Lymphoma, B-Cell, Marginal Zone, Lymphoma, Follicular, Lymphoma, Mantle-Cell, Lymphoma, Non-Hodgkin, Lymphoma, Small-Cell, Waldenstrom Macroglobulinemia
Conditions
Keywords
Bendamustine, Rituximab, Vincristine sulfate, Vincristine sulfate liposome injection, Phase I, Escalation With Overdose Control
Brief summary
This study evaluates addition of Vincristine Sulfate Liposome Injection (Marqibo®) to the standard regimen of Bendamustine and Rituximab in adult patients with indolent B-cell lymphoma. This is a dose-escalation study.
Detailed description
Bendamustine-rituximab is a standard chemotherapy regimen for treatment of many indolent B-cell lymphomas, but most patients experience a recurrence of the lymphoma. Vincristine sulfate has been a traditional component of chemotherapy regimens in non-Hodgkin lymphoma and it is possible that adding it to the bendamustine-rituximab regimen might provide a better quality of remissions or longer duration of remissions with acceptable toxicity. This is a phase 1, single-center, open-label, single-arm trial in patients with indolent B-cell non-Hodgkin lymphoma otherwise appropriate for bendamustine-rituximab as initial or subsequent line of therapy. Patients will receive the of rituximab and bendamustine in combination with escalating doses of vincristine sulfate liposome injection (Marqibo®). The objective of this study is to assess safety of this combination by establishing the maximum tolerated dose of vincristine sulfate liposome injection (Marqibo®) in the combination.
Interventions
DRUGRituximab
375 mg/m2 I.V. on Day 1 of each cycle
DRUGBendamustine
90 mg/m2 I.V. on Day 1 and 2 of each cycle
DRUGVincristine sulfate liposome injection
Dose per dose escalation protocol, I.V. on Day 2 of each cycle
Sponsors
Spectrum Pharmaceuticals, Inc
Rhode Island Hospital
The Miriam Hospital
Brown University
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed indolent B-cell non-Hodgkin lymphoma. * Radiological measurable disease. * Previous treatment for lymphoma is allowed, with the exception of use of bendamustine within 6 months or any prior use of vincristine sulfate liposome injection * Eastern Cooperative Oncology Group performance status 0 or 1; * Life expectancy of at least 6 months; * Adequate organ and marrow function; * Women of child-bearing potential and men must agree to use adequate contraception. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* History of allergic reactions attributed to any drug used in the study. * Any lymphoma-directed therapy within 4 weeks. * Any prior treatment with vincristine sulfate liposome injection. * Prior treatment with bendamustine or vincristine sulfate within 180 days of enrollment. * Patients who are receiving any other investigational agents with the exception of endocrine therapy for breast or prostate cancer. * Central nervous system involvement. * Peripheral sensory or motor neuropathy. * History of a demyelinating condition. * Positive test for the Human Anti-Chimeric Antibody (HACA). * Patients receiving any medications or substances that are strong inhibitors or inducers of Cytochrome P450, family 3, subfamily A (CYP3A) enzyme are ineligible. * Uncontrolled intercurrent illness. * Prisoners. * Pregnant or breast-feeding women. * Known Human Immunodeficiency Virus (HIV) or active Hepatitis B infection * Any prior or active cancer, which in the opinion of the investigator would preclude safe participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose | Up to 6 cycles of treatment (approximately 6 months) | Determined as the median of the marginal posterior distribution using data from all available patients |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Completed Six Cycles of Study Treatment | Up to 6 cycles of treatment (approximately 6 months) | — |
| Response Rate | Up to 6 cycles of treatment (approximately 6 months) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT: 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 |
| Complete Response Rate | Up to 6 cycles of treatment (approximately 6 months) | The number of patients achieving complete response during treatment on study |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vincristine Sulfate Liposome Injection: 1.8 mg/m^2 Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy.
Rituximab: 375 mg/m2 I.V. on Day 1 of each cycle
Bendamustine: 90 mg/m2 I.V. on Day 1 and 2 of each cycle
Vincristine sulfate liposome injection: Dose per dose escalation protocol, I.V. on Day 2 of each cycle | 2 |
| Vincristine Sulfate Liposome Injection: 1.95 mg/m^2 Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | 1 |
| Vincristine Sulfate Liposome Injection: 1.98 mg/m^2 Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | 1 |
| Vincristine Sulfate Liposome Injection: 2.04 mg/m^2 Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | 2 |
| Vincristine Sulfate Liposome Injection: 2.10 mg/m^2 Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | 1 |
| Vincristine Sulfate Liposome Injection: 2.14 mg/m^2 Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | 1 |
| Vincristine Sulfate Liposome Injection: 2.19 mg/m^2 Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | 1 |
| Vincristine Sulfate Liposome Injection: 2.22 mg/m^2 Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | 1 |
| Vincristine Sulfate Liposome Injection: 2.24 mg/m^2 Treatment with the combination of rituximab, bendamustine and vincristine sulfate liposome injection will be repeated every 4 weeks for a maximum of 6 cycles. Dose-limiting toxicities will be evaluated during the first cycle of therapy. | 1 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | 1 subject removed from study before any treatment due to temporary unavailability of study drug | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Vincristine Sulfate Liposome Injection: 1.95 mg/m^2 | Vincristine Sulfate Liposome Injection: 1.98 mg/m^2 | Vincristine Sulfate Liposome Injection: 2.04 mg/m^2 | Vincristine Sulfate Liposome Injection: 2.10 mg/m^2 | Vincristine Sulfate Liposome Injection: 1.8 mg/m^2 | Vincristine Sulfate Liposome Injection: 2.14 mg/m^2 | Vincristine Sulfate Liposome Injection: 2.19 mg/m^2 | Vincristine Sulfate Liposome Injection: 2.22 mg/m^2 | Vincristine Sulfate Liposome Injection: 2.24 mg/m^2 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 7 Participants |
| Age, Continuous | 40 years | 75 years | 69 years | 58 years | 70 years | 61 years | 54 years | 57 years | 39 years | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 8 Participants |
| Region of Enrollment United States | 1 participants | 1 participants | 2 participants | 1 participants | 2 participants | 1 participants | 1 participants | 1 participants | 1 participants | 11 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 2 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 1 / 1 | 2 / 2 | 1 / 1 | 1 / 1 | 1 / 1 | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 0 / 1 | 1 / 2 | 0 / 1 | 1 / 1 | 0 / 1 | 0 / 1 | 0 / 1 |
Outcome results
Primary
Maximum Tolerated Dose
Determined as the median of the marginal posterior distribution using data from all available patients
Time frame: Up to 6 cycles of treatment (approximately 6 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose-escalation Cohort | Maximum Tolerated Dose | 2.24 mg/m^2 |
Secondary
Complete Response Rate
The number of patients achieving complete response during treatment on study
Time frame: Up to 6 cycles of treatment (approximately 6 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-escalation Cohort | Complete Response Rate | 1 Participants |
| Vincristine Sulfate Liposome Injection: 1.95 mg/m^2 | Complete Response Rate | 0 Participants |
| Vincristine Sulfate Liposome Injection: 1.98 mg/m^2 | Complete Response Rate | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.04 mg/m^2 | Complete Response Rate | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.10 mg/m^2 | Complete Response Rate | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.14 mg/m^2 | Complete Response Rate | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.19 mg/m^2 | Complete Response Rate | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.22 mg/m^2 | Complete Response Rate | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.24 mg/m^2 | Complete Response Rate | 1 Participants |
Secondary
Number of Participants Who Completed Six Cycles of Study Treatment
Time frame: Up to 6 cycles of treatment (approximately 6 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose-escalation Cohort | Number of Participants Who Completed Six Cycles of Study Treatment | 1 Participants |
| Vincristine Sulfate Liposome Injection: 1.95 mg/m^2 | Number of Participants Who Completed Six Cycles of Study Treatment | 0 Participants |
| Vincristine Sulfate Liposome Injection: 1.98 mg/m^2 | Number of Participants Who Completed Six Cycles of Study Treatment | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.04 mg/m^2 | Number of Participants Who Completed Six Cycles of Study Treatment | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.10 mg/m^2 | Number of Participants Who Completed Six Cycles of Study Treatment | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.14 mg/m^2 | Number of Participants Who Completed Six Cycles of Study Treatment | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.19 mg/m^2 | Number of Participants Who Completed Six Cycles of Study Treatment | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.22 mg/m^2 | Number of Participants Who Completed Six Cycles of Study Treatment | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.24 mg/m^2 | Number of Participants Who Completed Six Cycles of Study Treatment | 1 Participants |
Secondary
Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT: 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
Time frame: Up to 6 cycles of treatment (approximately 6 months)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose-escalation Cohort | Response Rate | Complete Response | 1 Participants |
| Dose-escalation Cohort | Response Rate | Partial Response | 0 Participants |
| Dose-escalation Cohort | Response Rate | Stable Disease | 0 Participants |
| Vincristine Sulfate Liposome Injection: 1.95 mg/m^2 | Response Rate | Partial Response | 1 Participants |
| Vincristine Sulfate Liposome Injection: 1.95 mg/m^2 | Response Rate | Complete Response | 0 Participants |
| Vincristine Sulfate Liposome Injection: 1.95 mg/m^2 | Response Rate | Stable Disease | 0 Participants |
| Vincristine Sulfate Liposome Injection: 1.98 mg/m^2 | Response Rate | Partial Response | 1 Participants |
| Vincristine Sulfate Liposome Injection: 1.98 mg/m^2 | Response Rate | Complete Response | 0 Participants |
| Vincristine Sulfate Liposome Injection: 1.98 mg/m^2 | Response Rate | Stable Disease | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.04 mg/m^2 | Response Rate | Stable Disease | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.04 mg/m^2 | Response Rate | Partial Response | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.04 mg/m^2 | Response Rate | Complete Response | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.10 mg/m^2 | Response Rate | Stable Disease | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.10 mg/m^2 | Response Rate | Complete Response | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.10 mg/m^2 | Response Rate | Partial Response | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.14 mg/m^2 | Response Rate | Stable Disease | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.14 mg/m^2 | Response Rate | Complete Response | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.14 mg/m^2 | Response Rate | Partial Response | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.19 mg/m^2 | Response Rate | Complete Response | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.19 mg/m^2 | Response Rate | Partial Response | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.19 mg/m^2 | Response Rate | Stable Disease | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.22 mg/m^2 | Response Rate | Complete Response | 1 Participants |
| Vincristine Sulfate Liposome Injection: 2.22 mg/m^2 | Response Rate | Partial Response | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.22 mg/m^2 | Response Rate | Stable Disease | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.24 mg/m^2 | Response Rate | Stable Disease | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.24 mg/m^2 | Response Rate | Partial Response | 0 Participants |
| Vincristine Sulfate Liposome Injection: 2.24 mg/m^2 | Response Rate | Complete Response | 1 Participants |