Vorinostat, Rituximab, Ifosfamide, Carboplatin, and Etoposide in Treating Patients With Relapsed or Refractory Lymphoma or Previously Untreated T-Cell Non-Hodgkin Lymphoma or Mantle Cell Lymphoma
Study Details
Study Description
Brief Summary
This phase I/II trial is studying the side effects and best dose of vorinostat when given together with rituximab, ifosfamide, carboplatin, and etoposide and to see how well they work in treating patients with relapsed or refractory lymphoma or previously untreated T-cell non-Hodgkin lymphoma or mantle cell lymphoma. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving vorinostat together with rituximab and combination chemotherapy may kill more cancer cells
Detailed Description
OBJECTIVES:
-
To determine maximally tolerated dose of vorinostat that can be combined with RICE chemotherapy in patients with relapsed lymphoid malignancies.
-
To determine the safety and toxicity of the above regimen. III. To gain a preliminary assessment of the efficacy of the above regimen. IV. To determine the ability to proceed to peripheral blood stem cell collection following the above regimens (the impact of above regimen on stem cell reserve).
-
To describe vorinostat concentration attained at or near the MTD. VI. To evaluate the change of histone acetylation patterns and pro-apoptotic proteins of primary target (tumor) and non-target peripheral blood mononuclear cells (PBMC) cells following high-dose HDAC inhibition.
-
To describe the gene expression profile changes of tumor and non-tumor cells following high-dose HDAC inhibition.
OUTLINE: This is a phase I/II dose-escalation study of vorinostat.
Patients receive vorinostat orally (PO) once daily (QD) on days 1-5, ifosfamide IV continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1 hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 4 years.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (enzyme inhibitor, monoclonal antibody, chemotherapy Patients receive vorinostat PO QD on days 1-5, ifosfamide IV continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1 hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. |
Drug: vorinostat
Given PO
Other Names:
Biological: rituximab
Given IV
Other Names:
Drug: ifosfamide
Given IV
Other Names:
Drug: carboplatin
Given IV
Other Names:
Drug: etoposide
Given IV
Other Names:
Other: pharmacological study
Correlative studies
Other Names:
Other: laboratory biomarker analysis
Correlative studies
Genetic: gene expression analysis
Correlative studies
|
Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose of Vorinostat [28 days post last dose of study drug]
- Safety and Toxicity According to CTCAE v3.0 [3-5 weeks post end of treatment]
Common dose limiting toxicities.
- Efficacy (Response Rate) of Vorinostat Combined With RICE Chemotherapy [3-5 weeks post end of treatment]
- Ability to Proceed to Peripheral Blood Stem Cell Collection Following Treatment [1-3 weeks post end of treatment]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients must have relapsed or primary refractory lymphoid malignancy (including B-cell, T-cell, or Hodgkins disease), or untreated T-NHL or MCL
-
Patients with other lymphomas that have not received any prior therapy and are not candidates for anthracycline-based therapies, are eligible with PI review and approval
-
Revised European American classification (REAL), or World Health Organization (WHO) classification of patient's malignancies must be provided
-
Patients must have measurable disease defined as lesions that can be accurately measured in two dimensions by computed tomography (CT), magnetic resonance imaging (MRI), medical photograph (skin or oral lesion), plain x-ray, or other conventional technique and a greatest transverse diameter of 1 cm or greater; or palpable lesions with both diameters >= 2 cm
-
Patients must have a bone marrow aspirate and biopsy within 28 days of enrollment and no intervening anticancer therapy
-
Patients must have a CT of chest, abdomen, and pelvis within 28 days of enrollment; patients with evidence of adenopathy in the neck must have a CT of neck
-
Patients should not have evidence of active central nervous system lymphoma
-
Electrocardiogram (EKG) must be free of any arrhythmias (excluding sinus arrhythmia or infrequent premature ventricular contractions)
-
Patients must have a Southwest Oncology Group (SWOG) performance status of 0, 1, or 2
-
Absolute neutrophil count (ANC) >= 1,500/mm^3
-
Serum creatinine < 1.5 mg/dl or creatinine clearance greater than 60/ ml per minute by the following formula (all tests must be performed within 28 days prior to registration)
-
