Phase I Study of Adoptive Immunotherapy With Enriched and Expanded Autologous Natural Killer (NK) Cells for Patients With Ph+ Acute Lymphoblastic Leukemia (ALL)

Study Overview
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Brief Summary
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The present study aims at studying how safe and tolerable a new therapy for patients with Acute Lymphoblastic Leukemia (ALL) is. This new therapy consists of an immunotherapy, that is an approach focusing on the immune system, and it targets ALL patients in complete remission but who may still have the disease at a cellular level (this is called 'minimal residual disease'). For any further information, please, discuss with your treating physician.

Detailed Description
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This is an open label, multicenter, phase I study of adoptive immunotherapy with enriched and expanded autologous natural killer (NK) cells for patients with Ph+ acute lymphoblastic leukemia (ALL) in complete hematologic remission (CHR) but with persistent/recurrent minimal residual disease (MRD) ≥60 years or not eligible for other post-CHR treatment modalities. The study will investigate the safety and tolerability of a new type of NK-based immunotherapy based on the infusion of escalating doses of ex-vivo expanded autologous NK cells in Ph+ ALL patients. A maximum of 6 patients will be enrolled in two different steps. No conditioning therapies will be administered before the infusion of the expanded NK cells. Patients may receive tyrosine kinase inhibitor (TKI) maintenance.

Official Title
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Phase I Protocol of Adoptive Immunotherapy With Enriched and Expanded Autologous Natural Killer (NK) Cells for Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) in Complete Hematologic Remission (CHR) But With Persistent/Recurrent Minimal Residual Disease (MRD) ≥60 Years or Not Eligible for Other Post-CHR Treatment Modalities

Conditions
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Acute Lymphoblastic Leukemia, Complete Hematologic Remission (CHR), Persistent/Recurrent Minimal Residual Disease (MRD)

Intervention / Treatment
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* Other: Autologous NK cells infusions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects with Ph+ ALL in CHR (1st or 2nd) with MRD positivity confirmed at baseline, older or equal to 60 years or not eligible for other post-CHR treatment modalities. WHO score 0-1. Hematopoietic, liver and renal normal functions defined as follows: WBC bigger or equal to 2.000/mm3 lymphocytes bigger or equal to 500/mm3 neutrophils bigger or equal to 1.000/mm3 platelets bigger or equal to 50.000/mm3 Hb bigger or equal to 9 g/dl creatinine fewer or equal to 1.5 x ULN bilirubin fewer or equal to 1.5 x ULN AST and ALT less than 3 times the upper limit of normal. LDH less than 2 times the upper limit of normal. For male and female subjects of childbearing potential, agreement to use effective contraception. Authorization by Istituto Superiore di Sanità (ISS) according to DM 2 March 2004. Signed written informed consent according to ICH/EU/GCP and national local regulations. Exclusion Criteria: Concurrent chemotherapy or immunotherapy (TKI maintenance is permitted). Any contraindications to perform a leukapheretic procedure for mononuclear cell collection. Active or chronic infection, including Treponema, HIV, HBV and/or HCV unless antigen/PCR negative. Presence of autoimmune symptoms. Pregnant or lactating females. Simultaneous participation in another clinical trial. Any physical or psychological impediment in a patient that could lead the investigator to suspect his/her poor compliance to the protocol.

Ages Eligible for Study
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Minimum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous NK Cells infusions<br> | Other: Autologous NK cells infusions<br>* Each patient will receive repeated intravenous (IV) infusions of escalating doses of expanded autologous NK cells. The initial dose will be 1 x 106/kg of recipient body weight (BW), followed by half log increments of the dose level for each infusion, to a maximum of 1 x 108/kg of recipient BW or until they experience any toxicity, for a maximum of 5 infusions. The minimum interval between each infusion will be 28 days. No conditioning therapies will be administered before the infusion of the expanded NK cells. Patients may receive TKI maintenance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the MTD and the recommended final dose (RD) to be used for further investigations. |  | One year from start of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events. | To assess the safety and tolerabilty of the treatment by evaluating frequency, type and intensity of adverse events (AEs) according to the CTC classification, as well as the patients' compliance and clinically relevant changes in the laboratory parameters. | Two years from start of treatment. | 
| Number of patients able to complete the study. | To evaluate the feasibility of the procedure in terms of number of patients able to complete the study and time to complete enrolment. | One year from start of treatment. | 
| Time to complete enrolment. | Protocol feasibility. | Three years from first patient enrollment. | 
| Number and characteristics of immunologic modifications. | To assess the immunologic modifications induced by the procedure; in particular, to verify the functional and cytotoxic activity against tumor cell lines and primary fresh allogeneic and autologous blasts cryopreserved at diagnosis, and to monitor the frequency, phenotype and activation status of the infused NK cell populations by flow cytometry analyses, Chromium release cytotoxic assays and intracellular cytokine production. | One year from start of treatment. | 
| Number of patients who respond to treatment. | To evaluate the clinical response to the treatment in terms of control of MRD with quantitative (Q)- RT-PCR. | One year from treatment start. | 
| Number of patients alive after treatment conclusion. | To evaluate OS in terms of number of patients alive. | Two years from treatment start. | 
| Number of patients alive without progression. | To evaluate the TTP in terms of number of patients alive without progression. | One year from treatment start. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, Adoptive immunotherapy, Enriched and expanded autologous natural killer (NK) cells, Ph+ acute lymphoblastic leukemia, ≥60 years, Not eligible for other post-CHR treatment modalities