CIK2: Cytokine Induced Killer (CIK) Cells In Leukemia Patients

• Sponsor: A.O. Ospedale Papa Giovanni XXIII (Other)
• Overall Status: Completed
• CT.gov ID: NCT01186809
• Collaborator: Regional Hospital of Bolzano (Other), Azienda Ospedaliera San Gerardo di Monza (Other)
• Enrollment: 74
• Locations: 3
• Arm: 1
• Duration (Months): 94.5
• Patients Per Site: 24.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of the Phase IIA study are to:

1. define the safety profile

2. evaluate the efficacy of a sequential infusion of unmanipulated Donor Lymphocyte Infusions (DLI) and Cytokine Induced Killer (CIK) cells for the treatment of molecular, cytogenetic or hematologic relapse after hematopoietic stem cell transplantation and The progression free survival and the overall survival after the sequential infusion of Donor Lymphocyte Infusions (DLI) and Cytokine Induced Killer(CIK) cells.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Malignancies	Biological: in vitro expanded Cytokine Induced Killer (CIK) cells	Phase 2

Detailed Description

This study is an open-label, multicenter, exploratory phase IIA study to evaluate the safety (dose-finding) and efficacy of a sequential administration of donor derived unmanipulated DLI and in vitro expanded Cytokine Induced Killer(CIK) cells.

Two infusions of unmanipulated donor lymphocytes (1x106/Kg each) will be given with a minimum interval of 3 weeks. Three infusions of donor Cytokine Induced Killer (CIK) cells will be administered according to a dose escalating program, starting 3 weeks after second Donor Lymphocyte Infusions (DLI). In presence of grade 2 or more acute graft versus host disease(GVHD), the patient will not receive the next scheduled infusion. Only grade 4 acute graft versus host disease (aGVHD) is considered for the dose limiting toxicity (DLT). Once identified the maximally tolerated dose (MTD), this same combination of doses will be administered up to 24 patients in a two-stage minimax design.

Primary Endpoints

The primary endpoints of the Phase IIA study are:

1. the Maximally Tolerated Dose (MTD) - (safety end-point)

2. the cumulative incidence of molecular, karyotypic or haematologic responses at day +100 after the end of the cell therapy program - (efficacy end-point)

Secondary Endpoints Progression Free Survival (PFS) Progression Free Survival (PFS) will be defined as any evidence of molecular, cytogenetic or haematologic disease progression. Cytogenetic and/or molecular relapse will be defined where available as any evidence of a pre-transplant defined abnormality using conventional cytogenetics or FISH techniques or molecular probes. Assessments will be performed at 1 year after the end of the cell therapy program Overall Survival (OS) The Overall Survival(OS) will be assessed by 1 year after the end of the cell therapy program. For assessment of the Overall Survival (OS), events will be deaths for any causes, patients being censored if alive.

Study Design

• Study Type: Interventional
• Actual Enrollment: 74 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Sequential Infusion of Unmanipulated Donor Lymphocytes and Cytokine Induced Killer (CIK)Cells After Allogeneic Stem Cell Transplantation
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: May 15, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Cytokine Induced Killer Sequential Infusion of Unmanipulated Donor Lymphocytes and Cytokine Induced Killer (CIK)

Biological: in vitro expanded Cytokine Induced Killer (CIK) cells; Three infusions of donor Cytokine Induced Killer (CIK) cells will be administered according to a dose escalating program, starting 3 weeks after second Donor Lymphocyte Infusions (DLI). Cytokine Induced Killer administrations will be separated by 3 weeks intervals; Other Names: patients will be offered Cytokine Induced Killer(CIK) cells. Four combinations of escalating Cytokine Induced Killer (CIK) cells infusions will be provided, until the MTD will be defined. Combination 1st CIK cells infusion 2nd CIK cells infusion 3rd CIK cells infusion 1 1x106/Kg 1x106/Kg 5x106/kg 2 1x106/Kg 5x106/kg 5x106/kg 3 1x106/Kg 5x106/kg 10x106/kg 4 5x106/kg 5x106/kg 10x106/kg

