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Th1/Tc1 Immunotherapy Following Stem Cell Transplantation in Multiple Myeloma

Primary Purpose

Myeloma, Plasma-Cell, Myeloma-Multiple, Myelomatosis

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Adoptive Immunotherapy

Rapamycin-Generated Autologous Th1/Tc1 Cells (modified primary human T cells)

Th1/Tc1 Rapa Cell Therapy

About this trial

This is an interventional treatment trial for Myeloma, Plasma-Cell focused on measuring Multiple Myeloma, High Risk, Newly Diagnosed, Adoptive Immunotherapy, Autologous

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:

MULTIPLE MYELOMA CRITERIA:

Criteria for Cohort A (recently diagnosed subjects; to receive autologous hematopoietic cell transplantation (AHCT)):

Must have presence of clonal plasma cells in the bone marrow greater or equal to 10% or biopsy proven plasmacytoma
Must have either:
1. presence of an M-component (Immunoglobulin G (IgG) or Immunoglobulin G (IgA)) in serum greater or equal to 1g/dl or in urine greater or equal to 200 mg/24 h; or
2. presence of an abnormal serum free light chain (FLC) ratio on the serum FLC assay.

Criteria for Cohort B (multiply relapsed multiple myeloma):

Must have measurable multiple myeloma (MM), as defined by: serum M-protein greater than or equal to 1 g/dL, urine M-protein greater than or equal to 200 mg/24 hours, involved serum free light chain (FLC) level greater than or equal to 10 mg/dL, biopsy proven plasmacytoma, or more than 30% bone marrow plasma cells.
Must have received at least 2 different treatment regimens for MM.

Other eligibility criteria (applies to both Cohort A and Cohort B, unless specified):

Age greater than or equal to 18 years and less than or equal to 75 years. In subjects between 65 and 75 years of age, physiologic age and co-morbidity will be thoroughly evaluated before enrolling. Specifically, any history of cardio-vascular pathology or symptoms, not clearly fitting the exclusion criteria will prompt an evaluation by a Clinical Center Cardiologist and eligibility will be considered on a case-by-case basis.
For Cohort A only, high-dose chemotherapy and AHCT must be planned; with amendment K, post-transplant maintenance therapy will not be permitted.
Karnofsky performance status (KPS) of 70% or greater. Lower KPS down to 50% may be acceptable if the restriction of activity is solely due to intractable pain from myeloma lesions.
Ejection fraction (EF) by multi-gated acquisition scan (MUGA) or two-dimensional (2-D) echocardiogram within institution normal limits. In case of low EF, the subject may remain eligible after a stress echocardiogram is performed if the EF is more than 35% and if the increase in EF with stress is estimated at 10% or more.
Serum creatinine less than or equal to 2.5 mg/dl,
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 times the upper limit of normal.
Bilirubin less than or equal to1.5 (except if due to Gilbert's disease).
Corrected carbon monoxide diffusing capacity (DLCO) greater than or equal to 50% on Pulmonary Function Tests
No history of abnormal bleeding tendency or predisposition to repeated infections.
Patients must be able to give informed consent

EXCLUSION CRITERIA:

Prior allogeneic stem cell transplantation
Hypertension not adequately controlled by 3 or less medications.
History of cerebro-vascular accident within 6 months of enrollment.
History of documented pulmonary embolus within 6 months of enrollment.
Clinically significant cardiac pathology: myocardial infarction within 6 months prior to enrollment, Class III or IV heart failure according to New York Heart Association (NYHA), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
Patients with a history of coronary artery bypass grafting or angioplasty will receive a cardiology evaluation and be considered on a case-by-case basis.
Human immunodeficiency virus (HIV) seropositive
Patients known or found to be pregnant or who is unwilling to stop breast-feeding.
Patients of childbearing age who are unwilling to practice contraception or other means of avoiding pregnancy.

Patients may be excluded at the discretion of the principal investigator (PI) if it is deemed that allowing participation would represent an unacceptable medical or psychiatric risk.

Sites / Locations

National Institutes of Health (NIH) Clinical Center, 9000 Rockville Pike
Hackensack University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Cohort B - Relapsed Multiple Myeloma

Cohort A - Prevention of Relapse

Arm Description

Th1 (type 1 T helper cells)/Tc1 (T cytotoxic cells, type 1) .Rapamycin (Rapa) for Relapsed Multiple Myeloma

Th1/Tc1.Rapa Prevention of Relapse

Outcomes

Primary Outcome Measures

Number of Patients With an Adverse Event Attributable to the Investigational Therapy

Participants were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

Number of Participants With Progression Free Survival in Cohort A Th1 (Type 1 T Helper Cells)/Tc1 (T Cytotoxic Cells, Type 1) Rapa Prevention of Relapse

Progressive disease is assessed by the Consensus of the International Myeloma Working Group criteria and is defined as one or more of the following: Increases of greater or equal to 25% in serum M-component (minimum absolute increase of 0.5 g/dl) or urine M-component (minimum absolute increase of 200mg/24h) or percentage of bone marrow plasma cells (minimum absolute percentage of 10%) or size of bone lesions or new plasmacytoma, or development of hypercalcemia solely attributable to the disease.

