Early Administration of ATG Followed by Cyclophosphamide, Busulfan and Fludarabine Before a Donor Stem Cell Transplant in Patients With Hematological Cancer

NCT00787761 | Completed Phase 2 Results

• 2 other identifiers: CDR0000618483BMTGG-NSH-807
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

RATIONALE: Giving low doses of chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving antithymocyte globulin before the transplant and tacrolimus and methotrexate after the transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving antithymocyte globulin together with cyclophosphamide, busulfan, and fludarabine works in treating patients with hematological cancer or kidney cancer undergoing donor stem cell transplant.

Conditions

Myeloproliferative Disorders; Kidney Cancer; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases

Keywords

accelerated phase CML; blastic phase CML; Philadelphia chromosome positive CML; stage I CLL; stage II CLL; stage III CLL; stage IV CLL; stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma; adult AML with 11q23 (MLL) abnormalities; adult CML in remission; adult ALL in remission; stage IV renal cell cancer; de novo MDS; previously treated MDS; secondary MDS; atypical CML, BCR-ABL negative; chronic myelomonocytic leukemia; MDS/myeloproliferative neoplasm, unclassifiable; primary myelofibrosis; chronic neutrophilic leukemia; recurrent adult Hodgkin lymphoma; clear cell renal cell carcinoma; adult AML with inv(16)(p13;q22); adult AML with t(15;17)(q22;q12); adult AML with t(16;16)(p13;q22); adult AML with t(8;21)(q22;q22); adult nasal type extranodal NK/T-cell lymphoma; AML/transient myeloproliferative disorder; Burkitt lymphoma; chronic phase CML; extranodal marginal zone B-cell lymphoma of mucosa tissue; nodal marginal zone B-cell lymphoma; stage III adult Burkitt lymphoma; stage IV adult Burkitt lymphoma; recurrent adult Burkitt lymphoma; stage III adult diffuse large cell lymphoma; stage III adult diffuse mixed cell lymphoma; recurrent adult diffuse large cell lymphoma; stage IV adult diffuse large cell lymphoma; stage IV adult diffuse mixed cell lymphoma; recurrent adult diffuse mixed cell lymphoma; stage III adult immunoblastic large cell lymphoma; stage IV adult immunoblastic large cell lymphoma; stage III adult lymphoblastic lymphoma; stage IV adult lymphoblastic lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult lymphoblastic lymphoma; recurrent grade 3 follicular lymphoma; stage III grade 3 follicular lymphoma; stage IV grade 3 follicular lymphoma; recurrent mantle cell lymphoma; stage III mantle cell lymphoma; stage IV mantle cell lymphoma; contiguous st II adult diffuse small cleaved cell lymphoma; noncontiguous st II diffuse small cleaved cell lymphoma; recurrent adult diffuse small cleaved cell lymphoma; stage III adult diffuse small cleaved cell lymphoma; stage IV adult diffuse small cleaved cell lymphoma; contiguous stage II grade 1 follicular lymphoma; contiguous stage II grade 2 follicular lymphoma; noncontiguous stage II grade 1 follicular lymphoma; noncontiguous stage II grade 2 follicular lymphoma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; stage III grade 1 follicular lymphoma; stage III grade 2 follicular lymphoma; stage IV grade 1 follicular lymphoma; stage IV grade 2 follicular lymphoma; contiguous stage II marginal zone lymphoma; noncontiguous stage II marginal zone lymphoma; recurrent marginal zone lymphoma; stage III marginal zone lymphoma; stage IV marginal zone lymphoma; contiguous stage II small lymphocytic lymphoma; noncontiguous stage II small lymphocytic lymphoma; recurrent small lymphocytic lymphoma; stage III small lymphocytic lymphoma; stage IV small lymphocytic lymphoma; recurrent adult grade III lymphomatoid granulomatosis; relapsing chronic myelogenous leukemia; refractory chronic lymphocytic leukemia; splenic marginal zone lymphoma; Waldenstrom macroglobulinemia; recurrent adult T-cell leukemia/lymphoma; stage III adult T-cell leukemia/lymphoma; stage IV adult T-cell leukemia/lymphoma; anaplastic large cell lymphoma; angioimmunoblastic T-cell lymphoma

Outcome Measures

Primary Outcomes (1)

• Achievement of > 90% (Full) Donor Chimerism in the T-cell Lineage as Measured by PCR at Day 30 Post-transplantation

  Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism.