Outcome Measures

Primary Outcome Measures

1. Safety Measures [Clinical response was measured at 100 days after the completion of the cell therapy program.]

   The occurrence of a grade 4 acute graft versus host disease (GVHD), judged to be related to the study medication. Grading and staging will be performed using the Glucksberg scale

Secondary Outcome Measures

1. Efficacy Measures [The clinical response will be registered at day +100 after the last Cytokine Induced Killer (CIK) cell infusion]

   The proportion of patients achieving a complete, a partial or a hematologic improvement in responses to the experimental infusion of cytokine induced killer (CIK)cells

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with haematologic malignancies (excluding chronic myeloid Leukemia- CML) with a molecular, cytogenetic or haematologic relapse after allogeneic transplantation.

• Patients with an available donor willing to donate peripheral blood lymphocytes

• Immunosuppression must be withdrawn at the beginning of the cell therapy program

• Written informed consent prior to any study procedures being performed

Exclusion Criteria:

• Donors positive for HIV, HBV or HCV, or unfit to undergo leukapheresis

• Patients with active acute or chronic Graft versus host disease (GvHD)

• Patients with rapidly progressive disease or not controlled by palliative supportive treatments including chemotherapy and with a life expectancy less than 8 weeks

• Patients with severe psychiatric illness or any disorder that compromises ability to give truly informed consent for participation in this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Azienda Ospedaliera Papa Giovanni XXIII (Former:Ospedali Riuniti di Bergamo) Bergamo	Bergamo		Italy	24127
2	Ospedale Centrale di Bolzano	Bolzano		Italy
3	Ospedale San Gerardo	Monza		Italy

Sponsors and Collaborators

• A.O. Ospedale Papa Giovanni XXIII
• Regional Hospital of Bolzano
• Azienda Ospedaliera San Gerardo di Monza

Investigators

• Principal Investigator: Alessandro AR Rambaldi, Professor, Azienda Ospedaliera Papa Giovanni XXIII (Former:Ospedali Riuniti di Bergamo)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Rambaldi Alessandro, Prof, A.O. Ospedale Papa Giovanni XXIII
• ClinicalTrials.gov Identifier: NCT01186809
• Other Study ID Numbers: Eudract number: 2008-003185-26
• First Posted: Aug 23, 2010
• Last Update Posted: Jan 23, 2019
• Last Verified: Jan 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Rambaldi Alessandro, Prof, A.O. Ospedale Papa Giovanni XXIII: hematologic malignancies (excluding Chronic Myeloid Leukemia)
• Additional relevant MeSH terms: Neoplasms; Hematologic Neoplasms

Study Results

Participant Flow

Recruitment Details	A total of 74 patients were enrolled in the study from July 2009 to September 2016

Arm/Group Title	Cytokine Induced Killer
Arm/Group Description	Sequential Infusion of Unmanipulated Donor Lymphocytes and Cytokine Induced Killer (CIK) in vitro expanded Cytokine Induced Killer (CIK) cells: Three infusions of donor Cytokine Induced Killer (CIK) cells will be administered according to a dose escalating program, starting 3 weeks after second Donor Lymphocyte Infusions (DLI). Cytokine Induced Killer administrations will be separated by 3 weeks intervals This is a phase IIA study to evaluate the safety (dose-finding) and efficacy of a sequential administration of donor derived unmanipulated DLI and in vitro expanded CIK cells. Two infusions of unmanipulated donor lymphocytes (1x106/Kg each) will be given with a minimum interval of 3 weeks. Three infusions of donor CIK cells will be administered according to a dose escalating program, starting 3 weeks after second DLI. CIK administrations will be separated by 3 weeks intervals. Standard treatment with unmanipulated DLI will be offered to patients refusing the proposal.
Period Title: Overall Study
STARTED	73
COMPLETED	43
NOT COMPLETED	30