Total bilirubin < 1.5 times upper limit of normal, aspartate aminotransferase (AST) < 5 times upper limit of normal
-
Patients must have a serum lactate dehydrogenase (LDH) performed within 14 days prior to registration
-
All patients must be informed of the investigational nature of this study and have given written consent in accordance with institutional and federal guidelines
-
Patients must be anticipated to complete at least 2 cycles of chemotherapy
-
Platelets >= 100,000/mm^3 (without transfusion)
Exclusion Criteria:
-
Patients known to be human immunodeficiency virus (HIV) positive
-
Pregnant or nursing women; men or women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
-
Patients with other prior malignancies except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, cervical cancer in situ, or other cancer from which the patient has been disease free for 5 years or greater, unless approved by the protocol Chair or Co-Chair
-
Patients that are refractory (i.e. not responded or progressed within 6 months) to a carboplatin, cisplatin, ifosfamide, or etoposide-based regimen-based regimen
-
Patients that have other medical conditions that would contraindicate treatment with aggressive chemotherapy (including active infection, uncontrolled hypertension, congestive heart failure, unstable angina pectoris, or myocardial infarction within the past 6 months, or uncontrolled arrhythmia)
-
Patients with a history of impaired cardiac status (including history of severe coronary artery disease, cardiomyopathy, congestive heart failure or arrhythmia); if the patient's history is questionable, a measurement of left ventricular ejection fraction should be obtained within 42 days prior to registration; patients with left ventricular ejection fraction < 50% are not eligible
-
Autologous or allogeneic transplantation within 12 months or radioimmunotherapy within 6 months of registration
-
No concurrent treatment with valproic acid or on valproic acid within 2 weeks of study enrollment
-
No prior treatment with histone deacetylase inhibitors
-
No concurrent therapy for this malignancy
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Puget Sound Oncology Consortium | Seattle | Washington | United States | 98109 |
Sponsors and Collaborators
- University of Washington
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Lihua Budde, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Study Documents (Full-Text)
None provided.More Information
Publications
- PSOC 2302
- NCI-2010-00870
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy |
|---|---|
| Arm/Group Description | Patients receive vorinostat PO QD on days 1-5, ifosfamide IV continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1 hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. vorinostat: Given PO rituximab: Given IV ifosfamide: Given IV carboplatin: Given IV etoposide: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies gene expression analysis: Correlative studies |
| Period Title: Overall Study | |
| STARTED | 29 |
| COMPLETED | 29 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy |
|---|---|
| Arm/Group Description | Patients receive vorinostat PO QD on days 1-5, ifosfamide IV continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1 hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. vorinostat: Given PO rituximab: Given IV ifosfamide: Given IV carboplatin: Given IV etoposide: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies gene expression analysis: Correlative studies |
| Overall Participants | 29 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
56
|
| Sex: Female, Male (Count of Participants) | |
| Female |
7
24.1%
|
| Male |
22
75.9%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
0
0%
|
| Not Hispanic or Latino |
27
93.1%
|
| Unknown or Not Reported |
2
6.9%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
1
3.4%
|
| Asian |
1
3.4%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
0
0%
|
| White |
27
93.1%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
Outcome Measures
| Title | Maximum Tolerated Dose of Vorinostat |
|---|---|
| Description | |
| Time Frame | 28 days post last dose of study drug |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy |
|---|---|
| Arm/Group Description | Patients receive vorinostat PO QD on days 1-5, ifosfamide IV continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1 hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. vorinostat: Given PO rituximab: Given IV ifosfamide: Given IV carboplatin: Given IV etoposide: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies gene expression analysis: Correlative studies |
