Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer

A Phase II Trial of Haploidentical Allogeneic Stem Cell Transplantation Utilizing Mobilized Peripheral Blood Stem Cells

This phase II trial studies how well fludarabine phosphate, cyclophosphamide, total body irradiation, and donor stem cell transplant work in treating patients with blood cancer. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps 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. The donated stem cells may also replace the patient?s immune cells and help destroy any remaining cancer cells.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia; Polycythemia Vera; Myelofibrosis; Chronic Myelomonocytic Leukemia; Waldenstrom Macroglobulinemia; Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Secondary Acute Myeloid Leukemia; Sickle Cell Disease; Myelodysplastic Syndrome; Plasma Cell Myeloma; Chronic Granulomatous Disease; Thalassemia; B-Cell Non-Hodgkin Lymphoma; Congenital Amegakaryocytic Thrombocytopenia; Aplastic Anemia; Recurrent Non-Hodgkin Lymphoma; Refractory Non-Hodgkin Lymphoma; Myeloproliferative Neoplasm; Wiskott-Aldrich Syndrome; Secondary Myelodysplastic Syndrome; Paroxysmal Nocturnal Hemoglobinuria; Acute Leukemia in Remission; Severe Aplastic Anemia; Glanzmann Thrombasthenia; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Shwachman-Diamond Syndrome; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Myeloid Leukemia With FLT3/ITD Mutation; T-Cell Non-Hodgkin Lymphoma; Acute Myeloid Leukemia With Gene Mutations; Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; CD40 Ligand Deficiency; Chronic Leukemia in Remission; Congenital Neutropenia; Congenital Pure Red Cell Aplasia; Immunodeficiency Syndrome
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Cyclophosphamide; Radiation: Total-Body Irradiation; Drug: Fludarabine Phosphate; Procedure: Peripheral Blood Stem Cell Transplantation

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the rate of relapse, defined as recurrence of underlying disease or progression of underlying disease, at 1 year in patients who receive haploidentical peripheral blood stem cells (PBSCs) after reduced intensity conditioning and post-transplant cyclophosphamide and tocilizumab (or tocilizumab alternative).

SECONDARY OBJECTIVES:

I. To evaluate safety including development of acute graft versus host disease (GVHD) and death at 100 days post-transplant, as well as other treatment related toxicities including chronic GVHD, engraftment rate, non-relapse mortality, progression free survival (PFS) at one year, and overall survival (OS) at one year, as compared with historical controls.

TERTIARY OBJECTIVES:

I. Correlative studies will include chimerism analysis by molecular analysis and evaluation of immune reconstitution by cytomegalovirus (CMV) dextramer analysis using flow cytometry.

OUTLINE:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -6 to -2 and cyclophosphamide IV over 2 hours on days -6 and -5. Patients undergo total body irradiation (TBI) on days -1 and peripheral blood stem cell transplantation (PBSCT) on day 0.

After completion of study treatment, patients are followed up at 30 and 100 days.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Any disease that is considered transplant eligible per TCT standards
• Disease response noted (i.e. CR, non-CR, or not applicable): Assessed as per disease specific criteria

• Suitable related haploidentical donor identified per transplant service:

