Zoledronic Acid in Combination With Interleukin-2 to Expand Vγ9Vδ2 T Cells After T-replete Haplo-identical Allotransplant

NCT03862833 | Completed Phase 1

• 1 other identifier: RC18_0419
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Patients receiving haplo-SCT are at high-risk of relapse. Vγ9Vδ2 T cells exhibit is a well-known population able to exert cytotoxicity toward a large range of tumor in vitro or in vivo. Activating and expanding Vγ9Vδ2 T cells early after haplo-SCT by using a combination of Zoledronic acid and low-dose interleukine (IL) -2 may be of benefit for patients by reducing incidence of relapse. The optimal dose of IL-2 to use remains to be determined. This will be a Phase 1 3+3 escalation study. Three to 15 patients are planned. It will be proposed to Patients who refuse to participate to have samples collected until day +70 to study immune and gamma/delta T cells reconstitutions after haplo-transplant.

Conditions

Hematopoietic Stem Cell Transplantation

Keywords

Haplo-SCT; Phase 1; Zoledronic acid; IL-2; g/d T cells

Outcome Measures

Primary Outcomes (1)

• determine the maximum tolerated dose (MTD) of early administration of increasing doses of low-dose IL-2 in combination with a fixed dose of Zoledronic acid after haplo-SCT

  A dose-limiting toxicity (DLT) will be defined as: * non-hematological toxicity of grade 4, including grade 4 acute GVHD 4. * non-hematological toxicity of grade 3 non-reversible for \> 7 days or reappearance of the same grade 3 after reintroduction of IL2 in case of return to at least one grade 1. * an acute GVHD grade 2-3 for \> 7 days or reappearance of GVHD grade 2-3 acute GVHD after reintroduction of IL2 if at least grade 1 acute GVHD is restored. * a reappearance of a grade 3/4 IL2 allergic reaction after reintroduction of IL2 in the event of a return to at least grade 1 after the occurrence of an allergic reaction of grade 3/4 IL2 when of the administration. * grade 4 pancytopenia with hypocellular bone marrow (no disease detection) for \> 4 weeks after the last administration of IL2.

  28 days after the last injection of IL2

Secondary Outcomes (13)

• Engraftment

  day 30, 60,90/100, 6 months and 1 year post-transplant

• Chimerism (mixed, full or uncompleted)

  day 30, 60,90/100, 6 months and 1 year post-transplant

• overall survival

  last patient follow up : 36 months

• disease-free survival

  last patient follow up : 36 months

• relapse rate

  last patient follow up : 36 months

Study Arms (2)

experimental group

EXPERIMENTAL

Zoledronic acid and IL-2 Zoledronic acid: 4 mg Three IL2 levels will be tested: Level 1: 2 millions UI/Infusion Level 2: 4 millions UI/Infusion Level 3: 6 millions UI/Infusion

Drug: IL2; Drug: Zoledronic Acid

control group

NO INTERVENTION

no experimental treatment

Interventions

IL2 DRUG

Three IL2 levels will be tested: Level 1: 2 millions UI/Infusion Level 2: 4 millions UI/Infusion Level 3: 6 millions UI/Infusion 4 weeks, 5 days per week from day + 15 post graft to day + 40

experimental group

Zoledronic Acid DRUG

4 mg at day +15 post graft

experimental group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age: 18-70 years old
• Patients with a hematological disease eligible for a haplo-SCT using the Baltimore regimen as conditioning regimen (Luznik, BBMT, 2008) (See 5.1.2)
• Patients with no HLA matched sibling or unrelated donors
• ECOG \<=2
• Signed informed consent
• Patient affiliated to or beneficiary of the National Health Service
• Patients previously transplanted are eligible to the study

You may not qualify if:

• Patients with a HLA matched sibling or unrelated donor
• Active uncontrolled infections
• HIV positive, active Hepatitis B or C
• Childbearing or child-breastfeading women
• Women or men without effective contraceptive barrier if needed
• Left ventricular ejection fraction \< 50% with no previous severe cardiopathy
• Respiratory insufficiency defined as DLCO \<40% of the corrected value
• Creatinine clearance \<50 ml/min
• Serum bilirubin \>2.5 or transaminases \>5 fold of normal value except if due to the hematological disease
• Previous or concurrent second malignancy except for adequately treated basal cell carcinoma of the skin, curatively treated in situ carcinoma of the cervix, curatively treated solid cancer, with no evidence of disease for at least 2 years
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Participation at the same time in another study in which investigational drugs are used
• Absence of written informed consent
• Contra-indication to Zoledronic acid: known hypersensitivity to Zoledronic acid or other bisphosphonate or Zoledronic acid formulation (excipients)
• Recent or programmed dental care

Sponsors & Collaborators

• Nantes University Hospital: lead

Study Sites (1)

Nantes Uh

Nantes, France

Location

Related Publications (1)

• Jullien M, Guillaume T, Le Bourgeois A, Peterlin P, Garnier A, Eveillard M, Le Bris Y, Bouzy S, Tessoulin B, Gastinne T, Dubruille V, Touzeau C, Mahe B, Blin N, Lok A, Vantyghem S, Sortais C, Antier C, Moreau P, Scotet E, Bene MC, Chevallier P. Phase I study of zoledronic acid combined with escalated doses of interleukine-2 for early in vivo generation of Vgamma9Vdelta2 T-cells after haploidentical stem cell transplant with posttransplant cyclophosphamide. Am J Hematol. 2024 Mar;99(3):350-359. doi: 10.1002/ajh.27191. Epub 2024 Jan 2.

  PMID: 38165016 DERIVED

MeSH Terms

Interventions

Interleukin-2; Zoledronic Acid

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: a group of patient will received IL2+ zoledronic acid a group of patient will not received IL2+ zoledronic acid

Study Record Dates

• First Submitted: February 27, 2019
• First Posted: March 5, 2019
• Study Start: May 7, 2019
• Primary Completion: August 29, 2023
• Study Completion: August 29, 2023
• Last Updated: October 6, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)