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Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

Primary Purpose

Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

radiation therapy

cyclophosphamide

anti-thymocyte globulin

tacrolimus

methotrexate

allogeneic bone marrow transplantation

allogeneic hematopoietic stem cell transplantation

peripheral blood stem cell transplantation

laboratory biomarker analysis

About this trial

This is an interventional treatment trial for Adult Acute Lymphoblastic Leukemia in Remission

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with a diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndromes (MDS) with fewer than 10% myeloblasts or lymphoblasts in the bone marrow and no blasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen; if remission bone marrow is available beyond 30 days a new bone marrow evaluation is required to assess remission status
- The diagnosis of AML, ALL, or MDS will be based on World Health Organization (WHO) criteria
- Pre-transplant bone marrow sample must be evaluable for assessment of remission status (i.e. aspirate smear containing particles and/or evaluable bone marrow core biopsy)
- Patients with leukemia infiltration in the central nervous system (CNS) are eligible if cerebrospinal fluid (CSF) cytospin is negative for myeloblasts or lymphoblasts at time of enrollment
- If the patient has an intra-abdominal chloroma on presentation, and has a partial response or complete response to treatment (size reduction of chloroma and marrow blast < 10%), the patient is eligible; however the chloroma must be included as part of the treatment target
For patients receiving treatment of their AML, MDS or ALL prior to transplantation:
- Interval between the start of a cycle of conventional cytotoxic chemotherapy and the start of conditioning regimen must be at least 30 days
- Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and the start of conditioning regimen must be at least 10 days
Hematopoietic Cell Transplantation-Specific Comorbidity Index score (HCT-CI) =< 4 for patients in Cohort 1 and > 4 for Cohort 2
Patient must be able to lie still in full body cast for 45 minutes
Must have a suitable donor defined as a sibling matched at 5/6 or 6/6 antigens (human leukocyte antigen [HLA]-A, B, and DRB1) or an unrelated volunteer matched at 7/8 or 8/8 HLA alleles (HLA-A, B, C, and DRB1)
Signed informed consent
DONOR: "High resolution" typing at HLA-A, B, C and DRB1 alleles
- Single antigen mismatch for siblings and single allele mismatch for volunteer unrelated donors is acceptable
- Donors must be >= 17 years of age

Exclusion Criteria:

Circulating peripheral blood myeloblasts or lymphoblasts on morphologic analysis from time of last treatment to time of enrollment
Prior allograft or prior autograft
Active CNS disease as identified by positive CSF cytospin at time of enrollment
Karnofsky performance score < 70
Symptomatic uncontrolled coronary artery disease or ejection fraction < 40%
Total bilirubin >= 2 x the upper limit of normal
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >= 3 x the upper limit of normal
Diffusion capacity of the lung for carbon monoxide (DLCO) < 40%
Forced expiratory volume in one second (FEV1) < 50% (corrected for hemoglobin)
Receiving supplementary continuous oxygen
Creatinine clearance < 50 mL/min/1.73m^2
Patients with active uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms)
Patients seropositive for the human immunodeficiency virus (HIV)
Females who are pregnant or breastfeeding
Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment
Patients who had prior radiation to more than 20% bone marrow containing areas or to any areas exceeding 2000 cGy
DONOR:
- Donors will be excluded if they are an identical twin of the recipient
- Females who are pregnant (positive serum beta human chorionic gonadotropin beta [β HCG]) or uninterruptible breastfeeding
- HIV seropositive
- Donors receiving experimental therapy or investigational agents unless approved by the protocol chair

Sites / Locations

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (OSMI, allogeneic transplant)

Arm Description

CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation BID on days -6 to -4 and receive cyclophosphamide IV over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2. GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11. TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0.

Outcomes

Primary Outcome Measures

TRM, defined as death occurring in a patient from causes other than disease relapse

Proportions will be derived for incidence of TRM divided by all evaluable patients along with corresponding 95% binomial confidence intervals.

