Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Leukemia

NCT02446964 | Completed Phase 1 DMC

• 3 other identifiers: 14106NCI-2015-00788114382
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of total bone marrow and lymphoid irradiation when given together with chemotherapy before donor stem cell transplant in treating patients with myelodysplastic syndrome or acute leukemia. Total marrow and lymphoid irradiation is a type of radiation therapy that targets bone marrow and blood, where the cancer is, instead of applying radiation to the whole body. Stem cell transplants use high doses of chemotherapy and radiation therapy, such as total marrow and lymphoid irradiation, to kill cancer cells, but these treatments kill normal cells as well. After chemotherapy, healthy cells from a donor are given to the patient to help the patient grow new blood cells.

Conditions

Adult Acute Lymphoblastic Leukemia in Complete Remission; Acute Myeloid Leukemia in Remission; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Childhood Acute Lymphoblastic Leukemia in Complete Remission

Outcome Measures

Primary Outcomes (2)

• Incidence of dose-limiting toxicity (DLT) scored on both the Bearman Scale and National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03

  Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity.

  Up to 100 days

• Maximum tolerated dose of TMLI when given in combination with fludarabine phosphate and cyclophosphamide, defined as the highest dose where 6 patients have been treated and at most one patient experiences DLT

  Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity.

  Up to day -3

Secondary Outcomes (10)

• Complete remission proportion

  At day 30

• Immune reconstitution of B, T and NK cells

  Up to 1 year

• Incidence of acute GVHD of grades 2-4 and 3-4

  Within the first 100 days post-transplant

• Incidence of chronic GVHD

  After 180 days post-transplant assessed up to 5 years

• Incidence of infection

  Up to day 100

Study Arms (1)

Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)

EXPERIMENTAL

CONDITIONING: Patients undergo TMLI BID on days -7 to -4 or -3 (depending on the dose level). Patients also receive fludarabine phosphate IV on days -7 to -3 and cyclophosphamide IV on days -7, -6, 3, and 4. TRANSPLANT: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GHVD PROPHYLAXIS: Patients receive tacrolimus\* IV QD or PO BID on days 5-180. Patients also receive mycophenolate mofetil PO TID or IV on days 5-35. Treatment with tacrolimus and mycophenolate mofetil may continue in the presence of active GVHD. \*NOTE: Patients intolerant of tacrolimus may receive cyclosporine.

Procedure: Bone Marrow Transplantation; Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Tacrolimus; Radiation: Total Marrow Irradiation

Interventions

Bone Marrow Transplantation PROCEDURE

Undergo bone marrow transplant

Also known as: BMT, Bone Marrow Grafting, Bone Marrow Transplant, Marrow Transplantation

Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719

Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586

Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)

Mycophenolate Mofetil DRUG

Given PO or IV

Also known as: Cellcept, MMF

Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)

Peripheral Blood Stem Cell Transplantation PROCEDURE

Undergo peripheral blood stem cell transplant

Also known as: PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplantation

Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)

Tacrolimus DRUG

Given IV and PO

Also known as: FK 506, Fujimycin, Prograf, Protopic

Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)

Total Marrow Irradiation RADIATION

Undergo TMLI

Treatment (TMLI, chemotherapy, transplant, GVHD prophylaxis)

Eligibility Criteria

• Age: 12 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Eligible patients will have a histopathologically confirmed diagnosis of hematologic malignancy in one of the following categories:
• Acute myelogenous leukemia
• In first complete remission (CR1) with poor risk cytogenetics according to National Comprehensive Cancer Network (NCCN) guidelines for acute myeloid leukemia (AML): monosomal karyotype, -5, 5q-,-7,7q-, inv (3), t(3;3), t(6;9), t(9;22) and complex karyotypes (\>= 3 unrelated abnormalities \[abn\]) and normal cytogenetics with fms-related tyrosine kinase 3 (FLT3)-internal tandem duplications (ITD) mutation
• In pediatrics, all of the above and 11q23-non t(9;11)
• In second complete remission (CR2) or third complete remission (CR3)
• With chemosensitive primary refractory disease
• Acute lymphocytic leukemia
• In CR1 with poor risk cytogenetics:
• For adults according to NCCN guidelines for acute lymphoblastic leukemia (ALL): hypoploidy (\< 44 chromosomes); t(v;11q23): mixed lineage leukemia (MLL) rearranged; t(9;22) (q34;q11.2); complex cytogenetics (5 or more chromosomal abnormalities); high white blood cell (WBC) at diagnosis (\>= 30,000 for B lineage or \>= 50,000 for T lineage)
• For pediatrics t(9;22), intrachromosomal amplification of chromosome 21 (iAMP21)loss of 13q, and abnormal 17p
• In CR2 or CR3
• With chemosensitive primary refractory disease
• Myelodysplastic syndrome in high-intermediate (int-2) and high risk categories
• Karnofsky or Lansky performance status \>= 80
• A pretreatment measured creatinine clearance (absolute value) of \>= 50 ml/minute

You may not qualify if:

• Patients should not have any uncontrolled illness including ongoing or active bacterial, viral or fungal infection
• Patients may not be receiving any other investigational agents, or concurrent biological, intensive chemotherapy, or radiation therapy for the previous three weeks from conditioning
• \* (NOTE: Low dose chemotherapy or maintenance chemotherapy given within 7 days of planned study enrollment is permitted; these include: hydroxyurea, 6-meraptopurine, oral methotrexate, vincristine, oral etoposide, and tyrosine kinase inhibitors \[TKIs\]; FLT-3 inhibitors such as sorafenib, crenolanib, quizartinib, midostaurin can also be given up to 3 days before conditioning regimen)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the pre- or post-transplant regimen
• Pregnant women are excluded from this study
• Patients with other active malignancies are ineligible for this study, other than non-melanoma skin cancers
• The recipient has a medical problem or neurologic/psychiatric dysfunction which would impair his/her ability to be compliant with the medical regimen and to tolerate transplantation or would prolong hematologic recovery which in the opinion of the principal investigator would place the recipient at unacceptable risk
• Patients may not have had a prior autologous or allogeneic transplant
• HLA-matched or partially matched (7/8 or 8/8) related or unrelated donor is available to donate
• Patients may not have received more than 3 prior regimens, where the regimen intent was to induce remission
• Patients treatment history may not include anti-CD33 monoclonal antibody therapy (e.g., SGN-CD33 or Mylotarg)
• Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
• DONOR: Evidence of active infection
• DONOR: Medical or physical reason which makes the donor unlikely to tolerate or cooperate with growth factor therapy and leukapheresis
• DONOR: Factors which place the donor at increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute

Interventions

Bone Marrow Transplantation; Cyclophosphamide; fludarabine phosphate; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Tacrolimus

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Tissue Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Macrolides; Lactones

Study Officials

• Joseph Rosenthal

  City of Hope Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2015
• First Posted: May 18, 2015
• Study Start: June 25, 2015
• Primary Completion: May 20, 2025
• Study Completion: May 20, 2025
• Last Updated: June 22, 2025

Record last verified: 2025-06

Locations

US (1)