Number of Patients Who Developed a Partial Response (PR)+Complete Response (CR) in Cohort B at Any Time Point Post Therapy With PR/CR Being Maintained Until Study Completed

Patients whose tumors shrunk and were disease free after therapy in cohort B. Partial response and complete response were assessed by the Consensus of the International Myeloma Working Group criteria. Partial response is defined as 50% or greater reduction in serum M-protein and 90% or greater reduction in 24-h urinary M-protein (or to less than 200 mg per 24h), 50% or greater reduction in the size of soft tissue plasmacytomas, if present at baseline, no evidence of progressive or new bone lesions if radiographic studies were performed (X-rays not required in absence of clinical indication). Complete response is defined as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and 5% or less plasma cells in bone marrow and no evidence of progressive or new bone lesion if radiographic studies were performed. Progressive disease is increases of ≥25% in serum M-component/urine M-component, or size of bone lesions.

Secondary Outcome Measures

Immune Reconstitution in Recipients of Th1.(T Helper Cell) Rapa Cells.

Immune reconstitution in recipients of Th1.rapa cells was determined by flow cytometry.

Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Full Information

NCT ID

NCT01239368

First Posted

November 10, 2010

Last Updated

December 3, 2019

Sponsor

National Cancer Institute (NCI)

Collaborators

Hackensack Meridian Health, Georgetown University

1. Study Identification

Unique Protocol Identification Number

NCT01239368

Brief Title

Th1/Tc1 Immunotherapy Following Stem Cell Transplantation in Multiple Myeloma

Official Title

Rapamycin-Resistant T Cell Therapy of Multiple Myeloma: Relapse Prevention and Relapse Therapy

Study Type

Interventional

2. Study Status

Record Verification Date

December 2019

Overall Recruitment Status

Terminated

Why Stopped

Terminated due to insufficient accrual.

Study Start Date

November 10, 2010 (Actual)

Primary Completion Date

August 16, 2017 (Actual)

Study Completion Date

August 16, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Cancer Institute (NCI)

Collaborators

Hackensack Meridian Health, Georgetown University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Background: - Cancer development is associated with problems in immune system functions, which prevent the body from attacking and destroying the abnormal cells that lead to tumor growth. Research has suggested that certain white blood cells, known as Th1 (type 1 T helper cells) and Th2 T cells (type 2 T helper cells), are affected in individuals with some kinds of cancer -- when the proportion of Th2 cells is greater than Th1 cells, the immune systems ability to fight off the growth of malignant tumors is weakened. Researchers are interested in determining if an infusion of specially modified Th1 cells, in addition to stem cell transplant, is a safe and effective treatment for individuals with forms of multiple myeloma that might not respond well to standard treatments alone. Objectives: - To determine the safety and effectiveness of the infusion of modified Th1 white blood cells, in conjunction with standard treatment, as a treatment for individuals who have been diagnosed with high-risk forms of multiple myeloma. Eligibility: Individuals age 18 to 75 who have been newly diagnosed with high-risk multiple myeloma and who have received no or minimal treatment (Cohort A). Individuals age 18 to 75 who have relapsed multiple myeloma, as defined by measurable disease after at least 2 prior treatment regimens. Design: Participants will be screened with a medical history, physical examination, blood and urine tests, and imaging studies. Some participants may also have a bone marrow or other type biopsy to evaluate the state of their disease. White blood cells will be collected from the participants through an apheresis procedure, which will collect and separate the white blood cells and return the rest of the blood to the participant. The collected cells will be grown and expanded under special conditions in the laboratory and stored frozen until participants receive standard of care treatment for multiple myeloma, including a stem cell transplant. Participants will receive an infusion of the modified Th1 cells a few weeks after the transplant, and will remain in the hospital for a few days after receiving the cells to monitor the possible immediate effects of the treatment. Participants will have regular follow-up visits to study the long-term effects of the modified Th1 cell infusion.

