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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Hematopoietic Stem Cell Transplantation

Intervention / Treatment
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* Drug: IL2
* Drug: Zoledronic Acid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: experimental group<br>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<br>* 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<br>Drug: Zoledronic Acid<br>* 4 mg at day +15 post graft<br>|
| No Intervention: control group<br>no experimental treatment | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment | Concentration of sustained neutrophil recovery (>500 Giga/L) with full or mixed donor chimerism documentation | day 30, 60,90/100, 6 months and 1 year post-transplant | 
| Chimerism (mixed, full or uncompleted) | Evaluation of CD3+ T-cell chimerism | day 30, 60,90/100, 6 months and 1 year post-transplant | 
| overall survival | the time from day 0 of allo-SCT to death or last follow-up for surviving patients | last patient follow up : 36 months | 
| disease-free survival | 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. | last patient follow up : 36 months | 
| relapse rate | any event related to re-occurrence of the disease. | last patient follow up : 36 months | 
| Non relapse mortality | death from any cause without previous relapse or progression | day 100 post transplant and one year post-transplant | 
| Incidence of acute GVHD | 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. | day 100 post transplant one year post-transplant | 
| Hematologic and immune reconstitutions post-transplant | 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 | before the graft and at days 15, 22, 29, 36, 45, 70 | 
| Complete remission (CR) rate for lymphoma patients | Cheson criteria | day 100 post transplant | 
| g/d T cells detection after haplo-SCT | Evaluation of T CD3, CD4, CD8, NK, B, Tregs, g/d T cells | before the graft and at days 15, 22, 29, 36, 45, 70 | 
| Perturbation of ionic metabolism | Evaluation of Vitamin D, Ca, Ph, Na, K, serum creatinine, bilirubin (direct and total), alkaline phosphatase, gammaGT, ALAT, ASAT | before the graft and at days 15, 22, 29, 36, 45, 70 | 
| Detection of dysthyroid disease | Dosage of T3 T4 TSH | before the graft and at day 70 | 
| Incidence of acute and chronic GVHD | 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. | one year post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haplo-SCT, Phase 1, Zoledronic acid, IL-2, g/d T cells