  Day 30

Secondary Outcomes (7)

• T-cell and Myeloid Chimerism at Days 90 Post-transplantation (>90% Chimerism)

  Day 90

• T-cell and Myeloid Chimerism at Days 180 Post-transplantation (>90%)

  180 days

• Number of Patients Who Experience Severe (Grade 3 or 4) Acute Graft-versus-host Disease

  Day 100

• Number of Patients Experiencing Extensive Chronic Graft Versus Host Disease (GVHD)

  2 years

• Non-relapse Mortality (NRM) at Day 180 Post-transplantation

  Day 180

Study Arms (1)

ATG, Cytoxan, Bu/Flu based Allogeneic Transplant

EXPERIMENTAL

All patients will receive an ATG, Cyclosphosphamide, Busulfan and Fludarabine based Allogeneic Transplant

Biological: anti-thymocyte globulin; Drug: busulfan; Drug: cyclophosphamide; Drug: fludarabine phosphate; Drug: methotrexate; Drug: tacrolimus; Procedure: nonmyeloablative allogeneic HSCT

Interventions

anti-thymocyte globulin BIOLOGICAL

Anti-Thymocyte Globulin (ATG) is commercially available. The 1st vial contains 25 mg ATG, and the 2nd vial contains \> 5 mL SWFI diluent. Ampuls must be refrigerated (2º C - 8º C). Do not freeze. Reconstitute 25 mg vial with diluent provided by manufacturer. Roll vial gently to dissolve powder. Use contents of vial within 4 hours. Dilute dosage to a final concentration of 0.5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection. Gently invert admixture 1-2 times to mix. Use admixture solution immediately. Infuse the 1st dose over at least 6 hours, and subsequent doses over at least 4 hours. Infuse through a 0.22 micron in-line filter. Premeds include acetaminophen 650 mg PO, diphenhydramine 25-50 mg PO/IV, and methyprednisolone 1mg/kg at the initiation and half-way through ATG administration.

Also known as: Thymoglobulin, ATG

ATG, Cytoxan, Bu/Flu based Allogeneic Transplant

busulfan DRUG

Commercially available in 60 mg/10 mL ampuls. Dilute busulfan injection in 0.9% sodium chloride injection or dextrose 5% in water. The dilution volume should be 10 times the volume of busulfan injection, ensuring that the final concentration of busulfan is ≥ 0.5 mg/mL. Store unopened ampuls at 2º C to 8º C. The diluted solution is stable for up to 8 hours at room temperature (25º C) but the infusion must also be completed within that 8-hour time frame. Dilution of busulfan injection in 0.9% sodium chloride is stable for up to 12 hours under refrigeration (2º C to 8º C) but the infusion must also be completed within that 12-hour time frame. IV Bu should be administered via a central venous catheter as a 2-hour infusion every 6 hours for 2 consecutive days for a total of 8 doses.

ATG, Cytoxan, Bu/Flu based Allogeneic Transplant

cyclophosphamide DRUG

Cyclophosphamide is commercially available. Cyclophosphamide for injection is available in 2000 mg vials which are reconstituted with 100 ml sterile water for injection. The concentration of the reconstituted product is 20 mg/ml. The calculated dose will be diluted further in 250-500 ml of Dextrose 5% in water. Reconstituted solutions of lyophilized cyclophosphamide are chemically and physically stable for 24 hours at room temperature or for 6 days in the refrigerator. Specific temperatures are not provided by the manufacturer. Reconstitution of cyclophosphamide with bacteriostatic water containing benzyl alcohol preservative may result in decomposition. Each dose will be infused over 1-2 hr (depending on the total volume).

ATG, Cytoxan, Bu/Flu based Allogeneic Transplant

fludarabine phosphate DRUG

Fludarabine is commercially available as a white, lyophilized powder. Each vial contains 50 mg of fludarabine, 50 mg of mannitol and sodium hydroxide to adjust pH. Intact vials should be stored under refrigeration. Reconstituted vials are stable for 16 days and solutions diluted in D5W or NS are stable for 48 hours at room temperature or under refrigeration. Fludarabine should be reconstituted with 2 mL of Sterile Water for Injection, USP. Each mL of the resulting solution will contain 25 mg of fludarabine, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7-8.5. The product should be further diluted for intravenous administration in 5% Dextrose for Injection, USP or in 0.9% Sodium Chloride, USP. Fludarabine will be administered as an IV infusion over 30 minutes.

Also known as: Fludara

ATG, Cytoxan, Bu/Flu based Allogeneic Transplant

methotrexate DRUG

Commercially available for injection in 2 mL (2.5 mg/mL), 2 mL, 4 mL, 8 mL, 10 mL (25 mg/mL) vials, or 20 mg, 25 mg, 50 mg, or 100 mg vials for reconstitution. Vials requiring reconstitution should be reconstituted to a concentration of 25 mg/mL. Intact vials should be stored at room temperature and protected from light. Once opened, solutions containing preservatives are stable for 4 weeks at room temperature and up to 3 months refrigerated. Administer via slow IV push.

