Recurrent Mantle Cell Lymphoma, Recurrent Non-Hodgkin Lymphoma
Conditions
Brief summary
This phase II trial studies how well bortezomib and vorinostat work in treating patients with recurrent mantle cell lymphoma or recurrent and/or refractory diffuse large B-cell lymphoma. Bortezomib and vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Detailed description
This was a multicenter, non-randomized phase 2 trial using a Simon two-stage design with 3 cohorts. PRIMARY OBJECTIVES: I. Estimate the response rates of mantle cell and diffuse large B-cell lymphomas to bortezomib and vorinostat combination therapy. SECONDARY OBJECTIVES: I. Assess the safety and tolerability of the study regimen. II. Observe progression-free survival and response durations. III. Observe the relationship between pretreatment lymphoma cell nuclear v-rel reticuloendotheliosis viral oncogene homolog A (relA) and response. OUTLINE: Patients receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Patients also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
Interventions
DRUGBortezomib
Bortezomib: 1.3 mg/m\^2/d IV days 1, 4, 8, and 11.
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGVorinostat
Vorinostat: 400 mg (total daily dose as a single dose) days 1-5 and 8-12.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed mantle cell or diffuse large B-cell lymphoma; histological material must be available for central pathological review; unstained histological material -- slides or blocks -- must be available for correlative studies; archived material from previous biopsies is acceptable, unless a patient's lymphoma has been known to undergo histological transformation in the past, in which case a repeat biopsy to confirm histology prior to enrollment is required; availability of material must be confirmed at the time of registration, but material may be submitted subsequent to registration and initiation of study treatment * Measurable disease according to the Revised Response Criteria for Malignant Lymphoma; this requires at least one lesion greater than 1.0 cm in diameter in both the long and short axis as measured by spiral computed tomography (CT) scan or physical exam * Prior allogeneic stem cell transplant is allowed provided that all of the following conditions are met: * \>= 6 months have elapsed since allogeneic transplant * No graft vs. host disease (GVHD) is present * Not currently on immunosuppressive therapy * Prior therapy: * Mantle cell lymphoma: * Previously treated or untreated * No prior bortezomib * Diffuse large B-cell lymphoma: * At least one prior systemic therapy * No prior bortezomib * Note: Not intended for patients in first relapse who are candidates for high dose therapy with stem cell support * Life expectancy of greater than 3 months * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 * Able to tolerate loperamide or other anti-diarrheal medications * Absolute neutrophil count \>= 1.5 x 10\^9/L * Platelets \>= 75 x 10\^9/L * Total bilirubin =\< 1.5 x upper limit of normal (ULN) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transferase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal * Creatinine within normal institutional limits or calculated creatinine clearance \>= 60 mL/min according to the Cockcroft-Gault formula * For patients with known human immunodeficiency virus (HIV) infection, a cluster of differentiation (CD)4 count \>= 0.5 x 10\^9/L * For patients whose last treatment included bendamustine or fludarabine, a CD4 count \>= 0.4 x 10\^9/L * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and to report pregnancy or suspected pregnancy while participating in the study * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Chemotherapy or large field radiotherapy within 3 weeks prior to entering the study * Prior histone deacetylase inhibitor as cancer treatment * Concurrent treatment with other investigational agents * Plans for other concurrent cancer treatment; if steroids for cancer control have been used, patients must be off these agents for \>= 1 week before starting treatment; exception: maintenance therapy for non-malignant disease with prednisone or steroid equivalent dose \< 10 mg/day is permitted * History of brain metastasis including leptomeningeal metastasis * Grade \>= 2 neuropathy, regardless of cause * Unable to take oral medications * History of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib or vorinostat * Not sufficiently recovered from previous treatment * Medical or other condition (for example: uncontrolled infection; potentially life threatening changes on electrocardiogram \[EKG\]) or concurrent treatment (for example, marrow suppressive agents such as zidovudine) that represents an inappropriate risk to the patient or likely would compromise achievement of the primary study objective; patients should be closely monitored when given bortezomib in combination with the cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors and inducers * Pregnant women are excluded from this study; breastfeeding should be discontinued * Active concurrent malignancy, except adequately treated non-melanoma skin cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Up to 9 years | ORR: Complete Response (CR) + Partial Response (PR) assessed according to the Revised Response Criteria for Malignant Lymphoma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Response | Up to 9 years | Number of participants per category: Partial Response (PR), Stable Disease (SD), Progressive Disease (PD). PR: Regression of measurable disease and no new sites. SD: Failure to attain Complete Response (CR), /PR or PD. Relapsed or Progressive Disease: Any new lesion or increase by ≥ 50% of previously involved sites from nadir. |
| Progression-free Survival (PFS) | Up to 9 years | Median progression-free survival in months per cohort. |
| Duration of Partial Response | Up to 9 years | Median duration of response per cohort. |
| Duration of Stable Disease | Up to 9 years | Median duration of stable disease per cohort. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 12 participating cancer center sites in the United States, from July 2008 through December 2013.