Baseline Characteristics

Arm/Group Title	Cytokine Induced Killer
Arm/Group Description	Sequential Infusion of Unmanipulated Donor Lymphocytes and Cytokine Induced Killer (CIK) in vitro expanded Cytokine Induced Killer (CIK) cells: Three infusions of donor Cytokine Induced Killer (CIK) cells will be administered according to a dose escalating program, starting 3 weeks after second Donor Lymphocyte Infusions (DLI). Cytokine Induced Killer administrations will be separated by 3 weeks intervals
Overall Participants	73
Age (Count of Participants)
<=18 years	15 20.5%
Between 18 and 65 years	58 79.5%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	34 46.6%
Male	39 53.4%
Region of Enrollment (participants) [Number]
Italy	73 100%

Outcome Measures

1. Primary Outcome

Title	Safety Measures
Description	The occurrence of a grade 4 acute graft versus host disease (GVHD), judged to be related to the study medication. Grading and staging will be performed using the Glucksberg scale
Time Frame	Clinical response was measured at 100 days after the completion of the cell therapy program.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cytokine Induced Killer
Arm/Group Description	Sequential Infusion of Unmanipulated Donor Lymphocytes and Cytokine Induced Killer (CIK) in vitro expanded Cytokine Induced Killer (CIK) cells: Three infusions of donor Cytokine Induced Killer (CIK) cells will be administered according to a dose escalating program, starting 3 weeks after second Donor Lymphocyte Infusions (DLI). Cytokine Induced Killer administrations will be separated by 3 weeks intervals This is a phase IIA study to evaluate the safety (dose-finding) and efficacy of a sequential administration of donor derived unmanipulated DLI and in vitro expanded CIK cells. Two infusions of unmanipulated donor lymphocytes (1x106/Kg each) will be given with a minimum interval of 3 weeks. Three infusions of donor CIK cells will be administered according to a dose escalating program, starting 3 weeks after second DLI. CIK administrations will be separated by 3 weeks intervals. Standard treatment with unmanipulated DLI will be offered to patients refusing the proposal.
Measure Participants	73
Number [participants]	0 0%

2. Secondary Outcome

Title	Efficacy Measures
Description	The proportion of patients achieving a complete, a partial or a hematologic improvement in responses to the experimental infusion of cytokine induced killer (CIK)cells
Time Frame	The clinical response will be registered at day +100 after the last Cytokine Induced Killer (CIK) cell infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	three years;
Arm/Group Title	Cytokine Induced Killer
Arm/Group Description	Sequential Infusion of Unmanipulated Donor Lymphocytes and Cytokine Induced Killer (CIK) in vitro expanded Cytokine Induced Killer (CIK) cells: Three infusions of donor Cytokine Induced Killer (CIK) cells will be administered according to a dose escalating program, starting 3 weeks after second Donor Lymphocyte Infusions (DLI). Cytokine Induced Killer administrations will be separated by 3 weeks intervals This is a phase IIA study to evaluate the safety (dose-finding) and efficacy of a sequential administration of donor derived unmanipulated DLI and in vitro expanded CIK cells. Two infusions of unmanipulated donor lymphocytes (1x106/Kg each) will be given with a minimum interval of 3 weeks. Three infusions of donor CIK cells will be administered according to a dose escalating program, starting 3 weeks after second DLI. CIK administrations will be separated by 3 weeks intervals. Standard treatment with unmanipulated DLI will be offered to patients refusing the proposal.
All Cause Mortality
	Cytokine Induced Killer
	Affected / at Risk (%)	# Events
Total	31/73 (42.5%)
Serious Adverse Events
	Cytokine Induced Killer
	Affected / at Risk (%)	# Events
Total	8/73 (11%)
Blood and lymphatic system disorders
hemolitic anemia	1/73 (1.4%)	1
Gastrointestinal disorders
aGVHD grade III; IV	5/73 (6.8%)	5
severe chronic GVHD	2/73 (2.7%)	2
Other (Not Including Serious) Adverse Events
	Cytokine Induced Killer
	Affected / at Risk (%)	# Events
Total	16/73 (21.9%)
Skin and subcutaneous tissue disorders
aGvHD	7/73 (9.6%)	7
cGvHD	9/73 (12.3%)	9

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.