Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical Trial Summary
Patients with pleural mesothelioma (PM) that cannot be surgically removed will receive
standard chemotherapy (cisplatin or carboplatin and pemetrexed) given with durvalumab, a type
of immunotherapy, or a treatment chosen by the study doctor, which is either standard
chemotherapy or immunotherapy combination (ipilimumab and nivolumab).
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 PM.
Phase
Phase 3
Funding Agency/Sponsor
Industrial
Disease
Thoracic Oncology
Enrollment Eligibility
Inclusion Criteria:
- Adults (18 years or over) with a histological diagnosis of epithelioid 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 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 standard of
care 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) ≥ 45 mL/min (Cockcroft-Gault formula). NOTE:
Carboplatin AUC 5 must be the initial platinum agent of choice in patients with
creatinine Cl <60 mL/min but ≥ 45 mL/min, or those with clinically reported
hearing loss.
- 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:
- Non-epithelioid histology (biphasic or sarcomatoid).
- Prior chemotherapy or other systemic anti-cancer or immunotherapy for PM.
- 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 or ipilimumab or nivolumab
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, 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 administration of either cisplatin, carboplatin or pemetrexed.
- History of allergy or hypersensitivity to investigational product, cisplatin,
carboplatin, pemetrexed, ipilimumab, nivolumab 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, ipilimumab, nivolumab.
- 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.