Reduced Intensity Conditioning Before Partially Matched Donor Stem Cell Transplant in Treating Patients With Advanced Cutaneous T Cell Lymphoma

A Two-Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Advanced Cutaneous T Cell Lymphoma

This phase I trial studies the side effects and the best dose of donor lymphocyte infusion when given together with reduced intensity conditioning regimen before partially matched donor stem cell transplant in treating patients with stage IIB-IV mycosis fungoides or Sezary syndrome. Giving chemotherapy and low-dose total-body irradiation followed by high-dose cyclophosphamide 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Removing the T-cells from the donor cells and giving them before transplant may stop this from happening. Additionally, giving tacrolimus and mycophenolate mofetil before and after transplant may also stop this from happening.

Study Overview

• Status: Withdrawn
• Conditions: Recurrent Mycosis Fungoides and Sezary Syndrome; Cutaneous T-Cell Non-Hodgkin Lymphoma; Stage IIB Mycosis Fungoides and Sezary Syndrome; Stage IIIA Mycosis Fungoides and Sezary Syndrome; Stage IIIB Mycosis Fungoides and Sezary Syndrome; Stage IVA Mycosis Fungoides and Sezary Syndrome; Stage IVB Mycosis Fungoides and Sezary Syndrome
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Radiation: Total-Body Irradiation; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Biological: T Cell-Depleted Donor Lymphocyte Infusion; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation

Detailed Description

PRIMARY OBJECTVES:

I. To evaluate regimen related toxicity, engraftment and graft versus host disease (GVHD) in the first 100 days with new reduced intensity haploidentical regimen protocol, including fludarabine (fludarabine phosphate), low dose total body irradiation, and cyclophosphamide.

II. To determine an effective donor lymphocyte infusion (DLI) dose that provides successful engraftment without causing GVHD.

SECONDARY OBJECTIVES:

I. To assess myeloid and lymphoid engraftment rates of patients undergoing treatment on this regimen.

II. To determine the incidence and severity of GVHD in patients undergoing treatment on this regimen using a combination of tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.

III. To examine progression free survival and overall survival in patients with cytotoxic T-cell lymphoma (CTCL) undergoing treatment on this regimen.

IV. To assess the pace of lymphoid recovery in this patient population.

OUTLINE: This is a phase I, dose-escalation study of DLI.

REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -11 to -8 and undergo total body irradiation twice daily (BID) on day -7. Patients also receive donor cluster of differentiation (CD)3+ enriched T lymphocyte infusion on day -6 and high-dose cyclophosphamide IV over 2 hours on days -3 to -2.

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

GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV with taper (drug wean) by day 60 and mycophenolate mofetil IV BID on days -1 to 28 in the absence of GVHD.

After completion of treatment, patients are followed up periodically.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Stage IIB-IV mycosis fungoides and sezary syndrome who have failed at least one standard systemic therapy or are not candidates for standard therapy.
2. Patient should have a responsive skin disease including complete remission (CR) and partial remission (PR) (close to CR; 75%-99% clearance of skin disease from baseline without new tumors (T3) in patients with T1, T2 or T4 only skin disease) and should not have visceral organ or lymph node involvement prior to transplantation.
3. Patients must have a related donor who is a two or more allele mismatch at the HLA-A; B; C; DR and DQ loci. Patients who have sibling donors with a one antigen mismatch due to recombination will not be enrolled in this protocol.

4. Patients must have adequate organ function:

   • Left Ventricular Ejection Fraction (LVEF) of >50%
   • Carbon Monoxide Diffusing Capacity (DLCO) >50% of predicted corrected for hemoglobin
   • Adequate liver function as defined by a serum bilirubin <2.0 (unless hemolysis or Gilbert disease), Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) < 2.5 X upper limit of normal
   • Creatinine clearance of > 60 ml/min
5. Performance status > 80% (Karnofsky)
6. Hematopoietic Cell Transplantation Specific Comorbidity Index (HCT-CI) <5 for age < 65, HCT-CI <4 for age >65
7. Patients must be willing to use contraception if they have childbearing potential
8. Able to give informed consent, or their legally authorized representative can give informed consent.

