Overview

The SMARTEST trial is a phase II non-blinded randomized trial designed to evaluate the benefit of low dose cyclophosphamide in sequential combination with sub-ablative radiation (Arm A) versus sub-ablative radiation alone (Arm B) before surgery as well as the safety and efficacy of consolidation tremelimumab-durvalumab for eligible patients after surgery in both arms.

Eligibility

Inclusion Criteria:

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Age ≥ 18 years at the time of study entry
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
4. Body weight >30 kg
5. Adequate normal organ and marrow function as defined below:
6. Haemoglobin ≥9.0 g/dL
7. Absolute neutrophil count (ANC ≥1.0 × 109 /L)
8. Platelet count ≥75 × 109/L
9. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
10. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
11. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

    Males

Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

Females

             Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine
             (mg/dL)
         12. 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.
         13. Must have a life expectancy of at least 12 weeks
         14. Tumor amenable to biopsy
         15. Histologically proven mesothelioma
         16. Previously untreated mesothelioma
         17. Stage I to III according to the 8th edition of the TNM staging system based on CT
             chest-abdomen and fluorodeoxyglucose (FDG) PET scan. Tumor assessment by CT and PET
             scan must be performed within 60 days prior to randomization.
         18. Suitable for surgery and combined modality therapy in the opinion of the investigator
        Exclusion Criteria:
          1. Participation in another clinical study with an investigational product during the
             last 8 weeks
          2. 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
          3. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy (including
             radiation , surgery and low dose cyclophosphamide) with the exception of alopecia,
             vitiligo, and the laboratory values defined in the inclusion criteria
               1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                  consultation with the Study Physician.
               2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab or tremelimumab may be included only after consultation
                  with the Study Physician.
          4. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
             Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
             replacement therapy) is acceptable.
          5. Previous thoracic irradiation
          6. Serious non-malignant disease (cardiovascular, pulmonary, systemic lupus
             erythematosus, scleroderma) that would preclude definitive radiation therapy
          7. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of IP.
          8. History of allogenic organ transplantation.
          9. 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 but only
                  after consultation with the study physician
               5. Patients with celiac disease controlled by diet alone
         10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring AEs or compromise the ability of the patient to give written
             informed consent
         11. Patients with a history of other malignancies, except non-active malignancy that does
             not require treatment, nor anticipated to require treatment for the duration of the
             study, and in the opinion of the investigator would not pose a risk of increased
             toxicity, or difficulty to follow the protocol and assess endpoints of the study
         12. History of leptomeningeal carcinomatosis
         13. Patients with suspected brain metastases at screening should have an MRI (preferred)
             or CT each preferably with IV contrast of the brain prior to study entry.
         14. Distant metastatic disease (M1), including brain metastasis or spinal cord compression
         15. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
             calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
         16. History of active primary immunodeficiency
         17. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis
             B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening.
             Participants with a past or resolved HBV infection (defined as the presence of anti
             HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are
             eligible only if polymerase chain reaction is negative for HCV RNA. Adjust wording as
             necessary and consider evaluating at screening for studies with known hepatotoxicity
             or other relevant requirements.
         18. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2
             antibodies) or active tuberculosis infection (clinical evaluation that may include
             clinical history, physical examination and radiographic findings, or tuberculosis
             testing in line with local practice).
         19. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
               1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)
               2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent
               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)
               4. Use of immunosuppressive medications for the management of IP-related AEs
               5. Use in patients with contrast allergies
               6. A temporary period of steroids will be allowed if clinically indicated and
                  considered to be essential for the management of non-immunotherapy related events
                  experienced by the patient (e.g., chronic obstructive pulmonary disease,
                  radiation, nausea, etc.)
         20. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
             Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
             30 days after the last dose of IP.
         21. Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control from
             screening to 90 days after the last dose of durvalumab monotherapy or180 days after
             the last dose of durvalumab and tremelimumab combination therapy.
         22. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.
         23. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
             study regardless of treatment arm assignment.
         24. Judgment by the investigator that the patient is unsuitable to participate in the
             study and the patient is unlikely to comply with study procedures, restrictions and
             requirements.
         25. Failure to provide consent