Neoplasms

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Lymphoma

Lymphoma, T-Cell

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Neoplasms by Histologic Type

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Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

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Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

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Vorinostat

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Alkylating Agents

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Histone Deacetylase Inhibitors

Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)

Up to two 100 mg capsules of Vorinostat (dosage will vary from 100 mg orally (PO) twice daily (BID), 300 mg PO every evening and 200 mg PO BID with the starting dose at 300 mg PO every evening for the phase I trial) are to be administered orally twice daily (once in the morning and once in the evening, or if in the daily dosing cohort once in the evening) in repeated 21-day cycles consisting of 10 days dosing starting on days 5 through 14 followed by a 7-day rest period, during which no vorinostat will be administered.

Zolinza (vorinostat)

750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle

50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle

Yasuhiro Oki, MD

The goal of this clinical research study is to find out how well the drug Zolinza (vorinostat) works in combination with the drug combination called CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) to treat patients with untreated T-cell Non-Hodgkin's Lymphoma (NHL). The safety of these drugs in combination and the best dose of vorinostat when given in combination with CHOP will also be studied.

The Study Drugs:

Vorinostat is designed to cause chemical changes in different groups of proteins that are attached to DNA (the genetic material of cells), which may slow the growth of cancer cells or cause the cancer cells to die.

Cyclophosphamide is designed to interfere with the multiplication of cancer cells, which may slow or stop their growth. This may cause the cancer cells to die.

Doxorubicin is designed to stop the growth of cancer cells, which may cause the cells to die.

Vincristine is designed to interfere with the multiplication of cancer cells, which may slow or stop their growth. This may cause the cancer cells to die.

Prednisone is designed to decrease inflammation by preventing white blood cells from completing an inflammatory reaction. This drug can cause lymphocytes, a type of white blood cell, to break apart and die.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will begin to take vorinostat on the first day of treatment which is Day -1. Vorinostat capsules are taken by mouth, either 3 times a day or 2 times a day, depending on what the study doctor thinks is in your best interest. If you are taking vorinostat 3 times a day, it should be taken in the morning, afternoon and evening. If you are taking vorinostat 2 times a day, you will take the capsules in the morning and evening. The capsules must be taken with food (within 30 minutes after a meal). You will receive the vorinostat capsules on the first day of each cycle. You will also receive instructions on how to take the drug. You should return any unused vorinostat capsules back to study staff at the end of each cycle. You will take vorinostat for 5 days (Days -1 through 3) of each cycle and then beginning on Day 1, cyclophosphamide, vincristine, and doxorubicin will be given though a needle in your vein. This will happen for each 21-day study cycle. Cyclophosphamide is given over 1 hour. Vincristine is given over 15 minutes. Doxorubicin is also given over 15 minutes.

The starting dose of vorinostat may change On Days 1-5 of each cycle, you will take prednisone tablets by mouth.

If you begin to experience severe or intolerable side effects, the study drug schedule may be stopped for up to 3 weeks. If the side effects improve, you may be able to receive the study drugs again, with either a lower dose of vorinostat or if you are taking vorinostat three times daily, you may take it twice a day instead. The chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine, and prednisone) may also be lowered depending on what side effects are being experienced. If you continue to have severe or intolerable side effects with the lower dose of vorinostat and chemotherapy, you will taken off study.

Study Visits:

On Day 1 of all cycles, the following tests and procedures will be performed:

* Your medical history will be recorded, including any drugs that you are taking.
* You will be asked about any side effects you may have experienced.
* You will have a physical exam, including measurement of your vital signs and weight.
* Blood (about 5 teaspoons) will be drawn for routine tests.
* Your performance status will be recorded.

On Day 1 of Cycle 2 you will have an ECG.

On or before Day 1 of Cycle 3 the following tests and procedures will be performed if your doctor thinks necessary:

* You will have CT and/or PET scans to check the status of the disease.
* You may have a bone marrow aspirate and/or biopsy to check the status of the disease.

