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

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ClinicalTrials.gov Identifier: NCT03862833
Recruitment Status : Recruiting
First Posted : March 5, 2019
Last Update Posted : February 21, 2021
Sponsor:
Information provided by (Responsible Party):
Nantes University Hospital

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.


Condition or disease Intervention/treatment Phase
Hematopoietic Stem Cell Transplantation Drug: IL2 Drug: Zoledronic Acid Phase 1

Detailed Description:

Zoledronic acid will be administered as a single dose according to marketing and regulatory authorization at the dose of 4 mg over 15 min intravenously at day+15 post-transplant. Zoledronic acid infusion must be stopped in case of grade 3/4 adverse events during infusion.

IL-2 will be administered at a unique low-dose level 5 days per week for 4 consecutive weeks from Monday to Friday subcutaneously . IL-2 has already marketing authorization for various indications.

Three IL2 levels will be tested:

Level 1: 2 millions UI/Infusion Level 2: 4 millions UI/Infusion Level 3: 6 millions UI/Infusion Zoledronic acid and IL2 have to start at day+15 if it is a Monday or the first Monday following day+15 in order to avoid administration on week-end.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: a group of patient will received IL2+ zoledronic acid a group of patient will not received IL2+ zoledronic acid
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Dose Escalation of Early Infusion of Zoledronic Acid in Combination With Increasing Low-dose of Interleukin-2 in Order to Expand Vγ9Vδ2 T Cells After T-replete Haplo-identical Allogeneic Stem Cell Transplantation (SCT)
Actual Study Start Date : May 7, 2019
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: experimental group

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

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


Drug: Zoledronic Acid
4 mg at day +15 post graft

No Intervention: control group
no experimental treatment



Primary Outcome Measures :
  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 [ Time Frame: 28 days after the last injection of IL2 ]

    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.


Secondary Outcome Measures :
  1. Engraftment [ Time Frame: day 30, 60,90/100, 6 months and 1 year post-transplant ]
    Concentration of sustained neutrophil recovery (>500 Giga/L) with full or mixed donor chimerism documentation

  2. Chimerism (mixed, full or uncompleted) [ Time Frame: day 30, 60,90/100, 6 months and 1 year post-transplant ]
    Evaluation of CD3+ T-cell chimerism

  3. overall survival [ Time Frame: last patient follow up : 36 months ]
    the time from day 0 of allo-SCT to death or last follow-up for surviving patients

  4. disease-free survival [ Time Frame: last patient follow up : 36 months ]
    time from day 0 of allo-SCT to time without evidence of relapse or disease progression censored at the date of death or last follow-up.

  5. relapse rate [ Time Frame: last patient follow up : 36 months ]
    any event related to re-occurrence of the disease.

  6. Non relapse mortality [ Time Frame: day 100 post transplant and one year post-transplant ]
    death from any cause without previous relapse or progression

  7. Incidence of acute GVHD [ Time Frame: day 100 post transplant one year post-transplant ]
    Acute GVHD: Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, et al. International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016 Jan;22(1):4-10.

  8. Hematologic and immune reconstitutions post-transplant [ Time Frame: before the graft and at days 15, 22, 29, 36, 45, 70 ]
    median time for neutrophils recovery (first day with >0.5 Giga/L for three consecutive days) and platelets recovery >20, 50 and 100 Giga/L; T CD3, CD4, CD8, NK, B, Tregs, g/d T cells

  9. Complete remission (CR) rate for lymphoma patients [ Time Frame: day 100 post transplant ]
    Cheson criteria

  10. g/d T cells detection after haplo-SCT [ Time Frame: before the graft and at days 15, 22, 29, 36, 45, 70 ]
    Evaluation of T CD3, CD4, CD8, NK, B, Tregs, g/d T cells

  11. Perturbation of ionic metabolism [ Time Frame: before the graft and at days 15, 22, 29, 36, 45, 70 ]
    Evaluation of Vitamin D, Ca, Ph, Na, K, serum creatinine, bilirubin (direct and total), alkaline phosphatase, gammaGT, ALAT, ASAT

  12. Detection of dysthyroid disease [ Time Frame: before the graft and at day 70 ]
    Dosage of T3 T4 TSH

  13. Incidence of acute and chronic GVHD [ Time Frame: one year post-transplant ]
    Chronic GVHD: Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005 Dec;11(12):945-56.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • Contra-indication to IL-2: known hypersensitivity to IL-2 or IL-2 formulation (excipients)
  • No previous ou current use of zoledronic acid

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03862833


Contacts
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Contact: patrice chevalier, MD-PHD +33 2 40 08 39 94 patrice.chevallier@chu-nantes.fr

Locations
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France
Nantes Uh Recruiting
Nantes, France
Contact: Patrice CHEVALLIER, MD-PHD       patrice.chevallier@chu-nantes.fr   
Principal Investigator: Patrice CHEVALLIER, MD-PHD         
Sponsors and Collaborators
Nantes University Hospital
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Responsible Party: Nantes University Hospital
ClinicalTrials.gov Identifier: NCT03862833    
Other Study ID Numbers: RC18_0419
First Posted: March 5, 2019    Key Record Dates
Last Update Posted: February 21, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nantes University Hospital:
Haplo-SCT
Phase 1
Zoledronic acid
IL-2
g/d T cells
Additional relevant MeSH terms:
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Zoledronic Acid
Bone Density Conservation Agents
Physiological Effects of Drugs