Targeted Marrow Irradiation, Fludarabine Phosphate, and Busulfan Before Donor Progenitor Cell Transplant in Treating Patients With Hematologic Malignancies

NCT ID: NCT02129582

Last Updated: 2021-05-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-11-05
• Study Completion Date: 2020-03-05

Brief Summary

This phase I trial studies the side effects and best dose of targeted marrow irradiation when given with fludarabine phosphate and busulfan before donor progenitor cell transplant in treating patients with hematologic malignancies. Targeted marrow irradiation is a type of specialized radiation therapy that delivers a high dose of radiation directly to the cancer cells, which may kill more cancer cells and cause less damage to normal cells. Giving targeted marrow irradiation and chemotherapy drugs, such as fludarabine phosphate and busulfan, before a donor progenitor cell transplant may help stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's progenitor cells. When the healthy progenitor cells from a donor are infused into the patient they may help the patient's bone marrow make progenitor cells, red blood cells, white blood cells, and platelets.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of targeted marrow irradiation given in combination with fludarabine (fludarabine phosphate) and busulfan as conditioning regimen for allogeneic hematopoietic progenitor cell transplantation.

SECONDARY OBJECTIVES:

I. To describe the toxicity profile of the conditioning regimen of targeted marrow irradiation (TMI), fludarabine and busulfan for allogeneic hematopoietic progenitor transplantation.

II. To describe the use of two techniques of delivering TMI, volumetric modulated arc therapy (VMAT) and TomoTherapy, on patient's computed tomography (CT) simulation images and describe differences in organ avoidance and target coverage, planning time, and treatment delivery time.

III. To determine the disease response status 100 days after allogeneic hematopoietic progenitor cell transplantation with the conditioning regimen of TMI, fludarabine and busulfan.

IV. To determine the rates of acute graft versus host disease after allogeneic hematopoietic progenitor cell transplantation with the conditioning regimen of TMI, fludarabine and busulfan.

OUTLINE: This is a dose-escalation study of TMI.

CONDITIONING: Patients undergo TMI twice daily (BID) on days -10 to -7. Patients also receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and busulfan IV or orally (PO) on days -5 and -4.

TRANSPLANT: Patients undergo allogeneic hematopoietic progenitor cell transplant on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive anti-thymocyte globulin IV on days -3 and -2, tacrolimus IV or PO beginning on day -1 for at least 6 months with taper beginning at 4 months, and methotrexate IV on days 1, 3, 6, and 11.

After completion of study treatment, patients are followed up at 100 days, 6 months, and 12 months.

Conditions

Acute Myeloid Leukemia; Hematologic Malignancies; Acute Lymphocytic Leukemia; Non Hodgkin Lymphoma; Hodgkin Lymphoma; Multiple Myeloma; Myelodysplastic Syndrome; Chronic Lymphocytic Leukemia; Chronic Myeloid Leukemia; Myelofibrosis; Myeloproliferative Syndrome

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (TMI, fludarabine, busulfan, allogeneic HPCT)

CONDITIONING: Patients undergo TMI BID on days -10 to -7. Patients also receive fludarabine phosphate IV over 1 hour on days -6 to -2 and busulfan IV or PO on days -5 and -4.

TRANSPLANT: Patients undergo allogeneic hematopoietic progenitor cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive anti-thymocyte globulin IV on days -3 and -2, tacrolimus IV or PO beginning on day -1 for at least 6 months with taper beginning at 4 months, and methotrexate IV on days 1, 3, 6, and 11.

