Pan-lesions SBRT combined with lymphocyte support through ATRA-driven blockade of MDSC in patients with oligometastatic solid cancer (LySATRA)

Trial ID: 2022-500680-13-00
Protocol: LySATRA 2022/3511
Sponsor: Institut Gustave Roussy

Trial statistics

science

test molecule

location_city

research sites

public

country

medical_information

disease

person_search

investigators

Diseases & Conditions

Neoplasm

Objectives

The primary objective of this study is to evaluate the **safety** of pan-metastases directed stereotactic body radiation therapy (SBRT) combined with all-trans retinoic acid (ATRA) in patients with oligometastatic solid cancer. Additionally, the study aims to assess the lymphoprotective efficacy of ATRA in mitigating radiation-induced lymphopenia. These objectives are clinically relevant as they address the potential for enhanced treatment safety and efficacy in managing oligometastatic disease, which could lead to improved patient outcomes.

Secondary objectives include: - Assessing the overall safety profile of the combined treatment. - Evaluating the grade and evolution of lymphopenia during the first 15 weeks post-SBRT initiation. - Determining the clinical antitumor efficacy of the treatment. - Assessing treatment compliance. - Exploring the impact of treatment on lymphocyte number and activation status, including immunosenescence and myeloid-derived suppressor cell (MDSC) evolution. - Investigating the influence of the number and location of irradiated lesions on treatment outcomes. - Correlating ATRA serum concentration with treatment outcomes and blood cell kinetics. - Identifying predictive biomarkers of response, recurrence, and toxicity. - Studying the kinetics of circulating natural killer (NK) and T cells. - Estimating the biological radiation dose delivered to circulating lymphocytes and correlating it with real-time dosimetry monitoring. - Examining the role of genetic polymorphisms in lympho-sensitivity to radiation. - Investigating the biological mechanisms underlying the abscopal effect through sequential tumor biopsies and immune infiltrate characterization.

Participants

The clinical trial involves participants diagnosed with **oligometastatic solid cancer**. The study population includes adult male and female patients aged 18 years and older. Participants are required to have a histologically or cytologically confirmed solid cancer at the oligometastatic stage, with active tumor lesions that are amenable to pan-lesion SBRT. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Both genders are included, and the trial population is selected based on specific inclusion criteria, such as adequate organ function and a WHO or ECOG Performance Status of 0-1. Participants must comply with biopsy and blood sampling requirements and adhere to minimal wash-out periods from previous treatments. Lifestyle considerations, such as diet and physical activity, are not detailed in the trial data. The study includes a vulnerable population, and participants must be affiliated with a social security system or its equivalent. Female participants of reproductive potential must have a negative pregnancy test before the study and use effective contraception during the trial.

Plans and Procedures

The clinical trial is designed to evaluate the safety and efficacy of combining pan-metastases directed stereotactic body radiation therapy (SBRT) with **tretinoin** in patients diagnosed with oligometastatic solid cancer. This trial is structured as a randomized, double-blind, controlled study, divided into two parts. Part I focuses on assessing the safety of the treatment combination, while Part II evaluates the lymphoprotective efficacy of **tretinoin** against radiation-induced lymphopenia. The trial is expected to commence recruitment on March 30, 2024, and conclude by September 30, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, cancer stage, and organ function. Eligible participants will then proceed to the treatment phase, where they will receive the investigational product, **VESANOID 10 mg, capsule molle**, administered orally. Follow-up visits will be scheduled to monitor safety, treatment compliance, and the occurrence of any adverse events. The primary endpoint for Part I is the identification of dose-limiting toxicities within the first three weeks of treatment, while Part II focuses on the rate of lymphopenia at six weeks post-treatment.

The expected duration of participant involvement in the trial is approximately two years, with conditions for early termination including the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent. The end-of-study visit will involve a comprehensive assessment of the participant's health status and the collection of final data for analysis. Throughout the trial, secondary endpoints such as overall survival, progression-free survival, and the duration and grading of lymphopenia will be evaluated to provide a comprehensive understanding of the treatment's impact.

Treatment

The clinical trial involves the administration of **VESANOID 10 mg**, a soft capsule formulation containing the active substance **tretinoin**. Tretinoin is a chemical compound used in the treatment of certain types of cancer. The pharmaceutical form of the medication is a soft capsule, designed for **oral use**. The dosage of the experimental medication is 10 mg per capsule. The frequency of administration and specific dosing schedule are determined by the study protocol, which aims to evaluate the safety and efficacy of the treatment in patients with oligometastatic solid cancer. The medication is manufactured by CHEPLAPHARM ARZNEIMITTEL GMBH and is identified by the marketing authorization number 34009 365 869 7 0 in France.

