Vorinostat With Gemcitabine, Busulfan, and Melphalan With Stem Cell Transplant (SCT) in Relapsed or Refractory Lymphoid Malignancies

NCT01421173 | Completed Phase 1

• 2 other identifiers: 2011-0407NCI-2011-02891
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical research study is to find the highest tolerable dose of vorinostat that can be given with gemcitabine, busulfan, and melphalan with a stem cell transplant. Researchers also want to learn about the safety and level of effectiveness of this combination. Busulfan and melphalan are designed to kill cancer cells by binding to DNA (the genetic material of cells), which may cause cancer cells to die. Gemcitabine is designed to disrupt the growth of cancer cells, which may cause cancer cells to die. It may help to increase the effect of busulfan and melphalan on cancer cells by not allowing these cells to repair the DNA damage caused by busulfan or melphalan. Vorinostat is designed to open up the DNA and allow greater access to drugs that bind to DNA, such as gemcitabine, busulfan and melphalan.

Conditions

Lymphoma

Keywords

Lymphoma; Lymphoid malignancies; Relapsed; Refractory; Autologous hematopoietic cell support; Stem cell infusion; Hodgkin's lymphoma; non-Hodgkin's lymphoma; Vorinostat; SAHA; Suberoylanilide Hydroxamic Acid; MSK-390; Zolinza; Busulfan; Busulfex; Myleran; Gemcitabine; Gemcitabine Hydrochloride; Gemzar; Melphalan; Alkeran; Rituximab; Rituxan; Dexamethasone; Decadron; G-CSF; Filgrastim; NeupogenTM; Palifermin; Kepivance

Outcome Measures

Primary Outcomes (1)

• Recommended Dose of Vorinostat for combination with Gemcitabine/Busulfan/Melphalan (GemBuMel) based on Dose Limiting Toxicity (DLT)

  No more than 2 patients enrolled at one time in new dose level, until toxicities of at least 1 of those are assessed \& determined not to be DLT, no more patients enrolled at new dose level. Dose escalation of vorinostat starts at level 1a (200 mg/day) and Gemcitabine (2175 mg/m2/day). If level tolerable, dose proceeds from level 2a (300 mg) to level 11a (1000 mg) at increase of 100 mg per level. If level 1a were not tolerable, i.e., greater than 20% DLTs (determined by Continual Reassessment Method (CRM)), a decreased dose of gemcitabine (level 1b 1875 mg/m2) assigned and vorninostat escalation would be up to level 5b (600 mg) at increase of 100 mg per level instead. Dose limiting toxicity (DLT) is defined as any grade 4 non-hematological, non-infectious toxicity attributable to the preparative regimen, or any grade 3 mucositis or skin toxicity that lasts more than 3 days at peak severity, or any grade 4 mucositis or skin toxicity of any duration.

  About 100 days after the transplant

Study Arms (1)

Vorinostat + GemBuMel

EXPERIMENTAL

Vorinostat 200 mg by mouth on Days -8 to -2. Gemcitabine loading dose of 75 mg/m2 followed by continuous infusion. Remaining dose is 10 mg/m2/min on Day -8 and -3. Busulfan pharmacokinetics (PK) will be performed with the first dose of 105 mg/m2 by vein on Day -8. The doses of days -6 and -5 will be subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1. In the event that PK adjusting were not possible, a dose of busulfan of 105 mg/m2 will be administered on days -6 and -5. Melphalan 60 mg/m2 by vein on Days -2 and -3. Stem cells by vein over about 30-60 minutes on Day 0. Rituximab 375 mg/m2 on days +1 and +8 for cluster of differentiation antigen 20 (CD20+) tumors. G-CSF 5 mcg/kg/day subcutaneously beginning on Day +5 and continuing until neutrophil recovery is documented. Palifermin 60 mcg/kg by vein daily for 6 doses starting on Day 0. Dexamethasone 8 mg by vein twice a day from day -8 AM to day -2 PM.

Drug: Vorinostat; Drug: Gemcitabine; Drug: Busulfan; Drug: Melphalan; Procedure: Stem Cell Infusion; Drug: Rituximab; Drug: G-CSF; Drug: Palifermin; Drug: Dexamethasone acetate

Interventions

Vorinostat DRUG

Starting dose: 200 mg by mouth on Days -8 to -2.

Also known as: SAHA, Suberoylanilide Hydroxamic Acid, MSK-390, Zolinza

Vorinostat + GemBuMel

Gemcitabine DRUG

Starting dose: 2175 mg/m2 by vein on Days -8 and -3. This includes the gemcitabine 75 mg/m2 loading dose.

Also known as: Gemcitabine Hydrochloride, Gemzar

Vorinostat + GemBuMel

Busulfan DRUG

AUC: 4,000 micrometer (microM).min/day, or 105 mg/m2/day) on Days -8 to -5. Pharmacokinetics will be performed with the first dose of 32 mg/m2 by vein on Day -8. The doses on Days -6 and -5 will be subsequently adjusted to target an AUC of 4,000 microMol.min-1. In the event that PK adjusting not possible, a dose of busulfan of 105 mg/m2 will be administered on days -6 and -5.

Also known as: Busulfex, Myleran

Vorinostat + GemBuMel

Melphalan DRUG

60 mg/m2 by vein on Days -3 and -2.

Also known as: Alkeran

Vorinostat + GemBuMel

Stem Cell Infusion PROCEDURE

Infusion of stem cells by vein on Day 0.

Vorinostat + GemBuMel

Rituximab DRUG

375 mg/m2 on days +1 and +8 for patients with CD20+ tumors.

Also known as: Rituxan

Vorinostat + GemBuMel

G-CSF DRUG

5 mcg/kg/day (rounded up the nearest vial) subcutaneously beginning on Day +5 and continuing until neutrophil recovery is documented.

Also known as: Filgrastim, NeupogenTM

Vorinostat + GemBuMel

Palifermin DRUG

60 mcg/kg by vein daily for 6 doses. Three doses administrated prior to start chemo (24 hours must elapse between the last dose and first therapeutic dose of chemo) and three doses after the last chemo starting on day 0.

Also known as: Kepivance

Vorinostat + GemBuMel

Dexamethasone acetate DRUG

8 mg by vein twice a day from day -8 AM to day -2 PM.

Also known as: Decadron

Vorinostat + GemBuMel

Eligibility Criteria

• Age: 12 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 12 to 65 years
• Patients with primary refractory or recurrent non-Hodgkin's lymphoma (NHL) or HL that do not qualify for treatment protocols of higher priority.
• Patients with double-hit NHL, in any state of the disease.
• Patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) in any state of the disease.
• Angioimmunoblastic T-cell lymphoma (AITL) in any stage of the disease.
• Adequate renal function, as defined by estimated serum creatinine clearance \>/=50 ml/min and/or serum creatinine \</= 1.8 mg/dL.
• Adequate hepatic function, as defined by serum glutamate oxaloacetate transaminase (SGOT) and/or serum glutamate pyruvate transaminase (SGPT) \</= 3 x upper limit of normal; serum bilirubin and alkaline phosphatase \</= 2 x upper limit of normal.
• Adequate pulmonary function with forced expiratory volume at one second (FEV1), forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLCO) \>/= 50% of expected corrected for hemoglobin.
• Adequate cardiac function with left ventricular ejection fraction \>/= 40%. No uncontrolled arrhythmias or symptomatic cardiac disease.
• Zubrod performance status \<2.
• Negative Beta diffusing capacity of lung for carbon monoxide (HCG) text in a woman with child-bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization

You may not qualify if:

• Patients with grade \>/= 3 non-hematologic toxicity from previous therapy that has not resolved to \</= grade 1.
• Patients with prior whole brain irradiation
• Patients with active hepatitis B, either active carrier (HBsAg +) or viremic (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.
• Active infection requiring parenteral antibiotics
• HIV infection, unless the patient is receiving effective antiretroviral therapy with undetectable viral load and normal cluster of differentiation 4 (CD4) counts
• Patients having received radiation therapy in the month prior to enrollment.
• Patients with a cQT longer than 500 ms

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Nieto Y, Valdez BC, Thall PF, Ahmed S, Jones RB, Hosing C, Popat U, Shpall EJ, Qazilbash M, Gulbis A, Anderlini P, Alousi A, Shah N, Bashir Q, Liu Y, Oki Y, Hagemeister F, Fanale M, Dabaja B, Pinnix C, Champlin R, Andersson BS. Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas. Biol Blood Marrow Transplant. 2015 Nov;21(11):1914-20. doi: 10.1016/j.bbmt.2015.06.003. Epub 2015 Jun 11.

  PMID: 26071868 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Lymphoma; Recurrence; Hodgkin Disease; Lymphoma, Non-Hodgkin

Interventions

Vorinostat; Gemcitabine; Busulfan; Melphalan; Rituximab; Granulocyte Colony-Stimulating Factor; Filgrastim; Fibroblast Growth Factor 7; dexamethasone acetate; Calcium Dobesilate

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Fibroblast Growth Factors; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Arylsulfonates; Arylsulfonic Acids

Study Officials

• Yago Nieto, MD,PHD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2011
• First Posted: August 22, 2011
• Study Start: August 1, 2011
• Primary Completion: September 1, 2015
• Study Completion: September 1, 2015
• Last Updated: November 18, 2015

Record last verified: 2015-11

Locations

US (1)