Activated White Blood Cells With ASCT for Newly Diagnosed Multiple Myeloma

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT00566098
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 26
• Location: 1
• Arm: 1
• Actual Duration (Months): 131
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Activating white blood cells in the laboratory may help them kill more cancer cells when they are put back in the body. This may be an effective treatment for patients undergoing a stem cell transplant for multiple myeloma.

PURPOSE: This phase I/II trial is studying the side effects of activated white blood cells and to see how well they work in treating patients who are undergoing a stem cell transplant for newly diagnosed stage II or stage III multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Biological: MILs; Drug: Melphalan; Biological: PCV13	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

• Evaluate the safety and response rate of activated marrow infiltrating lymphocytes (aMILs) in patients undergoing autologous peripheral blood stem cell transplantation for newly diagnosed, stage II-III multiple myeloma.

• Determine the overall in vitro fold-expansion and assess pre- and post-expansion for myeloma T-cell specificity in assessing the feasibility of generating aMILs from myeloma patients.

• Assess the toxicity of aMILs.

• Evaluate the effect of aMILs on hematopoietic engraftment, including neutrophil engraftment, platelet engraftment, and primary graft failure (if failure occurs).

• Evaluate response rates utilizing the Blade criteria, including the complete response (CR) rate, near complete response (nCR) rate, very good partial response (VGPR) rate, partial response (PR) rate, minimal response (MR) rate, and overall response rate (CR, VGPR, PR, MR).

Secondary

• Evaluate T-cell reconstitution, including absolute lymphocyte counts, CD3+, CD4+, and CD8+ T-cell counts.

• Evaluate progression-free survival and overall survival.

• Evaluate anti-tumor immune response.

• Determine pneumococcal-specific vaccine responses.

• Determine delayed-type hypersensitivity (DTH) responses.

OUTLINE: Patients undergo collection of marrow infiltrating lymphocytes (MILs)* either at diagnosis prior to the initiation of induction therapy or upon completion of induction therapy. The MILs bone marrow product undergo ex vivo activation and expansion of T cells for 7-8 days to produce activated marrow infiltrating lymphocytes (aMILs). Patients then undergo stem cell mobilization and leukapheresis to collect the peripheral blood stem cells 12 days after mobilization. Patients receive melphalan IV over 20-30 minutes on days -2 and -1 and undergo a peripheral blood stem cell transplantation on day 0 as planned. Patients receive aMILs infusion on day 3. Patients receive pneumococcal polyvalent vaccine on day 21.

NOTE: *Patients who have completed induction therapy receive pneumococcal polyvalent vaccine approximately 2 weeks prior to MILs collection; patients undergoing MILs collection prior to starting induction therapy do not receive a pre-transplantation vaccine.

Blood and bone marrow samples are collected periodically for laboratory correlative studies.

After completion of study treatment, patients are followed periodically for up to 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Adoptive Immunotherapy Utilizing Activated Marrow Infiltrating Lymphocytes in the Autologous Transplant Setting in Multiple Myeloma
• Actual Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Oct 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ASCT+MILs Autologous stem cell transplant with a conditioning regimen of melphalan 100 mg/m^2 on each of Days -2 and -1. Infusion of activated marrow infiltrating lymphocytes (MILs) on Day 3. PCV13 vaccine will be given before and/or after Day 0 depending on when participants are enrolled.	Biological: MILs; Other Names: Marrow infiltrating lymphocytes Activated marrow infiltrating lymphocytes aMILs ; Drug: Melphalan; Other Names: Alkeran ; Biological: PCV13; Other Names: Prevnar

Outcome Measures

Primary Outcome Measures

1. Hematopoietic Engraftment [Up to 1 year]

   Days to absolute neutrophil count > 500 cells per microliter.

2. Disease Response [Up to 2 years]

   Percentage of participants with partial or complete response by Bladé criteria. Partial response is defined as a >= 50% decrease in serum paraprotein or 90% decrease in urinary light chains (for participants without measurable serum paraprotein). Complete response is defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells.

3. Feasibility of MILs Generation as Assessed by Percentage of Participants With Successful MIL Generation [Up to 1 year]

   Success rate of expanding MILs in vitro and obtaining a protocol-specified product.