Group Type: EXPERIMENTAL

total marrow irradiation

Intervention Type: RADIATION

Undergo TMI

fludarabine phosphate

Intervention Type: DRUG

Given IV

busulfan

Intervention Type: DRUG

Given IV or PO

myeloid progenitor cell transplantation

Intervention Type: PROCEDURE

Undergo allogeneic hematopoietic progenitor cell transplant

anti-thymocyte globulin

Intervention Type: BIOLOGICAL

Given IV

tacrolimus

Intervention Type: DRUG

Given IV or PO

methotrexate

Intervention Type: DRUG

Given IV

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

Interventions

total marrow irradiation

Undergo TMI

Intervention Type: RADIATION

fludarabine phosphate

Given IV

Intervention Type: DRUG

busulfan

Given IV or PO

Intervention Type: DRUG

myeloid progenitor cell transplantation

Undergo allogeneic hematopoietic progenitor cell transplant

Intervention Type: PROCEDURE

anti-thymocyte globulin

Given IV

Intervention Type: BIOLOGICAL

tacrolimus

Given IV or PO

Intervention Type: DRUG

methotrexate

Given IV

Intervention Type: DRUG

laboratory biomarker analysis

Correlative studies

Intervention Type: OTHER

Other Intervention Names

2-F-ara-AMP; Beneflur; Fludara; BSF; BU; Misulfan; Mitosan; Myeloleukon; MPCT; ATG; ATGAM; lymphocyte immune globulin; Thymoglobulin; FK 506; Prograf; amethopterin; Folex; methylaminopterin; Mexate; MTX

Eligibility Criteria

Inclusion Criteria

• Patients ineligible to receive full myeloablative conditioning regimen for allogeneic hematopoietic progenitor cell transplant due to age or comorbidities
• Patients must have histologically or cytologically diagnosis of hematologic malignancies with an indication for allogeneic hematopoietic progenitor cell transplantation, who are ineligible to receive a full ablative conditioning regimen as part of their transplantation, including:

• Acute myeloid leukemia
• Acute lymphocytic leukemia
• Non Hodgkin lymphoma
• Hodgkin lymphoma
• Multiple myeloma
• Myelodysplastic syndrome
• Chronic lymphocytic leukemia
• Chronic myeloid leukemia:
• Myeloproliferative syndromes including myelofibrosis
• Complete remission is not necessary for enrollment in this protocol
• Patients must have an allogeneic hematopoietic progenitor cell donor (HPCT), either a matched sibling, mismatched (1 allele) sibling, or a matched unrelated donor (MUD) or a mismatched (1 allele) unrelated donor

• Previous hematopoietic progenitor cell transplantation is allowed; a minimum of 6 months should have elapsed from prior autologous hematopoietic progenitor cell transplantation and a minimum of 6 months should have elapsed since prior allogeneic hematopoietic progenitor cell transplantation; prior transplantation with conditioning regimens using total body irradiation is not allowed
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Life expectancy of > 12 weeks, in the opinion of and as documented by the investigator
• Patients must have adequate hepatic, and renal function as defined below: there is no exclusion for the presence of cytopenias

• Total bilirubin ≤ 1.5 times the institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) ≤ 2.5 X institutional upper limit of normal
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X institutional upper limit of normal
• Creatinine clearance (calculated by the Cockroft-Gault formula) ≥ 60 ml/min
• Pulmonary Function Tests (FEV1, FVC, DLCO) 40%.
• Women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) from the time of study entry, for the duration of study participation and for 3 months after completing treatment; should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately
• Subjects must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Prior non-hematologic treatment toxicities must be resolved to ≤ grade 1 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, with the exception of the following grade 2 toxicities: alopecia; dry skin; spleen disorders, hearing impairment; tinnitus; hypothyroidism; hyperthyroidism; endocrine disorders; blurred vision; cataracts; constipation; gastroesophageal reflux; fatigue; abnormal coagulation tests INR and/or aPTT; weight gain or weight loss; anorexia; glucose intolerance; hypoalbuminemia; hypokalemia; muscle weakness; dysgeusia; paresthesias; peripheral motor and/or sensory neuropathy; hot flashes; hypertension.
• Patients must not have received other investigational agents within 14 days of initiation of the conditioning regimen
• Patients with untreated brain metastases should be excluded from this clinical trial
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to fludarabine and or busulfan or other agents used in this study
• Prior allogeneic hematopoietic progenitor cell transplantation
• Prior autologous hematopoietic progenitor cell transplantation if the conditioning regimen included total body irradiation
• Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; this exclusion criterion does not include the underlying disease for which the patient is undergoing hematopoietic progenitor cell transplantation
• Pregnant or breastfeeding women are excluded from this study; breastfeeding should be discontinued
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• Patients with a history of therapy with radiation therapy are excluded
• Due to technical limitations of TMI, patients must be no taller than 1.9 m (6 feet 4 inches), and no wider from elbow to elbow in the supine position than 60 cm.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Case Comprehensive Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Molly Gallogly, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Locations

University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center

Cleveland, Ohio, United States

Countries

United States

Other Identifiers

CASE9Z13

Identifier Type: -

Identifier Source: org_study_id