A Dose Escalation Study of Intensity Modulated Total Marrow Irradiation (IMRT-TMI) Followed by Fludarabine as a Myeloablative Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Relapsed and Refractory Hematologic Malignancies

NCT05201183 | Withdrawn Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: CTO-IUSCCC-0747
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase I/II clinical trial to determine the maximum tolerated dose (MTD) of total marrow irradiation (TMI) followed by fludarabine in the context of a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as to determine the efficacy of the regimen in patients with high-risk leukemia and myelodysplasia.

Conditions

Acute Myeloid Leukemia; Chronic Myeloid Leukemia; Acute Lymphocytic Leukemia; Myelodysplastic Syndromes

Keywords

Radiation; Total Marrow Irradiation; Fludarabine; Bone Marrow Transplant

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose of Total Marrow Irradiation (TMI) followed by 150 mg/m2 fludarabine- Phase I only

  Day -10 of conditioning regimen through 30 days post transplant (40 days)

• Overall survival (OS) rate 1 year post transplant-Phase II only

  1 year

Secondary Outcomes (17)

• Frequency of non hematologic toxicity

  100 days

• Incidence of mucositis

  100 days

• Incidence of acute graft versus host disease

  100 days

• Incidence of chronic graft versus host disease

  100 days

• Incidence of sinusoidal obstruction syndrome

  100 days

Study Arms (1)

Fludarabine + Total Marrow Irradiation

EXPERIMENTAL

Fludarabine will be administered sequentially after the administration of TMI. TMI will be delivered on Days -11, -10, -9, -8, and -7 (1.4-2.2 gray (GY)/fraction, twice a day) followed by fludarabine on Days -6, -5, -4, -3, and -2 (150 mg/m2, 30 mg/m2/day)

Combination Product: Fludarabine + Total Marrow Irradiation

Interventions

Fludarabine + Total Marrow Irradiation COMBINATION_PRODUCT

Patients will receive total marrow irradiation TMI on Day -11 to Day -7 in two fractions per day. The TMI dose will be escalated in successive cohorts compromised of 3-6 patients as follows: Cohort 1 1.4 (Gy/fraction) Cohort 2: 1.6 (Gy/fraction) Cohort 3 1.8 (Gy/fraction) Cohort 4 2.0 (Gy/fraction) Cohort 5 2.2 (Gy/fraction) Patients will receive Fludarabine (30 mg/m2/day) on Day -6 to Day -2 followed by allo-HSCT on Day 0.

Fludarabine + Total Marrow Irradiation

Eligibility Criteria

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

You may qualify if:

• Documentation of Disease: Patients must be diagnosed with one of the following conditions:
• Acute Myeloid Leukemia (AML), with no history of extramedullary disease, who are not in complete remission, who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors:
• Duration of first CR \< 6 months (if previously in CR), based on the best overall clinical assessment of the disease course, not solely based on blood test or bone marrow biopsy results
• Poor risk karyotype including any of the following: complex karyotype with ≥3 clonal abnormalities, 5q-/-5, 7q-/-7, 11q23 abnormalities, inv(3q), 20q or 21q abnormalities, t (6;9), t (9;22), 17p abnormalities \[or TP53 mutations\] or monosomal karyotype. Molecular typing (except for TP53 mutation) will not be used for eligibility criteria determination.
• Circulating peripheral blood blasts at time of enrollment
• Karnofsky performance status \<90%
• Acute Lymphocytic Leukemia (ALL) who are not in complete remission, who have either primary refractory or relapsed disease, and who do not have more than one of the following adverse factors:
• Primary refractory or first relapse. Patients in second or subsequent relapse are excluded.
• Bone marrow blasts \>25% within 30 days before the start of the conditioning regimen
• Age \>40 years
• Myelodysplasia with a Revised International Prognostic Score (IPSS-R) of greater than 4.5 (i.e., high- or very-high risk).
• Chronic Myelogenous Leukemia (CML) in accelerated phase, defined by any of the following:
• % blasts in peripheral blood white cells or bone marrow
• Peripheral blood basophils at least 20%
• Persistent thrombocytopenia (\< 100 x 109/l) unrelated to therapy, or persistent thrombocytosis (\>1000 x 109/l) unresponsive to therapy

You may not qualify if:

• HIV seropositive patients
• Pregnant or nursing females.
• Prior radiation therapy
• Patients who have had a prior autologous or allogeneic bone marrow or stem cell transplantation
• Gemtuzumab ozogamicin (trade name: Mylotarg) and/or inotuzumab ozogamicin (trade name: Besponsa) use within 60 days before start of the conditioning regimen

Sponsors & Collaborators

• Naoyuki G. Saito, M.D., Ph.D.: lead

Study Sites (1)

Indiana University Melvin and Bren Simon Comprehensive Cancer Center

Indianapolis, Indiana, 46202, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes

Interventions

fludarabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Naoyuki Saito, MD PhD

  Indiana University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Radiation Oncology

Model Details: A standard "3+3" phase I design of dose escalation using 3 patients per dose level cohort with an expansion to 6 patients at the MTD will be used in Phase I. We will treat 3 patients at the initial dose level of TMI. If no dose-limiting toxicity (DLT) is observed, the next cohort of three patients is treated at the next higher dose level. If 1 of the 3 patients demonstrates DLT, an additional 3 patients are treated at that dose level. If only 1 of the 6 shows DLT, the next cohort of three patients is entered at the next dose level. If 2 or more of the 6 demonstrate DLT, the MTD is defined as the previous dose level. If no DLT is observed in the final dose level, the number of patients treated will be expanded to 6. In phase II, we will enroll additional patients at the defined MTD level.

Study Record Dates

• First Submitted: January 7, 2022
• First Posted: January 21, 2022
• Study Start: October 1, 2023
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2029
• Last Updated: December 11, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)