomisation).
Safety Issue:
Description:Defined as the interval from date of randomisation to the date of first evidence of disease progression or death, whichever occurs first.
Measure:Objective Tumour Response Rate (OTRR)
Time Frame:Performed at baseline, then at weeks 6, 12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression (minimum follow-up is 24 months after randomisation).
Safety Issue:
Description:Percentage of participants with either Complete Response (CR) or Partial Response (PR) assessed according to modified Response Criteria in Solid Tumors (RECIST) 1.1 for response in malignant pleural mesothelioma.
Measure:Classify and grade participants adverse events as assessed by CTCAE V5.0
Time Frame:90 days after last dose of durvalumab or 30 days after last dose of chemotherapy, whichever is longer.
Safety Issue:
Description:Classify and grade participants abnormal laboratory values and/or adverse events.
Measure:Health-Related Quality of Life (QOL): QLQ-C30
Time Frame:Performed at baseline, then at weeks 6, 12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression (minimum follow-up is 24 months after randomisation).
Safety Issue:
Description:European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), Importance of QOL issues assessed using a four-point scale (1 = not at all, 4 = very much).
Measure:Health-Related QOL: LC29
Time Frame:Performed at baseline, then at weeks 6, 12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression (minimum follow-up is 24 months after randomisation).
Safety Issue:
Description:EORTC Quality of Life Lung Cancer Module (QLQ-LC29), Importance of QOL issues assessed using a four-point scale (1 = not at all, 4 = very much).
Measure:Health-Related QOL: EQ-5D-5L
Time Frame:Performed at baseline, then at weeks 6, 12, 18, 26, 34, 42, 50 and then every 12 weeks until disease progression (minimum follow-up is 24 months after randomisation).
Safety Issue:
Description:Euro-Quality of Life (EuroQoL) 5 dimension 5 level (EQ-5D-5L) questionnaire, comprising of 5 questions with a score from 1 (no problem) to 5 (extreme problem) and a visual analog scale from 0 (worst) to 100 (best).
Measure:Health Care Usage Costs: Hospitalization
Time Frame:Minimum follow-up is 24 months after randomisation.
Safety Issue:
Description:Australian Sites Only: Hospitalization costs calculated by applying Australian unit costs to Australian Refined Diagnostic Related Groups (AR DRG) costs for hospitalizations.
Measure:Health Care Usage Costs: Scheduled Visits to Health Professionals
Time Frame:Minimum follow-up is 24 months after randomisation.
Safety Issue:
Description:Australian Sites Only: Scheduled costs for visits to health professionals collected via Medical Benefits Schedule (MBS).
Measure:Health Care Usage Costs: Medications
Time Frame:Minimum follow-up is 24 months after randomisation.
Safety Issue:
Description:Australian Sites Only: Scheduled costs for medications collected via the Pharmaceutical Benefits Schedule (PBS).

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:PrECOG, LLC.

Trial Keywords

  • Unresectable Mesothelioma
  • Durvalumab
  • Anti-Programmed Death-Ligand 1 Antibody
  • Immune Checkpoint Inhibitor

Last Updated

January 19, 2021