Recurrent Chronic Lymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Small Lymphocytic Lymphoma
Conditions
Brief summary
This is an open-label non-randomized two-center phase 2 study evaluating the safety and efficacy of concurrent therapy with ibrutinib and venetoclax in subjects with relapsed or refractory CLL/SLL.
Detailed description
The primary objective of this study is to evaluate the efficacy of concurrent therapy with ibrutinib and venetoclax in patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). The secondary objectives of this study are to define the safety, tolerability, and dose-limiting toxicity (DLT) within 28 days of completion of dose-escalation.
Interventions
DRUGIbrutinib
Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1.
DRUGVenetoclax
Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg).
Sponsors
Steven E. Coutre
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
* Subject must voluntarily sign and date an informed consent approved by the Institutional Review Board prior to initiation of any study specific procedures * Subject must have a diagnosis of CLL that meets International Workshop on Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute (NCI)-Working Group (WG) criteria * Subject must have relapsed/refractory disease with an indication for treatment according to the 2008 IWCLL/NCI WG criteria * Measurable nodal disease by computed tomography (CT) * Absolute neutrophil count \> 750 cells/mm\^3 (0.75 x 10\^9/L) * Platelet count \> 30,000 cells/mm\^3 (30 x 10\^9/L) * Hemoglobin \> 8.0 g/dL * Serum aspartate transaminase (AST) or alanine transaminase (ALT) =\< 2.5 x upper limit of normal (ULN) * Estimated creatinine clearance \>= 30 mL/min (Cockcroft-Gault) * Bilirubin =\< 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) * Prothrombin time/international normalized ratio (PT/INR) \< 1.5 x ULN and partial thromboplastin time (PTT) (activated \[a\]PTT) \< 1.5 x ULN * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for \>= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); female subjects of childbearing potential must have a negative serum pregnancy test upon study entry * Male and female subjects must agree to use highly effective methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, some intrauterine devices \[IUDs\], sexual abstinence, or sterilized partner) during the period of therapy and for 90 days after the last dose of study drug
Exclusion criteria
* Subject has previously received either venetoclax or ibrutinib * Subject has received a live virus vaccine within 28 days prior to the initiation of study treatment * Subject has undergone an allogeneic stem cell transplant in the past 1 year and must not have active chronic graft versus host disease (cGVHD) if over 1 year post allogeneic transplant * Subject has developed Richter's transformation confirmed by biopsy * Chemotherapy =\< 21 days prior to first administration of study treatment and/or monoclonal antibody =\< 6 weeks prior to first administration of study treatment * History of other malignancies, except: * Malignancy treated with curative intent and with no known active disease present for \>= 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease * Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc, or chronic administration \[\> 14 days\] of \> 20 mg/day of prednisone) within 28 days of the first dose of study drug * Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug * Recent infection requiring systemic treatment that was completed =\< 14 days before the first dose of study drug * Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version \[v\]4), grade =\< 1, or to the levels dictated in the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) | 62 weeks | Complete Response (CR) will be assessed as the number of participants who, based on investigator assessment based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, achieve a complete remission. IWCLL complete remission is defined as follows. * Lymphadenopathy: none \> 1.5 cm * Blood lymphocytes: \< 4,000/µL * Hepatomegaly: none * Splenomegaly: none * Bone marrow: normocellular with \< 30 lymphocytes, no B lymphoid nodules. The outcome is reported as the number of participants who achieve CR, a number without dispersion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DoR) | 117 weeks | Duration of response (DoR) refers to a participant maintaining clinical response after achieving either complete response (CR) or partial response (PR). The outcome is reported as the number of subjects who have maintained clinical response through 117 weeks. Response defined as the following. CR. * Lymphadenopathy: none \> 1.5 cm * Blood lymphocytes: \< 4,000/µL * Hepatomegaly: none * Splenomegaly: none * Bone marrow: normocellular with \< 30 lymphocytes, no B lymphoid nodules. PR. * Lymphadenopathy: decrease ≥ 50% * Blood lymphocytes: decrease ≥ 50% * Hepatomegaly: decrease ≥ 50% * Splenomegaly: decrease ≥ 50% * Bone marrow: not considered. |
| Minimal Residual Disease (MRD) | 117 weeks | Minimal residual disease (MRD) refers to the small numbers of leukemic cells that can remain in the participant after treatment, and may not be associated with any symptoms (remission). Although the participant may feel healthy, the MRD is a major cause of eventual leukemic relapse. MRD-negative is the ideal treatment outcome. MRD negativity was defined as less than one leukemic cell per 10,000 leukocytes as assessed by bone marrow-based flow cytometry. The outcome is reported as the number of participants who were positive for MRD, or negative. |
