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

NCT05380713 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: 21-6216
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief 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 tremelimumab-durvalumab for eligible patients after surgery in both arms.

Conditions

Mesothelioma, Malignant

Outcome Measures

Primary Outcomes (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

  Up to five years

Secondary Outcomes (1)

• Survival

  Up to five years

Other Outcomes (1)

• Proportional change in circulating CD8 RA+ effector memory T cells, Proportional change in circulating CD4 RA+ effector memory T cells

  Up to five years

Study Arms (2)

Radiation+Drug (Arm A)

EXPERIMENTAL

sub-ablative radiation plus low dose cyclophosphamide followed by surgery and adjuvant immunotherapy

Drug: Cyclophosphamide; Drug: Tremelimumab; Drug: Durvalumab

Radiation alone (Arm B)

EXPERIMENTAL

sub-ablative radiation alone followed by surgery and adjuvant immunotherapy

Drug: Tremelimumab; Drug: Durvalumab

Interventions

Cyclophosphamide DRUG

Cyclophosphamide will be applied in the neoadjuvant setting

Radiation+Drug (Arm A)

Tremelimumab DRUG

tremelimumab-durvalumab in adjuvant setting

Radiation alone (Arm B); Radiation+Drug (Arm A)

Durvalumab DRUG

tremelimumab-durvalumab in adjuvant setting

Radiation alone (Arm B); Radiation+Drug (Arm A)

Eligibility Criteria

• Age: 18 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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)

You may not qualify if:

• 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
• 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.
• 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

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Ontario Institute for Cancer Research: collaborator

Study Sites (1)

Princess Margaret Cancer Centre

Toronto, Ontario, Canada

Location

MeSH Terms

Conditions

Mesothelioma, Malignant

Interventions

Cyclophosphamide; tremelimumab; durvalumab

Condition Hierarchy (Ancestors)

Mesothelioma; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 8, 2022
• First Posted: May 19, 2022
• Study Start: May 3, 2022
• Primary Completion: August 11, 2025
• Study Completion: December 20, 2025
• Last Updated: December 29, 2025

Record last verified: 2025-12

Locations

CA (1)