Length of Study:

You will receive the study drugs for up to 6 cycles. You may be taken off study early if the disease gets worse or if severe or intolerable side effects occur.

End-of-Study Visit:

If you go off study treatment for any reason, you will have an end-of-study visit within 4 weeks after your last dose of study drugs or before starting a new treatment. At this visit, the following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs.
* Your performance status will be recorded.
* You will be asked about any side effects you may have experienced.
* Blood (about 5 teaspoons) will be drawn for routine tests.
* You will have CT scans and PET scans to check the status of the disease.
* If you had skin lesions when you began the study, the skin lesions will be photographed.
* If the doctor thinks it is needed, you will have bone marrow biopsy and/or aspirate.

Follow-up Visits:

After you are off study treatment, you will have follow-up visits. You will go to these visits every 3 months for the1st year, every 4 months for the 2nd and 3rd years, and every 6 months for the 4th and 5th years. After this, you will return 1 time each year unless the lymphoma returns. The following tests and procedures will be performed:

* You will have a physical exam, including measurement of your vital signs.
* Your performance status will be recorded
* You will be asked about any side effects you may have experienced.
* Blood (about 5 teaspoons) will be drawn for routine tests.
* You will have CT scans and PET scans to check the status of the disease.
* If you had skin lesions when you began the study, the skin lesions will be photographed.
* If the doctor thinks it is needed, you will have bone marrow biopsy and/or aspirate.

This is an investigational study. Vorinostat is FDA approved and commercially available for the treatment of cutaneous T-cell lymphoma that has not come back or not responded to prior therapy. CHOP is currently FDA approved for treatment of patients with NHL. The use of vorinostat in combination with CHOP in patients with T-cell NHL is investigational.

Up to 52 patients will take part in this study. All will be enrolled at MD Anderson.

SAHA + CHOP in Untreated T-cell Non-Hodgkin's Lymphoma

A Phase I/II of Vorinostat Plus CHOP in Untreated T-cell Non-Hodgkin's Lymphoma

MTD of Vorinostat when administered in combination with Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) defined as highest dose level in which 6 patients have been treated with less than 2 instances of dose limiting toxicity (DLT). Continual reassessment during each 21-day cycle to assess dose limiting toxicity. Two schedules of Vorinostat were investigated: Phase I A) daily doses on days 5 to 14, or Phase II B) three times a day on days -2 to 3 of standard CHOP every 21 days. Vorinostat was administered orally on days 5 to 14 (Schedule A), first at 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle), and next at 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle); and for Phase II Schedule B Vorinostat administered orally 300 mg orally three times daily from days -2 to 3 (4500 mg over 5 days per cycle).

MTD of Vorinostat defined as highest dose level in which 6 patients have been treated with less than 2 instances of DLT. Continual reassessment during each 21-day cycle to assess DLT. Vorinostat was administered orally on days 5 to 14 (Schedule A), first at 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle), and next at 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle. The dose of Vorinostat escalated in successive 3+3 cohorts of participants to determine the MTD.

MTD of Vorinostat when administered in combination with Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) defined as highest dose level in which 6 patients have been treated with less than 2 instances of dose limiting toxicity (DLT). Continual reassessment during each 21-day cycle to assess dose limiting toxicity. Two schedules of Vorinostat were investigated: Phase I A) daily doses on days 5 to 14, or Phase II B) three times a day on days -2 to 3 of standard CHOP every 21 days. Vorinostat was administered orally on days 5 to 14 (Schedule A), first at 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle), and next at 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle); Schedule B Vorinostat administered orally 300 mg orally three times daily from days -2 to 3 (4500 mg over 5 days per cycle).

Merck Sharp & Dohme LLC

M.D. Anderson Cancer Center

Phase I: Vorinostat administered Days 5 to 14 at starting dose 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle), next administered dose 200 mg orally twice daily (4000 mg over 10 days per cycle).

Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 21 day cycle: Doxorubicin 50 mg/m\^2 IV Day 1; Prednisone 100 mg tablets orally/day Days 1-5; Cyclophosphamide 750 mg/m\^2 IV Day 1; Vincristine 1.4 mg/m\^2 IV Day 1.

Schedule A: Vorinostat Once or Twice Daily

Phase II: Vorinostat administered at starting dose 300 mg orally three times daily from Days -2 to 3 (4500 mg over 5 days per cycle).

Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 21 day cycle: Doxorubicin 50 mg/m\^2 IV Day 1; Prednisone 100 mg tablets orally/day Days 1-5; Cyclophosphamide 750 mg/m\^2 IV Day 1; Vincristine 1.4 mg/m\^2 IV Day 1.

Schedule B: Vorinostat Three Times Daily

Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)

Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle

Zolinza (vorinostat) : Starting oral dose (Schedule A) of 300 mg once a day on Days 5-14 of 21 day cycle.

Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle

Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Zolinza + CHOP

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

300 mg once daily on Days 5 to14

200 mg twice daily on Days 5 to14

300 mg three times daily on Days -2 to 3

Number of participants who received either Vorinostat treatment Schedule A (300 mg once daily or 200 mg twice daily) for Phase I or Schedule B (300 mg three times daily) for Phase II.

Vorinostat Treatment (Schedule A/Schedule B)

Yasuhiro Oki, MD/ Associate Professor

Vorinostat 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle or Vorinostat 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle

Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)

Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle

Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle

Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Schedule A - Vorinostat Once or Twice Daily

Phase I Maximum Tolerated Dose (MTD) of Vorinostat

Vorinostat 300 mg orally once daily (total doses of 3000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle

Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)

Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle

Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle

Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Schedule A - Vorinostat Once Daily

Vorinostat 200 mg orally twice daily (total doses of 4000 mg over 10 days per cycle) on Days 5-14 of 21 day cycle

Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)

Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle

Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle

Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Schedule A - Vorinostat Twice Daily

Number of Participants With Dose Limiting Toxicity for Determination Phase I (Schedule A) MTD of Vorinostat

Vorinostat administered orally 300 mg three times daily from days -2 to 3 (4500 mg over 5 days per cycle) of 21 day cycle.

Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)

Doxorubicin : 50 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Prednisone : 100 mg tablets by mouth once a day on Days 1-5 of 21 day cycle

Cyclophosphamide : 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle

Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Schedule B - Vorinostat Three Times Daily

Phase II MTD of Vorinostat

Zolinza (vorinostat) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)

Doxorubicin: 50 mg/m\^2 by vein/intravenous (IV) over 15 minutes on Day 1 of 21 day cycle

Prednisone: 100 mg tablets by mouth/orally (PO) once a day on Days 1-5 of 21 day cycle

Zolinza (vorinostat): Phase I Starting dose of 300 mg by mouth each evening on Days 5-14 of 21 day cycle.

Cyclophosphamide: 750 mg/m\^2 by vein over 1 hour on Day 1 of 21 day cycle

Vincristine : 1.4 mg/m\^2 by vein over 15 minutes on Day 1 of 21 day cycle

Overall Study

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Recurrence

Breast Neoplasms

Neoplasm Metastasis

Breast Diseases

Skin Diseases

Neoplastic Processes

Amino Acids

Lapatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

lapatinib 1,250 mg continuous daily and escalating doses of vorinistat (200mg run-up, 300mg, and 400mg 4 days on 3 days off)

lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days

300 mg 4 days on then 3 days off

As defined in the protocol, the dose of vorinostat was increased to 400 mg 4 days on then 3 days off in the pilot phase because the adverse event threshold was not met. In the Phase II cohort, the dose of vorinistat was 400 mg 4 days on and 3 days off.

Saranya Chumsri, MD

This research is being done to find out how safe and how well the combination of lapatinib and vorinostat works against advanced cancers.