| Overall Response (OR) | 62 weeks | Overall response (OR) is the overall number of subjects that begin treatment and achieve a complete response (CR); partial response (PR); or Stable Disease (SD) 62 weeks after the beginning of treatment, according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. IWCLL CR is defined as follows. The outcome is reported as the number of participants who achieve CR, PR, or SD, and number without dispersion. CR: * Lymphadenopathy: none \> 1.5 cm * Blood lymphocytes: \< 4,000/µL * Hepatomegaly: none * Splenomegaly: none * Bone marrow: normocellular with \< 30 lymphocytes, no B lymphoid nodules. PR: * Lymphadenopathy: decrease ≥ 50% * Blood lymphocytes: decrease ≥ 50% * Hepatomegaly: decrease ≥ 50% * Splenomegaly: decrease ≥ 50% * Bone marrow: not considered. SD: * Lymphadenopathy: change of ± 49% * Blood lymphocytes: change of ± 49% * Hepatomegaly: change of ± 49% * Splenomegaly: change of ± 49% * Bone marrow: not considered. |
| Progression-free Survival (PFS) | 117 weeks | Progression-free survival (PFS) is a term that means to remain alive with progressive disease (PD). PD is defined as * Lymphadenopathy: Increase ≥ 50% * Blood lymphocytes: Increase ≥ 50% * Hepatomegaly: Increase ≥ 50% * Splenomegaly: Increase ≥ 50% * Bone marrow: not considered. The outcome is reported as the number of participants who remained alive without PD 117 weeks after the beginning of treatment. |
| Time-to-progression (TTP) | Through 117 weeks | Time-to-progression (TTP) is a measure of the length of time from the beginning of treatment until progressive disease (PD). PD is defined as * Lymphadenopathy: Increase ≥ 50% * Blood lymphocytes: Increase ≥ 50% * Hepatomegaly: Increase ≥ 50% * Splenomegaly: Increase ≥ 50% * Bone marrow: not considered. The outcome will be reported as the median TTP as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI). |
| Overall Survival (OS) | Through 117 weeks | Overall survival (OS) represents the amount of time the participants remain alive after treatment. The outcome is reported as the number of participants remaining alive at 117 weeks (about 2 years and 3 months) after the start of treatment, a number without dispersion. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time-to-next-treatment (TTNT) | Through 117 weeks | The time-to-next-treatment (TTNT) is a measure of the period of time from the beginning of treatment until the patient has to receive a different treatment for his/her disease. TTNT was assessed as the time period until the participants next anti-chronic lymphocytic leukemia (CLL) treatment. The outcome will be reported as the median TTNT as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Ibrutinib, Venetoclax) Patients receive ibrutinib PO QD beginning on week 1 day 1. Treatment with ibrutinib continues in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD beginning on week 9 day 1. Treatment with venetoclax continues up to week 61 day 7 in the absence of disease progression or unacceptable toxicity.
Ibrutinib: Administered at 420 mg/day, as oral capsules (3 x 140 mg), starting Day 1, Week 1.
Venetoclax: Administered as tablets, starting Day 1, Week 9, with dose increasing every 7 days through 5 dose levels (20 mg; 50 mg; 100 mg; 200 mg; 400 mg). | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Treatment (Ibrutinib, Venetoclax) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 14 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 65.3 years STANDARD_DEVIATION 9.16 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 22 |
| other Total, other adverse events | 22 / 22 |
| serious Total, serious adverse events | 10 / 22 |
Outcome results
Primary
Complete Response (CR)
Complete Response (CR) will be assessed as the number of participants who, based on investigator assessment based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria, achieve a complete remission. IWCLL complete remission is defined as follows. * Lymphadenopathy: none \> 1.5 cm * Blood lymphocytes: \< 4,000/µL * Hepatomegaly: none * Splenomegaly: none * Bone marrow: normocellular with \< 30 lymphocytes, no B lymphoid nodules. The outcome is reported as the number of participants who achieve CR, a number without dispersion.
Time frame: 62 weeks
Population: Some participants withdrew consent before the assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Ibrutinib, Venetoclax) | Complete Response (CR) | 12 Participants |
Secondary
Duration of Response (DoR)
Duration of response (DoR) refers to a participant maintaining clinical response after achieving either complete response (CR) or partial response (PR). The outcome is reported as the number of subjects who have maintained clinical response through 117 weeks. Response defined as the following. CR. * Lymphadenopathy: none \> 1.5 cm * Blood lymphocytes: \< 4,000/µL * Hepatomegaly: none * Splenomegaly: none * Bone marrow: normocellular with \< 30 lymphocytes, no B lymphoid nodules. PR. * Lymphadenopathy: decrease ≥ 50% * Blood lymphocytes: decrease ≥ 50% * Hepatomegaly: decrease ≥ 50% * Splenomegaly: decrease ≥ 50% * Bone marrow: not considered.
