Clinical Trial of Expanded and Activated Autologous NK Cells to Treat Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to determine wether activated and expanded autologous Natural Killer cells (NKAEs) are effective in the treatment of patients with multiple myeloma on second or later relapse. NKAEs are used in combination with anti-myeloma drugs such as lenalidomide or bortezomib.

Detailed Description
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It is expected to enroll 10 to 15 patients within 18 months. Patients have to achieve stable disease after induction therapy. Peripheral blood from patients will be collected every cycle (n=4) to produce NKAEs under Good Manufacturing Practice (GMP) conditions peripheral blood mononuclear cell (PBMCs) will be co-cultured with a genetically modified cell line (K562-mb15-41BBL) and 100 IU/ml interleukin-2. Treatment consists of 4 cycles of anti-myeloma consolidation treatment with two infusions of NKAEs every day 1 and 8 of each cycle. Usually, chosen treatment regime will be bortezomib (Velcade) or lenalidomide (Revlimid). These treatments are used to be combined with corticosteroid medications which needs to be suspended before NKAEs infusions. A washout period of 2 weeks is required. NKAEs dose of cells will be constant, 7.5x106/kg. There will be an interim analysis intra-cohort one week after the first batch of two infusions. If at the analysis no grade IV adverse effect is observed we will proceed to the second cycle and the inclusion of other patients.

Official Title
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Phase 1 Clinical Trial to Evaluate Security and Dose of Expanded and Activated Autologous NK Cells Infusions in Consolidation of Multiple Myeloma Patients Treatment on Second or Later Relapse.

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Procedure: NKAE cells infusion
* Drug: Lenalidomide
* Drug: Bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects between 20 and 80 years old With multiple myeloma in 2nd or later relapse or showing resistance after 2 treatment lines Eastern Cooperative Oncology Group (ECOG) ≤ 2 Life expectancy greater than six months Creatinine clearance rate more than 30 ml / min Subjects who have received at least 4 cycles of rescue treatment under the procedures of the 12 de Octubre Hospital (rescue treatment will vary depending on previous anti-myeloma treatment). After treatment, patients must have shown chemosensitivity and disease stabilization. Will be included subjects with partial response or stable disease (for at least 2 cycles) after 75% of planned rescue treatment or patients at subclinical progression (defined as an increase of monoclonal component ≥ 25%) at any time of rescue treatment. Subjects have to show tolerance to rescue treatment, without G3/4 adverse effects, if G1/2 adverse effects exist they must be analyzed immediately before starting reinfusion program. Subjects have to agree to participate in the trial and they have to sign informed consent. Exclusion Criteria: Subjects with clinical progression or complete response will not be included. Any of the following abnormal laboratory results: Absolute Neutrophil Count < 1000/ µL Platelets Count < 50000/ µL in those patients with bone marrow infiltration lower than 50% Measured creatinine clearance <30 ml/min Hemoglobin level ≤ 8 g/dL Peripheral neuropathy ≥ Grade 2 Subjects have received allogeneic stem cell transplant. Subjects with heart disease which compromises patient's life or protocol accomplishment. Subjects with past clinical history of malignant disease within 3 years (exceptions are squamous or basal cell carcinoma). Subjects receiving another investigational drug or having received investigational drug within 30 days before screening. Subjects who require chronic steroid or immunosuppressive treatment. Any condition, including abnormally laboratory results, that might compromise the patient´s life if he participate in this study. Any concurrent medical condition, abnormally laboratory results or any psychological disorder that prevent the patient to sign the informed consent. Pregnant or fertile women. Patients known to be seropositive for human immunodeficiency virus (VIH) or having active hepatitis A, B or C.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 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: NKAE cells infusion + chemotherapy<br>Expanded and activated autologous NK cells (NKAEs) + chemotherapy (lenalidomide OR bortezomib). | Procedure: NKAE cells infusion<br>* Expanded and activated autologous NK cells infusion. Each patient will receive two infusions of 7.5 x 106 expanded and activated autologous NK cells/kg/cycle.<br>* Other names: Activated and expanded autologous NK cells infusion;Drug: Lenalidomide<br>* Lenalidomide, 10 mg oral/day during 21 days (cycle). Patients will receive 4 cycles.<br>* Other names: Revlimid;Drug: Bortezomib<br>* Bortezomib, 1.3 mg/m2, s.c., days 1, 4, 8 and 11/cycle. Patients will receive 4 cycles.<br>* Other names: Velcade;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events During NKAE Treatment | Toxicity will be assessed by adverse events count during NKAE treatment monitoring peripheral blood absolute neutrophil count (cells/μl). Toxicity will be evaluated monthly during NKAE treatment (4 months). During follow-up, it will be assessed monthly the first 6 months. After that, quarterly until one year of follow-up, based on Common Toxicity Criteria for Adverse Events of the National Cancer Institute (CTCAE) to v.4.03. | 16 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Peripheral Blood Monoclonal Protein Reduction or Stabilization | Efficacy will be assessed monthly during NKAE treatment (4 months) by peripheral blood monoclonal protein monitoring. During follow-up, efficacy will be evaluated monthly the first 6 months. After that, quarterly until one year of follow-up. | 16 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recurrent multiple myeloma, NK cells, cell therapy, NKAE, Relapsed multiple myeloma