Secondary Outcome Measures

1. T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC) [Days 14, 28, 60, 180, and 360]

   ALC counts trending over time.

2. Survival [Up to 129 months]

   Survival in months for participants who are alive (Overall Survival) and alive without disease progression (Progression-free survival). Disease progression is defined as a change from negative to positive on immunofixation or electrophoresis for participants previously in complete remission or a 25% increase in serum electrophoresis for participants not previously in complete remission. Partial response is defined as a >= 50% decrease in serum paraprotein or 90% decrease in urinary light chains (for participants without measurable serum paraprotein). Complete response is defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells.

3. Pneumococcal-specific Vaccine Responses [At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant]

   CRM-197 Prevnar-specific vaccine responses that measure the T-cell response of the vaccine quantified as %CD3+/CFSE-low/IFN-gamma+.

4. Anti-tumor Immune Responses [At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant]

   Myeloma lysate response that measures the T-cell response quantified as %CD3+/CFSE-low/IFN-gamma+.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of multiple myeloma

• Newly diagnosed disease

• Durie-Salmon stage II or III disease

• Measurable disease, defined by any of the following:

• Measurable serum and/or urine M-protein levels documented and available prior to induction therapy

• Positive serum free light chain assay

• Must have completed a minimum of 3 courses of myeloma specific therapy

• Candidate for autologous stem cell transplantation

• Patients who have achieved a complete remission at the time of bone marrow harvest for marrow infiltrating lymphocytes (MILs) expansion are not eligible

• No evidence of spinal cord compression

• Diagnosis of the following cancers are not allowed:

• POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)

• Non-secretory myeloma (no measurable protein on serum free light chain assay)

• Plasma cell leukemia

• No amyloidosis

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Life expectancy ≥ 6 months

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and up to day 180

• Corrected serum calcium < 11 mg/dL and no evidence of symptomatic hypercalcemia

• Total bilirubin ≤ 2.0 times upper limit of normal (ULN)

• ALT ≤ 2.0 times ULN

• Serum creatinine < 2.0 mg/dL

• No history of other malignancy within the past 5 years, except adequately treated basal cell or squamous cell skin cancer

• No history of autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus) requiring systemic treatment

• Hypothyroidism without evidence of Graves' disease or Hashimoto thyroiditis is allowed

• No infection requiring treatment with antibiotics, antifungal, or antiviral agents within the past 7 days

• No HIV infection

• No major organ system dysfunction including, but not limited to, the following:

• New York Heart Association class III or IV congestive heart failure

• Pulmonary disease requiring the use of inhaled steroids or bronchodilators

• Renal, hepatic, gastrointestinal, neurologic, or psychiatric dysfunction that would impair ability to participate in the study

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior hematopoietic stem cell transplantation

• At least 3 weeks since prior corticosteroids (i.e., glucocorticoids)

• At least 3 weeks since prior myeloma-specific therapy

• At least 4 weeks since participation in any clinical trial that involved an investigational drug or device

• No concurrent therapy with any of the following:

• Corticosteroids (e.g., hydrocortisone, prednisone, prednisolone, dexamethasone [Decadron])

• Inhaled steroids used for treatment of allergic rhinitis or pulmonary disease allowed

• Thalidomide

• Interferon

• Growth factors, interleukins, or other cytokines (except filgrastim [G-CSF] as outlined in the protocol, or erythropoietin)

• Cytotoxic chemotherapy agents (except cyclophosphamide for stem cell mobilization and high-dose melphalan)

• Immunosuppressive drugs

• Experimental therapies

• Radiotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• National Cancer Institute (NCI)

Investigators

• Study Chair: Ivan Borrello, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00566098
• Other Study ID Numbers: J0770; P30CA006973; NA_00012038
• First Posted: Dec 3, 2007
• Last Update Posted: Dec 19, 2018
• Last Verified: Nov 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: stage II multiple myeloma; stage III multiple myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Melphalan

Study Results

Participant Flow

Pre-assignment Detail	There was one screen failure.