  • Recipient should not have HLA antibodies to potential donor. If the recipient does have HLA antibodies to the potential donor, an alternative donor is preferred; however, if there are no suitable alternative donors, the anti-HLAt antibodies should be depleted per transplant service guidelines.
  • Haploidentical donors that are ABO compatible with the recipient are preferred. Minor ABO incompatibility is preferred to major ABO incompatibility. Major ABO incompatibility between recipient and donor is the least preferred but still acceptable for this study.
  • It is preferred that the haploidentical donor must be available to donate on day -1 and day 0, so that fresh product can be processed by the Stem Cell lab and administered to the patient on day 0.While less preferable, cryopreserved product may be utilized with this product.
• Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% predicted, corrected for hemoglobin and/or alveolar ventilation
• Left ventricular ejection fraction > 40%
• Bilirubin, liver alkaline phosphatase, serum glutamic-oxaloacetic transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) =< 3 x upper limit of normal
• Calculated creatinine clearance > 40 cc/min by the modified Cockcroft-Gault formula for adults or the Schwartz formula for pediatrics
• Have a Karnofsky (adult) or Lansky (for =< 16 years) performance status >= 60%
• Patient must be able to pass radiation evaluation (i.e.: able to receive 200 cGy)
• Patients who have failed a prior autologous transplant are eligible; however, at least 90 days must have elapsed between the start of this reduced intensity conditioning regimen and the last transplant if patient had a prior autologous BMT
• Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Participant must understand the investigational nature of this study and sign an independent ethics committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
• If patient is planned to use a fully matched donor, patient is excluded from trial; patient must be planned to undergo a haploidentical matched transplant to participate on study. Patient is still eligible for trial regardless of donor options if PI feels that haplo transplant is in the patient's best interest per clinical decision
• Exclusion Criteria:
• Participants who have had chemotherapy (not including molecularly targeted agents; examples include, but are not limited to, tyrosine kinase inhibitors such as FLT3 inhibitors and IDH2 inhibitors), radiation treatment and/or surgery 7 days prior to starting conditioning regimen. Those who have not recovered sufficiently from adverse events due to agents administered more than 2 weeks earlier are also ineligible. Exceptions may be made on a case-by-case basis after discussion with the PI
• Uncontrolled central nervous system (CNS) disease (for hematologic malignancies) Per PI discretion
• Child-Pugh class B and C liver failure
• Concomitant active malignancy that would be expected to require chemotherapy within 3 years of transplant (other than non-melanoma skin cancer) Exception would include any concurrently existing malignancy that could be treated with a transplant per PI discretion (Example: Patient has AML but a history of mastocytosis)
• Patients who have received maximally allowed doses (given in 2 Gy fractionations, or equivalent) of previous radiation therapy to various organs; patients who previously have received a higher than allowed dose of radiation to a small lung, liver and brain volume, will be evaluated by the radiation oncologist to determine if the patient is eligible for study
• Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or other condition which, in the opinion of treating physician, would make this protocol unreasonably hazardous for the patient
• Known human immunodeficiency virus (HIV) positive
• Pregnant or nursing female participants
• Patients who in the opinion of the treating physician are unlikely to comply with the restrictions of allogeneic stem cell transplantation based on formal psychosocial screening
• Patients with donor specific HLA antibodies with a titer greater than 3000 MFI (whether or not they have undergone a desensitization protocol)
• Patients who have undergone a prior allogeneic hematopoietic or (other organ) transplant
• Treating physician considers the potential HLA haploidentical donor to be ineligible to receive G-CSF, and/or concern on the part of the treating physician for risk of harm to the potential donor with administration of G-CSF, and/or refusal by the potential donor (or donor's guardian) to receive G-CSF
• Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug
• Received an investigational agent within 14 days prior to enrollment. Exceptions may be made on a case-by-case basis after discussion with PI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (fludarabine, cyclophosphamide, TBI, PBSCT); Patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 2 hours on days -6 and -5. Patients undergo TBI on days -1 and PBSCT on day 0.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation; TOTAL BODY IRRADIATION; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo PBSCT; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; peripheral stem cell support; peripheral stem cell transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse Rate	The number of participants that relapse within 1 year.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Engraftment Rate	Will be computed with corresponding exact 95% confidence intervals based on the methodology of Clopper and Pearson.	At 1 year post-transplant
Proportion of Participants With Acute Graft Versus Host Disease (GVHD)	Will be computed with corresponding exact 95% confidence intervals based on the methodology of Clopper and Pearson.	At 100 days post-transplant
Proportion of Participants With Chronic Graft Versus Host Disease (GVHD)	Will be computed with corresponding exact 95% confidence intervals based on the methodology of Clopper and Pearson.	At 1 year post-transplant
Overall Survival	Will be computed with corresponding exact 95% confidence intervals based on the methodology of Clopper and Pearson. Will be obtained using the product-limit based Kaplan-Meier method.	up to 6 years
Progression Free Survival	Will be computed with corresponding exact 95% confidence intervals based on the methodology of Clopper and Pearson. Will be obtained using the product-limit based Kaplan-Meier method.	up to 6 years
Transplant Related Mortality	Will be computed with corresponding exact 95% confidence intervals based on the methodology of Clopper and Pearson.	At 1 year post-transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune Reconstitution	Will be assessed by bone marrow transplantation SOC immunophenotyping panel and by analysis of cytomegalovirus-specific immunity.	Up to 1 year
Lymphoid Chimerism Expressed as a Percentage of Donor Cells	Mean lymphoid chimerism expressed as a percentage of donor cells	At 30 days
Myeloid Chimerism Expressed as a Percentage of Donor Cells	Mean myeloid chimerism expressed as a percentage of donor cells	At 100 days

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Investigators: Principal Investigator: Philip McCarthy, MD, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2017
• Primary Completion (Actual): August 28, 2023
• Study Completion (Estimated): August 28, 2024

Study Registration Dates

• First Submitted: November 2, 2017
• First Submitted That Met QC Criteria: November 2, 2017
• First Posted (Actual): November 7, 2017

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Urologic Diseases; Urological Manifestations; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Blood Coagulation Disorders, Inherited; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Urination Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplastic Processes; Neoplasms, Plasma Cell; Blood Coagulation Disorders; Lipid Metabolism Disorders; Blood Platelet Disorders; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Leukemia, Lymphoid; Leukemia, B-Cell; Pancreatic Diseases; Proteinuria; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Hypoplastic, Congenital; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Lipid Metabolism, Inborn Errors; Phagocyte Bactericidal Dysfunction; Bone Marrow Neoplasms; Hematologic Neoplasms; Primary Immunodeficiency Diseases; Lymphopenia; Lipomatosis; Exocrine Pancreatic Insufficiency; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Cytopenia; Lymphoma; Lymphoma, B-Cell; Syndrome; Myelodysplastic Syndromes; Multiple Myeloma; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasm Metastasis; Lymphoma, Non-Hodgkin; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Neutropenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Immunologic Deficiency Syndromes; Anemia; Anemia, Sickle Cell; Lymphoma, T-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Thrombocytopenia; Granulomatous Disease, Chronic; Thalassemia; Leukemia, Myeloid, Accelerated Phase; Myeloproliferative Disorders; Anemia, Aplastic; Red-Cell Aplasia, Pure; Polycythemia Vera; Polycythemia; Wiskott-Aldrich Syndrome; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Anemia, Diamond-Blackfan; Shwachman-Diamond Syndrome; Thrombasthenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Fludarabine phosphate
• Other Study ID Numbers: I 40916 (Other Identifier: Roswell Park Cancer Institute); NCI-2017-01949 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No