| Measure Participants | 29 |
| Number [mg twice daily X 5 days] |
500
|
| Title | Safety and Toxicity According to CTCAE v3.0 |
|---|---|
| Description | Common dose limiting toxicities. |
| Time Frame | 3-5 weeks post end of treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy |
|---|---|
| Arm/Group Description | Patients receive vorinostat PO QD on days 1-5, ifosfamide IV continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1 hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. vorinostat: Given PO rituximab: Given IV ifosfamide: Given IV carboplatin: Given IV etoposide: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies gene expression analysis: Correlative studies |
| Measure Participants | 29 |
| Infection |
2
6.9%
|
| Hypokalemia |
2
6.9%
|
| Transaminitis |
2
6.9%
|
| Grade 3 related gastrointestinal toxicity |
9
31%
|
| Title | Efficacy (Response Rate) of Vorinostat Combined With RICE Chemotherapy |
|---|---|
| Description | |
| Time Frame | 3-5 weeks post end of treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy |
|---|---|
| Arm/Group Description | Patients receive vorinostat PO QD on days 1-5, ifosfamide IV continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1 hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. vorinostat: Given PO rituximab: Given IV ifosfamide: Given IV carboplatin: Given IV etoposide: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies gene expression analysis: Correlative studies |
| Measure Participants | 29 |
| Count of Participants [Participants] |
19
65.5%
|
| Title | Ability to Proceed to Peripheral Blood Stem Cell Collection Following Treatment |
|---|---|
| Description | |
| Time Frame | 1-3 weeks post end of treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy |
|---|---|
| Arm/Group Description | Patients receive vorinostat PO QD on days 1-5, ifosfamide IV continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1 hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. vorinostat: Given PO rituximab: Given IV ifosfamide: Given IV carboplatin: Given IV etoposide: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies gene expression analysis: Correlative studies |
| Measure Participants | 21 |
| Count of Participants [Participants] |
20
69%
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy | |
| Arm/Group Description | Patients receive vorinostat PO QD on days 1-5, ifosfamide IV continuously over 24 hours and carboplatin IV over 1 hour on day 4, and etoposide IV over 1 hour on days 3-5. Patients who are CD20+ also receive rituximab IV once on day 3, 4, or 5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. vorinostat: Given PO rituximab: Given IV ifosfamide: Given IV carboplatin: Given IV etoposide: Given IV pharmacological study: Correlative studies laboratory biomarker analysis: Correlative studies gene expression analysis: Correlative studies | |
All Cause Mortality |
||
| Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy | ||
| Affected / at Risk (%) | # Events | |
| Total | 10/29 (34.5%) | |
| Blood and lymphatic system disorders | ||
| Febrile neutropenia | 3/29 (10.3%) | |
| Gastrointestinal disorders | ||
| Nausea/Vomiting | 1/29 (3.4%) | |
| Diarrhea | 1/29 (3.4%) | |
| Immune system disorders | ||
| Allergic reaction | 1/29 (3.4%) | |
| Nervous system disorders | ||
| Encephalopathy | 1/29 (3.4%) | |
| Syncope | 1/29 (3.4%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 1/29 (3.4%) | |
| Vascular disorders | ||
| Hypotension | 1/29 (3.4%) | |
Other (Not Including Serious) Adverse Events |
||
| Treatment (Enzyme Inhibitor, Monoclonal Antibody, Chemotherapy | ||
| Affected / at Risk (%) | # Events | |
| Total | 25/29 (86.2%) | |
| Blood and lymphatic system disorders | ||
| Febrile neutropenia | 8/29 (27.6%) | |
| Gastrointestinal disorders | ||
| Nausea | 6/29 (20.7%) | |
| Vomiting | 2/29 (6.9%) | |
| General disorders | ||
| DVT | 2/29 (6.9%) | |
| Elevated PTT | 3/29 (10.3%) | |
| Pain | 4/29 (13.8%) | |
| Fatigue | 3/29 (10.3%) | |
| Infections and infestations | ||
| Infection | 8/29 (27.6%) | |
| Investigations | ||
| AST/ALT | 4/29 (13.8%) | |
| Metabolism and nutrition disorders | ||
| Dehydration | 5/29 (17.2%) | |
| Anorexia | 3/29 (10.3%) | |
| Hypophasphataemia | 12/29 (41.4%) | |
| Hypokalaemia | 10/29 (34.5%) | |
| Hyponatraemia | 4/29 (13.8%) | |
| Hypercalcemia | 4/29 (13.8%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Hypoxia | 2/29 (6.9%) | |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Ajay Gopal |
|---|---|
| Organization | Fred Hutchinson Cancer Research Center |
| Phone | 206-288-2037 |
| akgopal@fhcrc.org |
- PSOC 2302
- NCI-2010-00870