Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in

Funding

Commercial sector/Industry,AstraZeneca Pty Ltd

Scientific enquiries

Prof Anna Nowak

Brief Summary

This study will investigate the effectiveness of durvalumab in combination with standard chemotherapy for mesothelioma. Who is it for? You may be eligible to join this study if you are aged 18 years or above, have had a diagnosis of malignant pleural mesothelioma that is not amenable to curative surgical resection. Study details All participants in the study will receive standard first-line chemotherapy for mesothelioma and the new treatment, durvalumab, intravenously on day 1 of each 3 week cyc .... This study will investigate the effectiveness of durvalumab in combination with standard chemotherapy for mesothelioma. Who is it for? You may be eligible to join this study if you are aged 18 years or above, have had a diagnosis of malignant pleural mesothelioma that is not amenable to curative surgical resection. Study details All participants in the study will receive standard first-line chemotherapy for mesothelioma and the new treatment, durvalumab, intravenously on day 1 of each 3 week cycle for a maximum number of 18 cycles. Participants will be followed-up for a minimum of 12 months to determine progression free survival and tumour response rate. Durvalumab is an antibody (a type of human protein) that works by blocking a body substance called PD-L1. Blocking PD-L1 helps the body’s immune system to attack cancer cells. Research has shown that durvalumab can slow tumour growth and shrink tumours in some people with cancer. We plan to enrol 54 participants in this study from hospitals and clinics throughout Australia. Durvalumab is currently an experimental treatment. This means that it is not yet approved for the treatment of mesothelioma, or any other condition, in Australia, or in other countries.
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Key Inclusion Criteria

1. Adults (18 years or over) with a histological or cytological diagnosis of malignant pleural mesothelioma that is not amendable to curative surgical resection 2. Measurable disease as per modified RECIST criteria for assessment of response in malignant pleural mesothelioma 3. ECOG performance status of 0 or 1 4. Tumour tissue (FFPE) available for PD-L1 testing at a central laboratory 5. Must have measurable disease without prior radiotherapy to these sites 6. Adequate bone marrow function (don .... 1. Adults (18 years or over) with a histological or cytological diagnosis of malignant pleural mesothelioma that is not amendable to curative surgical resection 2. Measurable disease as per modified RECIST criteria for assessment of response in malignant pleural mesothelioma 3. ECOG performance status of 0 or 1 4. Tumour tissue (FFPE) available for PD-L1 testing at a central laboratory 5. Must have measurable disease without prior radiotherapy to these sites 6. Adequate bone marrow function (done within 28 days prior to registration and with values within the ranges specified below). Blood transfusions are permissible. * Haemoglobin greater than or equal to 90 g/L * Absolute neutrophil count greater than or equal to 1.5 x 109/L * Platelets greater than or equal to 100 x 109/L 7. Adequate liver function (done within 28 days prior to registration and with values within the ranges specified below): * Alanine transaminase less than or equal to 3 x upper limit of normal (ULN), unless liver metastases or invasion are present, in which case it must be less than or equal to 5 x ULN * Aspartate aminotransferase less than or equal to 3 x ULN, unless liver metastases or invasion are present, in which case it must be less than or equal to 5 x ULN * Total bilirubin less than or equal to 1.5 x ULN (except participants with Gilbert’s Syndrome, who are eligible with bilirubin less than or equal to 2.5 ULN) 8. Adequate renal function (done within 28 days prior to registration and with values within the ranges specified below): * Serum creatinine less than or equal to 1.5 x ULN or * Creatinine clearance (CrCl) greater than or equal to 60 mL/min (use Cockroft-Gault formula) 9. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments 10. Signed, written informed consent 11. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative serum pregnancy test done within 24 hours prior to enrolment. Men must have been surgically sterilised or use a (double if required) barrier method of contraception if they are sexually active with a woman of child bearing potential.
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Key Exclusion Criteria

1. Prior chemotherapy or other systemic anti-cancer or immunotherapy for MPM 2. Active, known or suspected autoimmune disease. Participants are not excluded if they have vitiligo, type 1 diabetes mellitus, Grave’s disease, residual hypothyroidism due to an autoimmune condition requiring only hormone replacement, or psoriasis not requiring systemic treatment within the past 2 years. 3. Any condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone or equivalent dos .... 1. Prior chemotherapy or other systemic anti-cancer or immunotherapy for MPM 2. Active, known or suspected autoimmune disease. Participants are not excluded if they have vitiligo, type 1 diabetes mellitus, Grave’s disease, residual hypothyroidism due to an autoimmune condition requiring only hormone replacement, or psoriasis not requiring systemic treatment within the past 2 years. 3. Any condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone or equivalent dose of an alternative corticosteroid) or other immunosuppressive medications within 28 days of durvalumab administration. Intranasal, inhaled or topical steroids are permitted in the absence of active autoimmune disease. 4. Participants with symptomatic or uncontrolled brain metastases or leptomeningeal disease are excluded. Controlled brain metastases are those which have been treated and are radiologically and/or clinically stable, and the patient is asymptomatic and does not require corticosteroids. 5. 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 6. Current treatment or treatment within the last 12 months with any investigational products 7. Life expectancy of less than 24 weeks 8. History of another malignancy within 5 years prior to enrolment. Participants with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Participants with a history of other malignancies are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment. 9. Mean QT interval corrected for heart rate (QTc) greater than or equal to 470 ms calculated from 3 electrocardiograms using Fridericia’s Correction (QTc equal to QT/RR1/3) 10. Hearing loss or peripheral neuropathy considered by the investigators to contraindicate cisplatin administration 11. History of hypersensitivity to investigational product, cisplatin/pemetrexed or any excipient 12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive cardiac failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, hepatitis B, hepatitis C or human immunodeficiency virus 13. Known history of interstitial lung disease from any cause 14. Known history of primary immunodeficiency, allogeneic organ transplant, inflammatory bowel disease (e.g. Crohn’s disease or ulcerative colitis), pneumonitis or active tuberculosis 15. Receipt of live attenuated vaccination within 30 days prior to enrolment or within 30 days of receiving durvalumab 16. Specific comorbidities or conditions or concomitant medications which may interact with the investigational product(s) 17. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results 18. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol.
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