Time frame: 117 weeks
Population: Some participants withdrew consent before the assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Ibrutinib, Venetoclax) | Duration of Response (DoR) | 15 Participants |
Secondary
Minimal Residual Disease (MRD)
Minimal residual disease (MRD) refers to the small numbers of leukemic cells that can remain in the participant after treatment, and may not be associated with any symptoms (remission). Although the participant may feel healthy, the MRD is a major cause of eventual leukemic relapse. MRD-negative is the ideal treatment outcome. MRD negativity was defined as less than one leukemic cell per 10,000 leukocytes as assessed by bone marrow-based flow cytometry. The outcome is reported as the number of participants who were positive for MRD, or negative.
Time frame: 117 weeks
Population: Test results were not available for all participants. Negligible was considered as negative.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Ibrutinib, Venetoclax) | Minimal Residual Disease (MRD) | Minimal residual disease (MRD)-negative | 13 Participants |
| Treatment (Ibrutinib, Venetoclax) | Minimal Residual Disease (MRD) | Minimal residual disease (MRD)-positive | 3 Participants |
Secondary
Overall Response (OR)
Overall response (OR) is the overall number of subjects that begin treatment and achieve a complete response (CR); partial response (PR); or Stable Disease (SD) 62 weeks after the beginning of treatment, according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. IWCLL CR is defined as follows. The outcome is reported as the number of participants who achieve CR, PR, or SD, and number without dispersion. CR: * Lymphadenopathy: none \> 1.5 cm * Blood lymphocytes: \< 4,000/µL * Hepatomegaly: none * Splenomegaly: none * Bone marrow: normocellular with \< 30 lymphocytes, no B lymphoid nodules. PR: * Lymphadenopathy: decrease ≥ 50% * Blood lymphocytes: decrease ≥ 50% * Hepatomegaly: decrease ≥ 50% * Splenomegaly: decrease ≥ 50% * Bone marrow: not considered. SD: * Lymphadenopathy: change of ± 49% * Blood lymphocytes: change of ± 49% * Hepatomegaly: change of ± 49% * Splenomegaly: change of ± 49% * Bone marrow: not considered.
Time frame: 62 weeks
Population: Some participants withdrew before the assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Ibrutinib, Venetoclax) | Overall Response (OR) | Complete Response (CR) | 12 Participants |
| Treatment (Ibrutinib, Venetoclax) | Overall Response (OR) | Partial Response (PR) | 8 Participants |
| Treatment (Ibrutinib, Venetoclax) | Overall Response (OR) | Stable Disease (SD) | 0 Participants |
Secondary
Overall Survival (OS)
Overall survival (OS) represents the amount of time the participants remain alive after treatment. The outcome is reported as the number of participants remaining alive at 117 weeks (about 2 years and 3 months) after the start of treatment, a number without dispersion.
Time frame: Through 117 weeks
Population: Those participants who withdrew consent or were withdrawn for other medical treatments before 117 weeks are not included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Ibrutinib, Venetoclax) | Overall Survival (OS) | 16 Participants |
Secondary
Progression-free Survival (PFS)
Progression-free survival (PFS) is a term that means to remain alive with progressive disease (PD). PD is defined as * Lymphadenopathy: Increase ≥ 50% * Blood lymphocytes: Increase ≥ 50% * Hepatomegaly: Increase ≥ 50% * Splenomegaly: Increase ≥ 50% * Bone marrow: not considered. The outcome is reported as the number of participants who remained alive without PD 117 weeks after the beginning of treatment.
Time frame: 117 weeks
Population: Some participants withdrew consent before the assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Ibrutinib, Venetoclax) | Progression-free Survival (PFS) | 15 Participants |
Secondary
Time-to-progression (TTP)
Time-to-progression (TTP) is a measure of the length of time from the beginning of treatment until progressive disease (PD). PD is defined as * Lymphadenopathy: Increase ≥ 50% * Blood lymphocytes: Increase ≥ 50% * Hepatomegaly: Increase ≥ 50% * Splenomegaly: Increase ≥ 50% * Bone marrow: not considered. The outcome will be reported as the median TTP as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI).
Time frame: Through 117 weeks
Population: An insufficient number of participants have experienced disease progression to determine a median value for that time period. This is expressed statistically as Median Not Reached.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Ibrutinib, Venetoclax) | Time-to-progression (TTP) | NA months |
Other Pre-specified
Time-to-next-treatment (TTNT)
The time-to-next-treatment (TTNT) is a measure of the period of time from the beginning of treatment until the patient has to receive a different treatment for his/her disease. TTNT was assessed as the time period until the participants next anti-chronic lymphocytic leukemia (CLL) treatment. The outcome will be reported as the median TTNT as determined by Kaplan-Meier methodology, with 95% confidence interval (95% CI).
Time frame: Through 117 weeks
Population: An insufficient number of participants have advanced to a next treatment to determine a median value for that time period. This is expressed statistically as Median Not Reached.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Ibrutinib, Venetoclax) | Time-to-next-treatment (TTNT) | NA months |