Rate of grade II/III organ toxicity, defined by the Bearman Regimen-Related Toxicities Scale

Toxicities will be tabulated by grade for each cohort, by type of toxicity, as well as the maximum grade overall. Toxicity frequencies will be described for the day +30, day +100, and one year time intervals as well as cumulative over time. Proportions will be derived for incidence of grade II/III organ toxicity divided by all evaluable patients along with corresponding 95% binomial confidence intervals.

Secondary Outcome Measures

TRM

Proportions will be derived for incidence of toxicity divided by all evaluable patients along with corresponding 95% binomial confidence intervals.

Donor chimerism

Donor chimerism is used to assess failure of engraftment rate.

Incidence of aGVHD, graded according to Ohio State University Bone Marrow Transplant (OSU BMT) Program policy

The first day of aGVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade.

Incidence of chronic GVHD, scored according to the OSU BMT Program policy

The first day of chronic GVHD onset will be used to calculate cumulative incidence curves. Rates and severity of chronic GHVD will be calculated.

Cumulative incidence of grade II organ toxicity

Toxicity will be tabulated by grade for each cohort, by type of toxicity as well as the maximum grade overall.

Incidence of hematopoietic recovery

The rate and kinetics of hematopoietic recovery will be assessed. The kinetics of post-transplant recovery of both neutrophil and platelet engraftment will be assessed.

Incidence of graft failure

Primary graft failure (defined by the lack of neutrophil engraftment by 28 days) and secondary graft failure (defined by initial neutrophil engraftment followed by subsequent decline in neutrophil counts < 500/uL unresponsive to growth factor therapy) will be assessed on days 30 and 100 and at 1 year post-transplant.

Rate of infectious complications

The number of infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after transplant. The cumulative incidence of severe, life-threatening, or fatal infections will be tabulated.

Incidence of relapse

Overall survival

Progression-free survival

Patients are considered a failure of this endpoint if they die or suffer from disease relapse or progression.

Immune reconstitution

Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19, and CD56 positive lymphocytes will be done throw flow cytometric analysis at baseline, 100 days, and 12 months post transplantation.

Full Information

NCT ID

NCT02122081

First Posted

April 22, 2014

Last Updated

September 15, 2023

Sponsor

Sumithira Vasu

1. Study Identification

Unique Protocol Identification Number

NCT02122081

Brief Title

Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

Official Title

A Feasibility Study of Organ-Sparing Marrow-Targeted Irradiation (OSMI) to Condition Patients With High-Risk Hematologic Malignancies Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

July 27, 2015 (Actual)

Primary Completion Date

September 6, 2022 (Actual)

Study Completion Date

September 6, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Sumithira Vasu

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This pilot clinical trial aims to assess feasibility and tolerability of using an LINAC based "organ-sparing marrow-targeted irradiation" to condition patients with high-risk hematological malignancies who are otherwise ineligible to undergo myeloablative Total body irradiation (TBI)-based conditioning prior to allogeneic stem cell transplant. The target patient populations are those with ALL, AML, MDS who are either elderly (>50 years of age) but healthy, or younger patients with worse medical comorbidities (HCT-Specific Comorbidity Index Score (HCT-CI) > 4). The goal is to have the patients benefit from potentially more efficacious myeloablative radiation based conditioning approach without the side effects associated with TBI.

Detailed Description

PRIMARY OBJECTIVES: I. To assess feasibility and tolerability of OSMI based hematopoietic stem cell transplant (HSCT) as defined by transplant-related mortality (TRM) at day 30 as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. SECONDARY OBJECTIVES: I. Day 100 transplant-related mortality (TRM). II. Donor chimerism assessment at day 100 (to assess failure of engraftment rate). III. Incidence of acute graft-versus-host disease (aGVHD) by day 100. IV. Incidence of chronic GVHD at one year. V. Cumulative incidence of grade II organ toxicity through day 100. VI. Rate and kinetics of hematopoietic recovery. VII. Incidence of graft failure (primary and secondary). VIII. Rate of infectious complications. IX. Cumulative incidence of relapse, overall survival, and progression-free survival at 1 year. OUTLINE: CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation twice daily (BID) on days -6 to -4 and receive cyclophosphamide intravenously (IV) over 1-2 hours every 24 hours on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every 24 hours on days -4 to -2. GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) beginning on day -1 and continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11. TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0. After completion of study treatment, patients are followed up weekly for 12 weeks, at day 100, and then at 6 and 12 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

