Intensity Modulated Total Marrow Irradiation, Fludarabine Phosphate, and Melphalan in Treating Patients With Relapsed Hematologic Cancers Undergoing a Second Donor Stem Cell Transplant

The University of Chicago

Status and phase

Enrolling

Phase 1

Conditions

Previously Treated Myelodysplastic Syndrome

Recurrent Adult Acute Lymphoblastic Leukemia

Recurrent Hematologic Malignancy

Recurrent Adult Acute Myeloid Leukemia

Treatments

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Procedure: Peripheral Blood Stem Cell Transplantation

Drug: Tacrolimus

Radiation: Intensity-Modulated Radiation Therapy

Radiation: Total Marrow Irradiation

Drug: Mycophenolate Mofetil

Procedure: Allogeneic Bone Marrow Transplantation

Drug: Melphalan

Drug: Fludarabine Phosphate

Other: Laboratory Biomarker Analysis

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT02333162

NCI-2014-02469 (Registry Identifier)

IRB14-0709 (Other Identifier)

P30CA014599 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This phase I trial studies the side effects and the best dose of intensity modulated total marrow irradiation (IMTMI) when given together with fludarabine phosphate and melphalan in treating patients with cancers of the blood (hematologic) that have returned after a period of improvement (relapsed) undergoing a second donor stem cell transplant. IMTMI is a type of radiation therapy to the bone marrow that may be less toxic and may also reduce the chances of cancer to return. Giving fludarabine phosphate, melphalan, and IMTMI before a donor stem cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Full description

PRIMARY OBJECTIVES:

I. The determine the maximum tolerated dose (MTD) of intensity-modulate total marrow irradiation (IMTMI) in combination with fludarabine (fludarabine phosphate)/melphalan as conditioning for second allogeneic stem cell transplantation for patients with hematologic malignancies.

SECONDARY OBJECTIVES:

I. To determine the overall toxicity and day 100 transplant related mortality after second allogeneic hematopoietic stem cell transplantation conditioned with increasing doses of intensity-modulate total marrow irradiation (IMTMI) in combination with fludarabine/melphalan.

II. To determine the time to neutrophil and platelet engraftment after second allogeneic hematopoietic stem cell transplantation conditioned with increasing doses of intensity-modulate total marrow irradiation (IMTMI) in combination with fludarabine/melphalan.

III. To determine the overall survival (OS) and event-free-survival (EFS) in patients with hematologic undergoing second allogeneic hematopoietic stem cell transplant (HSCT) after conditioning with fludarabine/melphalan and IMTMI.

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

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes daily on days -7 to -3 and melphalan IV on day -2. Patients also undergo IMTMI twice daily (BID) for 2 to 5 days between days -7 to -3.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) or bone marrow transplant (BMT) on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or orally (PO) BID on days -2 to 180 with taper thereafter and mycophenolate mofetil IV every 8 hours or PO on days 0-28 (for matched donors) or days 0-40 (for alternative donors) with taper to day 60.

After completion of treatment, patients are followed up periodically for 1 year and then yearly for 2 years.

Enrollment

30 estimated patients

Sex

All

Ages

18 to 75 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

Patients with the following diseases: acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS) undergoing second allogeneic (allo)-stem cell transplant (SCT) using the same donor or different donor for disease relapse; patients with other hematologic malignancies, including acute lymphoblastic leukemia (ALL), will be at the discretion of the investigators
Karnofsky performance status of 70 or above
Life expectancy is not severely limited by concomitant illness
Adequate cardiac and pulmonary function; patients with decreased left ventricular ejection fraction (LVEF) =< 40% or diffusion capacity of carbon monoxide (DLCO) =< 50% of predicted will be evaluated by cardiology or pulmonary prior to enrollment on this protocol
Serum creatinine =<1.5 mg/dL or creatinine clearance > 50 ml/min; some patients with minor deviations may be accepted on protocol after discussion with the principal investigator (PI)
Serum bilirubin =< 2.0 mg/dl; some patients with minor deviations may be accepted on protocol after discussion with the PI
Serum glutamic oxaloacetic transaminase (SGPT) < 5 x upper limit of normal; some patients with minor deviations may be accepted on protocol after discussion with the PI
No evidence of chronic active hepatitis or cirrhosis
Human immunodeficiency virus (HIV)-negative
Patient is not pregnant
Patient or guardian able to sign informed consent
DONOR: Since these patients already had first allo-SCT; in the majority time, the same matched donor has been used for second allo-SCT; if the patients have multiple donors, alternative matched (8/8 or 10/10) donor could be used for the second allo-SCT; the donor could be matched related donors or matched unrelated donors from registry
DONOR: If more than one potential volunteer unrelated donor is considered suitable, further selection of the most suitable donor will be prioritized as follows or will follow our institutional guideline from our stem cell transplant standard operating procedure (SOP):
- Age of donor (18-24 > 25-34 > 35-44 > 45+)
- Sex of donor (male > female, nulliparous female > parous, multiparous female)
- Cytomegalovirus (CMV) status, if recipient is CMV seronegative (CMV- > CMV+

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

30 participants in 1 patient group

Treatment (IMTMI, combination chemotherapy, PBSCT or BMT)

Experimental group

Description:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes daily on days -7 to -3 and melphalan IV on day -2. Patients also undergo IMTMI BID for 2 to 5 days between days -7 to -3. TRANSPLANT: Patients undergo allogeneic PBSCT or BMT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously over 24 hours or PO BID on days -2 to 180 with taper thereafter and mycophenolate mofetil IV every 8 hours or PO on days 0-28 (for matched donors) or days 0-40 (for alternative donors) with taper to day 60.

Treatment: