Vorinostat and Combination Chemotherapy Before Donor Stem Cell Transplantation for the Treatment of Relapsed Aggressive B-cell or T-cell Non-Hodgkin Lymphoma

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04220008

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

Anticipated Duration (Months)

4.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies how well vorinostat and combination chemotherapy before donor stem cell transplantation work in treating patients with aggressive B-cell or T-cell non-Hodgkin lymphoma that has come back (relapsed). Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as busulfan, gemcitabine, and clofarabine, 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. Giving vorinostat together with combination chemotherapy before donor stem cell transplantation may help to control lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Aggressive Non-Hodgkin Lymphoma Recurrent B-Cell Non-Hodgkin Lymphoma Recurrent Burkitt Lymphoma Recurrent Diffuse Large B-Cell Lymphoma Recurrent High Grade B-Cell Lymphoma Recurrent T-Cell Non-Hodgkin Lymphoma Recurrent Transformed B-Cell Non-Hodgkin Lymphoma	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Busulfan Drug: Clofarabine Drug: Cyclophosphamide Drug: Gemcitabine Drug: Mycophenolate Mofetil Biological: Rituximab Drug: Tacrolimus Drug: Vorinostat	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

Estimate the progression-free survival (PFS) time.

SECONDARY OBJECTIVES:

Estimate the day 100 non-relapse mortality (NRM) of allogeneic stem cell transplantation (allo SCT) using vorinostat/gemcitabine/clofarabine/busulfan (SAHA/Gem/Clo/Bu) with post-transplant cyclophosphamide (PT-CY).
Estimate the graft versus host disease (GVHD)-free/relapse free survival (GRFS) in patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.
Estimate the overall survival (OS) in patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.
Assess the 1-year NRM in patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.
Assess the relapse rate in patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.
Assess the graft failure rate in patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.
Assess the time to neutrophil and platelet engraftment in patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.
Assess the incidence of grade 2-4 and grade 3-4 acute graft versus host disease (GVHD) in patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.
Assess the overall and severe chronic GVHD in patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.
Determine the incidence of grade 3 and 4 nonhematological adverse events in patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.

TERTIARY OBJECTIVE:

Describe changes of deoxyribonucleic acid (DNA) damage response and repair, poly (ADP-ribose) polymerase (PARP) inhibition and downstream cellular effects in peripheral blood mononuclear cells (PBMNC), and, when available, malignant lymphocytes obtained by fine needle aspiration (FNA) of peripheral lymph nodes of patients with refractory lymphoma receiving an allo SCT with SAHA/Gem/Clo/Bu with PT-CY.

OUTLINE:

Patients receive a low-level "test" dose of busulfan intravenously (IV) over up to 1 hour on days -15 to -9, vorinostat orally (PO) once daily (QD) on days -8 to -4, gemcitabine IV over about 90 minutes on days -7 and -5, clofarabine IV over about 1 hour and high-dose busulfan IV over 3 hours on days -7 to -4. Patients with CD20 positive (+) lymphoma also receive rituximab IV over 3 to 6 hours on days -15, -8, 1, and 8. Patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) on day 0. Patients then receive cyclophosphamide IV over 2 hours on days 3 and 4. Beginning day 5, patients receive standard of care tacrolimus IV over 24 hours and mycophenolate mofetil IV over 2 hours three times daily (TID) until they can be tolerated PO. Once tolerated PO, patients receive tacrolimus PO twice daily (BID) for 6 months and mycophenolate mofetil PO TID for up to 30 days in the absence of disease progression or unacceptable toxicity. After 30 days, patients who develop GVHD continue treatment with mycophenolate mofetil at physician's discretion.

After completion of study treatment, patients are followed up at 3, 6, and 12 months after stem cell transplant, then every 6 months for 4 years.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Vorinostat With Gemcitabine/Clofarabine/Busulfan for Allogeneic Transplantation for Aggressive Lymphomas

