Hodgkin's Disease, Non-Hodgkin's Lymphoma
Conditions
Keywords
Hodgkin's Disease, Non-Hodgkin's Lymphoma
Brief summary
The purpose of this study is to test the safety of a combination of two anticancer medicines, called vorinostat and etoposide, with a high dose of a vitamin called niacinamide. These medications will be tested at different dose levels. The investigators want to find out what effects, good and/or bad, it has on patients and their recurrent lymphoma. The first two drugs, vorinostat and niacinamide, suppress survival signals that lymphoma cells depend on. The third drug, etoposide can kill sensitive lymphoma cells alone or in combination with other chemotherapy drugs. Vorinostat is an anticancer agent that been approved by the Food and Drug Administration for use in cutaneous T-cell lymphoma. It is being evaluated in this study in combination with other anticancer medicines for use in other types of lymphoma. Vorinostat's use in combination with anticancer regimens is experimental. Niacinamide is a vitamin that is investigational or experimental when given at high doses as an anticancer agent. Niacinamide has not yet been approved by the Food and Drug Administration for use in lymphoma. Etoposide has been approved by the Food and Drug Administration for use in aggressive non-Hodgkin's lymphoma. However, the way it will be given in this clinical study is experimental.
Detailed description
Subjects will be treated with vorinostat administered orally with daily dosing for 14 days of a 21-day treatment cycle in combination with niacinamide administered orally for 14 days in 21-day treatment cycle and etoposide administered intravenously on days 8,9 and 10 of a 21-day treatment cycle. Etoposide dose will be escalated until maximum tolerated dose (MTD) is determined.
Interventions
DRUGVorinostat
Dose escalation scheme (400 mg) Vorinostat is used to treat cutaneous T-cell lymphoma (CTCL, a type of cancer) in people whose disease has not improved, has gotten worse, or has come back after taking other medications. Vorinostat is in a class of medications called histone deacetylase (HDAC) inhibitors. It works by killing or stopping the growth of cancer cells.
DRUGNiacinamide
Dose escalation scheme (20, 40, 60, 80, 100 mg/kg rounded to 100 mg) Niacinamide is a water soluble B-vitamin that has been evaluated for use in the treatment of pellagra, bullous pemphigoid, and as a radiation sensitizer in head and neck cancer.
DRUGEtoposide
Dose escalation scheme (0, 25, 50, 100 mg/m2) Etoposide is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. This medication is classified as a plant alkaloid and topoisomerase II inhibitor.
Sponsors
Merck Sharp & Dohme LLC
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's Disease (WHO criteria), for which they are unwilling or unable to undergo an autologous stem cell transplant 2. Must have received first line chemotherapy. No upper limit to number of prior therapies 3. Evaluable Disease 4. Age \>18 years 5. Eastern Cooperative Oncology Group (ECOG) performance status \<2 6. Life expectancy of greater than 3 months 7. Patients must have adequate organ and marrow function 8. Adequate Contraception 9. Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
1. Prior Therapy * Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier * Patient is on any systemic steroids that have not been stabilized to the equivalent of ≤10 mg/day prednisone during the 7 days prior to the start of the study drugs * No monoclonal antibody within 3 months unless evidence of progression 2. Patients may not be receiving any other investigational agents 3. Patients with known central nervous system metastases, including lymphomatous meningitis 4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat, niacinamide or etoposide 5. Uncontrolled intercurrent illness 6. Pregnant women 7. Nursing women 8. Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix). If there is a history of prior malignancy, the patient must be disease-free for ≥ 3 years 9. Patient is known to be Human Immunodeficiency Virus (HIV)-positive 10. Active Hepatitis A, Hepatitis B, or Hepatitis C infection 11. Patient has a history of surgery that would interfere with the administration or absorption of the oral study drugs
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Maximum Tolerated Dose (MTD) of Niacinamide in the Combination of Vorinostat and Niacinamide | 3 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Greatest Number of Cycles Received in Each Treatment Group | up to 45 weeks | The highest number of cycles received by an individual participant in the treatment groups. Each cycle was 21 days long. |
| The Number of Dose Delays and Reductions at the MTD | continuous | — |
| The Prevalence of Anti-tumor Activity | continuous | — |
| Pharmacodynamic Markers of Target Effect in Paired Tissue Biopsies | continuous | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| V/N: Level 1 Vorinostat: 400mg Niacinamide: 20 mg/kg rounded to 100mg
Vorinostat (SAHA) and Niacinamide: dose escalation scheme | 5 |
| V/N: Level 2 Vorinostat: 400mg Niacinamide: 40 mg/kg rounded to 100mg
Vorinostat (SAHA) and Niacinamide: dose escalation scheme | 3 |
| V/N: Level 3 Vorinostat: 400mg Niacinamide: 60 mg/kg rounded to 100mg
Vorinostat (SAHA) and Niacinamide: dose escalation scheme | 3 |
| V/N: Level 4 Vorinostat: 400mg Niacinamide: 80 mg/kg rounded to 100mg
Vorinostat (SAHA) and Niacinamide: dose escalation scheme | 9 |
| V/N: Level 5 Vorinostat: 400mg Niacinamide: 100 mg/kg rounded to 100mg
Vorinostat (SAHA) and Niacinamide: dose escalation scheme | 5 |
| V/N/E: Level 1 Vorinostat: 400mg Niacinamide: 80 mg/kg rounded to 100mg Etoposide: 25 mg/m2
Vorinostat, Niacinamide and Etoposide: dose escalation scheme | 7 |
| V/N/E: Level 2 Vorinostat: 400mg Niacinamide: 80 mg/kg rounded to 100mg Etoposide: 50 mg/m2
Vorinostat, Niacinamide and Etoposide: dose escalation scheme | 6 |
| V/N/E: Level 3 Vorinostat: 400mg Niacinamide: 80 mg/kg rounded to 100mg Etoposide: 100 mg/m2
Vorinostat, Niacinamide and Etoposide: dose escalation scheme | 0 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 |
| Overall Study | Progression of Disease | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | V/N: Level 1 | V/N: Level 2 | V/N: Level 3 | V/N: Level 4 | V/N: Level 5 | V/N/E: Level 1 | V/N/E: Level 2 | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 2 Participants | 3 Participants | 7 Participants | 3 Participants | 6 Participants | 4 Participants | 30 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 4 Participants | 2 Participants | 2 Participants | 2 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 2 Participants | 5 Participants | 3 Participants | 5 Participants | 4 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 3 / 3 | 3 / 3 | 9 / 9 | 5 / 5 | 7 / 7 | 6 / 6 |
| serious Total, serious adverse events | 2 / 5 | 1 / 3 | 0 / 3 | 5 / 9 | 3 / 5 | 2 / 7 | 1 / 6 |
Outcome results
Primary
The Maximum Tolerated Dose (MTD) of Niacinamide in the Combination of Vorinostat and Niacinamide
Time frame: 3 years
Population: There were no evaluable patients at these levels.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat (SAHA) and Niacinamide: Level 1 | The Maximum Tolerated Dose (MTD) of Niacinamide in the Combination of Vorinostat and Niacinamide | 100 mg/kg |
Secondary
Pharmacodynamic Markers of Target Effect in Paired Tissue Biopsies
Time frame: continuous
Secondary
The Greatest Number of Cycles Received in Each Treatment Group
The highest number of cycles received by an individual participant in the treatment groups. Each cycle was 21 days long.
Time frame: up to 45 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat (SAHA) and Niacinamide: Level 1 | The Greatest Number of Cycles Received in Each Treatment Group | 9 cycles |
| Vorinostat (SAHA) and Niacinamide: Level 2 | The Greatest Number of Cycles Received in Each Treatment Group | 12 cycles |
| Vorinostat (SAHA) and Niacinamide: Level 3 | The Greatest Number of Cycles Received in Each Treatment Group | 15 cycles |
| Vorinostat (SAHA) and Niacinamide: Level 4 | The Greatest Number of Cycles Received in Each Treatment Group | 10 cycles |
| Vorinostat (SAHA) and Niacinamide: Level 5 | The Greatest Number of Cycles Received in Each Treatment Group | 14 cycles |
| Vorinostat, Niacinamide and Etoposide: Level 1 | The Greatest Number of Cycles Received in Each Treatment Group | 3 cycles |
| Vorinostat, Niacinamide and Etoposide: Level 2 | The Greatest Number of Cycles Received in Each Treatment Group | 4 cycles |
Secondary
The Number of Dose Delays and Reductions at the MTD
Time frame: continuous
Secondary
The Prevalence of Anti-tumor Activity
Time frame: continuous