Also known as: Amethopterin, MTX

ATG, Cytoxan, Bu/Flu based Allogeneic Transplant

tacrolimus DRUG

Tacrolimus is commercially available as an injection (5 mg/mL; 1 mL ampuls) and as oral capsules (1 mg and 5 mg). Tacrolimus injection must be diluted prior to IV infusion with 0.9% sodium chloride or 5% dextrose injection to a concentration of 4-20 μg/mL. Solutions should be prepared in non-PVC plastic or glass. Tacrolimus injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Oral therapy should be started as possible as per protocol and 8 to 12 hours after stopping intravenous therapy. Oral doses will be administered twice a day. Store tacrolimus capsules and injection at controlled room temperature, 15-30º C (59-86º F).

Also known as: Prograf, FK506

ATG, Cytoxan, Bu/Flu based Allogeneic Transplant

nonmyeloablative allogeneic HSCT PROCEDURE

As demonstrated by groups in Houston, Jerusalem \& Seattle, RICT has been used to treat hematologic \& solid malignancies with related \& unrelated donors. Although adequate comparisons of RICT versus ablative alloHCT remain to be reported, the studies of RICT so far suggest that TRM is generally less than would be expected for similar patients undergoing ablative alloHCT; incidence of acute \& chronic GVHD is similar or less than ablative alloHCT; autologous hematopoietic recovery is more common than seen following ablative alloHCT if graft failure occurs; powerful GVT effects can be seen but are dependent on high levels of donor T-cell chimerism and RICT are less effective than ablative alloHCT in controlling aggressive malignancies

ATG, Cytoxan, Bu/Flu based Allogeneic Transplant

Eligibility Criteria

• Age: Up to 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

DISEASE CHARACTERISTICS: * Histologically confirmed diagnosis of one of the following: * Chronic myeloid leukemia (CML) * Philadelphia chromosome (Ph)- and/or BCR-ABL-positive disease * In chronic or accelerated phase * Suboptimal response to imatinib mesylate (i.e., no hematologic complete response by 3 months, no major cytogenetic response by 6 months, or no complete cytogenetic response by 1 year) * CML in blastic transformation allowed provided patient achieved complete remission (CR) or second chronic phase after treatment with imatinib mesylate or chemotherapy * Chronic lymphocytic leukemia meeting one of the following criteria: * Rai stage III or IV disease * Rai stage I or II disease that failed standard therapy (i.e., disease is progressing after ≥ 1 course of standard therapy) * Non-Hodgkin lymphoma (NHL) meeting one of the following criteria: * Indolent NHL * Clinical stage III or IV disease or bulky stage II disease (i.e., ≥ one lymphoid mass \> 5 cm in ≥ one dimension) * Relapsed after primary therapy OR is refractory to therapy * Aggressive NHL * Is not considered curable with standard chemotherapy or autologous stem cell transplantation (i.e., relapsed after autologous stem cell transplantation) * Chemotherapy-responsive disease * Multiple myeloma * Durie-Salmon stage II or III disease * Durie Salmon stage I disease allowed provided β2 microglobulin level \> 3 mg/dL * Acute myeloid leukemia or acute lymphocytic leukemia * In CR (defined as \< 5% blasts in bone marrow and no circulating blasts) AND has any of the following poor prognostic features: * WBC \> 100,000/mm\^3 at presentation * In second or greater remission * Adverse-risk cytogenetics (i.e., Ph1-positive, 11q23 translocation, -5, -7, complex translocations, or other recognized adverse-risk cytogenetics) * Renal cell carcinoma * Stage IV disease * Clear cell morphology * Myelodysplastic syndromes * Bone marrow blasts ≤ 10% on last bone marrow biopsy prior to transplantation * Myeloproliferative disease * Anticipated life expectancy on conventional therapy \< 10 years * No uncomplicated essential thrombocythemia or primary polycythemia * Hodgkin lymphoma * Relapsed after ≥ 1 standard-dose chemotherapy regimen * Not considered curable by autologous stem cell transplantation * No clinical evidence of active CNS involvement * Previously treated leptomeningeal disease allowed provided CSF cytology is negative at the time of assessment for transplantation * Available 6/6 allele match (i.e., HLA-A, B, DRβ1)matched related donor PATIENT CHARACTERISTICS: * ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100% * Bilirubin \< 3 times normal (unless abnormality due to malignancy) * AST and ALT \< 3 times normal (unless abnormality due to malignancy) * Creatinine ≤ 2.0 mg/dL * LVEF ≥ 40% by MUGA or ECHO * DLCO ≥ 40% of predicted * FEV-1 ≥ 50% of predicted * Not pregnant or nursing * Fertile patients must use effective contraception * Deemed to be an appropriate candidate for allogeneic SCT * No evidence of myocardial infarction within the past 6 months * No psychological or social condition that may interfere with study participation * No serious uncontrolled localized or active systemic infection * No second malignancy within the past 3 years except for completely excised nonmelanotic skin cancer or in situ carcinoma of the cervix * No chronic inflammatory disorder requiring the continued use of glucocorticoids or other immunosuppressive medications * No known HIV positivity * No hypersensitivity to E. coli-derived proteins