Arm/Group Title	MILs in Patients Undergoing an Autologous Peripheral SCT
Arm/Group Description	therapeutic autologous lymphocytes therapeutic tumor infiltrating lymphocytes melphalan autologous hematopoietic stem cell transplantation
Period Title: Collection of MILs
STARTED	25
COMPLETED	23
NOT COMPLETED	2
Period Title: Collection of MILs
STARTED	23
COMPLETED	22
NOT COMPLETED	1
Period Title: Collection of MILs
STARTED	22
COMPLETED	4
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	MILs in Patients Undergoing an Autologous Peripheral SCT
Arm/Group Description	therapeutic autologous lymphocytes therapeutic tumor infiltrating lymphocytes melphalan autologous hematopoietic stem cell transplantation
Overall Participants	22
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	8 36.4%
Male	14 63.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 13.6%
White	18 81.8%
More than one race	0 0%
Unknown or Not Reported	1 4.5%
Region of Enrollment (Count of Participants)
United States	22 100%

Outcome Measures

1. Primary Outcome

Title	Hematopoietic Engraftment
Description	Days to absolute neutrophil count > 500 cells per microliter.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MILs in Patients Undergoing an Autologous Peripheral SCT
Arm/Group Description	therapeutic autologous lymphocytes therapeutic tumor infiltrating lymphocytes melphalan autologous hematopoietic stem cell transplantation
Measure Participants	22
Median (Full Range) [days]	17.9

2. Primary Outcome

Title	Disease Response
Description	Percentage of participants with partial or complete response by Bladé criteria. Partial response is defined as a >= 50% decrease in serum paraprotein or 90% decrease in urinary light chains (for participants without measurable serum paraprotein). Complete response is defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MILs in Patients Undergoing an Autologous Peripheral SCT
Arm/Group Description	therapeutic autologous lymphocytes therapeutic tumor infiltrating lymphocytes melphalan autologous hematopoietic stem cell transplantation
Measure Participants	22
Complete Response	7 31.8%
Partial Response	6 27.3%
Stable Disease	6 27.3%
Progressive Disease	3 13.6%

3. Primary Outcome

Title	Feasibility of MILs Generation as Assessed by Percentage of Participants With Successful MIL Generation
Description	Success rate of expanding MILs in vitro and obtaining a protocol-specified product.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MILs in Patients Undergoing an Autologous Peripheral SCT
Arm/Group Description	therapeutic autologous lymphocytes therapeutic tumor infiltrating lymphocytes melphalan autologous hematopoietic stem cell transplantation
Measure Participants	22
Number [percentage of participants]	100 454.5%

4. Secondary Outcome

Title	T-cell Reconstitution as Determined by Absolute Lymphocyte Count (ALC)
Description	ALC counts trending over time.
Time Frame	Days 14, 28, 60, 180, and 360

Outcome Measure Data

Analysis Population Description

Data was not collected on one participant at the Day 28 and 180 timepoints, and data was not collected for eight participants at the Day 360 timepoint. Data was not collected on CD3+/CD4+/CD8+ cells for all participants.

Arm/Group Title	MILs in Patients Undergoing an Autologous Peripheral SCT
Arm/Group Description	therapeutic autologous lymphocytes therapeutic tumor infiltrating lymphocytes melphalan autologous hematopoietic stem cell transplantation
Measure Participants	22
Day 14	756
Day 28	1768
Day 60	1700
Day 180	1430
Day 360	1660

5. Secondary Outcome

Title	Survival
Description	Survival in months for participants who are alive (Overall Survival) and alive without disease progression (Progression-free survival). Disease progression is defined as a change from negative to positive on immunofixation or electrophoresis for participants previously in complete remission or a 25% increase in serum electrophoresis for participants not previously in complete remission. Partial response is defined as a >= 50% decrease in serum paraprotein or 90% decrease in urinary light chains (for participants without measurable serum paraprotein). Complete response is defined as negative serum and urine immunofixation and a bone marrow aspirate with < 5% plasma cells.
Time Frame	Up to 129 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MILs in Patients Undergoing an Autologous Peripheral SCT
Arm/Group Description	therapeutic autologous lymphocytes
Measure Participants	22
Overall survival	112.1
Progression-free survival	12.3

