NK-VS-MM: Clinical Trial of Expanded and Activated Autologous NK Cells to Treat Multiple Myeloma

• Sponsor: Joaquín Martínez López, MD, PhD (Other)
• Overall Status: Completed
• CT.gov ID: NCT02481934
• Collaborator: Hospital Infantil Universitario Niño Jesús, Madrid, Spain (Other)
• Enrollment: 5
• Location: 1
• Arm: 1
• Duration (Months): 43
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Procedure: NKAE cells infusion; Drug: Lenalidomide; Drug: Bortezomib	Phase 1

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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.
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: NKAE cells infusion + chemotherapy Expanded and activated autologous NK cells (NKAEs) + chemotherapy (lenalidomide OR bortezomib).

Procedure: NKAE cells infusion; 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.; Other Names: NKAE infusion Activated and expanded autologous NK cells infusion ; Drug: Lenalidomide; Lenalidomide, 10 mg oral/day during 21 days (cycle). Patients will receive 4 cycles.; Other Names: Revlimid ; Drug: Bortezomib; Bortezomib, 1.3 mg/m2, s.c., days 1, 4, 8 and 11/cycle. Patients will receive 4 cycles.; Other Names: Velcade

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events During NKAE Treatment [16 months]

   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.

Secondary Outcome Measures

1. Number of Participants With Peripheral Blood Monoclonal Protein Reduction or Stabilization [16 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Universitario 12 de Octubre	Madrid		Spain	28041

Sponsors and Collaborators

• Joaquín Martínez López, MD, PhD
• Hospital Infantil Universitario Niño Jesús, Madrid, Spain

Investigators

• Principal Investigator: Joaquín Martínez López, M.D, Ph.D, Hospital Universitario 12 de Octubre

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Joaquín Martínez López, MD, PhD, Hematology Head of department, M.D., Ph.D., Hospital Universitario 12 de Octubre
• ClinicalTrials.gov Identifier: NCT02481934
• Other Study ID Numbers: NK-VS-MM
• First Posted: Jun 25, 2015
• Last Update Posted: Aug 20, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Joaquín Martínez López, MD, PhD, Hematology Head of department, M.D., Ph.D., Hospital Universitario 12 de Octubre: Recurrent multiple myeloma; NK cells; cell therapy; NKAE; Relapsed multiple myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Lenalidomide; Bortezomib

Study Results

Participant Flow

Recruitment Details	Recruitment was performed between march 2013 and october 2014 at Hospital 12 de Octubre in Madrid.

Arm/Group Title	NKAE Cells Infusion + Chemotherapy
Arm/Group Description	Expanded and activated autologous NK cells (NKAEs) + chemotherapy (lenalidomide OR bortezomib). NKAE cells infusion: 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. Lenalidomide: Lenalidomide, 10 mg oral/day during 21 days (cycle). Patients will receive 4 cycles. Bortezomib: bortezomib, 1.3 mg/m2, s.c., days 1, 4, 8 and 11/cycle. Patients will receive 4 cycles.
Period Title: Overall Study
STARTED	5
COMPLETED	3
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	NKAE Cells Infusion + Chemotherapy
Arm/Group Description	Expanded and activated autologous NK cells (NKAEs) + chemotherapy (lenalidomide OR bortezomib). NKAE cells infusion: 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. Lenalidomide: Lenalidomide, 10 mg oral/day during 21 days (cycle). Patients will receive 4 cycles. Bortezomib: bortezomib, 1.3 mg/m2, s.c., days 1, 4, 8 and 11/cycle. Patients will receive 4 cycles.
Overall Participants	5
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	3 60%
Male	2 40%
Region of Enrollment (participants) [Number]
Spain	5 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events During NKAE Treatment
Description	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.
Time Frame	16 months

Outcome Measure Data

Analysis Population Description

Analysis per protocol

Arm/Group Title	NKAE Cells Infusion + Chemotherapy
Arm/Group Description	Expanded and activated autologous NK cells (NKAEs) + chemotherapy (lenalidomide OR bortezomib). NKAE cells infusion: 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. Lenalidomide: Lenalidomide, 10 mg oral/day during 21 days (cycle). Patients will receive 4 cycles. Bortezomib: bortezomib, 1.3 mg/m2, s.c., days 1, 4, 8 and 11/cycle. Patients will receive 4 cycles.
Measure Participants	5
Number [participants]	2 40%

2. Secondary Outcome

Title	Number of Participants With Peripheral Blood Monoclonal Protein Reduction or Stabilization
Description	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.
Time Frame	16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	NKAE Cells Infusion + Chemotherapy
Arm/Group Description	Expanded and activated autologous NK cells (NKAEs) + chemotherapy (lenalidomide OR bortezomib). NKAE cells infusion: 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. Lenalidomide: Lenalidomide, 10 mg oral/day during 21 days (cycle). Patients will receive 4 cycles. Bortezomib: bortezomib, 1.3 mg/m2, s.c., days 1, 4, 8 and 11/cycle. Patients will receive 4 cycles.
Measure Participants	5
Number [participants]	5 100%

Adverse Events

Time Frame	4 months during treatment with NKAE cells.
Arm/Group Title	NKAE Cells Infusion + Chemotherapy
Arm/Group Description	Expanded and activated autologous NK cells (NKAEs) + chemotherapy (lenalidomide OR bortezomib). NKAE cells infusion: 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. Lenalidomide: Lenalidomide, 10 mg oral/day during 21 days (cycle). Patients will receive 4 cycles. Bortezomib: bortezomib, 1.3 mg/m2, s.c., days 1, 4, 8 and 11/cycle. Patients will receive 4 cycles.
All Cause Mortality
	NKAE Cells Infusion + Chemotherapy
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	NKAE Cells Infusion + Chemotherapy
	Affected / at Risk (%)	# Events
Total	2/5 (40%)
Gastrointestinal disorders
Gastrointestinal bleeding	1/5 (20%)	1
Musculoskeletal and connective tissue disorders
Vertebral compression	1/5 (20%)	2
Other (Not Including Serious) Adverse Events
	NKAE Cells Infusion + Chemotherapy
	Affected / at Risk (%)	# Events
Total	2/5 (40%)
Immune system disorders
Neutropenia	2/5 (40%)	2

Limitations/Caveats

Volume of the peripheral blood from patients was limiting in order to perform different cohorts with more NKAE cells infusions.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.