Trial of Vorinostat in Combination With Cyclophosphamide, Etoposide, Prednisone and Rituximab for Elderly Patients With Relapsed Diffuse Large B-Cell Lymphoma (DLBCL)
Study Details
Study Description
Brief Summary
The purpose of this study is to replace a drug with many side effects, procarbazine, with a new novel drug, vorinostat, in a drug combination for the treatment of patients with diffuse large B-cell lymphoma. Vorinostat is the first of a new type of chemotherapy drug, known as a histone deacetylase inhibitor, to be approved by the Food and Drug Administration. It is approved for the treatment of certain lymphomas of the skin. It alters the cancer cell pathway by preventing cancer cells from reproducing. Vorinostat will be added to a combination of four other effective chemotherapy drugs that have been used for many years for the treatment of diffuse large B-cell lymphoma: rituximab, cyclophosphamide, etoposide and prednisone. The doses of vorinostat will be increased or decreased depending on the side effects that occur in each of the first few patients in the trial to find the safest dose with the least side effects. This is termed the phase I part of the clinical trial. Once the best dose of vorinostat is found, the rest of the patients in the clinical trial will be treated with this dose. This is termed the phase II part of the trial. The object of the trial is to find out what effects, good and/or bad, the combination of vorinostat, rituximab, cyclophosphamide, etoposide and prednisone will have on you and your lymphoma.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 1 vorinostat in combination with cyclophosphamide, etoposide,prednisone and rituximab,peg-filgrastim or filgrastim |
Drug: rituximab, cyclophosphamide, etoposide, prednisone, vorinostat and QOL questionnaire, peg-filgrastim or filgrastim
Patients will be treated with 6 cycles of rituximab, cyclophosphamide, etoposide, prednisone and vorinostat every 4 weeks. Quality of life determinations will be obtained at the beginning of each cycle of chemotherapy and at each visit during the first year of followup.
|
Outcome Measures
Primary Outcome Measures
- Maximum Tolerated Dose (MTD) of Vorinostat Given Orally for 10 Days in Combination With Cyclophosphamide, Etoposide, Prednisone and Rituximab for Elderly Patients With Relapsed Diffuse Large B-cell Lymphoma [through study completion, an average of 1 year]
Maximum Tolerated Dose (MTD) of Vorinostat reflects the highest dose of Ridaforolimus and Vorinostat that did not cause a new Grade 2 toxicity in >= 50% of participants
Secondary Outcome Measures
- Complete Response Rate to Rituximab and a Combination of Vorinostat With Cyclophosphamide, Etoposide, and Prednisone in Elderly Pts With Relapsed Diffuse Large B-cell Lymphoma Who Aren't Candidates for Autologous Stem Cell Transplantation. [through study completion, an average of 1 year]
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.", or similar definition that is accurate and appropriate.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
MSKCC or Weill Cornell biopsy confirmation of relapsed/refractory diffuse large B-cell lymphoma.Patients with large cell transformation of a low-grade B-cell lymphoma will be eligible.
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One or two prior chemotherapy regimens not including autologous stem cell transplantation.
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Age ≥ 60 years.
-
Not a candidate for autologous stem cell transplantation.
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Patient must have performance status of ≤2 on the ECOG Performance Scale.
-
Measurable disease
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Adequate organ and bone marrow function: ANC ≥ 1000/mm3, platelet count ≥ 50,000/mm3, total bilirubin ≤ 1.5 ULN (with exception of Gilbert's disease), AST/ALT ≤ 2.5 ULN, creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 ml/min, potassium and magnesium within normal limits.
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Male patients agree to use an adequate method of contraception for the duration of the study.
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Patient is available for periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study.
Exclusion Criteria:
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Patient who has had chemotherapy, radiotherapy, or biological therapy [including growth factors], within 30 days (42 days for nitrosoureas or mitomycin C) prior to initial dosing with study drug(s) or who has not recovered from adverse events due to agents administered more than 30 days earlier. Patients on a stable dose of steroids for at least 4 weeks prior to onset of study therapy may be included.
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Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug(s).
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Patient had prior treatment with an HDAC inhibitor (e.g., romidespin (Depsipeptide),NSC-630176, MS 275, LAQ-824, belinostat (PXD-101), LBH589, MGCD0103,CRA024781, etc). Patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study. Patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period.
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Patients with active CNS lymphoma and/or lymphomatous meningitis are excluded. However, patients with a history of CNS lymphoma and/or lymphomatous meningitis who have been stable without evidence of CNS and/or leptomeningeal recurrence would be eligible. They must be off steroids or on a stable dose of steroids.
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Patient with a primary central nervous system lymphoma.
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Patient has known hypersensitivity to the components of study drug or its analogs.
