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

Condition(s) targeted: Lymphoma

Intervention: Zolinza (vorinostat) (Drug); Cyclophosphamide (Drug); Doxorubicin (Drug); Vincristine (Drug); Prednisone (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Barbara Pro, MD, Principal Investigator, Affiliation: UT MD Anderson Cancer Center

Overall contact:
Barbara Pro, MD, Phone: 713-792-2860

Primary Objectives:

Phase I

1. Determine the toxicity profile and the maximum tolerated dose (MTD) of vorinostat when administered in combination with Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP)

Phase II

2. To evaluate the progression free survival for patients with T-cell NHL receiving the combination of vorinostat and CHOP

Secondary Objectives (Phase I and II):

1. To evaluate the response rate for patients with T-cell NHL receiving the combination of vorinostat and CHOP

2. To assess overall survival in patients with T-cell NHL treated with the combination of vorinostat and CHOP.

3. Correlative studies will be done to assess the role of vorinostat mediated apoptosis in combination with cytotoxic chemotherapy. Changes in marker expression from baseline to post treatment will be correlated with patient clinical response.

4. Correlative studies will be done to assess cytokine, gene, and protein array signatures for the various subsets of T-cell NHL.

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

Study design: Treatment, Open Label, Single Group Assignment, Safety/Efficacy Study

Primary outcome: Maximum tolerated dose (MTD) of vorinostat

Detailed description: 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.

Screening Tests:

Signing this consent form does not mean that you will be able to take part in this study. You will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests and procedures will be performed:

- You will be asked questions about your general health and well-being, as well as any

drugs (prescription, non-prescription, herbs, and/or vitamins) that you may be taking.

- You will have a physical exam, including measurement of your vital signs (heart rate,

blood pressure, temperature, and breathing rate), height, and weight.

- You will have a neurological exam (tests to check the functioning of your nerves,

including tests of your balance and reflexes).

- You will have an electrocardiogram (ECG - a test that measures the electrical activity

of the heart).

- Blood (about 5-10 teaspoons) will be drawn for routine tests and to check the status of

the disease. This routine blood draw will include a pregnancy test for women who are able to have children. To take part in this study, the pregnancy test must be negative.

- You will have computed tomography (CT) scans and positron emission tomography (PET)

scans to check the location of the disease.

- You will have a bone marrow aspiration and biopsy. To collect a bone marrow aspiration

and/or biopsy, an area of the hip is numbed with anesthetic, and a small of amount of bone marrow and bone is withdrawn through a large needle.

- If you have skin lesions and the doctor thinks it is needed, you will have photographs

taken to compare with photographs that will be taken after treatment. The photos of the lesions will be close-up photos of the lesions and small area of surrounding skin.

The study doctor will discuss the screening test results with you. If the screening tests show that you are not eligible to take part in the study, you will not be enrolled. Other treatment options will be discussed with you.

Study Drug Administration:

If you are found to be eligible to take part in this study, cyclophosphamide, vincristine, and doxorubicin will be given though a needle in your vein on Day 1 of each 21-day study cycle. Cyclophosphamide is given over 1 hour. Vincristine is given over 15 minutes. Doxorubicin is also given over 15 minutes.

On Days 1-5 of each cycle, you will take prednisone tablets by mouth.

On Days 5-14 of each study cycle, you will take vorinostat. Vorinostat capsules are taken by mouth, either once or twice a day. If you are taking vorinostat 1 time a day, it should be taken in the 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 Day 1 of each cycle. You will also receive instructions on how to take the drug. You will be instructed to return any unused vorinostat capsules back to study staff at the end of each cycle.

If you begin to experience severe or intolerable side effects, the study drug schedule may be stopped for up to 2 weeks. If the side effects improve, you may be able to receive the study drugs again, with a lower dose of vorinostat. 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.

- You will have a neurological exam.

- Blood (about 5 teaspoons) will be drawn for routine tests.

- You will be asked how well you are able to perform the normal activities of daily

living (performance status).

On or before Day 1 of every other cycle (Cycles 2, 4, 6 and so on), 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 months (8 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 drug 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.

- You will have a neurological exam.

- Your performance status will be recorded.

- 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.

Follow-up Visits:

After you are off study treatment, you will be contacted by phone call every 2 months for up to 5 years to check how you are doing. These phone calls will last about 5 minutes.

Additional Information:

- While you are on study, you will be asked to report any side effects or symptoms to the

study staff.

- If your doctor thinks it is needed, you may have additional tests and/or procedures

performed at any time during the study.

- You should take no more than 1 multi-vitamin a day while on study.

- You may not receive any chemotherapy, generalized radiotherapy, biological therapy,

and/or any other investigational cancer therapies while on study.