Detailed Description

Background: Autologous Hematopoietic Cell Transplantation (AHCT), which represents the standard of care for newly diagnosed Multiple Myeloma (MM), is not curative therapy. New approaches to prevent relapse after AHCT and to treat relapse are needed. In murine models, we used ex vivo culture to generate rapamycin-resistant, Th1 (type 1 T helper cells)/Tc1 (T cytotoxic cells, type 1) polarized T cells (Th1/Tc1.Rapamycin (Rapa) cells) that were both rapamycin-resistant and apoptosis-resistant with an increased in vivo survival and in vivo function. Because Th1 /Tc1 polarized lymphocytes are pivotal in anti-tumor effects, we hypothesize that adoptive transfer of Th1/Tc1Rapa cells will be of benefit to MM patients. Objectives: Primary Dose escalation study Evaluate the feasibility and toxicity of an infusion of autologous, ex vivo rapamycin-generated, anti-cluster of differentiation 3 (CD3) and anti-cluster of differentiation 28 (CD28) co-stimulated, Th1/Tc1 lymphocytes (Th1/Tc1.Rapa cells) in subjects diagnosed with high-risk multiple myeloma following AHCT. MM Relapse Prevention and Treatment Cohorts For Cohort A, in newly diagnosed MM patients who have received AHCT, evaluate the safety of a defined regimen of Th1/Tc1.Rapa cell therapy and determine progression-free survival. For Cohort B, in relapsed MM, determine the partial response (PR)/complete response (CR) rate of Th1/Tc1.Rapa cell therapy. Eligibility: For Cohort A relapse prevention, patients with MM (normal- or high-risk) who are receiving induction therapy and subsequent AHCT. For Cohort B relapse therapy, patients with MM who have measurable disease after at least 2 prior treatment regimens. Design: For Cohort A, patients will receive two infusions of autologous Th1/Tc1.Rapa cells (at one and two months post-AHCT; each infusion preceded by a 7-day course of immune modulating chemotherapy [pentostatin plus low-dose cyclophosphamide; PC regimen]. For Cohort B relapse therapy, patients will up to four infusions of Th1/Tc1.Rapa cells, with each infusion preceded by either a 7-day or 14-day PC regimen.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myeloma, Plasma-Cell, Myeloma-Multiple, Myelomatosis

Keywords

Multiple Myeloma, High Risk, Newly Diagnosed, Adoptive Immunotherapy, Autologous

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

34 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort B - Relapsed Multiple Myeloma

Arm Type

Experimental

Arm Description

Th1 (type 1 T helper cells)/Tc1 (T cytotoxic cells, type 1) .Rapamycin (Rapa) for Relapsed Multiple Myeloma

Arm Title

Cohort A - Prevention of Relapse

Arm Type

Experimental

Arm Description

Th1/Tc1.Rapa Prevention of Relapse

Intervention Type

Procedure

Intervention Name(s)

Adoptive Immunotherapy

Intervention Description

Th1 (type 1 T helper cells)/Tc1 (T cytotoxic cells, type 1) Rapa cell infusion will be evaluated after administration of a 7-day or 14-day course of immune depleting chemotherapy (pentostatin plus cyclophosphamide regimen).

Intervention Type

Biological

Intervention Name(s)

Rapamycin-Generated Autologous Th1/Tc1 Cells (modified primary human T cells)

Intervention Description

Six Th1/Tc1 Rapa cell doses will be tested in cohorts of 1-6 subjects each: ranging from 10e(5) to 15 x 10e(6) cells/kg of body weight.

Intervention Type

Biological

Intervention Name(s)

Th1/Tc1 Rapa Cell Therapy

Intervention Description

Th1/Tc1Rapa: 5 x 10e(6) cells/kg

Primary Outcome Measure Information:

Title

Number of Patients With an Adverse Event Attributable to the Investigational Therapy

Description

Participants were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

Time Frame

2 months

Title

Number of Participants With Progression Free Survival in Cohort A Th1 (Type 1 T Helper Cells)/Tc1 (T Cytotoxic Cells, Type 1) Rapa Prevention of Relapse

Description

Time Frame

Study completion at 22 months

Title

Number of Patients Who Developed a Partial Response (PR)+Complete Response (CR) in Cohort B at Any Time Point Post Therapy With PR/CR Being Maintained Until Study Completed

Description

Time Frame

Study completion at 22 months

Secondary Outcome Measure Information:

Title

Immune Reconstitution in Recipients of Th1.(T Helper Cell) Rapa Cells.

Description

Immune reconstitution in recipients of Th1.rapa cells was determined by flow cytometry.

