Trial Title:
Lymphocyte Support to SBRT in Patients With Oligo-metastatic Solid Cancer
NCT ID:
NCT06439888
Condition:
Oligometastatic Disease
Solid Tumor, Adult
Conditions: Official terms:
Tretinoin
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
all-trans retinoic acid
Description:
per os treatment, started from the same day as SBRT, during 3 successive days, every 3
weeks, for a maximum of 4 cycles
Arm group label:
Part I : Stereotactic Body Radiation Therapy + All-trans retinoic acid
Arm group label:
Part II : Stereotactic Body Radiation Therapy + All-trans retinoic acid
Other name:
Tretinoin
Other name:
VESANOID
Intervention type:
Radiation
Intervention name:
Stereotactic Body Radiation Therapy
Description:
Standard of Care, planned over 1 or 2 weeks, every lesions must be irradiated
Arm group label:
Part I : Stereotactic Body Radiation Therapy + All-trans retinoic acid
Arm group label:
Part II : Stereotactic Body Radiation Therapy + All-trans retinoic acid
Arm group label:
Part II : Stereotactic Body Radiation Therapy alone
Summary:
The goal of this clinical trial is to assess safety of pan-metastases directed SBRT
combined with ATRA and the lympho-protective efficacy of ATRA upon radiation-induced
lymphopenia.
This is a French bicentric, open label, phase I/II clinical study that will comprise two
parts. Part I will evaluate the safety of the combination based on a single-arm safety
run design, while Part II will be randomized (ratio 1:1) and will study SBRT with or
without ATRA.
Patients enrolled will be treated with:
- SBRT to all lesions more than 1.5cm, on week days (from Monday to Friday), over a
maximum of 2 weeks,
- With or without (for part II patients randomized in the control arm) ATRA therapy:
ATRA 150 mg/m^2/day for 3 days every 3 weeks for a maximum of 4 cycles (about 3
months), starting on the first day of radiation therapy.
The expected rate of patients who will have lymphopenia of grade 2 or higher in the
control arm at 6 weeks post-radiotherapy is 50%.
At a one-sided level of statistical significance of 0.07, the randomization of 52
patients (26 patients in each arm) will provide 85% power to detect a decrease in this
rate to 15% in the SBRT+ATRA arm, using Fisher's exact test.
Detailed description:
Ablative radiotherapy - also called stereotactic body radiation therapy (SBRT) - can
achieve durable control of tumor lesions and appears as a highly promising strategy to
extend overall survival of patients with oligo-metastatic diseases. Radiotherapy has
recognized immunomodulatory effects: it triggers immunogenic cell death and reprogramming
of the tumor immune microenvironment, which eventually results in a systemic antitumor
response following focal radiation treatment. This is called the abscopal effect (distant
out-of-the-field lesions that shrink after focal irradiation). Unfortunately, evidences
show that this is directly counteracted by the toxic effects of radiotherapy on cytotoxic
lymphocytes, which are highly radiosensitive.
Recent data support the fact that radiation-induced lymphopenia is mostly driven by the
deregulation of the myeloid-lymphoid imbalance following radiation therapy, with aberrant
myelopoiesis and high levels of tumor infiltration by myeloid-derived suppressive cells
(MDSC). In preclinical models, pharmacological blockade of MDSC combined with radiation
therapy successfully abrogated radiation-induced lymphopenia and significantly improved
survival outcomes.
All trans retinoic acid (ATRA, also known as tretinoin) is a vitamin A derivative that
has a market authorization for the treatment of acute promyelocytic leukemia as it
efficiently induces differentiation of abnormal promyelocytes. Similarly, several
clinical studies report that ATRA can differentiate MDSCs into mature myeloid cells, with
a positive effect on the count of activated cluster of differentiation 8 (CD8+)
lymphocytes.
This clinical trial will provide the clinical proof-of-concept that adding ATRA to
pan-metastases SBRT is safe in humans, prevents severe and prolonged lymphopenia and
therefore, may foster a radiation-induced systemic anticancer immune response sufficient
to increase survival in patients with cancer at the oligo-metastatic stage.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Adult male or female patients (older than 18 years of age at inclusion);
- Histologically or cytologically proven solid cancer at the oligo-metastatic stage
amenable to pan-lesion SBRT, as defined by:
1. 2 to 5 tumor lesions measurable as per RECIST V1.1 (including primary) with a
largest diameter comprised between 1.5 and 5 cm,
2. The disease can be either genuinely oligo-metastatic, oligo-progressive, or an
induced oligo-metastatic disease,
3. All tumor lesions that match criterion I2a must be eligible to SBRT in terms of
location and radiotherapy constraints,
4. SBRT to all lesions must be feasible over a two-week period,
5. 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:
1. Systemic chemotherapy including cytotoxic, immunotherapy, targeted therapy,
hormone therapy, any investigational agent during the last 4 weeks,
2. Immunosuppressive medication during the last 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,
3. Live attenuated vaccination during the last 4 weeks,
4. Major surgery during the last 4 weeks;
- World Health Organization (WHO) 0 or 1 and Eastern Cooperative Oncology Group (ECOG)
Performance Status 0 or 1;
- Patients must have adequate organ function defined as follows:
1. White blood cell count of equal to or higher than 1,500/mm^3,
2. Lymphocyte count of equal to or higher than 800/mm^3,
3. Platelet count of equal to or higher than 100,000/mm^3,
4. Hemoglobin higher than 9 g/dL,
5. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) equal
to or less than 2.5 upper level norm (or if liver metastases are present must
be equal to or less than 5x upper level norm)
6. Serum creatinine clearance higher than 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.
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
Exclusion Criteria:
- Evidence of disease rapidly progressing at the time of screening according to the
two last best-fitted imaging modalities (CT-scans, MRI, positron emission
tomography), 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 less than 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 or 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 at least 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 tumor necrosis factor-α
(TNF-α) blockers. Use of immunosuppressive medications for the management of
investigational product-related Adverse Events 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 and
higher 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);
- Patients at risk of QT prolongation (including patients with hypokaliemia, baseline
QT/corrected QT interval more than 470 ms (for women) and more than 450 ms (for
men));
- 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Centre Léon Bérard
Address:
City:
Lyon
Zip:
69000
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Gwenaëlle GARIN-FOURNIER, PhD
Phone:
+33 (0)4 26 55 68 24
Email:
gwenaelle.garin@lyon.unicancer.fr
Investigator:
Last name:
Vincent GREGOIRE, PhD, MD
Email:
Principal Investigator
Facility:
Name:
Gustave Roussy
Address:
City:
Villejuif
Zip:
94800
Country:
France
Status:
Recruiting
Contact:
Last name:
Eric DEUTSCH, PhD, MD
Phone:
+33 (0)1 42 11 42 11
Email:
eric.deutsch@gustaveroussy.fr
Investigator:
Last name:
Eric DEUTSCH, PhD, MD
Email:
Principal Investigator
Start date:
July 11, 2024
Completion date:
January 2027
Lead sponsor:
Agency:
Gustave Roussy, Cancer Campus, Grand Paris
Agency class:
Other
Source:
Gustave Roussy, Cancer Campus, Grand Paris
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06439888
