Hematopoetic Stem Cell Transplant, Hematopoetic Stem Cell Transplantation, Leukaemia (Acute Lymphoblastic), Leukaemia (Acute Myeloid), Leukaemia, Lymphoblastic, Acute, Leukemia Acute Myeloid, Leukemia Acute Myeloid - AML, Leukemia (Both ALL and AML), Neuroblastoma, Neuroblastoma, Metastatic
Conditions
Keywords
Thinkk, NK cells, pdc, immunotherapy
Brief summary
A first-in-class adoptive immunotherapy we called ThINKK, for Therapeutic Inducers of Natural Killer (NK) cell Killing, have been designed for use after hematopoietic stem cell transplantation (HSCT), where the proper stimulation of graft-derived NK cells has been shown to prevent relapse. ThINKK immunotherapy builds on our earlier research on NK cells and plasmacytoid dendritic cells (PDC) in cord blood and after HSCT. PDC are the sentinels of the immune system. Upon viral nucleic acids detection, PDC secrete a vast array of chemokines and cytokines that stimulate NK cells. PDC stimulation enhances NK cells killing of infected cells that express stress-induced molecules. Cancer cells also express stress-related molecules at their surface. However, NK cells do not receive PDC stimulation when fighting cancer. ThINKK therapy is designed to provide this necessary stimulation.
Detailed description
Primary Objective: To assess the safety and tolerability of ThINKK adoptive immunotherapy by determination of the Maximum Tolerated Dose (MTD) in patients who has undergone allogenic HSCT for acute leukemia (ALL or AML) or neuroblastoma. * Secondary Objectives: * To demonstrate the feasibility of delivering (manufacturing and administrating) ThINKK adoptive immunotherapy after HSCT. * To assess biological effect at MTD (pharmacodynamic studies).
Interventions
DRUGTherapeutic Inducers of Natural Killer Killing (ThINKK)
This study uses an adaptation of the classical 3+3 dose-escalation model. The Maximum Tolerated Dose (MTD) is determined as the highest dose level at which six patients are treated with no unacceptable increase in acute GvHD risk and with no more than one patient experiencing a DLT. The first cohort (3 patients) will receive 7.5 M ThINKK/m2 weekly for 4 weeks. Dose distribution for the escalation levels will be guided by the pharmacodynamic data from the initial cohort.. If the preliminary data show that TRAIL expression remains stable at Day +8, dose level 2 will be set at 15 × 10\^6 / m2 BSA weekly, and dose level 3 at 30 × 10\^6 / m2 BSA weekly. If the data instead indicate the need to shorten the dosing interval to maintain TRAIL expression, dose level 2 will be set at 7.5 × 10\^6 / m2 BSA bi-weekly and dose level 3 at 15 × 10\^6 / m2 BSA bi-weekly.
Sponsors
Michel Duval
Héma-Québec
ExCellThera inc.
Centre C3i
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Adapted 3+3 design
Eligibility
Sex/Gender
ALL
Age
2 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
1. Between 2 and less than 13 years old at time of informed consent form signature. 2. Diagnosis of acute leukemia or neuroblastoma. 3. Allogenic hematopoietic stem cell transplantation 30 to 90 days prior to eligibility confirmation. 4. Blood NK cell counts ≥ 100 x 10E+6 cells/L at least once before eligibility confirmation. 5. Life expectancy of ≥ 3 months per investigator's judgment at time of eligibility confirmation. 6. Patient or legally acceptable representative has provided informed consent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
Exclusion criteria
1. Current grade 3 or 4 acute GvHD (per MAGIC criteria). 2. Relapse of primary malignancy, or any other active malignancy. 1. For leukemia, defined as either morphological relapse or Minimal Residual Disease (MRD) ≥0.01% as measured by flow cytometry. MRD detected by polymerase chain reaction (PCR) does not constitute an exclusion criterion. 2. For neuroblastoma, defined as a progressive disease. 3. Ongoing therapy with systemic corticosteroids (equivalent to a prednisone dose \>0.5 mg/kg/day). Patients actively undergoing corticosteroid tapering during Screening may be enrolled once they have reached a prednisone-equivalent dose ≤ 0.5 mg/kg/day with Sponsor-Investigator approval, with the expectation that the taper will continue. 4. Ongoing systemic therapy with cyclosporine. 5. Administration or planned administration of any prohibited treatment listed in ad hoc section. 6. Aspartate aminotransferase and alanine aminotransferase serum levels ≥5 times the upper limit of normal. 7. Direct bilirubin serum levels ≥3 times the ULN (unless due to Gilbert syndrome). 8. Baseline estimated glomerular filtration rate \< 50 mL/min/1.73 m2, as determined using the Bedside Schwartz equation for \< 18 years of age. 9. Grade 4 diarrhea (ie, life-threatening consequences with urgent intervention indicated). 10. O2 Sat saturation \<90% on room air by pulse oximetry. 11. Uncontrolled life-threatening symptomatic infection(s). 12. Blood pressure below the 5th percentile for age, sex, and height last 24 hours. 13. Ongoing therapy with intravenous vasopressor agent. 14. Any condition that, in the opinion of the Investigator, would compromise the safety of the patient, would prevent full participation in this study, or would interfere with the evaluation of any study endpoints. 15. Pregnancy or breastfeeding or absence of highly effective methods of contraception for males and females of childbearing potential who engage in heterosexual intercourse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of treatment-emergent adverse events and serious adverse events | From first study drug administration to 4 weeks after last administration | — |
| Incidence of dose-limiting toxicities | From first study drug administration to 4 weeks after last administration | Defined as: (1) Adverse event (excluding cytopenias) grade ≥ 3 considered to be possibly, probably or definitively related to the investigational product, (2) Cytopenia (anemia, neutropenia or thrombocytopenia) grade ≥ 4 considered to be possibly, probably or definitively related to the investigational product, (3) Grade ≥ 3 ICANS, (4) Grade ≥ 3 CRS and (5) Overall clinical grade ≥ 3 acute GvHD (MAGIC criteria) |
| Incidence and severity of treatment-related adverse events | From first study drug administration to 4 weeks after last administration | — |
Secondary
| Measure | Time frame |
|---|---|
| Number of patients who received all infusions | At the end of week 4 |
| Number of infusions received per patient | At the end of week 4 |
| Time elapsed between confirmation of eligibility and first infusion | At day 1 |
| Percentage (%) of viable ThINKK cells at the time of infusion | Day of infusion |
| Assessment of NK surface biomarkers | From first study drug administration to 1 week after last administration |
| Assessment of plasmatic biomarkers by Olink® | From first study drug administration to 1 week after last administration |
| Assessment of the global immune responses by single cell RNA sequencing | Prior to first infusion and up to 1 week post last infusion |
Countries
Canada
Contacts
CONTACTMichel Duval, MD
CONTACTKarine Leveille
PRINCIPAL_INVESTIGATORMichel Duval, MD
St. Justine's Hospital
STUDY_DIRECTORSabine Herblot, PhD
St. Justine's Hospital
Outcome results
None listed