Th1/Tc1 Immunotherapy Following Stem Cell Transplantation in Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT01239368
• Recruitment Status: Terminated
• First Posted: November 11, 2010
• Results First Posted: October 16, 2018
• Last Update Posted: December 10, 2019
• Sponsor: National Cancer Institute (NCI)
• Collaborators: Hackensack Meridian Health; Georgetown University
• Information provided by (Responsible Party): Steven Pavletic, M.D., National Cancer Institute (NCI)

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.

Condition or disease	Intervention/treatment	Phase
Myeloma, Plasma-Cell; Myeloma-Multiple; Myelomatosis	Procedure: Adoptive Immunotherapy; Biological: Rapamycin-Generated Autologous Th1/Tc1 Cells (modified primary human T cells); Biological: Th1/Tc1 Rapa Cell Therapy	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Rapamycin-Resistant T Cell Therapy of Multiple Myeloma: Relapse Prevention and Relapse Therapy
• Actual Study Start Date: November 10, 2010
• Actual Primary Completion Date: August 16, 2017
• Actual Study Completion Date: August 16, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort B - Relapsed Multiple Myeloma; Th1 (type 1 T helper cells)/Tc1 (T cytotoxic cells, type 1) .Rapamycin (Rapa) for Relapsed Multiple Myeloma	Procedure: Adoptive Immunotherapy; 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).; Biological: Th1/Tc1 Rapa Cell Therapy; Th1/Tc1Rapa: 5 x 10e(6) cells/kg
Experimental: Cohort A - Prevention of Relapse; Th1/Tc1.Rapa Prevention of Relapse	Procedure: Adoptive Immunotherapy; 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).; Biological: Rapamycin-Generated Autologous Th1/Tc1 Cells (modified primary human T cells); 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.; Biological: Th1/Tc1 Rapa Cell Therapy; Th1/Tc1Rapa: 5 x 10e(6) cells/kg

Outcome Measures

Primary Outcome Measures :

1. Number of Patients With an Adverse Event Attributable to the Investigational Therapy [ Time Frame: 2 months ]
   Participants were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
2. 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 [ Time Frame: Study completion at 22 months ]
   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.
3. 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 [ Time Frame: Study completion at 22 months ]
   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 :

1. Immune Reconstitution in Recipients of Th1.(T Helper Cell) Rapa Cells. [ Time Frame: Baseline, prior to chemotherapy, and 2 weeks, 1, 2, and 3 months after final T cell infusion ]
   Immune reconstitution in recipients of Th1.rapa cells was determined by flow cytometry.
2. Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) [ Time Frame: Date treatment consent signed to last date off study, 81 months and 6 days ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

  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.

Contacts and Locations

Locations

United States, Maryland

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

Bethesda, Maryland, United States, 20892

United States, New Jersey

Hackensack University Medical Center

Hackensack, New Jersey, United States, 07601

Sponsors and Collaborators

National Cancer Institute (NCI)

Hackensack Meridian Health

Georgetown University

Investigators

• Principal Investigator: Steven Z Pavletic, M.D.; National Cancer Institute (NCI)

  Study Documents (Full-Text)

Documents provided by Steven Pavletic, M.D., National Cancer Institute (NCI):

Study Protocol and Statistical Analysis Plan  [PDF] November 6, 2017

Informed Consent Form  [PDF] February 16, 2017

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

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.

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.

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.

• Responsible Party: Steven Pavletic, M.D., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01239368
• Other Study ID Numbers: 110016; 11-C-0016
• First Posted: November 11, 2010
• Results First Posted: October 16, 2018
• Last Update Posted: December 10, 2019
• Last Verified: December 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Steven Pavletic, M.D., National Cancer Institute (NCI):

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

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Sirolimus; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs