Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System

NCT00520130 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 07019507-C-0195
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without a human leukocyte-antigen (HLA) tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patients immune system attacks the transplanted donor cells. This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic. Objectives: To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system. To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant. Eligibility: People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling. Design: All patients receive chemotherapy before transplant to treat the cancer and suppress immune function. All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant. Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows:

• Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continues for 6 months following SCT.
• Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months. Patients receive the donors stem cells and immune cells 2 days after completing the conditioning regimen. Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status. A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD. ...

Conditions

Myelodysplastic Syndrome; Hodgkin's Lymphoma; Non-Hodgkin's Disease; Acute Leukemia; Multiple Myeloma

Keywords

Unrelated Donors; Reduced Intensity Stem Cell Transplant; Leukemia; Lymphoma; Allogeneic Stem Cell Transplant; Myelodysplastic Syndrome; Multiple Myeloma

Outcome Measures

Primary Outcomes (6)

• Percentage of Participants With Grade II-IV Acute Graft Versus Host Disease (GVHD)

  Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria.

  6 months

• Percentage of Participants With Chronic Graft Versus Host Disease (cGVHD)

  Chronic GVHD is assessed by the 2005 Chronic GVHD Consensus Project. First the individual organ scoring is done, and then based on that the Global score is determined (mild-moderate-severe). See Citation: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11:945-56., for grading criteria.

  2 years post transplant

• Recovery of Naïve Cluster of Differentiation 4 (CD4) T Cells

  The percentage of C-C motif chemokine receptor 7 (CCR7)+CD45RA+ naïve T cells within the CD4 T cell populations was determined by flow cytometry.

  Recipient recovery at 6, 12 and 24 months post transplant

• Recovery of Naïve Cluster of Differentiation 8 (CD8) T Cells

  The percentage of CCR7+CD45RA+ naïve T cells within the CD4 and CD8 T cell populations was determined by flow cytometry.

  Recipient recovery at 6, 12 and 24 months post transplant

• Changes in Cluster of Differentiation 4 (CD4) T Cell Receptor Vbeta Repertoire

  Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lower numbers are consistent with a more normal highly diverse repertoire, and high numbers represent a highly skewed, oligoclonal repertoire. The assay is described in Memon SA et al, J Immunol Methods, 2012, 375: 84-92. The repertoire diversity of the CD4 and CD8 T cells of the donor infusion is shown for comparison.

  Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant

• Changes in CD8 T Cell Receptor Vbeta Repertoire

  Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lower numbers are consistent with a more normal highly diverse repertoire, and high numbers represent a highly skewed, oligoclonal repertoire. The assay is described in Memon SA et al, J Immunol Methods, 2012, 375: 84-92. The repertoire diversity of the CD4 and CD8 T cells of the donor infusion is shown for comparison.

  Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant

Secondary Outcomes (12)

• Percentage of Participants With Grade III-IV Acute Graft Versus Host Disease (GVHD)

  6 months

• Toxicities

  103 months and 22 days

• Days to Engraftment of Neutrophils

  2 years

• Days to Engraftment of Platelets

  2 years

• Days to Engraftment of Lymphocytes

  2 years

Study Arms (2)

A - Tacrolimus, methotrexate, sirolimus (TMS) Arm

EXPERIMENTAL

TMS Arm

Biological: Rituximab; Drug: Allogenic stem cell transplant (ASCT); Drug: Conditioning Chemotherapy; Drug: TMS; Drug: FLAG; Drug: EPOCH-F

B - Cyclosporine (AC) Arm

EXPERIMENTAL

AC Arm

Biological: Rituximab; Drug: Cyclosporine; Drug: Allogenic stem cell transplant (ASCT); Drug: Conditioning Chemotherapy; Drug: FLAG; Drug: EPOCH-F; Biological: Alemtuzumab

Interventions

Rituximab BIOLOGICAL

Rituximab: 375 mg/m(2) intravenous (IV), day 1 for patients with cluster of differentiation 20 (CD20)-positive disease.

Also known as: Rituxan

A - Tacrolimus, methotrexate, sirolimus (TMS) Arm; B - Cyclosporine (AC) Arm

Cyclosporine DRUG

Cyclosporine: IV over 2 hours or orally every 12 hours on days -1 to 100, followed by a taper if graft versus host disease (GVHD) does not develop.

Also known as: Neoral

B - Cyclosporine (AC) Arm

Allogenic stem cell transplant (ASCT) DRUG

Allogenic stem cell transplant

A - Tacrolimus, methotrexate, sirolimus (TMS) Arm; B - Cyclosporine (AC) Arm

Conditioning Chemotherapy DRUG

Fludarabine:30 mg/m(2) per day IV infusion over 30 minutes, daily. On days -6, -5, -4, and -3. Cyclophosphamide:1200 mg/m(2) per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m(2) per day IV infusion, Daily on days 6, -5,-4, and -3

A - Tacrolimus, methotrexate, sirolimus (TMS) Arm; B - Cyclosporine (AC) Arm

TMS DRUG

Tacrolimus: starting day -3 before transplant, given initially at 0.02 mg/kg/day CIV. Continue IV and then switch to an equivalent oral dose (when patient taking po) titrated for a goal level of 5 to 10 ng/ml; Sirolimus: given as an initial loading dose of 12 mg p.o. on day -3 pre-transplant, 4 mg starting day -2 pre-transplant and titrated for levels 3-12 ng/ml; Methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11 post-transplant. Tacrolimus and sirolimus will be tapered at day +63, day +119 and day +180 post-transplant as tolerated.

Also known as: Prograf

A - Tacrolimus, methotrexate, sirolimus (TMS) Arm

FLAG DRUG

Fludarabine:25 mg/m(2) per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m(2) IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day subcutaneous (SC) beginning 24 hours PRIOR to initiation of chemotherapy

Also known as: Fludarabine+high-dose cytarabine+G-CSF (Filgrastim))

A - Tacrolimus, methotrexate, sirolimus (TMS) Arm; B - Cyclosporine (AC) Arm

EPOCH-F DRUG

Fludarabine:25 mg/m(2) per day IV infusion over 30 minutes, daily on days 1-4 Etoposide :50 mg/m(2) per day continuous IV infusion over 24 hours on days 1-4 Doxorubicin:10 mg/m(2)/day CIV, days 1-4 Vincristine:0.4 mg/m(2) per day continuous IV infusion over 24 hours daily on days 1-4 Cyclophosphamide:750 mg/m(2) IV infusion over 30 minutes on day 5

A - Tacrolimus, methotrexate, sirolimus (TMS) Arm; B - Cyclosporine (AC) Arm

Alemtuzumab BIOLOGICAL

Alemtuzumab:20 mg/day IV over 8 h on days 8 to 4 pre-transplant.

Also known as: Campath

B - Cyclosporine (AC) Arm

Eligibility Criteria

• Age: 18 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Human immunodeficiency virus (HIV) infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.
• Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (6)

• Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW, Turner ML, Akpek G, Gilman A, McDonald G, Schubert M, Berger A, Bross P, Chien JW, Couriel D, Dunn JP, Fall-Dickson J, Farrell A, Flowers ME, Greinix H, Hirschfeld S, Gerber L, Kim S, Knobler R, Lachenbruch PA, Miller FW, Mittleman B, Papadopoulos E, Parsons SK, Przepiorka D, Robinson M, Ward M, Reeve B, Rider LG, Shulman H, Schultz KR, Weisdorf D, Vogelsang GB; Response Criteria Working Group. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006 Mar;12(3):252-66. doi: 10.1016/j.bbmt.2006.01.008.

  PMID: 16503494 BACKGROUND

• Shaffer BC, Modric M, Stetler-Stevenson M, Arthur DC, Steinberg SM, Liewehr DJ, Fowler DH, Gale RP, Bishop MR, Pavletic SZ. Rapid complete donor lymphoid chimerism and graft-versus-leukemia effect are important in early control of chronic lymphocytic leukemia. Exp Hematol. 2013 Sep;41(9):772-8. doi: 10.1016/j.exphem.2013.04.015. Epub 2013 May 18.

  PMID: 23689118 BACKGROUND

• Pavletic SZ, Lee SJ, Socie G, Vogelsang G. Chronic graft-versus-host disease: implications of the National Institutes of Health consensus development project on criteria for clinical trials. Bone Marrow Transplant. 2006 Nov;38(10):645-51. doi: 10.1038/sj.bmt.1705490. Epub 2006 Sep 18.

  PMID: 16980994 BACKGROUND

• Hardy NM, Fellowes V, Rose JJ, Odom J, Pittaluga S, Steinberg SM, Blacklock-Schuver B, Avila DN, Memon S, Kurlander RJ, Khuu HM, Stetler-Stevenson M, Mena E, Dwyer AJ, Levine BL, June CH, Reshef R, Vonderheide RH, Gress RE, Fowler DH, Hakim FT, Bishop MR. Costimulated tumor-infiltrating lymphocytes are a feasible and safe alternative donor cell therapy for relapse after allogeneic stem cell transplantation. Blood. 2012 Mar 22;119(12):2956-9. doi: 10.1182/blood-2011-09-378398. Epub 2012 Jan 30.

  PMID: 22289893 BACKGROUND

• Holtzman NG, Curtis LM, Salit RB, Shaffer BC, Pirsl F, Ostojic A, Steinberg SM, Schulz E, Wilder JS, Hughes TE, Rose J, Memon S, Korngold R, Gea-Banacloche JC, Fowler DH, Hakim FT, Gress RE, Bishop MR, Pavletic SZ. High-dose alemtuzumab and cyclosporine vs tacrolimus, methotrexate, and sirolimus for chronic graft-versus-host disease prevention. Blood Adv. 2024 Aug 27;8(16):4294-4310. doi: 10.1182/bloodadvances.2023010973.

  PMID: 38669315 DERIVED

• Assmann JC, Farthing DE, Saito K, Maglakelidze N, Oliver B, Warrick KA, Sourbier C, Ricketts CJ, Meyer TJ, Pavletic SZ, Linehan WM, Krishna MC, Gress RE, Buxbaum NP. Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI. Blood. 2021 Jan 7;137(1):126-137. doi: 10.1182/blood.2020005770.

  PMID: 32785680 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Myelodysplastic Syndromes; Hodgkin Disease; Multiple Myeloma; Leukemia; Lymphoma

Interventions

Rituximab; Cyclosporine; Tacrolimus; Filgrastim; Alemtuzumab

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Macrolides; Lactones; Organic Chemicals; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Biological Factors; Antibodies, Monoclonal, Humanized

Results Point of Contact

• Title: Dr. Steven Z. Pavletic
• Organization: National Cancer Institute

sp326h@nih.gov

301- 402-4899

Study Officials

• Steven Z Pavletic, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 21, 2007
• First Posted: August 23, 2007
• Study Start: October 30, 2007
• Primary Completion: October 14, 2015
• Study Completion: December 31, 2018
• Last Updated: March 5, 2019
• Results First Posted: August 24, 2017

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)