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Mesothelioma, MalignantPhase 2NCT05380713

......SMARTEST Trial......

A Phase 2 study testing Cyclophosphamide, Tremelimumab and Durvalumab in people with Mesothelioma, Malignant, run by University Health Network, Toronto at 1 site in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 18 to 95 years
Conditions the study is for
Mesothelioma, Malignant
What is being tested?
Cyclophosphamide, Tremelimumab and Durvalumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteCanada
Study dates
3 May 2022to 20 Dec 2025
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 95 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • Age ≥ 18 years at the time of study entry
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Body weight >30 kg
  • Adequate normal organ and marrow function as defined below:
  • Haemoglobin ≥9.0 g/dL
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  • Absolute neutrophil count (ANC ≥1.0 × 109 /L)
  • Platelet count ≥75 × 109/L
  • 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.
  • 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
  • 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)
  • 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.
  • Must have a life expectancy of at least 12 weeks
  • Tumor amenable to biopsy
  • Histologically proven mesothelioma
  • Previously untreated mesothelioma
  • 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.
  • Suitable for surgery and combined modality therapy in the opinion of the investigator

Who cannot join

  • Participation in another clinical study with an investigational product during the last 8 weeks
  • 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
  • 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
  • Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
  • 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.
  • 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.
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  • Previous thoracic irradiation
  • Serious non-malignant disease (cardiovascular, pulmonary, systemic lupus erythematosus, scleroderma) that would preclude definitive radiation therapy
  • Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
  • History of allogenic organ transplantation.
  • 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:
  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician
  • Patients with celiac disease controlled by diet alone
  • 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
  • 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
  • History of leptomeningeal carcinomatosis
  • 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.
  • Distant metastatic disease (M1), including brain metastasis or spinal cord compression
  • 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)
  • History of active primary immunodeficiency
  • 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.
  • 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).
  • 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:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  • Use of immunosuppressive medications for the management of IP-related AEs
  • Use in patients with contrast allergies
  • 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.)
  • 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.
  • 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.
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
  • Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
  • 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.
  • Failure to provide consent

Trial locations and contacts

1 site in 1 country.

Canada1 site

  • Princess Margaret Cancer Centre

    Toronto, Ontario

Other trials in Canada

About this study

Official title: Surgery for Mesothelioma After Radiation Therapy Using Exquisite Systemic Therapy

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.

Read the detailed description

This study has two parts. In the first part of the study the investigators are exploring the benefit of using low dose Cyclophosphamide in combination with low dose radiation before surgery and in the second part of the study the investigators are exploring safety and efficacy of using a combination of immunotherapy drugs, tremelimumab-durvalumab, after surgery.

Being tested
Cyclophosphamide, Tremelimumab, Durvalumab
Medical subject headings
Mesothelioma, Malignant

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CyclophosphamideDrug

    Cyclophosphamide will be applied in the neoadjuvant setting

  • TremelimumabDrug

    tremelimumab-durvalumab in adjuvant setting

  • DurvalumabDrug

    tremelimumab-durvalumab in adjuvant setting

Study groups in NCT05380713
Study groupRoleWhat they receive
Radiation+Drug (Arm A)Experimentalsub-ablative radiation plus low dose cyclophosphamide followed by surgery and adjuvant immunotherapy
Receives: Drug: Cyclophosphamide; Drug: Tremelimumab; Drug: Durvalumab
Radiation alone (Arm B)Experimentalsub-ablative radiation alone followed by surgery and adjuvant immunotherapy
Receives: Drug: Tremelimumab; Drug: Durvalumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. CD8 TILs density / gross tumor volume (GTV)

    The primary objective of the study is to demonstrate that low dose cyclophosphamide in combination with sub-ablative radiation can enhance the anti-tumoral immune response compared to sub-ablative radiation alone

    Measured: Up to five years

Secondary outcomes (1)

  1. Survival

    Demonstrate the safety and efficacy of tremelimumab-durvalumab in the adjuvant setting after sub-ablative radiation and surgery with and without low dose cyclophosphamide

    Measured: Up to five years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 May 2022
  2. Study start3 May 2022
  3. Primary completion11 Aug 2025
  4. Study completion20 Dec 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
This 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.
Masking
None (open label)
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05380713
Sponsor's protocol ID
21-6216
Status last verified
Dec 2025
First submitted
8 Apr 2022
Last updated
29 Dec 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Cyclophosphamide, Tremelimumab and Durvalumab in people with Mesothelioma, Malignant, run by University Health Network, Toronto at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

CD8 TILs density / gross tumor volume (GTV) (time frame: Up to five years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05380713.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Dec 2025.

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