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Multi-Center Phase I Study of Th1/Tc1 Immunotheraphy Following Autologous Hematopoietic Progenitor Cell Transplantation in High Risk Multiple Myeloma

Phase 1
18 Years
Open (Enrolling)
Multiple Myeloma

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Trial Information

Multi-Center Phase I Study of Th1/Tc1 Immunotheraphy Following Autologous Hematopoietic Progenitor Cell Transplantation in High Risk Multiple Myeloma


- Single or tandem Autologous Hematopoietic Cell Transplantation (AHCT) are the standard
of care for newly diagnosed Multiple Myeloma (MM) which, despite recent progress both
with ASCT and the introduction of new drugs, continues to be mostly incurable. While
non-myeloablative allogeneic transplant is being investigated with encouraging results,
subjects who are not candidates are left without satisfactory therapeutic alternatives.

- A new investigational approach to MM treatment consists of adoptive autologous
immunotherapy. Both pre-clinical and preliminary clinical data suggest that this
approach can mediate both immune reconstitution and anti-tumor effects following AHCT.
Potentially, it may be possible to harness such T cell-mediated effects without the
need for myeloablative high-dose chemotherapy and AHCT.

- We will evaluate this new form of therapy using an anti-CD3, anti-CD28 co-stimulated
autologous T cells ex vivo expansion in a short term (6 days) culture with high-dose
rapamycin, a system found in murine models to generate Th1 / Tc1 polarized T cells
(Th1.rapa cells) that are both rapamycin-resistant and apoptosis-resistant with a
greatly increased in vivo survival.

- As Th1 /Tc1 polarized lymphocytes are pivotal in immune mediated tumor surveillance or
eradication and based on our and others' pre-clinical data, we hypothesize that
adoptive transfer of Th1.rapa cells to moderately immune depleted subjects
(post-transplant subjects) will yield Th1 cytokine polarity and thereby will represent
a T cell population of potential therapeutic benefit for patients with MM. [NOTE: we
are assessing cytokine polarity but not able to assess in vivo persistence].



-Evaluate the feasibility and toxicity of an infusion of autologous, ex vivo
rapamycin-generated, anti-CD3 and anti-CD28 co-stimulated, Th1/Tc1 lymphocytes (Th1.rapa
cells) in subjects newly diagnosed with high-risk multiple myeloma who are 6 weeks post-


- Characterize the cellular aspects and cytokine phenotype of immune reconstitution in
recipients of Th1.rapa cells.

- Characterize potential clinical anti-tumor responses in a preliminary manner through
determination of disease-free survival, relapse-free and overall survival

- Characterize the safety and potential anti-tumor effects of the Th1.rapa cell
population in the

context of immune-depleting chemotherapy consisting of either a 7-day or 14-day course of

pentostatin combined with low-dose cyclophosphamide.


-Adults newly diagnosed with or receiving induction therapy for MM with established adverse
prognostic features.


- Subjects must have first received induction therapy or salvage therapy followed by 1 or
2 ASCT as indicated clinically.

- Phase I dose escalation study of the administration of Th1.rapa cells.

- Th1.rapa cells infusion at approximately 6 weeks following the last ASCT.

Seven Th1.rapa cell doses will be tested in cohorts of 1-6 subjects each: ranging from 10(5)
to 45 x 10(6) cells/Kg of body weight.

In a subset of patients, Th1.rapa cell infusion will be evaluated after administration of a
7-day or 14-day course of immune-depleting chemotherapy (pentostatin plus cyclophosphamide

Inclusion Criteria



Criteria for newly or recently diagnosed subjects

-Presence of clonal plasma cells in the bone marrow greater or equal to 10% or a
documented clonal plasmacytoma


-Presence of an M-component; an M-component (IgG or IgA) in serum greater or equal to
1g/dl or in urine greater or equal to 200 mg/24 h.

ALTERNATIVELY, in absence of an M-component greater or equal to 1g/dl:

- an abnormal serum free light chain (FLC) ratio on the serum FLC assay or if the FLC
ratio is normal,

- baseline bone marrow must have 10% or greater clonal plasma cells.


- Presence, of one or more of the following attributable to the disease (in the
presence or absence of an M component):

- Calcium elevation greater than 11.5 mg/dl (2.65 mmol/l)

- Renal insufficiency: serum creatinine greater than 2 mg/dl (177 mmol/l)

- Hemoglobin less than 10g/dl (12.5 mmol/l) or 2 g/dl (1.25 mmol/l) below lower

- Bone disease (lytic lesions or osteopenia)

- Other evidence of disease activity: repeated infections, secondary amyloidosis,
hyperviscosity, hypogammablobulinemia

- Must have high risk disease defined as the presence of any of the following:

- Stage II and III of the International Staging System defined as follows:

- stage I: - serum (Beta)2-microglobulin less than 3.5 mg/l plus

-----serum albumin greater or equal to 3.5 g/dl

- stage II: neither stage I nor III

- stage III: serum (Beta)2-microglobulin greater or equal to 5.5 mg/L

- del 13 or aneuploidy (by metaphase analysis33)

- del 17p13 by FISH or mutated p53

- (4;14) by FISH31

- (14;16) or t(14;20) by FISH

- plasmablastic morphology at diagnosis(35)

- circulating myeloma cells by FACS (CD38+/CD45low) post induction

- High-risk disease as defined in a 70-gene ( MyPRS (TM)) or the 17-gene
condensed microarrays


- 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 wil be considered on a case-by-case basis

- Must have received no more than 6 cycles of induction therapy for Multiple Myeloma.

- The planned High-Dose chemotherapy must consist of melphalan only and may be followed
by a post-ASCT consolidation.

- Karnofsky performance status of 70% or greater (ECOG 0 or 1). Lower KPS down to 50%
or ECOG of 2 may be acceptable if the restriction of activity is solely due to
intractable pain from myeloma lesions.

- Ejection fraction (EF) by MUGA or 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,

- AST and 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 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


The decision to enroll on cohort 5B or on cohort 6 will be made as follows:

- A subject will be enrolled on the cohort that has the smallest number of accrued
subjects of these two cohorts.

- In case of a tie, the subject will be enrolled on the cohort that did not enroll the
previous subject.


- 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 NYHY, 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.

- HIV seropositive

- Patients known or found to be pregnant.

- Patients of childbearing age who are unwilling to practice contraception.

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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Evaluate the feasibility and toxicity of an infusion of autologous, ex vivo rapamycin-generated, anti-CD3 and anti-CD28 co-stimulated, Th1/Tc1 lymphocytes (Th1.rapa cells) in subjects newly diagnosed with high-risk multiple myeloma.

Principal Investigator

Claude Sportes, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

October 2010

Completion Date:

November 2013

Related Keywords:

  • Multiple Myeloma
  • Multiple Myeloma
  • High Risk
  • Newly Diagnosed
  • Adoptive Immunotherapy
  • Autologous
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
Hackensack University Medical CenterHackensack, New Jersey  07601