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Jan 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (busulfan, vorinostat, gemcitabine, clofarabine) Patients receive a low-level "test" dose of busulfan IV over up to 1 hour on days -15 to -9, vorinostat PO QD on days -8 to -4, gemcitabine IV over about 90 minutes on days -7 and -5, clofarabine IV over about 1 hour and high-dose busulfan IV over 3 hours on days -7 to -4. Patients with CD20 positive (+) lymphoma also receive rituximab IV over 3 to 6 hours on days -15, -8, 1, and 8. Patients undergo HSCT on day 0. Patients then receive cyclophosphamide IV over 2 hours on days 3 and 4. Beginning day 5, patients receive standard of care tacrolimus IV over 24 hours and mycophenolate mofetil IV over 2 hours TID until they can be tolerated PO. Once tolerated PO, patients receive tacrolimus PO BID for 6 months and mycophenolate mofetil PO TID for up to 30 days in the absence of disease progression or unacceptable toxicity. After 30 days, patients who develop GVHD continue treatment with mycophenolate mofetil at physician's discretion	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Undergo allogeneic HSCT Other Names: Allogeneic Hematopoietic Cell Transplantation Allogeneic Stem Cell Transplantation HSC HSCT Stem Cell Transplantation, Allogeneic Drug: Busulfan Given IV Other Names: 1, 4-Bis[methanesulfonoxy]butane BUS Bussulfam Busulfanum Busulfex Busulphan CB 2041 CB-2041 Glyzophrol GT 41 GT-41 Joacamine Methanesulfonic Acid Tetramethylene Ester Methanesulfonic acid, tetramethylene ester Mielucin Misulban Misulfan Mitosan Myeleukon Myeloleukon Myelosan Mylecytan Myleran Sulfabutin Tetramethylene Bis(methanesulfonate) Tetramethylene bis[methanesulfonate] WR-19508 Drug: Clofarabine Given IV Other Names: Clofarex Clolar Drug: Cyclophosphamide Given IV Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 Drug: Gemcitabine Given IV Other Names: dFdC dFdCyd Difluorodeoxycytidine Drug: Mycophenolate Mofetil Given IV Other Names: Cellcept MMF Biological: Rituximab Given IV Other Names: ABP 798 BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Rituxan Rituximab ABBS Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar GB241 Rituximab Biosimilar IBI301 Rituximab Biosimilar JHL1101 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SAIT101 rituximab biosimilar TQB2303 rituximab-abbs RTXM83 Truxima Drug: Tacrolimus Given IV Other Names: FK 506 Fujimycin Hecoria Prograf Protopic Drug: Vorinostat Given PO Other Names: L-001079038 MSK-390 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid Zolinza

Arm

Intervention/Treatment

Experimental: Treatment (busulfan, vorinostat, gemcitabine, clofarabine)

Patients receive a low-level "test" dose of busulfan IV over up to 1 hour on days -15 to -9, vorinostat PO QD on days -8 to -4, gemcitabine IV over about 90 minutes on days -7 and -5, clofarabine IV over about 1 hour and high-dose busulfan IV over 3 hours on days -7 to -4. Patients with CD20 positive (+) lymphoma also receive rituximab IV over 3 to 6 hours on days -15, -8, 1, and 8. Patients undergo HSCT on day 0. Patients then receive cyclophosphamide IV over 2 hours on days 3 and 4. Beginning day 5, patients receive standard of care tacrolimus IV over 24 hours and mycophenolate mofetil IV over 2 hours TID until they can be tolerated PO. Once tolerated PO, patients receive tacrolimus PO BID for 6 months and mycophenolate mofetil PO TID for up to 30 days in the absence of disease progression or unacceptable toxicity. After 30 days, patients who develop GVHD continue treatment with mycophenolate mofetil at physician's discretion

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Undergo allogeneic HSCT

Other Names:

Allogeneic Hematopoietic Cell Transplantation

Allogeneic Stem Cell Transplantation

HSC

HSCT

Stem Cell Transplantation, Allogeneic

Drug: Busulfan

Given IV

Other Names:

1, 4-Bis[methanesulfonoxy]butane

BUS

Bussulfam

Busulfanum

Busulfex

Busulphan

CB 2041

CB-2041

Glyzophrol

GT 41

GT-41

Joacamine

Methanesulfonic Acid Tetramethylene Ester

Methanesulfonic acid, tetramethylene ester

Mielucin

Misulban

Misulfan

Mitosan

Myeleukon

Myeloleukon

Myelosan

Mylecytan

Myleran

Sulfabutin

Tetramethylene Bis(methanesulfonate)

Tetramethylene bis[methanesulfonate]

WR-19508

Drug: Clofarabine

Given IV

Other Names:

Clofarex

Clolar

Drug: Cyclophosphamide

Given IV

Other Names:

(-)-Cyclophosphamide

2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate

Carloxan

Ciclofosfamida

Ciclofosfamide

Cicloxal

Clafen

Claphene

CP monohydrate

CTX

CYCLO-cell

Cycloblastin

Cycloblastine

Cyclophospham

Cyclophosphamid monohydrate

Cyclophosphamide Monohydrate

Cyclophosphamidum

Cyclophosphan

Cyclophosphane

Cyclophosphanum

Cyclostin

Cyclostine

Cytophosphan

Cytophosphane

Cytoxan

Fosfaseron

Genoxal

Genuxal

Ledoxina

Mitoxan

Neosar

Revimmune

Syklofosfamid

WR- 138719

Drug: Gemcitabine

Given IV

Other Names:

dFdC

dFdCyd

Difluorodeoxycytidine

Drug: Mycophenolate Mofetil

Given IV

Other Names:

Cellcept

MMF

Biological: Rituximab

Given IV

Other Names:

ABP 798

BI 695500

C2B8 Monoclonal Antibody

Chimeric Anti-CD20 Antibody

CT-P10

IDEC-102

IDEC-C2B8

IDEC-C2B8 Monoclonal Antibody

MabThera

Monoclonal Antibody IDEC-C2B8

PF-05280586

Rituxan

Rituximab ABBS

Rituximab Biosimilar ABP 798

Rituximab Biosimilar BI 695500

Rituximab Biosimilar CT-P10

Rituximab Biosimilar GB241

Rituximab Biosimilar IBI301

Rituximab Biosimilar JHL1101

Rituximab Biosimilar PF-05280586

Rituximab Biosimilar RTXM83

Rituximab Biosimilar SAIT101

rituximab biosimilar TQB2303

rituximab-abbs

RTXM83

Truxima

Drug: Tacrolimus

Given IV

Other Names:

FK 506

Fujimycin

Hecoria

Prograf

Protopic

Drug: Vorinostat

Given PO

Other Names:

L-001079038

MSK-390

SAHA

Suberanilohydroxamic Acid

Suberoylanilide Hydroxamic Acid

Zolinza

Outcome Measures

Primary Outcome Measures

Progression-free survival [Up to 3 years]
Will be estimated by the method of Kaplan and Meier.

Secondary Outcome Measures

Early treatment success [Up to 100 days post-transplant]
Will be defined as the compound event that the patient is alive, engrafted and in remission at 100 days post-transplant and does not experience grade 4 regimen-related toxicity or grade 4 acute graft versus host disease within 100 days post transplant. Will be tabulated and estimated.
Overall survival [Up to 4 years]
Will be estimated by the method of Kaplan and Meier.
Objective response rate [Up to 100 days post-transplant]
Will be tabulated and estimated.
Complete response rate [Up to 100 days post-transplant]
Will be tabulated and estimated.

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Relapsed aggressive B-cell non-Hodgkin lymphoma (B-NHL) (diffuse large B-cell lymphoma [DLBCL], transformed B-NHL, high-grade B-cell lymphoma [HGBL] or Burkitt) or T-cell non-Hodgkin lymphoma (T-NHL) who meet both of the following criteria: a. High or very high disease risk index (DRI), and b. No response to at least 1 line of salvage chemotherapy, or relapse after a prior autologous SCT
An 8/8 human leukocyte antigen (HLA) matched (high resolution typing at A, B, C, DRB1) sibling or unrelated donor, or a haploidentical donor
Left ventricular ejection fraction (EF) >= 45%
Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and corrected diffusion capacity of the lung for carbon monoxide (DLCO) >= 50%
Estimated serum creatinine clearance >= 50 ml/min (using the Cockcroft-Gault formula)
Serum bilirubin =< 2 x upper limit of normal
Serum glutamate pyruvate transaminase (SGPT) =< 2 x upper limit of normal
Able to sign informed consent
Men and women of reproductive potential must agree to follow accepted birth control methods for the duration of the study. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study

Exclusion Criteria:

Patient with active central nervous system (CNS) disease
Pregnancy (positive beta human chorionic gonadotropin [HCG] test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization) or currently breast-feeding. Pregnancy testing is not required for post-menopausal or surgically sterilized women
Active hepatitis B, either active carrier (hepatitis B surface antigen positive [HBsAg +]) or viremic (hepatitis B virus [HBV] DNA >= 10,000 copies/mL, or >= 2,000 IU/mL)
Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology
Human immunodeficiency virus (HIV) infection
Active uncontrolled bacterial, viral or fungal infections
Exposure to other investigational drugs within 4 weeks before enrollment
Grade >= 3 non-hematologic toxicity from previous therapy that has not resolved to =< grade 1
Radiation therapy to head and neck (excluding eyes), and internal organs of chest, abdomen or pelvis in the month prior to enrollment
Prior whole brain irradiation
Prior autologous SCT in the prior 3 months