33 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (OSMI, allogeneic transplant)

Arm Type

Experimental

Arm Description

Intervention Type

Radiation

Intervention Name(s)

radiation therapy

Other Intervention Name(s)

irradiation, radiotherapy, therapy, radiation

Intervention Description

Undergo organ-sparing marrow irradiation BID on days -6 to -4

Intervention Type

Drug

Intervention Name(s)

cyclophosphamide

Other Intervention Name(s)

CPM, CTX, Cytoxan, Endoxan, Endoxana

Intervention Description

Given IV over 1-2 hours every 24 hours on days -3 to -2.

Intervention Type

Biological

Intervention Name(s)

anti-thymocyte globulin

Other Intervention Name(s)

ATG, ATGAM, lymphocyte immune globulin, Thymoglobulin

Intervention Type

Drug

Intervention Name(s)

tacrolimus

Other Intervention Name(s)

FK 506, Prograf

Intervention Description

Given IV or PO

Intervention Type

Drug

Intervention Name(s)

methotrexate

Other Intervention Name(s)

amethopterin, Folex, methylaminopterin, Mexate, MTX

Intervention Description

Given IV

Intervention Type

Procedure

Intervention Name(s)

allogeneic bone marrow transplantation

Other Intervention Name(s)

bone marrow therapy, allogeneic, bone marrow therapy, allogenic, transplantation, allogeneic bone marrow, transplantation, allogenic bone marrow

Intervention Description

Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant on day 0

Intervention Type

Procedure

Intervention Name(s)

allogeneic hematopoietic stem cell transplantation

Intervention Description

Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant

Intervention Type

Procedure

Intervention Name(s)

peripheral blood stem cell transplantation

Other Intervention Name(s)

PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell

Intervention Description

Undergo allogeneic peripheral blood progenitor cell or bone marrow transplant

Intervention Type

Other

Intervention Name(s)

laboratory biomarker analysis

Intervention Description

Correlative studies

Primary Outcome Measure Information:

Title

TRM, defined as death occurring in a patient from causes other than disease relapse

Description

Proportions will be derived for incidence of TRM divided by all evaluable patients along with corresponding 95% binomial confidence intervals.

Time Frame

At day 30 post-transplant

Title

Rate of grade II/III organ toxicity, defined by the Bearman Regimen-Related Toxicities Scale

Description

Time Frame

Up to 30 days

Secondary Outcome Measure Information:

Title

TRM

Description

Proportions will be derived for incidence of toxicity divided by all evaluable patients along with corresponding 95% binomial confidence intervals.

Time Frame

Day 100 post-transplant

Title

Donor chimerism

Description

Donor chimerism is used to assess failure of engraftment rate.

Time Frame

Day 100

Title

Incidence of aGVHD, graded according to Ohio State University Bone Marrow Transplant (OSU BMT) Program policy

Description

The first day of aGVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade.

Time Frame

Up to day 100

Title

Incidence of chronic GVHD, scored according to the OSU BMT Program policy

Description

The first day of chronic GVHD onset will be used to calculate cumulative incidence curves. Rates and severity of chronic GHVD will be calculated.

Time Frame

At 1 year

Title

Cumulative incidence of grade II organ toxicity

Description

Toxicity will be tabulated by grade for each cohort, by type of toxicity as well as the maximum grade overall.

Time Frame

Up to day 100

Title

Incidence of hematopoietic recovery

Description

The rate and kinetics of hematopoietic recovery will be assessed. The kinetics of post-transplant recovery of both neutrophil and platelet engraftment will be assessed.