Exclusion Criteria:

1. Performance status of < 80% (Karnofsky)
2. HIV positive
3. Active involvement of the central nervous system with malignancy
4. Psychiatric disorder that would preclude patients from signing an informed consent
5. Pregnancy, or unwillingness to use contraception if they are have childbearing potential.
6. Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder or complications there from.
7. Patients who have received alemtuzumab within 8 weeks of transplant admission, or who have recently received horse or rabbit anti-thymocyte globulin (ATG) and have ATG levels of > 2 μgm/ml.
8. Patients who cannot receive cyclophosphamide

9. Patients with evidence of another malignancy (exclusive of a skin cancer that requires only local treatment);

   • Patients with prior malignancies diagnosed> 5 years ago without evidence of disease are eligible.
   • Patients with prior malignancy treated < 5 years ago but have a life expectancy of > 5 years for that malignancy are eligible.
10. Uncontrolled active infection

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: Reduced Intensity Conditioning, DLI, PBSCT; REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -11 to -8 and undergo total body irradiation BID on day -7. Patients also receive donor CD3+ enriched T lymphocyte infusion on day -6 and high-dose cyclophosphamide IV over 2 hours on days -3 to -2. TRANSPLANT: Patients undergo allogeneic PBSCT on day 0. GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV with taper (drug wean) by day 60 and mycophenolate mofetil IV BID on days -1 to 28 in the absence of GVHD.

Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; Cycloblastin; Cytophosphane; Neosar; Revimmune; Procytox; CP; Drug: Fludarabine; Given IV; Other Names: Fludara; Fludarabine phosphate; Radiation: Total-Body Irradiation; Undergo TBI; Drug: Tacrolimus; Given IV; Other Names: Prograf; Fujimycin; Protopic; FK-506; Advagraf; Drug: Mycophenolate mofetil; Given IV; Other Names: MMF; Biological: T Cell-Depleted Donor Lymphocyte Infusion; Undergo donor CD3+ enriched T lymphocyte infusion; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic HSC transplant; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of regimen-related toxicities	Estimate of dose-specific rates of toxicity will be presented with corresponding confidence intervals using the exact method. The method of Atkinson and Brown will be used for any rate related to definition of dose limiting toxicity, due to two-stage sampling.	Up to 100 days post-transplant
Rate for hematopoietic engraftment	Estimate of dose-specific rate for engraftment will be presented with corresponding confidence intervals using the exact method. The method of Atkinson and Brown will be used for any rate related to definition of dose limiting toxicity, due to two-stage sampling.	Up to 100 days post-transplant
Rate for immune reconstitution	Estimate of dose-specific rate for immune reconstitution will be presented with corresponding confidence intervals using the exact method. The method of Atkinson and Brown will be used for any rate related to definition of dose limiting toxicity, due to two-stage sampling.	Up to 100 days post-transplant
Incidence of GVHD		Up to 100 days post-transplant
Maximum tolerated dose of DLI, determined according to dose limiting toxicities		day -4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myeloid engraftment rate		Up to 6 months post-transplant
Lymphoid engraftment rate		Up to 6 months post-transplant
Incidence of GVHD using tacrolimus and mycophenolate mofetil prophylaxis		Up to 6 months post-transplant
Progression free survival	Progression free survival will be estimated by the Kaplan-Meier method.	Up to 6 months post-transplant
Overall survival (OS)	OS will be estimated by the Kaplan-Meier method.	Up to 6 months post-transplant
Rate of lymphoid recovery		Up to 6 months post-transplant
Incidence of adverse events	All estimates of dose-specific rates (e.g., toxicity) will be presented with corresponding confidence intervals using the exact method. The method of Atkinson and Brown will be used for any rate related to definition of dose limiting toxicity, due to two-stage sampling.	Up to 6 months

Collaborators and Investigators

• Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
• Investigators: Principal Investigator: S. Onder Alpdogan, MD, Thomas Jefferson University

Publications and helpful links

Helpful Links

• Sidney Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center
• Jefferson University Hospitals

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2015
• Primary Completion (Actual): January 23, 2017
• Study Completion (Actual): March 16, 2017

Study Registration Dates

• First Submitted: September 8, 2015
• First Submitted That Met QC Criteria: September 10, 2015
• First Posted (Estimate): September 14, 2015

Study Record Updates

• Last Update Posted (Actual): April 19, 2017
• Last Update Submitted That Met QC Criteria: April 17, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Disease; Bacterial Infections and Mycoses; Lymphoma; Syndrome; Mycoses; Lymphoma, T-Cell; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Sezary Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: 15D.237