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Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
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Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs, substance abuse or had a recent history (within the last year) of drug or alcohol abuse.
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Patient is expecting to father children within the projected duration of the study.
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Patient has uncontrolled intercurrent illness or circumstances that could limit compliance with the study, including, but not limited to the following: active infection, acute or chronic graft versus host disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric conditions.
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Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study or is not in the best interest of the patient to participate.
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Patient has a history of a gastrointestinal surgery or other procedures that might, in the opinion of the investigator, interfere with the absorption or swallowing of the study drugs.
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Patient with a "currently active" second malignancy, other than non-melanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled. Patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for >5 years or are considered by their physician to be at less than 30% risk of relapse.
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Patient is HIV +.
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Patient has active hepatitis B or C.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Memorial Sloan Kettering Cancer Center @ BaskingRidge | Basking Ridge | New Jersey | United States | 07920 |
| 2 | Memorial Sloan Kettering Cancer Center @ Suffolk | Commack | New York | United States | 11725 |
| 3 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 4 | Weill Cornell Medical Center | New York | New York | United States | |
| 5 | Memorial Sloan Kettering Cancer Center @ Phelps | Sleepy Hollow | New York | United States | 10591 |
Sponsors and Collaborators
- Memorial Sloan Kettering Cancer Center
- Merck Sharp & Dohme LLC
- Northwestern University
- NorthShore University HealthSystem
- Weill Medical College of Cornell University
Investigators
- Principal Investigator: David Straus, MD, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 08-045
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Relapsed or Refractory Diffuse Large B-cell Lymphoma |
|---|---|
| Arm/Group Description | Patients will be treated with 6 cycles of rituximab, cyclophosphamide, etoposide, prednisone and vorinostat every 4 weeks. |
| Period Title: Overall Study | |
| STARTED | 30 |
| COMPLETED | 30 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Relapsed or Refractory Diffuse Large B-cell Lymphoma |
|---|---|
| Arm/Group Description | Patients will be treated with 6 cycles of rituximab, cyclophosphamide, etoposide, prednisone and vorinostat every 4 weeks. |
| Overall Participants | 30 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
76
|
| Sex: Female, Male (Count of Participants) | |
| Female |
16
53.3%
|
| Male |
14
46.7%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
4
13.3%
|
| Not Hispanic or Latino |
24
80%
|
| Unknown or Not Reported |
2
6.7%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
1
3.3%
|
| White |
25
83.3%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
4
13.3%
|
| Region of Enrollment (participants) [Number] | |
| United States |
30
100%
|
Outcome Measures
| Title | Maximum Tolerated Dose (MTD) of Vorinostat Given Orally for 10 Days in Combination With Cyclophosphamide, Etoposide, Prednisone and Rituximab for Elderly Patients With Relapsed Diffuse Large B-cell Lymphoma |
|---|---|
| Description | Maximum Tolerated Dose (MTD) of Vorinostat reflects the highest dose of Ridaforolimus and Vorinostat that did not cause a new Grade 2 toxicity in >= 50% of participants |
| Time Frame | through study completion, an average of 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Relapsed or Refractory Diffuse Large B-cell Lymphoma |
|---|---|
| Arm/Group Description | Patients will be treated with 6 cycles of rituximab, cyclophosphamide, etoposide, prednisone and vorinostat every 4 weeks. |
| Measure Participants | 30 |
| Number [mg/m2] |
300
|
| Title | Complete Response Rate to Rituximab and a Combination of Vorinostat With Cyclophosphamide, Etoposide, and Prednisone in Elderly Pts With Relapsed Diffuse Large B-cell Lymphoma Who Aren't Candidates for Autologous Stem Cell Transplantation. |