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Northside Hospital, Inc.: lead
• Blood and Marrow Transplant Group of Georgia: collaborator

Study Sites (1)

Blood and Marrow Transplant Group of Georgia

Atlanta, Georgia, 30342, United States

Location

Related Publications (8)

• Rao SS, Peters SO, Crittenden RB, Stewart FM, Ramshaw HS, Quesenberry PJ. Stem cell transplantation in the normal nonmyeloablated host: relationship between cell dose, schedule, and engraftment. Exp Hematol. 1997 Feb;25(2):114-21.

  PMID: 9015211 BACKGROUND

• Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem HP, Leisenring W, Shulman H. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997 Apr 15;89(8):3048-54.

  PMID: 9108426 BACKGROUND

• Giralt S, Estey E, Albitar M, van Besien K, Rondon G, Anderlini P, O'Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, Andersson B, Beran M, Przepiorka D, Koller C, Kornblau S, Korbling M, Keating M, Kantarjian H, Champlin R. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997 Jun 15;89(12):4531-6.

  PMID: 9192777 BACKGROUND

• Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998 Feb 1;91(3):756-63.

  PMID: 9446633 BACKGROUND

• McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, Chauncey TR, Gooley TA, Hegenbart U, Nash RA, Radich J, Wagner JL, Minor S, Appelbaum FR, Bensinger WI, Bryant E, Flowers ME, Georges GE, Grumet FC, Kiem HP, Torok-Storb B, Yu C, Blume KG, Storb RF. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001 Jun 1;97(11):3390-400. doi: 10.1182/blood.v97.11.3390.

  PMID: 11369628 BACKGROUND

• Champlin R, Khouri I, Anderlini P, De Lima M, Hosing C, McMannis J, Molldrem J, Ueno N, Giralt S. Nonmyeloablative preparative regimens for allogeneic hematopoietic transplantation. Biology and current indications. Oncology (Williston Park). 2003 Jan;17(1):94-100; discussion 103-7.

  PMID: 12599934 BACKGROUND

• Platzbecker U, Ehninger G, Schmitz N, Bornhauser M. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation in myeloid diseases. Ann Hematol. 2003 Aug;82(8):463-468. doi: 10.1007/s00277-003-0680-7. Epub 2003 Jun 21.

  PMID: 12910373 BACKGROUND

• Storb R. Non-myeloablative allogeneic transplantation -- state-of-the-art. Pediatr Transplant. 2004 Jun;8 Suppl 5:12-8. doi: 10.1111/j.1398-2265.2004.00189.x.

  PMID: 15125701 BACKGROUND

MeSH Terms

Conditions

Myeloproliferative Disorders; Kidney Neoplasms; Leukemia; Lymphoma; Multiple Myeloma; Neoplasms, Plasma Cell; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid, Accelerated Phase; Blast Crisis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Congenital Abnormalities; Carcinoma, Renal Cell; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Leukemia, Myelomonocytic, Chronic; Primary Myelofibrosis; Leukemia, Neutrophilic, Chronic; Hodgkin Disease; Leukemia, Promyelocytic, Acute; Lymphoma, Extranodal NK-T-Cell; Burkitt Lymphoma; Leukemia, Myeloid, Chronic-Phase; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Lymphoma, Large-Cell, Immunoblastic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Waldenstrom Macroglobulinemia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Large-Cell, Anaplastic; Immunoblastic Lymphadenopathy

Interventions

Antilymphocyte Serum; thymoglobulin; Busulfan; Cyclophosphamide; fludarabine phosphate; Methotrexate; Tacrolimus

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Leukemia, Myeloid; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cell Transformation, Neoplastic; Carcinogenesis; Neoplastic Processes; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Leukemia, Myeloid, Acute; Lymphoma, T-Cell; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Lymphoma, B-Cell; Leukemia, Lymphoid; Leukemia, B-Cell; Lymphadenopathy

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Macrolides; Lactones

Results Point of Contact

• Title: Asad Bashey, MD, PhD, Principal Investigator
• Organization: Blood and Marrow Transplant Group of Georgia

abashey@bmtga.com

404-255-1930

Study Officials

• Asad Bashey, MD, PhD

  Blood and Marrow Transplant Group of Georgia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 7, 2008
• First Posted: November 10, 2008
• Study Start: April 1, 2007
• Primary Completion: July 1, 2010
• Study Completion: May 1, 2012
• Last Updated: October 1, 2012
• Results First Posted: October 1, 2012

Record last verified: 2012-08

Locations

US (1)