Chronic Lymphocytic Leukemia (CLL)
Conditions
Keywords
CLL, TRU-016, chronic lymphocytic leukemia, relapsed CLL, bendamustine
Brief summary
The objective of the first part of the study is to determine a safe dose of TRU-016 that can be used in combination with bendamustine in patients with relapsed CLL. The objectives of the second part of the study are to compare the safety and efficacy of TRU-016 in combination with bendamustine to bendamustine alone in patients with relapsed CLL.
Detailed description
This study consisted of two parts. The initial dose escalation stage was a Phase 1b study evaluating the safety and tolerability of two doses of TRU-016 administered in combination with bendamustine to patients with relapsed chronic lymphocytic leukemia (CLL). In the randomized Phase 2 stage of the study, the efficacy and safety of the selected dose of 20 mg/kg TRU-016 combined with bendamustine was compared to bendamustine alone. The pharmacokinetics and pharmacodynamics of TRU-016 and the development of antibodies to TRU-016 were evaluated in both phases of the study.
Interventions
DRUGTRU-016 and bendamustine
TRU-016 at 20 mg/kg, weekly by IV infusion x 2 cycles, then every 14 days x 4 cycles PLUS bendamustine (70 mg/m2 by IV infusion on Days 1 and 2 of every 28-day cycle, for 6 cycles
DRUGBendamustine
Bendamustine at 70 mg/m2 by IV infusion on Days 1 and 2 of every 28-day cycle, for 6 cycles
DRUG15 mg/kg TRU-016 and bendamustine
TRU-016 at 15 mg/kg, weekly by IV infusion x 2 cycles, then every 14 days x 4 cycles PLUS bendamustine (70 mg/m2 by IV infusion on Days 1 and 2 of every 28-day cycle, for 6 cycles
DRUG20 mg/kg TRU-016 and bendamustine
TRU-016 at 20 mg/kg, weekly by IV infusion x 2 cycles, then every 14 days x 4 cycles PLUS bendamustine (70 mg/m2 by IV infusion on Days 1 and 2 of every 28-day cycle, for 6 cycles
Sponsors
Aptevo Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of relapsed CLL with 1 to 3 prior treatments * Demonstrated active disease requiring treatment * No prior bendamustine treatment * Not refractory to fludarabine or other purines, either as a single agent or in combination * Age \>/=18 years; male or female * Eastern Cooperative Oncology Group (ECOG) performance status of \</= 2 * Creatinine clearance \> 40 mL/min * Absolute neutrophil count (ANC) \>/= 1,200/mm3 * Platelets \>/= 75,000/mm3 * Lymphocytes \>/= 5,000/mm3 in Phase 1b
Exclusion criteria
* Treatment with rituximab or other B-cell depleting agent within 30 days or alemtuzumab within 12 weeks * Previous anticancer therapy within 30 days * Refractory to prior fludarabine or other purine analog therapy either as a single agent or in combination * Receipt of prior bendamustine or TRU-016 * Receipt of an investigational therapy or major surgery within 30 days * Previous or concurrent additional malignancy (some exceptions apply) * Any significant concurrent medical diseases or conditions * Positive serology for HIV or hepatitis C, hepatitis B surface antigen positive or hepatitis B core antibody positive. * Pregnant or breast feeding * Drug or alcohol abuse * Allergic to mannitol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria | 1 and 2 months after end of treatment, then every 3 months until disease progression, death, initiation of new therapy, study withdrawal, or 2 years | Patients had full clinical response assessment monthly during treatment, at the end of treatment (EOT) visit, 30 and 60 days after the EOT visit, and subsequently every 3 months until the earliest of progression of CLL, death, initiation of new therapy, withdrawal from the study, or completion of 18 months of follow-up evaluations. Clinical response assessment included physical examination with measurement of spleen, liver, and lymph nodes, disease-related symptoms, and laboratory measurements, specifically complete blood count (CBC) with differential. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Per NCI Criteria | 1 and 2 months after end of treatment, then every 3 months until disease progression, death, initiation of new therapy, study withdrawal, or 2 years | Overall response rate per National Cancer Institute (NCI) Working group criteria. |
Countries
Austria, Germany, Poland, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: 15 mg/kg TRU-016 TRU-016 (15 mg/kg) and bendamustine (70 mg/m2)