|---|---|
| Description | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.", or similar definition that is accurate and appropriate. |
| Time Frame | through study completion, an average of 1 year |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Relapsed or Refractory Diffuse Large B-cell Lymphoma |
|---|---|
| Arm/Group Description | Patients will be treated with 6 cycles of rituximab, cyclophosphamide, etoposide, prednisone and vorinostat every 4 weeks. |
| Measure Participants | 30 |
| Number [percentage of participants with CR] |
32
106.7%
|
Adverse Events
| Time Frame | 5 years | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Relapsed or Refractory Diffuse Large B-cell Lymphoma | |
| Arm/Group Description | Patients will be treated with 6 cycles of rituximab, cyclophosphamide, etoposide, prednisone and vorinostat every 4 weeks. | |
All Cause Mortality |
||
| Relapsed or Refractory Diffuse Large B-cell Lymphoma | ||
| Affected / at Risk (%) | # Events | |
| Total | 25/30 (83.3%) | |
Serious Adverse Events |
||
| Relapsed or Refractory Diffuse Large B-cell Lymphoma | ||
| Affected / at Risk (%) | # Events | |
| Total | 19/30 (63.3%) | |
| Blood and lymphatic system disorders | ||
| Febrile Neutropenia | 6/30 (20%) | |
| Hemorrhage | 1/30 (3.3%) | |
| Cardiac disorders | ||
| Atrial fibrillation | 1/30 (3.3%) | |
| Cardiac Arrhythmia, other | 1/30 (3.3%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 4/30 (13.3%) | |
| Hemorrhage, Upper GI NOS | 1/30 (3.3%) | |
| Mucositis (func/sympt)- Stomach | 1/30 (3.3%) | |
| General disorders | ||
| Death NOS | 4/30 (13.3%) | |
| Fatigue | 4/30 (13.3%) | |
| Fever | 2/30 (6.7%) | |
| Hepatobiliary disorders | ||
| Cholecystitis | 1/30 (3.3%) | |
| Infections and infestations | ||
| Infection - lung (pneumonia) | 2/30 (6.7%) | |
| Infection - other | 1/30 (3.3%) | |
| Investigations | ||
| Creatinine | 1/30 (3.3%) | |
| Hemoglobin | 5/30 (16.7%) | |
| White blood cell | 4/30 (13.3%) | |
| Neutrophils/granulocytes (ANC/AGC) | 2/30 (6.7%) | |
| Platelets | 6/30 (20%) | |
| Metabolism and nutrition disorders | ||
| Dehydration | 1/30 (3.3%) | |
| Nervous system disorders | ||
| CNS cerebrovascular ischemia | 1/30 (3.3%) | |
| Memory impairment | 1/30 (3.3%) | |
| Neurology - other | 1/30 (3.3%) | |
| Syncope | 2/30 (6.7%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 1/30 (3.3%) | |
| Hypoxia | 1/30 (3.3%) | |
| Pneumonitis | 1/30 (3.3%) | |
| Vascular disorders | ||
| Thrombosis | 1/30 (3.3%) | |
Other (Not Including Serious) Adverse Events |
||
| Relapsed or Refractory Diffuse Large B-cell Lymphoma | ||
| Affected / at Risk (%) | # Events | |
| Total | 30/30 (100%) | |
| Blood and lymphatic system disorders | ||
| Hemoglobin | 13/30 (43.3%) | |
| Febrile neutropenia | 5/30 (16.7%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 7/30 (23.3%) | |
| Constipation | 6/30 (20%) | |
| Nausea | 6/30 (20%) | |
| Pain - throat | 4/30 (13.3%) | |
| Gastrointestinal, other | 3/30 (10%) | |
| Dyspepsia | 3/30 (10%) | |
| Vomiting | 3/30 (10%) | |
| General disorders | ||
| Fatigue | 13/30 (43.3%) | |
| Constitutional Symptoms, other | 5/30 (16.7%) | |
| Pain | 5/30 (16.7%) | |
| Hemorrhage | 4/30 (13.3%) | |
| Edema - limb | 3/30 (10%) | |
| Fever | 3/30 (10%) | |
| Infections and infestations | ||
| Infection, other | 4/30 (13.3%) | |
| Investigations | ||
| White blood cells | 13/30 (43.3%) | |
| Platelets | 12/30 (40%) | |
| Lymphocytes | 11/30 (36.7%) | |
| Neutrophils | 9/30 (30%) | |
| AST | 7/30 (23.3%) | |
| ALT | 6/30 (20%) | |
| INR | 6/30 (20%) | |
| Alkaline phosphatase | 4/30 (13.3%) | |
| Hyperbilirubinemia | 3/30 (10%) | |
| Metabolism and nutrition disorders | ||
| Hypoalbuminemia | 11/30 (36.7%) | |
| Hyperglycemia | 10/30 (33.3%) | |
| Anorexia | 7/30 (23.3%) | |
| Hyponatremia | 7/30 (23.3%) | |
| Hypophosphatemia | 5/30 (16.7%) | |
| Hypoglycemia | 4/30 (13.3%) | |
| Hypokalemia | 4/30 (13.3%) | |
| Dehydration | 3/30 (10%) | |
| Hypermagnesemia | 3/30 (10%) | |
| Nervous system disorders | ||
| Dysarthria | 4/30 (13.3%) | |
| Dysgeusia | 3/30 (10%) | |
| Psychiatric disorders | ||
| Insomnia | 4/30 (13.3%) | |
| Renal and urinary disorders | ||
| Urinary frequency | 3/30 (10%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 7/30 (23.3%) | |
| Dyspnea | 6/30 (20%) | |
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 | David Straus MD |
|---|---|
| Organization | Memorial Sloan Kettering Cancer Center |
| Phone | 212-639-8365 |
| strausd@mskcc.org |
- 08-045