Participants by arm
| Arm | Count |
|---|---|
| Treatment: Cohort A - MCL; No Prior Bortezomib Mantle Cell Lymphoma (MCL): Treatment (vorinostat, bortezomib). Participants receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Participants also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Vorinostat precedes bortezomib on days of concurrent administration. Courses repeat every 3 weeks in the absence of disease progression - or unacceptable toxicity. After completion of study therapy, participants are followed periodically. | 22 |
| Treatment: Cohort B - MCL; Prior Bortezomib Mantle Cell Lymphoma MCL: Treatment (vorinostat, bortezomib). Participants receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Participants also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Vorinostat precedes bortezomib on days of concurrent administration. Courses repeat every 3 weeks in the absence of disease progression - or unacceptable toxicity. After completion of study therapy, participants are followed periodically. | 4 |
| Treatment: Cohort C - DLBCL; No Prior Bortezomib Diffuse Large B-Cell Lymphoma (DLBCL): Treatment (vorinostat, bortezomib). Participants receive vorinostat orally (PO) once daily (QD) on days 1-5 and 8-12. Participants also receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11. Vorinostat precedes bortezomib on days of concurrent administration. Courses repeat every 3 weeks in the absence of disease progression - or unacceptable toxicity. After completion of study therapy, participants are followed periodically. | 39 |
| Total | 65 |
Baseline characteristics
| Characteristic | Total | Treatment: Cohort A - MCL; No Prior Bortezomib | Treatment: Cohort C - DLBCL; No Prior Bortezomib | Treatment: Cohort B - MCL; Prior Bortezomib |
|---|---|---|---|---|
| Age, Continuous | 60 years | 64 years | 57 years | 63 years |
| Eastern Cooperative Oncology Group (ECOG) Status Status: 0 | 27 Participants | 13 Participants | 11 Participants | 3 Participants |
| Eastern Cooperative Oncology Group (ECOG) Status Status: 1 | 29 Participants | 9 Participants | 19 Participants | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) Status Status: 2 | 9 Participants | 0 Participants | 9 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 2 Participants | 5 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 1 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) White | 53 Participants | 19 Participants | 30 Participants | 4 Participants |
| Region of Enrollment United States | 65 Participants | 22 Participants | 39 Participants | 4 Participants |
| Sex: Female, Male Female | 18 Participants | 5 Participants | 13 Participants | 0 Participants |
| Sex: Female, Male Male | 47 Participants | 17 Participants | 26 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 4 | 4 / 39 |
| other Total, other adverse events | 22 / 22 | 4 / 4 | 39 / 39 |
| serious Total, serious adverse events | 9 / 22 | 1 / 4 | 22 / 39 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR: Complete Response (CR) + Partial Response (PR) assessed according to the Revised Response Criteria for Malignant Lymphoma.
Time frame: Up to 9 years
Population: All participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A - MCL | Overall Response Rate (ORR) | 31.8 percentage of participants |
| Cohort B - MCL | Overall Response Rate (ORR) | 0 percentage of participants |
| Cohort C - DLBCL | Overall Response Rate (ORR) | 7.7 percentage of participants |
Secondary
Best Response
Number of participants per category: Partial Response (PR), Stable Disease (SD), Progressive Disease (PD). PR: Regression of measurable disease and no new sites. SD: Failure to attain Complete Response (CR), /PR or PD. Relapsed or Progressive Disease: Any new lesion or increase by ≥ 50% of previously involved sites from nadir.
Time frame: Up to 9 years
Population: All participants evaluable and available at time of assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A - MCL | Best Response | Stable Disease | 5 Participants |
| Cohort A - MCL | Best Response | Partial Response | 7 Participants |
| Cohort A - MCL | Best Response | Progressive Disease | 7 Participants |
| Cohort B - MCL | Best Response | Stable Disease | 2 Participants |
| Cohort B - MCL | Best Response | Partial Response | 0 Participants |
| Cohort B - MCL | Best Response | Progressive Disease | 2 Participants |
| Cohort C - DLBCL | Best Response | Partial Response | 3 Participants |
| Cohort C - DLBCL | Best Response | Progressive Disease | 23 Participants |
| Cohort C - DLBCL | Best Response | Stable Disease | 8 Participants |
Secondary
Duration of Partial Response
Median duration of response per cohort.
Time frame: Up to 9 years
Population: All participants with Partial Response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A - MCL | Duration of Partial Response | 4.2 months |
| Cohort C - DLBCL | Duration of Partial Response | 2.1 months |
Secondary
Duration of Stable Disease
Median duration of stable disease per cohort.
Time frame: Up to 9 years
Population: All participants with stable disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A - MCL | Duration of Stable Disease | 3.8 months |
| Cohort B - MCL | Duration of Stable Disease | 3.8 months |
| Cohort C - DLBCL | Duration of Stable Disease | 1.3 months |
Secondary
Progression-free Survival (PFS)
Median progression-free survival in months per cohort.
Time frame: Up to 9 years
Population: All evaluable participants at time of analysis. Cohort B was closed early due to lack of accrual.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A - MCL | Progression-free Survival (PFS) | 7.6 months |
| Cohort C - DLBCL | Progression-free Survival (PFS) | 1.8 months |