TRU-016 and bendamustine: TRU-016 (20 mg/kg) weekly by IV infusion x 2 cycles, then every 14 days x 4 cycles PLUS bendamustine (70 mg/m2 by IV infusion on Days 1 and 2 of every 28-day cycle, for 6 cycles | 6 |
| Phase 1: 20 mg/kg TRU-016 TRU-016 (20 mg/kg) and bendamustine (70 mg/m2)
TRU-016 and bendamustine: TRU-016 (20 mg/kg) weekly by IV infusion x 2 cycles, then every 14 days x 4 cycles PLUS bendamustine (70 mg/m2 by IV infusion on Days 1 and 2 of every 28-day cycle, for 6 cycles | 6 |
| Phase 2: TRU-016 and Bendamustine TRU-016 (20 mg/kg) and bendamustine (70 mg/m2)
TRU-016 and bendamustine: TRU-016 (20 mg/kg) weekly by IV infusion x 2 cycles, then every 14 days x 4 cycles PLUS bendamustine (70 mg/m2 by IV infusion on Days 1 and 2 of every 28-day cycle, for 6 cycles | 32 |
| Phase 2: Bendamustine Bendamustine alone (70 mg/m2)
Bendamustine: 70 mg/m2 by IV infusion on Days 1 and 2 of every 28-day cycle, for 6 cycles | 33 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | bladder cancer | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase 1: 15 mg/kg TRU-016 | Phase 1: 20 mg/kg TRU-016 | Phase 2: TRU-016 and Bendamustine | Phase 2: Bendamustine | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 3 Participants | 16 Participants | 12 Participants | 36 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 3 Participants | 16 Participants | 21 Participants | 41 Participants |
| Age, Continuous | 66.3 years STANDARD_DEVIATION 5.8 | 67.7 years STANDARD_DEVIATION 8.9 | 64.1 years STANDARD_DEVIATION 9.4 | 62.2 years STANDARD_DEVIATION 8.1 | 62.3 years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 32 Participants | 33 Participants | 77 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 5 Participants | 30 Participants | 32 Participants | 72 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 12 Participants | 8 Participants | 24 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 20 Participants | 25 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 24 / 32 | 25 / 33 |
| serious Total, serious adverse events | 3 / 6 | 1 / 6 | 10 / 32 | 15 / 33 |
Outcome results
Primary
Response Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria
Patients had full clinical response assessment monthly during treatment, at the end of treatment (EOT) visit, 30 and 60 days after the EOT visit, and subsequently every 3 months until the earliest of progression of CLL, death, initiation of new therapy, withdrawal from the study, or completion of 18 months of follow-up evaluations. Clinical response assessment included physical examination with measurement of spleen, liver, and lymph nodes, disease-related symptoms, and laboratory measurements, specifically complete blood count (CBC) with differential.
Time frame: 1 and 2 months after end of treatment, then every 3 months until disease progression, death, initiation of new therapy, study withdrawal, or 2 years
Population: Treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 15 mg/kg TRU-016 | Response Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria | 66.7 percentage of patients |
| Phase 1 20 mg/kg TRU-016 | Response Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria | 83.3 percentage of patients |
| TRU-016 and Bendamustine | Response Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria | 68.8 percentage of patients |
| Bendamustine | Response Per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Criteria | 39.4 percentage of patients |
Secondary
Response Per NCI Criteria
Overall response rate per National Cancer Institute (NCI) Working group criteria.
Time frame: 1 and 2 months after end of treatment, then every 3 months until disease progression, death, initiation of new therapy, study withdrawal, or 2 years
Population: Safety data for all patients who received any study drug and efficacy data for randomized patients who received some study treatment and have some post baseline data are presented here.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 15 mg/kg TRU-016 | Response Per NCI Criteria | 81.3 percentage of patients |
| Phase 1 20 mg/kg TRU-016 | Response Per NCI Criteria | 66.7 percentage of patients |
| TRU-016 and Bendamustine | Response Per NCI Criteria | 66.7 percentage of patients |
| Bendamustine | Response Per NCI Criteria | 100 percentage of patients |