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 M. D. Anderson Cancer Center.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Patients must have a new diagnosis of T-cell NHL eligible histologies include: Peripheral T-cell lymphoma (unspecified), CD 30 + anaplastic large cell lymphoma ( ALK-1 positive and ALK-1 negative), angioimmunoblastic T-cell lymphoma, intestinal T-cell lymphoma, subcutaneous panniculitic T-cell lymphoma.

2. Patients who are eligible for blood and marrow transplant can receive this treatment to maximal reduction of tumor bulk. A minimum of four cycles of therapy will be given before evaluation for to hematopoetic stem cell transplant.

3. Patients must have at least one clear-cut bi-dimensionally measurable site (> 10mm by

spiral computerized tomography - CT - scan or > 20mm by conventional measures).

Baseline measurements of measurable sites and evaluation of evaluable disease must be obtained within four weeks prior to registration of this study.

4. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

5. Patients must be age 18 years old and above. There is no dosing or adverse event data are currently available on the use of vorinostat in patients <18 years of age, children are excluded from this study but may be eligible for future pediatric phase 2 combination trials.

6. Patients are required to have adequate bone marrow reserve as indicated: Absolute neutrophil count (ANC) >/= 1000/mm^3, Platelets >/= 80,000/mm^3, Hemoglobin >/= 8g/dL. If there is bone marrow involvement by lymphoma then there is no minimum level of counts required. These values must be obtained within two weeks before protocol entry.

7. Patients must have adequate liver function as indicated by: Bilirubin 8. Patients are required to have adequate renal function as indicated by a serum creatinine 9. Left ventricular ejection fraction must be evaluated by nuclear medicine scan or echocardiography and measure >/= 50%.

10. Concomitant steroids may continue provided they have been on a stable dosage for at least 3 months prior to enrollment. Patients may continue to receive systemic corticosteroids as premedications for chemotherapy, antibiotics, and transfusions.

11. Male patients must agree to use a barrier method of contraception or agree to abstain from heterosexual activity for the duration of the study

12. Female patients must be willing to use two adequate barrier methods of contraception to prevent pregnancy or agree to abstain from heterosexual activity throughout the study or be post menopausal (free from menses > two years or surgically sterilized).

13. Female patients of childbearing potential must have a negative serum pregnancy test (Beta hCG) within 72 hours of receiving the first dose of vorinostat.

14. Patients must have the ability able to give informed consent.

Exclusion Criteria:

1. 1. Patients with a) T-cell lymphoma with skin involvement only are excluded if they have no evidence of systemic disease b)T-cell prolymphocytic leukemia (T-PLL) c) T-cell large granular lymphocytic leukemia d) Primary cutaneous CD30+ disorders: anaplastic large cell lymphoma and lymphomatoid papulosis e) Angiocentric/nasal type T/NK-cell lymphoma f) Hepatosplenic gamma-delta T-cell lymphoma

2. Patients with active Hepatitis B and/or Hepatitis C infection.

3. Patients with known HIV infection are excluded. a) These patients are excluded secondary to potential to target activated T-cells, in a population of patients already at risk for T-cell depletion, would be a contraindication to therapy.

4. Patients with active infections requiring specific anti-infective therapy are not eligible until all signs of infections are resolved.

5. Patients with pre-existing cardiovascular disease requiring ongoing treatment. This includes: a) Congestive heart failure, b) Severe CAD, c) Cardiomyopathy, d) Uncontrolled cardiac arrhythmia, e) Unstable angina pectoris, f) Recent MI (within 6 months).

6. Patients with prior exposure to either vorinostat (including other HDAC inhibitors except valproic acid) or anthracyclines: a) Patients who have received valproic acid (VPA) for the treatment of seizures may be enrolled on this study, but must not have received VPA within 30 days of study enrollment.

7. Patients who are pregnant or breast-feeding. a)Effects of this treatment on the fetus and young children are unknown at this time.

8. Patients who have had an invasive solid tumor malignancy in the past five years except non-melanoma skin cancers or cervical carcinoma in situ or ductal/lobular carcinoma in situ of the breast who is currently without evidence of disease.

9. Patients undergoing anti-neoplastic chemotherapy, radiation, hormonal (excluding contraceptives) or immunotherapy, or investigational medications within the past four weeks.

10. Patients with deep vein thrombosis within three months.

11. Patient with concurrent use of complementary or alternative medicines.

12. Patients with psychiatric illness and/or social situations that would limit compliance with the study medication and requirements.

13. Patients with grade 2 or more neuropathy.

14. Patients with known CNS lymphoma.

Barbara Pro, MD, Phone: 713-792-2860

UT MD Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting
Barbara Pro, MD, Principal Investigator

UT MD Anderson Cancer Center website

Starting date: November 2008
Last updated: October 6, 2009