Trial Outcomes & Findings for Adoptive Cellular Immunotherapy Following Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma (NCT NCT00439465)

Results Overview

To establish the safety (toxicity) of myeloma patients treated with high dose melphalan, autologous peripheral blood stem cell transplantation (APBSCT) \& adoptive transfer of cytotoxic effector cells with Interleukin-2 (IL-2) and Recombinant Human Granulocyte Colony Stimulating Factor (GM-CSF).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

23 participants

Primary outcome timeframe

From initiation of treatment on protocol until Day 100

Results posted on

2019-03-26

Participant Flow

Participant milestones

Participant milestones
Measure	Ex-vivo Expanded Effector Cells Infusing Interleukin-2 (IL-2) and Recombinant Human Granulocyte Colony Stimulating Factor (GM-CSF)post-Hematopoietic stem cell transplant (HSCT) Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Overall Study STARTED	23
Overall Study COMPLETED	19
Overall Study NOT COMPLETED	4

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ex-vivo Expanded Effector Cells n=23 Participants Infusing IL-2 and GM-CSF post-HCST Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Age, Categorical <=18 years	0 Participants n=23 Participants
Age, Categorical Between 18 and 65 years	17 Participants n=23 Participants
Age, Categorical >=65 years	6 Participants n=23 Participants
Age, Continuous	60 Years n=23 Participants
Sex: Female, Male Female	9 Participants n=23 Participants
Sex: Female, Male Male	14 Participants n=23 Participants
Region of Enrollment United States	23 Participants n=23 Participants

PRIMARY outcome

Timeframe: From initiation of treatment on protocol until Day 100

To establish the safety (toxicity) of myeloma patients treated with high dose melphalan, autologous peripheral blood stem cell transplantation (APBSCT) \& adoptive transfer of cytotoxic effector cells with Interleukin-2 (IL-2) and Recombinant Human Granulocyte Colony Stimulating Factor (GM-CSF).

Outcome measures

Outcome measures
Measure	Ex-vivo Expanded Effector Cells n=23 Participants Infusing IL-2 and GM-CSF post-Hematopoietic Stem-Cell Transplant (HSCT) Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Number of Participants With Adverse Events in All Subjects	11 Participants

SECONDARY outcome

Timeframe: Day 15 post-transplant and between days 21 to 28 post-transplant

Population: Sixteen out of nineteen subject samples were analyzed. Three subject's samples were not available for analysis.

To demonstrate that the effector cell infusions result in a clinical effect, phenotypic analyses of blood samples using flow cytometry will be performed prior to, and after each infusion, focusing on the CD8 + populations (CD3+CD8+, CD8+CD56+). As a complement to flow cytometry, the following assays will be used to identify cell subset precursor frequencies, subset proliferation, and cytokine production: * Dye Dilution Proliferation Assay (DDPA) 36 - Evaluation of CD8+ T Cell Precursors * ELISPOT-Quantifying cytokine producing T cells:

Outcome measures

Outcome measures
Measure	Ex-vivo Expanded Effector Cells n=16 Participants Infusing IL-2 and GM-CSF post-Hematopoietic Stem-Cell Transplant (HSCT) Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Count of Participants With Increased CD3+CD8+, CD8+ and CD56+ Concentrations Between Day 15 Post-Transplant and Days 21 to 28 Post-transplant Day 15 · Increase	7 Participants
Count of Participants With Increased CD3+CD8+, CD8+ and CD56+ Concentrations Between Day 15 Post-Transplant and Days 21 to 28 Post-transplant Day 15 · No Increase	9 Participants
Count of Participants With Increased CD3+CD8+, CD8+ and CD56+ Concentrations Between Day 15 Post-Transplant and Days 21 to 28 Post-transplant Days 21-28 · Increase	7 Participants
Count of Participants With Increased CD3+CD8+, CD8+ and CD56+ Concentrations Between Day 15 Post-Transplant and Days 21 to 28 Post-transplant Days 21-28 · No Increase	9 Participants

SECONDARY outcome

Timeframe: From initiation of treatment on protocol until Day 100

To establish the time to engraftment of myeloma patients treated with high dose melphalan, APBSCT\& adoptive transfer of cytotoxic effector cells with IL-2 and GM-CSF.

Outcome measures

Outcome measures
Measure	Ex-vivo Expanded Effector Cells n=19 Participants Infusing IL-2 and GM-CSF post-Hematopoietic Stem-Cell Transplant (HSCT) Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Time to Recovery of Absolute Neutrophil Count	13 Days Interval 12.0 to 16.0

SECONDARY outcome

Timeframe: From initiation of treatment on protocol until Day 100

To establish the time to engraftment of myeloma patients treated with high dose melphalan, APBSCT\& adoptive transfer of cytotoxic effector cells with IL-2 and GM-CSF.

Outcome measures

Outcome measures
Measure	Ex-vivo Expanded Effector Cells n=19 Participants Infusing IL-2 and GM-CSF post-Hematopoietic Stem-Cell Transplant (HSCT) Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Time to Recovery of Platelet Count	16 days Interval 10.0 to 26.0

SECONDARY outcome

Timeframe: From initiation of treatment on protocol until Day 100

To establish the disease response of myeloma patients treated with high dose melphalan, APBSCT\& adoptive transfer of cytotoxic effector cells with IL-2 and GM-CSF.

