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

Sponsor

Nantes University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03862833

Collaborator

(none)

Enrollment

Location

Arms

49.8

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

26 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 acida 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

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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 [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

Engraftment [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
Chimerism (mixed, full or uncompleted) [day 30, 60,90/100, 6 months and 1 year post-transplant]
Evaluation of CD3+ T-cell chimerism
overall survival [last patient follow up : 36 months]
the time from day 0 of allo-SCT to death or last follow-up for surviving patients
disease-free survival [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.
relapse rate [last patient follow up : 36 months]
any event related to re-occurrence of the disease.
Non relapse mortality [day 100 post transplant and one year post-transplant]
death from any cause without previous relapse or progression
Incidence of acute GVHD [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.
Hematologic and immune reconstitutions post-transplant [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
Complete remission (CR) rate for lymphoma patients [day 100 post transplant]
Cheson criteria
g/d T cells detection after haplo-SCT [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
Perturbation of ionic metabolism [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
Detection of dysthyroid disease [before the graft and at day 70]
Dosage of T3 T4 TSH
Incidence of acute and chronic GVHD [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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