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

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

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.

Study Overview

• Status: Completed
• Conditions: Non-Hodgkin's Lymphoma; Hodgkin's Disease
• Intervention / Treatment: Drug: Vorinostat; Drug: Niacinamide; Drug: Etoposide

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10019
      • Center for Lymphoid Malignancies at CUMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Owen A O'Connor, MD, Ph.D., Columbia University

Publications and helpful links

General Publications

• Amengual JE, Clark-Garvey S, Kalac M, Scotto L, Marchi E, Neylon E, Johannet P, Wei Y, Zain J, O'Connor OA. Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma. Blood. 2013 Sep 19;122(12):2104-13. doi: 10.1182/blood-2013-02-485441. Epub 2013 Aug 2.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: June 3, 2008
• First Submitted That Met QC Criteria: June 4, 2008
• First Posted (Estimate): June 5, 2008

Study Record Updates

• Last Update Posted (Actual): November 20, 2020
• Last Update Submitted That Met QC Criteria: November 5, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Non-Hodgkin's Lymphoma; Hodgkin's Disease
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Hodgkin Disease; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Histone Deacetylase Inhibitors; Etoposide; Vorinostat; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: AAAJ3001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No