In addition to the experimental treatment, the study may include standard-of-care therapies as deemed necessary by the clinical investigators. These therapies are not specified in the provided data but are typically aligned with current medical guidelines for the management of oligometastatic solid cancer. The trial does not mention the use of a placebo or comparator treatment, focusing instead on the combination of pan-metastases directed SBRT and ATRA-driven blockade of MDSC. Participant compliance with the treatment regimen is monitored throughout the study to ensure adherence to the protocol and to accurately assess the outcomes of the intervention.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the evaluation of lymphoprotective effects of ATRA in patients undergoing radiation therapy. The primary endpoint for efficacy is the rate of patients experiencing **lymphopenia** grade ≥ 2 at six weeks post-treatment, defined by an absolute lymphocyte count of less than 800/mm³, as per CTCAE Version 5.0. Secondary endpoints include the duration and grading of lymphopenia over time, overall safety, treatment compliance, reasons for discontinuation, overall survival, and progression-free survival. Exploratory endpoints involve immunomonitoring, including the characterization of circulating T cell immune infiltrate before and during treatment using immunohistochemistry and RNA-sequencing of tumor lesions. Biological dosimetry on circulating lymphocytes will also be conducted.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

I1. Adult male or female patients (≥ 18 years of age at inclusion);
I2. Histologically or cytologically proven solid cancer at the oligometastatic stage and/or oligoprogressive amenable to pan-lesion SBRT, as defined by: a. [1-5] active tumor lesions with a largest diameter comprised between [1-5] cm, b. The disease can be either genuinely oligometastatic, oligoprogressive, or an induced oligometastatic disease, c. All active tumor lesions (progressive and/or hypermetabolic) that match criterion I2a must be eligible to SBRT in terms of location and radiotherapy constraints. 'Active lesion' is defined as either: hypermetabolic on PET-scan, recent increase of >20% of its largest diameter on CT-scan, and/or any new lesion of ≥ 1cm on the most recent CT-scan, d. SBRT to all active lesions must be feasible over a two-week period, e. Whatever the primary tumor type;
Patients must agree to comply with biopsy and blood sampling for research purpose;
Minimal wash-out periods from last administration of treatments to the first day of SBRT must be: a. Systemic chemotherapy including cytotoxic, immunotherapy, targeted therapy, hormone therapy, any investigational agent > 4 weeks, b. Immunosuppressive medication > 4 weeks, with the exceptions of intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceeding 10 mg/day of prednisone, or an equivalent corticosteroid, c. Live attenuated vaccination > 4 weeks, d. Major surgery > 4 weeks;
WHO 0-1 and ECOG Performance Status 0-1;
Patients must have adequate organ function defined as follows: a. White blood cell count of ≥ 1,500/mm3, b. Lymphocyte count of ≥ 800/mm3, c. Platelet count of ≥ 100,000/mm3, d. Hemoglobin > 9 g/dL, e. Serum ALT and AST ≤2.5 ULN (or if liver metastases are present must be ≤ 5x ULN) f. Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance;
Female patients must either be of non-reproductive potential or must have a negative serum pregnancy test within 3 days prior to the initiation of the study drug and/or perform a urine test in addition to the serum test before the first dose of ATRA, if the result of the serum test cannot be obtained within 3 days.. Fertile men with a female partner of childbearing potential must agree to use male condom plus spermicide and childbearing potential women must have agreed to use at least one highly effective contraceptive method during treatment on this trial and for up to 1 month after the last dose of ATRA; Pregnancy testing and contraception counseling should be repeated monthly throughout the period of ATRA treatment.
Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol;
Patients must be affiliated to a social security system or beneficiary of the same.

cancel

Exclusion Criteria

Evidence of disease rapidly progressing at the time of screening according to the two last best-fitted imaging modalities (CT-scans, MRI, PET-scan), at the discretion of the investigator and the multidisciplinary board (RCP);
Any evidence of brain metastasis;
Any situation where irradiation of the target site(s) would imply re-irradiation of a formerly irradiated tumor site;
Bone metastasis located in a femoral bone if risk of pending fracture is high;
Liver metastasis adjacent to the stomach or small bowel and liver metastasis that leads to a volume of uninvolved liver < 700 cc;
Patients with any concurrent severe condition (grade 3 or beyond according to CTCAE V5.0) and/or uncontrolled medical condition that could compromise participation in the study;
Any psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent;
Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of safety and is approved by the Sponsor. Examples of the latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, and isolated elevation of prostate-specific antigen. Patients with a completely treated prior malignancy who are no longer treated (including maintenance therapy) and no evidence of disease for ≥ 2 years are eligible;
Chronic treatment with systemic corticosteroids or another immunosuppressant including, but not limited to systemic corticosteroids at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and TNF-α blockers. Use of immunosuppressive medications for the management of investigational product-related AEs or in subjects with contrast allergies is acceptable. The use of topical, inhaled and intranasal corticosteroids is permitted;
Patients with tumor(s) that invade major vessels, as shown unequivocally by imaging studies;
Patients with central lung metastasis (i.e within 2 cm from hilum) that are cavitary as shown unequivocally by imaging studies;
Persisting significant toxicities related to prior treatments i.e. ≥ Grade 2 adverse event according to CTCAE V5.0 criteria, except for alopecia and biological values defined in inclusion criteria I6;
Known allergy or hypersensitivity to the study drug. The study drug is contraindicated in patients with soy or peanut allergy ;
Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
Pregnant or breastfeeding women.
Persons deprived of their freedom or under guardianship, or for whom it would be impossible to undergo the medical follow-up required by the trial, for geographic, social or psychological reasons.