6. Secondary Outcome

Title	Pneumococcal-specific Vaccine Responses
Description	CRM-197 Prevnar-specific vaccine responses that measure the T-cell response of the vaccine quantified as %CD3+/CFSE-low/IFN-gamma+.
Time Frame	At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MILs in Patients Undergoing an Autologous Peripheral SCT
Arm/Group Description	therapeutic autologous lymphocytes therapeutic tumor infiltrating lymphocytes melphalan autologous hematopoietic stem cell transplantation
Measure Participants	22
At time of bone marrow harvest	21.5
Day 60 post-transplant	14.4
Day 180 post-transplant	23.4
Day 360 post-transplant	20.1

7. Secondary Outcome

Title	Anti-tumor Immune Responses
Description	Myeloma lysate response that measures the T-cell response quantified as %CD3+/CFSE-low/IFN-gamma+.
Time Frame	At time of bone marrow harvest, Day 60 post-transplant, Day 180 post-transplant, and Day 360 post-transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MILs in Patients Undergoing an Autologous Peripheral SCT
Arm/Group Description	therapeutic autologous lymphocytes therapeutic tumor infiltrating lymphocytes melphalan autologous hematopoietic stem cell transplantation
Measure Participants	22
At time of bone marrow harvest	1.58
Day 60 post-transplant	14.1
Day 180 post-transplant	18.1
Day 360 post-transplant	12.7

Adverse Events

Time Frame	Up to Day 360
Adverse Event Reporting Description	Per protocol, only adverse events (AEs) that were attributed to the study product (MILs) were collected and reported. AEs were collected daily through the date of engraftment, weekly through Day 28, and then at Days 60, 180, and 360.
Arm/Group Title	ASCT+MILs
Arm/Group Description	Autologous stem cell transplant with a conditioning regimen of melphalan 100 mg/m^2 on each of Days -2 and -1. Infusion of activated marrow infiltrating lymphocytes (MILs) on Day 3. PCV13 vaccine will be given before and/or after Day 0 depending on when participants are enrolled.
All Cause Mortality
	ASCT+MILs
	Affected / at Risk (%)	# Events
Total	10/22 (45.5%)
Serious Adverse Events
	ASCT+MILs
	Affected / at Risk (%)	# Events
Total	1/22 (4.5%)
Nervous system disorders
Syncope	1/22 (4.5%)	1
Other (Not Including Serious) Adverse Events
	ASCT+MILs
	Affected / at Risk (%)	# Events
Total	21/22 (95.5%)
Cardiac disorders
Hypotension	6/22 (27.3%)	6
Tachycardia	3/22 (13.6%)	3
Gastrointestinal disorders
Constipation	5/22 (22.7%)	5
Anorexia	9/22 (40.9%)	9
Diarrhea	12/22 (54.5%)	13
Mucositis	9/22 (40.9%)	11
Nausea	16/22 (72.7%)	18
Vomiting	11/22 (50%)	11
General disorders
Fatigue	17/22 (77.3%)	19
Infections and infestations
Neutropenic fever	5/22 (22.7%)	5
Upper respiratory infection	2/22 (9.1%)	3
Investigations
Fever	4/22 (18.2%)	4
Musculoskeletal and connective tissue disorders
Pain - abdomen	5/22 (22.7%)	5
Bone pain	3/22 (13.6%)	3
Back pain	3/22 (13.6%)	3
Pain - calf	2/22 (9.1%)	2
Nervous system disorders
Blurred vision	2/22 (9.1%)	2
Depression	2/22 (9.1%)	2
Headache	7/22 (31.8%)	8
Insomnia	2/22 (9.1%)	2
Lightheadedness	2/22 (9.1%)	2
Neuropathy	15/22 (68.2%)	21
Renal and urinary disorders
Urinary frequency	4/22 (18.2%)	4
Respiratory, thoracic and mediastinal disorders
Cough	4/22 (18.2%)	4
Dyspnea	5/22 (22.7%)	5
Skin and subcutaneous tissue disorders
Alopecia	3/22 (13.6%)	3
Itching	2/22 (9.1%)	3
Rash	12/22 (54.5%)	22
Sore throat	7/22 (31.8%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.