Lapatinib is an anti-cancer drug that is approved by the Food and Drug Administration (FDA) for the treatment of metastatic HER2-positive breast cancer. HER2 is a protein involved in the growth of some cancer cells. In lab tests and small clinical studies, lapatinib is also found to kill other types of cancer that have another related protein called epidermal growth factor receptor (EGFR). For participants who have other cancers, the use of lapatinib in this study is investigational. This means the drug is not FDA approved for this use.

Vorinostat is only FDA approved for the treatment of cutaneous T cell lymphoma (a type of cancer). Vorinostat is not currently FDA approved for breast cancer or any other type of cancer. The use of vorinostat in this study is investigational.

Cancer cells can travel through the blood stream and spread to other organs. This process is called metastasis. Lab tests and small clinical trials have shown that vorinostat kills some cancer cells and prevents these cancer cells from traveling through the blood stream. These trials have shown that vorinostat improves how well lapatinib kills cancer cells.

Newer studies have also shown that a subset of cells, called "cancer stem cells," can come back, spread, and become resistant to the usual chemotherapy. In laboratory tests, we found that vorinostat and lapatinib can reduce the number of cancer stem cells. We are looking at combining vorinostat and lapatinib in the hope that we can reduce the number of cancer stem cells and cancer cells traveling through the blood stream.

There are two parts to this study.

First part- We want to learn more about the best dose of vorinostat to be given with lapatinib. We want to learn about how much vorinostat and lapatinib goes into the blood during treatment. We also want to learn the side effects (safety) of the combination of vorinostat and lapatinib. All patients will receive the FDA-approved dose of lapatinib. The first group of patients will get a slightly lower dose of vorinostat than is given normally. If the side effects are not too serious, the next group of patients will get the dose of vorinostat that is given normally.

Second part- We will find out how well the combination of vorinostat and lapatinib works in patients with HER2-positive metastatic breast cancer.

GCC 0845:Vorinostat and Lapatinib in Advanced Solid Tumors and Advanced Breast Cancer to Evaluate Response and Biomarkers

GCC 0845: Pilot and Phase II- Vorinostat and Lapatinib in Patients With Advanced Solid Tumor Malignancies and Women With Recurrent Local-Regional or Metastatic Breast Cancer to Evaluate Response and Biomarkers of EMT and Breast Cancer Stem Cells

Safety and tolerability were assessed. Adverse events and dose limiting toxicities were recorded during an escalting dose pilot phase.

The Clinical Benefit Rate is the number of patients with either Complete Response (CR), Partial Response (PR), or Stable Disease (SD) for ≥ 6 months

University of Maryland Greenebaum Cancer Center

University of Maryland, Baltimore

Pilot Phase - Vornistat 200 to 400mg + Lapatinib

Phase II - Vorinistat 400mg + Lapatinib

Total

Age, Customized

The most important limitation of this study is that the Phase II efficacy portion was terminated early by the sponsor.

Michelle Medeiros

The pilot phase consisted of an escalating dose design. Three patients received lapatinib 1,250 mg daily plus 300 mg vorinistat 4 days on then 3 days off. This dose was tolerated so six more patients recieved lapatinib 1,250 mg daily plus 400 mg vorinistat 4 days on 3 days off.

Pilot Phase

Dose Limiting Toxicities

lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
SAHA + CHOP in Untreated T-cell Non-Hodgkin's Lymphoma	NCT00787527	Lymphoma	Zolinza (vorino... Cyclophosphamid... Doxorubicin Vincristine Prednisone	18 Years -	M.D. Anderson Cancer Center
GCC 0845:Vorinostat and Lapatinib in Advanced Solid Tumors and Advanced Breast Cancer to Evaluate Response and Biomarkers	NCT01118975	Breast Cancer Neoplasm Metast...	Vorinostat Lapatinib	18 Years -	University of Maryland, Baltimore

Spots Global Cancer Trial Database for zolinza (vorinostat)