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
Inclusion Criteria:
- Adults (18 years or over) with a histological diagnosis of malignant pleural
mesothelioma that is not amenable to curative surgical resection. Histological
diagnosis requires tumour tissue from an open biopsy, or a core biopsy with a needle
of 19 gauge or wider.
- 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 or legal representative 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 based only on cytology or aspiration biopsy with a needle narrower than 19
gauge.
- 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 testing an anticancer treatment.
- 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 study treatment on protocol. Note: Local surgery of isolated lesions for
palliative intent is acceptable. Limited pleural biopsy procedures do not apply.
- 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.