Time Frame

Baseline, prior to chemotherapy, and 2 weeks, 1, 2, and 3 months after final T cell infusion

Title

Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

Description

Time Frame

Date treatment consent signed to last date off study, 81 months and 6 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA: MULTIPLE MYELOMA CRITERIA: Criteria for Cohort A (recently diagnosed subjects; to receive autologous hematopoietic cell transplantation (AHCT)): Must have presence of clonal plasma cells in the bone marrow greater or equal to 10% or biopsy proven plasmacytoma Must have either: presence of an M-component (Immunoglobulin G (IgG) or Immunoglobulin G (IgA)) in serum greater or equal to 1g/dl or in urine greater or equal to 200 mg/24 h; or presence of an abnormal serum free light chain (FLC) ratio on the serum FLC assay. Criteria for Cohort B (multiply relapsed multiple myeloma): Must have measurable multiple myeloma (MM), as defined by: serum M-protein greater than or equal to 1 g/dL, urine M-protein greater than or equal to 200 mg/24 hours, involved serum free light chain (FLC) level greater than or equal to 10 mg/dL, biopsy proven plasmacytoma, or more than 30% bone marrow plasma cells. Must have received at least 2 different treatment regimens for MM. Other eligibility criteria (applies to both Cohort A and Cohort B, unless specified): Age greater than or equal to 18 years and less than or equal to 75 years. In subjects between 65 and 75 years of age, physiologic age and co-morbidity will be thoroughly evaluated before enrolling. Specifically, any history of cardio-vascular pathology or symptoms, not clearly fitting the exclusion criteria will prompt an evaluation by a Clinical Center Cardiologist and eligibility will be considered on a case-by-case basis. For Cohort A only, high-dose chemotherapy and AHCT must be planned; with amendment K, post-transplant maintenance therapy will not be permitted. Karnofsky performance status (KPS) of 70% or greater. Lower KPS down to 50% may be acceptable if the restriction of activity is solely due to intractable pain from myeloma lesions. Ejection fraction (EF) by multi-gated acquisition scan (MUGA) or two-dimensional (2-D) echocardiogram within institution normal limits. In case of low EF, the subject may remain eligible after a stress echocardiogram is performed if the EF is more than 35% and if the increase in EF with stress is estimated at 10% or more. Serum creatinine less than or equal to 2.5 mg/dl, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 times the upper limit of normal. Bilirubin less than or equal to1.5 (except if due to Gilbert's disease). Corrected carbon monoxide diffusing capacity (DLCO) greater than or equal to 50% on Pulmonary Function Tests No history of abnormal bleeding tendency or predisposition to repeated infections. Patients must be able to give informed consent EXCLUSION CRITERIA: Prior allogeneic stem cell transplantation Hypertension not adequately controlled by 3 or less medications. History of cerebro-vascular accident within 6 months of enrollment. History of documented pulmonary embolus within 6 months of enrollment. Clinically significant cardiac pathology: myocardial infarction within 6 months prior to enrollment, Class III or IV heart failure according to New York Heart Association (NYHA), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients with a history of coronary artery bypass grafting or angioplasty will receive a cardiology evaluation and be considered on a case-by-case basis. Human immunodeficiency virus (HIV) seropositive Patients known or found to be pregnant or who is unwilling to stop breast-feeding. Patients of childbearing age who are unwilling to practice contraception or other means of avoiding pregnancy. Patients may be excluded at the discretion of the principal investigator (PI) if it is deemed that allowing participation would represent an unacceptable medical or psychiatric risk.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Steven Z Pavletic, M.D.

Organizational Affiliation

National Cancer Institute (NCI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health (NIH) Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

Facility Name

Hackensack University Medical Center

City

Hackensack

State/Province

New Jersey

ZIP/Postal Code

07601

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

18287387

Citation

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. doi: 10.3322/CA.2007.0010. Epub 2008 Feb 20.

Results Reference

background

PubMed Identifier

2301376

Citation

Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol. 1990 Feb;33(2):86-9. doi: 10.1002/ajh.2830330203.

Results Reference

background

PubMed Identifier

15693790

Citation

Tosi P, Zamagni E, Cellini C, Plasmati R, Cangini D, Tacchetti P, Perrone G, Pastorelli F, Tura S, Baccarani M, Cavo M. Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple myeloma. Eur J Haematol. 2005 Mar;74(3):212-6. doi: 10.1111/j.1600-0609.2004.00382.x.

Results Reference

background

Links:

URL

https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2011-C-0016.html

Description

NIH Clinical Center Detailed Web Page

Learn more about this trial

Th1/Tc1 Immunotherapy Following Stem Cell Transplantation in Multiple Myeloma

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