Chronic Lymphocytic Leukemia (CLL)
Conditions
Brief summary
This study consists of 2 parts: Phase 1b and Phase 2. Phase 1b will evaluate the safety and tolerability of the combination of idelallisib with the anti-CD37 monoclonal antibody BI 836826 in participants with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), and establish the high recommended Phase 2 combination dose (highRP2D) as well as an alternate lower recommended Phase 2 combination dose (lowRP2D). Phase 2 will determine the rates of complete response (CR) and of minimal residual disease (MRD) negativity with the combination at the highRP2D and the lowRP2D in participants with R/R CLL.
Interventions
DRUGIdelalisib
Tablets administered orally twice daily
DRUGBI 836826
Intravenous administration as a rate-controlled infusion
Sponsors
Boehringer Ingelheim
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1b: sequential assignment, Phase 2: parallel assignment
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosis of B-cell CLL, established according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and having received at least 2 prior treatment regimens * CLL that warrants treatment * Clinically quantifiable disease burden defined as: * For Phase 1b individuals: absolute lymphocyte count (ALC) \> 5000/μL in peripheral blood. * For Phase 2 individuals either: * At least 1 node ≥ 2 cm on computed tomography (CT) or magnetic resonance imaging (MRI) or * bone marrow exam is performed at screening and demonstrates quantifiable CLL. * Discontinuation of all cytotoxic chemotherapy and anti-CD20 antibody therapy for ≥ 4 weeks, alemtuzumab for ≥ 8 weeks, targeted therapy for ≥ 2 weeks, and investigational therapy for ≥ 3 weeks before enrollment (Phase 1b) or randomization (Phase 2). For individuals with relapsed CLL most recently treated with B-cell receptor (BCR) pathway inhibitors who, in the opinion of the investigator, will not tolerate waiting 3 weeks, a washout period of \> 5 half-lives is allowed. If on a systemic corticosteroid, the dose must be stable for the previous 4 weeks. * Eastern Cooperative Oncology Group (ECOG) score of ≤ 2 Key
Exclusion criteria
* Known histological transformation from CLL to an aggressive lymphoma (ie, Richter transformation) * Known presence of myelodysplastic syndrome * History of a non-CLL malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to enrollment, other adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 2 years. * Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of enrollment * Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension. * History of drug-induced pneumonitis * Ongoing inflammatory bowel disease * Ongoing alcohol or drug addiction * History of prior allogeneic bone marrow progenitor cell or solid organ transplantation * Ongoing systemic immunosuppressive therapy other than corticosteroids * History of prior therapy with any phosphatidylinositol 3-kinase (PI3K) inhibitor (including idelalisib), or any anti-CD37 agent * Ongoing infection with, or treatment or prophylaxis for, CMV within the past 28 days. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| For Phase 2: Minimal Residual Disease (MRD) Negativity Rate in Bone Marrow by Week 50 | Week 50 | MRD defined as the percentage of participants with MRD \< 10\^-4, assessed by flow cytometry in bone marrow, achieved by Week 50. |
| Phase 1b: Percentage of Participants Experienced Dose Limiting Toxicities (DLTs) During the First 7 Weeks of Study Therapy | Up to 7 weeks | DLTs refer to toxicities experienced during the final 6 weeks of 7-week study treatment that have been judged to be clinically significant and related to study treatment. Events occurring during the initial 7-day idelalisib monotherapy run-in period and resolving by Day 8 were not included. |
| For Phase 2: Complete Response Rate (CRR) | Up to 18 months | CRR was defined as the percentage of participants who achieve a complete response (CR). CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| For Phase 2: Overall Survival (OS) | Up to 18 months | OS was defined as the interval from the randomization to the date of death from any cause. |
| Phase 1b: Percentage of Participants Experienced DLTs During the Treatment Period | Up to 18 months | DLTs refer to toxicities experienced during the final 6 weeks of 7-week study treatment that have been judged to be clinically significant and related to study treatment. Events occurring during the initial 7-day idelalisib monotherapy run-in period and resolving by Day 8 were not included. |
| For Phase 1b and Phase 2: Number of Participants Experiencing Any Serious Adverse Events (SAE) | Up to 18 months | An SAE is defined as an event that, at any dose, results in the following: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect or a medically important event or reaction. |
| For Phase 1b and Phase 2: Number of Participants Who Permanently Discontinued Study Treatment Due to an Adverse Event | Up to 18 months | An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The severity of AEs was graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. |
| For Phase 2: Overall Response Rate (ORR) | Up to 18 months | ORR was defined as the percentage of participants achieving a complete response (CR) or partial response (PR). CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. |
| For Phase 2: Duration of Complete Response (DCR) | Up to 18 months | DCR was defined as the interval from the first documentation of CR to the earlier of the first documentation of definitive disease progression or death from any cause. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. |
| For Phase 2: Duration of Response (DOR) | Up to 18 months | DOR was defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions. |
| For Phase 2: Progression-Free Survival (PFS) | Up to 18 months | PFS was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression was defined as evidence of any new disease, worsening of index lesions, spleen or liver, or non-index disease, decrease in platelet count or hemoglobin that is attributable to chronic lymphocytic leukemia (CLL) or more than 4 weeks after the discontinuation of idelalisib: an increase in the number of blood lymphocytes by 50% or more. |
| For Phase 2: MRD Negativity Rate in Blood at Any Time | Up to 18 months | MRD negativity rate in blood was defined as the percentage of participants with MRD \< 10\^-4, assessed by flow cytometry in blood, at any time on study. |
| For Phase 2: MRD Negativity Rate in Bone Marrow at Any Time | Up to 18 months | MRD negativity rate in bone marrow was defined as the percentage of participants with MRD \< 10\^-4, assessed by flow cytometry in bone marrow, at any time on study. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States. The first participant was screened on 29 December 2015. The last study visit occurred on 05 July 2017.