Outcome measures

Outcome measures
Measure	Ex-vivo Expanded Effector Cells n=19 Participants Infusing IL-2 and GM-CSF post-Hematopoietic Stem-Cell Transplant (HSCT) Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Assessment of Disease Response to Treatment Partial Response	1 Participants
Assessment of Disease Response to Treatment Complete Response	12 Participants
Assessment of Disease Response to Treatment Very Good Partial Response	5 Participants
Assessment of Disease Response to Treatment Progressive disease	1 Participants

SECONDARY outcome

Timeframe: Pre-transplant and following the third and fourth cellular infusions

Population: Sixteen out of nineteen participants samples were analyzed. Three participants' samples were not available for analysis.

* Isolate CD3+CD8+ and CD8+CD56+ from patients' blood following transplant. * Identify NKG2D and DAP10 expression. * Determine the mechanism of tumor cell killing and the relationship to NKG2D or DAP 10 expression. After isolating CD8+ cells from patient's blood samples using the AutoMACS, we will evaluate the expression of NKG2D and DAP10 on all CD8+ cells (CD3+CD8+ and CD8+CD56+cells) pre-transplant (Baseline) and following the third and fourth cellular infusions using phenotypic analysis. We postulate the increased expression of both DAP10 and NKG2D on the CD8 population immediately following APSCT and effector cell infusions when compared to baseline.

Outcome measures

Outcome measures
Measure	Ex-vivo Expanded Effector Cells n=16 Participants Infusing IL-2 and GM-CSF post-Hematopoietic Stem-Cell Transplant (HSCT) Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Number of Participants With Increased Expression of DAP10 and NKG2D on the CD8 Cell Population Increased abs. NKG2D+CD3+CD8 Tcells	12 Participants
Number of Participants With Increased Expression of DAP10 and NKG2D on the CD8 Cell Population Increased abs. NKG2D+CD3-CD56+ T cells	12 Participants

SECONDARY outcome

Timeframe: Pre-transplant and following the third and fourth cellular infusions.

Population: Autologous myeloma cells were isolated for only 4 study participants. There is no information on the remaining participant provided.

We will isolate the CD8+ populations (CD3+CD8+, CD8+CD56+) using the Auto MACS (Miltenyi) and then identify the mechanisms of tumor cell killing by the CD8+ cells obtained pre-transplant (Baseline) and following the third and fourth cellular infusions. We will examine mechanisms of tumor cell killing through NKG2D receptor, major histocompatibility complex (MHC) Class I molecules or through the T cell receptor. We postulate the CD8+ cells obtained from patient's blood will kill tumor cells both via MHC Class I and through the NKG2D receptor.

Outcome measures

Outcome measures
Measure	Ex-vivo Expanded Effector Cells n=5 Participants Infusing IL-2 and GM-CSF post-Hematopoietic Stem-Cell Transplant (HSCT) Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Determine the Methods of Tumor Cell Killing of the in Vivo CD8+ Cells: Cytotoxicity Assays, Blocking Experiments, Analysis of T-cell Receptor (TCR) Autologous Myeloma Cells · Increased tumor lysis	4 Participants
Determine the Methods of Tumor Cell Killing of the in Vivo CD8+ Cells: Cytotoxicity Assays, Blocking Experiments, Analysis of T-cell Receptor (TCR) Autologous Myeloma Cells · Failure of tumor lysis	0 Participants
Determine the Methods of Tumor Cell Killing of the in Vivo CD8+ Cells: Cytotoxicity Assays, Blocking Experiments, Analysis of T-cell Receptor (TCR) Peripheral blood mononuclear cells · Increased tumor lysis	5 Participants
Determine the Methods of Tumor Cell Killing of the in Vivo CD8+ Cells: Cytotoxicity Assays, Blocking Experiments, Analysis of T-cell Receptor (TCR) Peripheral blood mononuclear cells · Failure of tumor lysis	0 Participants

Adverse Events

Ex-vivo Expanded Effector Cells

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Ex-vivo Expanded Effector Cells n=23 participants at risk Infusing IL-2 and GM-CSF post-HCST Ex-vivo expanded effector cells: This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Infections and infestations Moderate infection	13.0% 3/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Infections and infestations Severe infection	4.3% 1/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Gastrointestinal disorders Nausea	8.7% 2/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Gastrointestinal disorders Vomiting	8.7% 2/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Hepatobiliary disorders Increased liver function tests	8.7% 2/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Metabolism and nutrition disorders anorexia	13.0% 3/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Gastrointestinal disorders Mucositis - oral	4.3% 1/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Gastrointestinal disorders Constipation	4.3% 1/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
General disorders Fever	8.7% 2/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Cardiac disorders Tachycardia	8.7% 2/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Cardiac disorders Hypotension	8.7% 2/23 • Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010

Additional Information

Kenneth Meehan, MD

Dartmouth-Hitchcock Medical Center

Phone: 603-650-6432

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place