Time Frame

Up to day 100

Title

Incidence of graft failure

Description

Time Frame

Up to 1 year post-transplant

Title

Rate of infectious complications

Description

Time Frame

Up to 12 months

Title

Incidence of relapse

Time Frame

Time from start of conditioning to relapse, assessed at 1 year

Title

Overall survival

Time Frame

Time from start of conditioning to death, loss to follow up, or end of study, whichever comes first, assessed at 1 year

Title

Progression-free survival

Description

Patients are considered a failure of this endpoint if they die or suffer from disease relapse or progression.

Time Frame

Time from start of conditioning to relapse, progression, death, initiation of non-protocol therapy, loss to follow up or end of study, whichever comes first, assessed at 1 year

Title

Immune reconstitution

Description

Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19, and CD56 positive lymphocytes will be done throw flow cytometric analysis at baseline, 100 days, and 12 months post transplantation.

Time Frame

Up to 12 months post transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with a diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndromes (MDS) with fewer than 10% myeloblasts or lymphoblasts in the bone marrow and no blasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen; if remission bone marrow is available beyond 30 days a new bone marrow evaluation is required to assess remission status The diagnosis of AML, ALL, or MDS will be based on World Health Organization (WHO) criteria Pre-transplant bone marrow sample must be evaluable for assessment of remission status (i.e. aspirate smear containing particles and/or evaluable bone marrow core biopsy) Patients with leukemia infiltration in the central nervous system (CNS) are eligible if cerebrospinal fluid (CSF) cytospin is negative for myeloblasts or lymphoblasts at time of enrollment If the patient has an intra-abdominal chloroma on presentation, and has a partial response or complete response to treatment (size reduction of chloroma and marrow blast < 10%), the patient is eligible; however the chloroma must be included as part of the treatment target For patients receiving treatment of their AML, MDS or ALL prior to transplantation: Interval between the start of a cycle of conventional cytotoxic chemotherapy and the start of conditioning regimen must be at least 30 days Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and the start of conditioning regimen must be at least 10 days Hematopoietic Cell Transplantation-Specific Comorbidity Index score (HCT-CI) =< 4 for patients in Cohort 1 and > 4 for Cohort 2 Patient must be able to lie still in full body cast for 45 minutes Must have a suitable donor defined as a sibling matched at 5/6 or 6/6 antigens (human leukocyte antigen [HLA]-A, B, and DRB1) or an unrelated volunteer matched at 7/8 or 8/8 HLA alleles (HLA-A, B, C, and DRB1) Signed informed consent DONOR: "High resolution" typing at HLA-A, B, C and DRB1 alleles Single antigen mismatch for siblings and single allele mismatch for volunteer unrelated donors is acceptable Donors must be >= 17 years of age Exclusion Criteria: Circulating peripheral blood myeloblasts or lymphoblasts on morphologic analysis from time of last treatment to time of enrollment Prior allograft or prior autograft Active CNS disease as identified by positive CSF cytospin at time of enrollment Karnofsky performance score < 70 Symptomatic uncontrolled coronary artery disease or ejection fraction < 40% Total bilirubin >= 2 x the upper limit of normal Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >= 3 x the upper limit of normal Diffusion capacity of the lung for carbon monoxide (DLCO) < 40% Forced expiratory volume in one second (FEV1) < 50% (corrected for hemoglobin) Receiving supplementary continuous oxygen Creatinine clearance < 50 mL/min/1.73m^2 Patients with active uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) Patients seropositive for the human immunodeficiency virus (HIV) Females who are pregnant or breastfeeding Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment Patients who had prior radiation to more than 20% bone marrow containing areas or to any areas exceeding 2000 cGy DONOR: Donors will be excluded if they are an identical twin of the recipient Females who are pregnant (positive serum beta human chorionic gonadotropin beta [β HCG]) or uninterruptible breastfeeding HIV seropositive Donors receiving experimental therapy or investigational agents unless approved by the protocol chair

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sumithira Vasu, MD

Organizational Affiliation

Ohio State University Comprehensive Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

http://cancer.osu.edu

Description

The Jamesline

Learn more about this trial

Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

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