PREDOSTAR - PREventing second cancers with DOSTARlimab - A multicenter, open-label, randomized phase II study aiming to assess the clinical impact of dostarlimab on occurrence of second primary cancer in patients with cured primary cancer

Trial ID: 2022-501316-34-00
Protocol: PREDOSTAR/ET22-215
Sponsor: Centre Leon Berard

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Diseases & Conditions

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Objectives

The primary objective of this study is to assess whether a short treatment with **dostarlimab** following the curative treatment of a first primary cancer (FPC) reduces the risk of developing a second primary cancer (SPC) in patients who have been cured of their initial cancer. This is clinically relevant as it aims to prevent the occurrence of additional malignancies, thereby potentially improving long-term patient outcomes and survival rates.

Secondary objectives include:

To further evaluate the clinical impact of the proposed strategy.
To document the safety of **dostarlimab** in the target population.

Participants

The clinical trial involves a study population comprising both **male and female** participants aged 18 years and older. The participants are individuals who have been cured of a primary cancer and are at risk of developing a second primary cancer. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include patients with a history of one or two primary solid tumors, with specific stages eligible for curative treatment, and those with at least one risk factor for a second primary cancer, such as tobacco use or genetic predispositions. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, indicating they are fully active and able to carry on all pre-disease performance without restriction. Adequate hematologic and end-organ function is required, as defined by specific laboratory test results. Lifestyle considerations such as diet and physical activity are not specified. The trial includes both genders, and women of child-bearing potential must have a negative pregnancy test and agree to use contraception. Fertile men must also agree to use effective contraception during the study and for a specified period after the last dose of dostarlimab.

Plans and Procedures

The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the impact of **dostarlimab** on the occurrence of second primary cancer in patients who have been cured of a primary cancer. The trial will involve participants who are at least 18 years old and have a history of one or two primary solid tumors, with specific inclusion criteria such as adequate hematologic and end-organ function, and a performance status of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale. The study aims to determine whether a short treatment with dostarlimab after curative treatment of a first primary cancer reduces the risk of developing a second primary cancer.

The trial is expected to last until December 2027, with recruitment having started in January 2023. Participants will be involved in the study for a maximum treatment period of 12 months. The study visits will include an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor the participants' health and response to the treatment. The end-of-study visit will conclude the participants' involvement, where final assessments will be conducted. The primary endpoint is the incidence of second primary cancer, which must be histologically confirmed. Secondary endpoints include the rate of second primary cancer at three years, time to second primary cancer, event-free survival, overall survival, and recurrence of the first primary cancer.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The study will utilize **JEMPERLI 500 mg concentrate for solution for infusion**, administered intravenously, with a maximum daily dose of 500 mg and a total dose not exceeding 20,000 mg. The trial is not classified as a low-intervention study and is categorized as a phase IV trial. The study's findings will contribute to understanding the potential benefits of dostarlimab in preventing second primary cancers in patients with a history of primary cancer.

Treatment

The clinical trial involves the administration of **dostarlimab**, marketed under the name JEMPERLI, which is a **concentrate for solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for intravenous administration. Each dose contains 500 mg of the active substance, dostarlimab, which is a protein-based therapeutic agent. The maximum daily dose is set at 500 mg, with a total maximum dose of 20,000 mg over the course of the treatment. The treatment period is limited to a maximum of 12 months. The administration schedule and dosing frequency are determined by the study protocol, ensuring adherence to the specified treatment regimen.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the clinical impact of dostarlimab in preventing the occurrence of second primary cancer in patients who have been cured of their primary cancer. Participant compliance with the dosing schedule is monitored throughout the trial to ensure accurate assessment of the treatment's efficacy and safety. The trial is conducted under the sponsorship of GlaxoSmithKline (Ireland) Limited, with the product authorized for use in the European Union under the marketing authorization number EU/1/21/1538/001.

Efficacy

Efficacy in the clinical trial titled "PREDOSTAR - PREventing second cancers with DOSTARlimab" will be assessed using both primary and secondary endpoints. The primary endpoint is the incidence of second primary cancer (SPC) in patients who have completed curative treatment for a first primary cancer (FPC). The occurrence of SPC must be histologically confirmed and classified according to the International Classification of Diseases for Oncology and IARC rules.

Secondary endpoints include the rate of SPC at 3 years, time to SPC, event-free survival, overall survival since randomization and since SPC, and recurrence of FPC. Additionally, adverse events (AE) and serious adverse events (SAE) will be evaluated according to the NCI-CTCAE V5.0. These efficacy parameters will be measured and collected at specified timepoints throughout the study duration, which is estimated to conclude by December 2027.

