Belinostat Combined With Azacitidine/Gemcitabine/Busulfan/Melphalan With Autologous Stem-Cell Transplantation in Refractory or Relapsed Lymphoma

May 3, 2016 updated by: M.D. Anderson Cancer Center
The goal of this clinical research study is to find the highest tolerable dose of belinostat that can be given in combination with azacitidine, gemcitabine, busulfan, and melphalan to patients who are scheduled to have a stem cell transplant. If you have diffuse large B-cell lymphoma (DLBCL), you will also receive rituximab. Researchers also want to learn about the safety and effectiveness of this combination.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose level of belinostat based on when you join this study. Up to 5 dose levels of belinostat will be tested. At least 2 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. Each new group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of belinostat is found.

All participants will receive the same dose level of azacitidine, gemcitabine, busulfan, melphalan. All patients with DLBCL will also receive the same dose of rituximab. However, if the first group has intolerable side effects, the dose level of gemcitabine may be lowered for all other groups.

Busulfan Test Dose:

In stem cell transplants, the days before you receive your stem cells are called minus days. The day you receive the stem cells is called Day 0. The days after you receive your stem cells are called plus days.

You will receive a test dose of busulfan by vein over about 60 minutes. This low-level test dose of busulfan is to check how the level of busulfan in your blood level changes over time. This information will be used to decide the next dose needed to reach the dose level that matches your body size. You will most likely receive this as an outpatient during the week before you are admitted to the hospital. If busulfan cannot be given to you as an outpatient, you will be admitted to the hospital on Day -11 (11 days before your stem cells are returned to your body) and the test dose will be given on Day -10.

On either Day -11 or -10, blood (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK) testing 11 times over the 11 hours after your test dose of busulfan. PK testing measures the amount of study drug in the body at different time points and will help the study doctor determine what your dose of busulfan should be on study. The PK blood draws will be repeated again on the first day of high-dose busulfan treatment (Day -8). A temporary heparin lock line will be placed in your vein to lower the number of needle sticks needed for these draws. If it is not possible for the PK tests to be performed for technical or scheduling reasons, you will receive the standard fixed dose of busulfan.

About 2 or 3 days before receiving the test dose of busulfan (depending on if you are an inpatient or outpatient), you will receive palifermin by vein over about 30 seconds each day to help decrease the risk of side effects in the mouth and throat.

Study Drug Administration (all patients):

Beginning on Day -8, you will swish caphosol and glutamine in your mouth 4 times a day for about 2 minutes each time. You will swish these liquids every day until you leave the hospital. You will swallow the glutamine. These drugs are used to help decrease the risk of side effects in the mouth and throat.

On Day -9 through Day -2, you will receive belinostat continuously by vein. You will also receive azacitidine by vein on each of these days over about 30 minutes. Depending on the type of cancer you have, you will also receive rituximab by vein over 3-6 hours as part of standard care on Day -9. The study staff will tell you if you will receive rituximab.

On Day -8, you will receive gemcitabine by vein over 4½ hours.

On Days -8, -7, -6, and -5, you will receive busulfan by vein over 2 hours.

On Day -3, you will receive gemcitabine by vein over 4½ hours and then melphalan by vein over 30 minutes.

On Day -2, you will receive melphalan by vein over 30 minutes.

On Day -1, you will rest (you will not receive chemotherapy).

On Day 0, you will receive your stem cells by vein over about 30-60 minutes.

You will receive 3 more doses of palifermin by vein over 15-30 seconds on Days 0, +1, and +2.

As part of standard care, you will receive G-CSF (filgrastim) as an injection just under your skin 1 time each day starting on Day +5 until your blood cell levels return to normal.

Length of Study:

As part of standard care, you will remain in the hospital for about 3-4 weeks after the transplant. After you are released from the hospital, you will continue as an outpatient in the Houston area to be monitored for infections and transplant-related complications.

You will be taken off study about 100 days after the transplant. You may be taken off study early if the disease gets worse, if intolerable side effects occur, if you are unable to follow study directions, or if you choose to leave the study early.

If for any reason you want to leave the study early, you must talk to the study doctor. It may be life-threatening to leave the study after you have started to receive the study drugs but before you receive the stem cell transplant because your blood cell counts will be dangerously low.

Follow-Up:

About 100 days after the transplant:

  • You will have a physical exam.
  • Blood (about 4 teaspoons) and urine will be collected for routine tests and to check your kidney and liver function.
  • If the doctor thinks it is needed, you will have a computed tomography (CT) and/or positron emission tomography (PET) scan to check the status of the disease.
  • If the doctor thinks it is needed, you will have a bone marrow aspiration and biopsy to check the status of the disease. To collect a bone marrow aspiration/biopsy, an area of the hip or other site is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle.

This is an investigational study. Belinostat, busulfan, and rituximab are FDA approved and commercially available for the treatment of lymphoma. Gemcitabine is FDA approved and commercially available for the treatment of breast cancer, non-small cell lung cancer (NSCLC), ovarian cancer, and pancreatic cancer. Melphalan is FDA approved and commercially available for the treatment of multiple myeloma (MM). Azacitidine is FDA approved and commercially available for the treatment of myelodysplastic syndrome (MDS). The use of these study drugs in combination to treat lymphoma is considered investigational.

Up to 60 participants will take part in this study. All will be enrolled at MD Anderson.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2
  • Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

15 years to 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Age 15-65
  2. Patients with: 2. 1. DLBCL with one of the following: 2.1.1. Primary refractory (no CR to 1st line). 2.1.2. High-risk relapse (CR1 <6 months, secondary IPI >1, high LDH). 2.1.3. Refractory relapse: No response (SD or PD) to >/= 1 line of salvage. 2.2. Hodgkin's with one of the following: 2.2.1. Primary refractory (no CR to 1st line or PD within 3 months). 2.2.2. High-risk relapse (CR1 <1 year, extranodal relapse, B symptoms). 2.2.3. Refractory relapse: No response (SD or PD) to >/= 1 line of salvage. 2.3. T-NHL with one of the following: 2.3.1. Primary refractory (</= CR to 1st line or relapse within 6 months). 2.3.2. Nonresponsive (SD/PD) to >/= 1 line of salvage. 2.4. Burkitt's or lymphoblastic lymphoma with one of the following: 2.4.1. Primary refractory (</= CR to 1st line or relapse within 6 months). 2.4.2. Refractory to at least 1 line of salvage (SD/PD).
  3. Adequate renal function, as defined by estimated serum creatinine clearance >/= 50 ml/min and/or serum creatinine </= 1.8 mg/dL.
  4. Adequate hepatic function (SGOT and/or serum glutamate pyruvate transaminase (SGPT) </= 3 x upper limit of normal (ULN); bilirubin and ALP </= 2 x ULN.
  5. Adequate pulmonary function with forced expiratory volume at one second (FEV1), forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLCO) (corrected for Hgb) >/= 50%.
  6. Adequate cardiac function with left ventricular ejection fraction >/= 40%. No uncontrolled arrhythmias or symptomatic cardiac disease.
  7. PS <2.
  8. Negative Beta human chorionic gonadotropin (HCG) in woman with child-bearing potential.

Exclusion Criteria:

  1. Grade >/= 3 non-hematologic toxicity from previous therapy that has not resolved to </= G1.
  2. Prior whole brain irradiation.
  3. Corrected QT interval (QTc) longer than 500 ms.
  4. Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/= 10,000 copies/mL, or >/= 2,000 IU/mL).
  5. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.
  6. Active infection requiring parenteral antibiotics.
  7. HIV infection, unless receiving effective antiretroviral therapy with undetectable viral load and normal cluster of differentiation 4 (CD4) counts.
  8. Radiation therapy in the month prior to enrollment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Belinostat/Gem/Bu/Mel + AutoSCT

Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an area under curve (AUC) of 4,000 microMol.min-1.

Caphosol oral rinses 30 mL four times a day used from Day -8. Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.

Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1. Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2. Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2. Participants with cluster of differentiation antigen 20 (CD20+) tumors receive Rituximab 375 mg/m2 by vein on Day -9.

Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.

Melphalan 60 mg/m2/d by vein on Day -2. Stem cell transplant by vein given on Day 0.
Drug: Caphosol
Caphosol oral rinses 30 mL four times a day used from Day -8.
Procedure: Stem Cell Transplant
Stem cell transplant performed on Day 0.
Drug: Busulfan
Busulfan "test dose" administered by vein on Day -10. Test dose of 32 mg/m2 based on actual body weight. Busulfan pharmacokinetics performed with the test dose and the first dose on Day -8. Doses on Days -6 and -5 subsequently adjusted to target an AUC of 4,000 microMol.min-1.
Other Names:
  • Busulfex
  • Myleran
Drug: Glutamine
Oral Glutamine, 15 g swished, gargled and swallowed four times a day starting on Day -8.
Other Names:
  • Enterex
  • Glutapak-10
  • NutreStore
  • Resource
  • GlutaSolve
  • Sympt-X G.I.
  • Sympt-X
Drug: Pyridoxine
Pyridoxine 100 mg by vein or mouth three times a day staring on Day -1
Drug: Belinostat
Starting dose of Belinostat 100 mg/ m2/day by vein on Day -9 through Day -2.
Drug: Azacitidine
Azacitidine 15 mg/m2/day by vein on Day -9 through Day -2.
Drug: Gemcitabine
Gemcitabine 75 mg/m2 by vein administered as a loading dose followed by prolonged infusion on Days -8 and -3.
Drug: Melphalan
Melphalan 60 mg/m2 by vein on Days -3 and -2.
Other Names:
  • Alkeran

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD) of Belinostat Combined with Azacitidine and Gemcitabine/Busulfan/Melphalan (AZA-GemBuMel) in Participants with Refractory or Poor-Risk Relapsed Lymphoma
Time Frame: 30 days

For purpose of dose-finding, "toxicity" defined as any of the following events occurring within 30 days from the start of Belinostat infusion :

  1. any grade 4 or 5 non-hematologic toxicity, or
  2. any grade 3 or 4 mucositis, or
  3. any grade 3 or 4 skin toxicity lasting > 5 days at peak severity

Optimal dose defined as that for which the posterior mean of Pr(toxicity within 30 days | dose) given the current data is closest to 0.30.
30 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Treatment Related Mortality (TRM100)
Time Frame: 100 days after stem cell transplant
Treatment related mortality (TRM100), defined as death due to any cause without disease recurrence within 100 days post stem cell transplant (SCT).
100 days after stem cell transplant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
M.D. Anderson Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2016

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 2, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 2, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 8, 2016

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 4, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 3, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2015-0560

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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