Pre-assignment details
5 participants were screened. Due to the early study termination, phase 2 was not initiated. Enrollment to this study was closed during Phase 1b. The 2 enrolled participants were allowed to remain on the study.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Idelalisib + BI 836826 Idelalisib 50 mg tablet was administered orally twice daily each day until the end of treatment. BI 836826 was administered intravenously as a rate-controlled infusion. An initial dose of 10 mg was administered on Day 8. Doses of 50 mg were administered on Day 9 and Day 15. The full assigned dose of 100 mg was administered on Day 22, every 2 weeks thereafter through Week 18, and every 4 weeks thereafter through Week 46. | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Progressive Disease | 2 |
Baseline characteristics
| Characteristic | Phase 1b: Idelalisib + BI 836826 |
|---|---|
| Age, Customized >= 65 Years | 2 Participants |
| Race/Ethnicity, Customized Ethnicity-Data not Reported | NA Participants |
| Race/Ethnicity, Customized Race-Data not reported | NA Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 2 / 2 |
Outcome results
Primary
For Phase 2: Complete Response Rate (CRR)
CRR was defined as the percentage of participants who achieve a complete response (CR). CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease.
Time frame: Up to 18 months
Population: Due to early study termination this outcome measure was not assessed.
Primary
For Phase 2: Minimal Residual Disease (MRD) Negativity Rate in Bone Marrow by Week 50
MRD defined as the percentage of participants with MRD \< 10\^-4, assessed by flow cytometry in bone marrow, achieved by Week 50.
Time frame: Week 50
Population: Due to early study termination this outcome measure was not assessed.
Primary
Phase 1b: Percentage of Participants Experienced Dose Limiting Toxicities (DLTs) During the First 7 Weeks of Study Therapy
DLTs refer to toxicities experienced during the final 6 weeks of 7-week study treatment that have been judged to be clinically significant and related to study treatment. Events occurring during the initial 7-day idelalisib monotherapy run-in period and resolving by Day 8 were not included.
Time frame: Up to 7 weeks
Population: Due to early study termination this outcome measure was not assessed.
Secondary
For Phase 1b and Phase 2: Number of Participants Experiencing Any Serious Adverse Events (SAE)
An SAE is defined as an event that, at any dose, results in the following: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect or a medically important event or reaction.
Time frame: Up to 18 months
Population: The Safety Analysis Set included all participants who received at least 1 dose of any study drug, with treatment group designated according to the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Idelalisib + BI 836826 | For Phase 1b and Phase 2: Number of Participants Experiencing Any Serious Adverse Events (SAE) | 2 Participants |
Secondary
For Phase 1b and Phase 2: Number of Participants Who Permanently Discontinued Study Treatment Due to an Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The severity of AEs was graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
Time frame: Up to 18 months
Population: The Safety Analysis Set included all participants who received at least 1 dose of any study drug, with treatment group designated according to the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Idelalisib + BI 836826 | For Phase 1b and Phase 2: Number of Participants Who Permanently Discontinued Study Treatment Due to an Adverse Event | 0 Participants |
Secondary
For Phase 2: Duration of Complete Response (DCR)
DCR was defined as the interval from the first documentation of CR to the earlier of the first documentation of definitive disease progression or death from any cause. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease.
Time frame: Up to 18 months
Population: Due to early study termination this outcome measure was not assessed.
Secondary
For Phase 2: Duration of Response (DOR)
DOR was defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause. CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions.
Time frame: Up to 18 months
Population: Due to early study termination this outcome measure was not assessed.
Secondary
For Phase 2: MRD Negativity Rate in Blood at Any Time
MRD negativity rate in blood was defined as the percentage of participants with MRD \< 10\^-4, assessed by flow cytometry in blood, at any time on study.
Time frame: Up to 18 months
Population: Due to early study termination this outcome measure was not assessed.
Secondary
For Phase 2: MRD Negativity Rate in Bone Marrow at Any Time
MRD negativity rate in bone marrow was defined as the percentage of participants with MRD \< 10\^-4, assessed by flow cytometry in bone marrow, at any time on study.
Time frame: Up to 18 months
Population: Due to early study termination this outcome measure was not assessed.
Secondary
For Phase 2: Overall Response Rate (ORR)
ORR was defined as the percentage of participants achieving a complete response (CR) or partial response (PR). CR was defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease. PR was defined as a ≥ 50% reduction in the sum of the products of the longest perpendicular diameters of all index lesions, with no new lesions.
Time frame: Up to 18 months
Population: Due to early study termination this outcome measure was not assessed.
Secondary
For Phase 2: Overall Survival (OS)
OS was defined as the interval from the randomization to the date of death from any cause.
Time frame: Up to 18 months
Population: Due to early study termination this outcome measure was not assessed.
Secondary
For Phase 2: Progression-Free Survival (PFS)
PFS was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression was defined as evidence of any new disease, worsening of index lesions, spleen or liver, or non-index disease, decrease in platelet count or hemoglobin that is attributable to chronic lymphocytic leukemia (CLL) or more than 4 weeks after the discontinuation of idelalisib: an increase in the number of blood lymphocytes by 50% or more.
Time frame: Up to 18 months
Population: Due to early study termination this outcome measure was not assessed.
Secondary
Phase 1b: Percentage of Participants Experienced DLTs During the Treatment Period
DLTs refer to toxicities experienced during the final 6 weeks of 7-week study treatment that have been judged to be clinically significant and related to study treatment. Events occurring during the initial 7-day idelalisib monotherapy run-in period and resolving by Day 8 were not included.
Time frame: Up to 18 months
Population: Due to early study termination this outcome measure was not assessed.