Phase I Clinical Trial of ThINKK Adoptive Immunotherapy After Allogeneic Hematopoietic Transplantation in Children With Leukemia or Neuroblastoma

Official title

Phase I Clinical Trial of Therapeutic Inducers of Natural Killer Killing (ThINKK) Adoptive Immunotherapy: Feasibility, Safety and Pharmacodynamics in Children Undergoing Allogenic Hematopoietic Transplantation for Leukemia or Neuroblastoma

Overview

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

• Drug Therapeutic 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

Primary outcome measures

• Incidence and severity of treatment-emergent adverse events and serious adverse events [Time frame: From first study drug administration to 4 weeks after last administration]
• Incidence of dose-limiting toxicities [Time frame: From first study drug administration to 4 weeks after last administration]
• Incidence and severity of treatment-related adverse events [Time frame: From first study drug administration to 4 weeks after last administration]

Secondary outcome measures (7)

• Number of patients who received all infusions [Time frame: At the end of week 4]
• Number of infusions received per patient [Time frame: At the end of week 4]
• Time elapsed between confirmation of eligibility and first infusion [Time frame: At day 1]
• Percentage (%) of viable ThINKK cells at the time of infusion [Time frame: Day of infusion]
• Assessment of NK surface biomarkers [Time frame: From first study drug administration to 1 week after last administration]
• Assessment of plasmatic biomarkers by Olink® [Time frame: From first study drug administration to 1 week after last administration]
• Assessment of the global immune responses by single cell RNA sequencing [Time frame: Prior to first infusion and up to 1 week post last infusion]

Eligibility criteria

Inclusion criteria

• Between 2 and less than 13 years old at time of informed consent form signature.
• Diagnosis of acute leukemia or neuroblastoma.
• Allogenic hematopoietic stem cell transplantation 30 to 90 days prior to eligibility confirmation.
• Blood NK cell counts ≥ 100 x 10E+6 cells/L at least once before eligibility confirmation.
• Life expectancy of ≥ 3 months per investigator's judgment at time of eligibility confirmation.
• 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

• Current grade 3 or 4 acute GvHD (per MAGIC criteria).
• Relapse of primary malignancy, or any other active malignancy.

• 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.
• For neuroblastoma, defined as a progressive disease.
• 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.
• Ongoing systemic therapy with cyclosporine.
• Administration or planned administration of any prohibited treatment listed in ad hoc section.
• Aspartate aminotransferase and alanine aminotransferase serum levels ≥5 times the upper limit of normal.
• Direct bilirubin serum levels ≥3 times the ULN (unless due to Gilbert syndrome).
• Baseline estimated glomerular filtration rate < 50 mL/min/1.73 m2, as determined using the Bedside Schwartz equation for < 18 years of age.
• Grade 4 diarrhea (ie, life-threatening consequences with urgent intervention indicated).
• O2 Sat saturation <90% on room air by pulse oximetry.
• Uncontrolled life-threatening symptomatic infection(s).
• Blood pressure below the 5th percentile for age, sex, and height last 24 hours.
• Ongoing therapy with intravenous vasopressor agent.
• 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.
• Pregnancy or breastfeeding or absence of highly effective methods of contraception for males and females of childbearing potential who engage in heterosexual intercourse

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 2 centers

• The Hospital for Sick Children — Toronto
• CHU Sainte-Justine — Montreal

Publications

• Cordeau M, Belounis A, Lelaidier M, Cordeiro P, Sartelet H, Herblot S, Duval M. Efficient Killing of High Risk Neuroblastoma Using Natural Killer Cells Activated by Plasmacytoid Dendritic Cells. PLoS One. 2016 Oct 7;11(10):e0164401. doi: 10.1371/journal.pone.0164401. eCollection 2016. PMID 27716850
• Belounis A, Ayoub M, Cordeiro P, Lemieux W, Teira P, Haddad E, Herblot S, Duval M. Patients' NK cell stimulation with activated plasmacytoid dendritic cells increases dinutuximab-induced neuroblastoma killing. Cancer Immunol Immunother. 2020 Sep;69(9):1767-1779. doi: 10.1007/s00262-020-02581-0. Epub 2020 Apr 27. PMID 32342128
• Poirier N, Paquin V, Leclerc S, Lisi V, Marmolejo C, Affia H, Cordeiro P, Theoret Y, Haddad E, Andelfinger G, Lavallee VP, Duval M, Herblot S. Therapeutic Inducers of Natural Killer cell Killing (ThINKK): preclinical assessment of safety and efficacy in allogeneic hematopoietic stem cell transplant settings. J Immunother Cancer. 2024 May 15;12(5):e008435. doi: 10.1136/jitc-2023-008435. PMID 38754915
• Diaz-Rodriguez Y, Cordeiro P, Belounis A, Herblot S, Duval M. In vitro differentiated plasmacytoid dendritic cells as a tool to induce anti-leukemia activity of natural killer cells. Cancer Immunol Immunother. 2017 Oct;66(10):1307-1320. doi: 10.1007/s00262-017-2022-y. Epub 2017 May 29. PMID 28555259
• Lelaidier M, Diaz-Rodriguez Y, Cordeau M, Cordeiro P, Haddad E, Herblot S, Duval M. TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells. Oncotarget. 2015 Oct 6;6(30):29440-55. doi: 10.18632/oncotarget.4984. PMID 26320191
• Charrier E, Cordeiro P, Brito RM, Mezziani S, Herblot S, Le Deist F, Duval M. Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children. Bone Marrow Transplant. 2013 Mar;48(3):376-82. doi: 10.1038/bmt.2012.176. Epub 2012 Oct 15. PMID 23064038
• Charrier E, Cordeiro P, Brito RM, Harnois M, Mezziani S, Herblot S, Le Deist F, Duval M. Impaired interferon-alpha production by plasmacytoid dendritic cells after cord blood transplantation in children: implication for post-transplantation toll-like receptor ligand-based immunotherapy. Biol Blood Marrow Transplant. 2014 Oct;20(10):1501-7. doi: 10.1016/j.bbmt.2014.06.007. Epub 2014 Aug 14. PMID 25128615

Identifiers

NCT: NCT07518654 · ThINKK-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