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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy, Institut Gustave Roussy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Jul 2024 → ongoing

Decision date (initial)

2024-03-04

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

RHU

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Diagnosis, Safety

Part I: The primary objective of Part I is to assess the safety of pan-metastases directed SBRT combined with ATRA.
Part II: The primary objective of Part II is to assess the lymphoprotective efficacy of ATRA upon radiation-induced lymphopenia.

Secondary objectives 12

1. To assess the overall safety profile of pan-metastases directed SBRT combined with ATRA;
2. To assess grade of lymphopenia and evolution during the first 15 weeks after SBRT start
3. To assess the clinical antitumor efficacy of pan-metastases directed SBRT combined with ATRA;
4. To assess treatment compliance
5. Exploratory objectives: - To study the impact of treatment on lymphocytes number and activation status up to 3 months after treatment initiation, including by assessing immunosenescence induction and resolution, and MDSC evolution;
6. Exploratory objective: To study the impact of irradiated lesions number and locations within the body (liver, thorax, upper abdomen etc) on treatment outputs;
7. Exploratory objective: To study ATRA serum concentration 3 hours after the first intake and correlate it with treatment outcomes and blood cells kinetics;
8. Exploratory objective: To study blood, image, metabolomics and metagenomics biomarkers predictive of response/recurrence/toxicity following treatment;
9. Exploratory objective: To study the kinetic of circulating NK and T cells during and following treatment;
10. Exploratory objective: To estimate the biological radiation dose delivered to circulating lymphocytes (T cell dosimetry) and to correlate with personalized real-time dosimetry monitoring upon SBRT delivery;
11. Exploratory objective: To study the role of genetic polymorphisms in the lympho-sensitivity to radiations
12. Exploratory objective: To study the biological mechanisms underlying abscopal effect based on the sequential tumor biopsies performed before and during treatment and characterize the immune infiltrates before/after treatment.

Conditions and MedDRA coding

Oligometastatic solid cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. I1. Adult male or female patients (≥ 18 years of age at inclusion);
2. 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;
3. Patients must agree to comply with biopsy and blood sampling for research purpose;
4. 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;
5. WHO 0-1 and ECOG Performance Status 0-1;
6. 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;
7. 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.
8. 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;
9. Patients must be affiliated to a social security system or beneficiary of the same.

Exclusion criteria 16

1. 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);
2. Any evidence of brain metastasis;
3. Any situation where irradiation of the target site(s) would imply re-irradiation of a formerly irradiated tumor site;
4. Bone metastasis located in a femoral bone if risk of pending fracture is high;
5. Liver metastasis adjacent to the stomach or small bowel and liver metastasis that leads to a volume of uninvolved liver < 700 cc;
6. 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;
7. Any psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent;
8. 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;
9. 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;
10. Patients with tumor(s) that invade major vessels, as shown unequivocally by imaging studies;
11. Patients with central lung metastasis (i.e within 2 cm from hilum) that are cavitary as shown unequivocally by imaging studies;
12. 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;
13. Known allergy or hypersensitivity to the study drug. The study drug is contraindicated in patients with soy or peanut allergy ;
14. Positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
15. Pregnant or breastfeeding women.
16. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Part I: safety Dose-limiting toxicity (DLT) is defined as an adverse event reported during the first three weeks of treatment that is possibly related to study intervention and fulfills any one of the following criteria using CTCAE Version 5.0: (...)Part II: efficacy on lymphoprotection The primary evaluation criterion is the rate of patients with lymphopenia grade ≥ 2 at 6 weeks after treatment completion, defined as an absolute lymphocyte count < 800/mm3 (CTCAE V5.0).

Secondary endpoints 2

1. Secondary endpoints include: - Duration and grading of lymphopenia over time; - Overall safety; - Treatment compliance, rate and reasons of discontinuation; -Overall Survival; -Progression Free Survival
2. Exploratory endpoints include (and may not be limited to): s immunomonitoring - Characterization of the i- Circulating T cellmmune infiltrate before/during treatment using immunohistochemistry and RNA-sequencing of tumor lesions, respectively on FFPE and freshly frozen biopsies (in-field and out of the radiation field) - Biological dosimetry on circulating lymphocytes (as in Gruel G et al., Rad Res 2013) -(...)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Regulatory Affairs Officer

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

39 Rue Camille Desmoulins

City

Villejuif Cedex

Postcode

94805

Country

France

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications