Phase I Vorinostat in Combination With Niacinamide and Etoposide for Lymphoid Malignancies

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase I Study of Vorinostat in Combination With Niacinamide, and Etoposide for the Treatment of Patients With Relapsed and Refractory Lymphoid Malignancies

Conditions
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Hodgkin's Disease, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Vorinostat
* Drug: Niacinamide
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Must have received first line chemotherapy. No upper limit to number of prior therapies Evaluable Disease Age >18 years Eastern Cooperative Oncology Group (ECOG) performance status <2 Life expectancy of greater than 3 months Patients must have adequate organ and marrow function Adequate Contraception Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: 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 Patients may not be receiving any other investigational agents Patients with known central nervous system metastases, including lymphomatous meningitis History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat, niacinamide or etoposide Uncontrolled intercurrent illness Pregnant women Nursing women 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 Patient is known to be Human Immunodeficiency Virus (HIV)-positive Active Hepatitis A, Hepatitis B, or Hepatitis C infection Patient has a history of surgery that would interfere with the administration or absorption of the oral study drugs

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: V/N: Level 1<br>Vorinostat: 400mg Niacinamide: 20 mg/kg rounded to 100mg | Drug: Vorinostat<br>* 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.<br>* Other names: SAHA;Drug: Niacinamide<br>* 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.<br>* Other names: Nicotinamide;|
| Experimental: V/N: Level 2<br>Vorinostat: 400mg Niacinamide: 40 mg/kg rounded to 100mg | Drug: Vorinostat<br>* 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.<br>* Other names: SAHA;Drug: Niacinamide<br>* 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.<br>* Other names: Nicotinamide;|
| Experimental: V/N: Level 3<br>Vorinostat: 400mg Niacinamide: 60 mg/kg rounded to 100mg | Drug: Vorinostat<br>* 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.<br>* Other names: SAHA;Drug: Niacinamide<br>* 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.<br>* Other names: Nicotinamide;|
| Experimental: V/N: Level 4<br>Vorinostat: 400mg Niacinamide: 80 mg/kg rounded to 100mg | Drug: Vorinostat<br>* 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.<br>* Other names: SAHA;Drug: Niacinamide<br>* 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.<br>* Other names: Nicotinamide;|
| Experimental: V/N: Level 5<br>Vorinostat: 400mg Niacinamide: 100 mg/kg rounded to 100mg | Drug: Vorinostat<br>* 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.<br>* Other names: SAHA;Drug: Niacinamide<br>* 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.<br>* Other names: Nicotinamide;|
| Experimental: V/N/E: Level 1<br>Vorinostat: 400mg Niacinamide: 80 mg/kg rounded to 100mg Etoposide: 25 mg/m2 | Drug: Vorinostat<br>* 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.<br>* Other names: SAHA;Drug: Niacinamide<br>* 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.<br>* Other names: Nicotinamide;Drug: Etoposide<br>* 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.<br>* Other names: VP-16;|
| Experimental: V/N/E: Level 2<br>Vorinostat: 400mg Niacinamide: 80 mg/kg rounded to 100mg Etoposide: 50 mg/m2 | Drug: Vorinostat<br>* 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.<br>* Other names: SAHA;Drug: Niacinamide<br>* 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.<br>* Other names: Nicotinamide;Drug: Etoposide<br>* 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.<br>* Other names: VP-16;|
| Experimental: V/N/E: Level 3<br>Vorinostat: 400mg Niacinamide: 80 mg/kg rounded to 100mg Etoposide: 100 mg/m2 | Drug: Vorinostat<br>* 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.<br>* Other names: SAHA;Drug: Niacinamide<br>* 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.<br>* Other names: Nicotinamide;Drug: Etoposide<br>* 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.<br>* Other names: VP-16;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Tolerated Dose (MTD) of Niacinamide in the Combination of Vorinostat and Niacinamide |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 45 weeks | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hodgkin's Disease, Non-Hodgkin's Lymphoma