Inclusion and Exclusion Criteria

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Inclusion Criteria

I1. Male or female patient ≥18 years of age at time of informed consent form signature. Note - Patients with childhood primary cancer are eligible.
I2. Patients with prior histologically proven 1 or 2 maximum primary solid tumors (any type), AJCC stage I, II or III or IV if M0, eligible to curative treatment. Note - Time between end of treatment for last cancer and randomisation must be <6 months. Note: Note: Patients with 2 prior cancers are eligible if the first primary cancer: a. Was diagnosed > 5 years prior to entry in this study b. Was localized with no evidence of metastatic disease c. Remains without evidence of recurrence at time of enrolment on this study
I3. Patients with at least one risk factor for new cancer including: a. Exposure to exogenous risk factor : tobacco (>20YP) ≥ 10 years and still active at time of last cancer diagnosis or b. Endogenous risk factors (genetic predisposition including for instance germ line mutations of p53 or BRCA genes, Lynch syndrome, or any mutations of genes known to be associated with higher risk of cancer according to current list from French National Cancer institute [Appendix 18.1]). c. HPV-related primary cancer
I4. Availability of FFPE tumor sample from prior cancer initial diagnosis for histological comparison in case/at time of new cancer. Note - Histological report must be sent to the sponsor with archival FFPE tumor block within 14 days after randomisation.
I5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or.
I6. Adequate hematologic and end-organ function, defined by the following laboratory test results: - WBC ≥ 2.5 x 10 9/L - Hemoglobin ≥ 9.0 g/dL. Patients may be transfused (> 2 weeks before randomisation) to meet this criterion- Absolute neutrophil count (ANC) ≥ 1.5 x 10 9/L without granulocyte colony-stimulating factor support within 2 weeks before randomisation - Platelets ≥ 100 x 10 9/L - Lymphocyte count ≥ 0.5 x 10 9/L - Serum creatinine clearance ≥30 mL/min/1.73m2 (MDRD or CKD-EPI formula – Appendix in 18.4) or serum creatinine ≤1.5ULN - Serum bilirubin ≤ 1.5 × Upper Limit of Normal (ULN), with the following exception: Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled - Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤ 2.5 x ULN - Prothrombin time/INR ≤ 1.5, or, if patient is receiving therapeutic anticoagulation, prothrombin time/INR < 3.0 - aPTT ≤ ULN OR, if patient is receiving therapeutic anticoagulation, aPTT must be < 1.5 ULN. Note: Patient receiving therapeutic anticoagulation must be on stable dose - Proteinuria by urine dipstick < 2+ or 24-hour proteinuria ≤ 1.0 g
I7. Corrected QT interval (QTc) <450 msec (or QTc <480 msec for participants with bundle branch block).
I8. Women patients of child-bearing potential are eligible, provided they have a negative serum or urine pregnancy and agrees to use adequate contraception for up to 4 months after the final dose of dostarlimab.
I9. Fertile men must agree to use an effective method of contraception during the study and for up to 6 months after the last dose of dostarlimab.
I10. Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed and should be able and willing to comply with study visits and procedures as per protocol.
I11. Patients must be covered by a medical insurance in country where applicable.

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Exclusion Criteria

E1.Previous treatment with immunotherapy (any types) for cured first primary cancer.
E10. History of autoimmune disease including (see Appendix 18.5 for a more comprehensive list of pre-existing autoimmune diseases and immune deficiencies and exceptions in the protocol.
E11. Infectious diseases: • active infection requiring IV antibiotics, • severe infection within 4 weeks prior to randomisation, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, • active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening), • active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA at screening, • HIV infection, • active tuberculosis, • influenza vaccination should be given during influenza season. Patients must not receive live attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to randomisation or at any time during the study.
E5. Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) are prohibited within 4 weeks or five half-lives of the drug (whichever is longer) prior to randomisation.
E13. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.
E14. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome).
E15. Patient with FPC known to be at high risk of relapse defined as ≥ 70% relapse from FPC within 2 years.
E16. Patients who are solid organ recipients.
E17. Patient with primary cancer of unknown origin (CUP).
E2.Patient with more than 2 prior primary cancers.
E3.Acute and ongoing toxicities from previous therapy that have not resolved to Grade ≤ 1, except for alopecia, neuropathy and lab values presented in inclusion criteria
E4.Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomisation, or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 days prior to randomisation or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure.
E5. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to randomisation, or anticipation of need for systemic immunosuppressive medication during study treatment; with the exceptions of intranasal, inhaled, or topical corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
E6. Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) are prohibited within 4 weeks or five half-lives of the drug (whichever is longer) prior to randomisation.
E7. Oral or IV antibiotics within 14 days of randomisation.
E8. History of severe allergic or other hypersensitivity reactions to: • chimeric or humanized antibodies or fusion proteins, • biopharmaceuticals produced in Chinese hamster ovary cells, or • any component of the dostarlimab formulation.
E9. Concurrent treatment with any approved or investigational anti-cancer treatment or participation in another clinical trial with therapeutic intent. Note - Hormonotherapy as part of standard of care is allowed.
E18. Pregnant or lactating women