Chronic Lymphocytic Leukemia, CLL, Refractory Chronic Lymphocytic Leukemia, Refractory Small Lymphocytic Lymphoma, Relapsed Chronic Lymphocytic Leukemia, Relapsed CLL, Relapsed Small Lymphocytic Lymphoma, SLL, Small Lymphocytic Lymphoma
Conditions
Keywords
venetoclax, idelalisib, rituximab
Brief summary
To determine the recommended phase 2 dose (RP2D) of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory Chronic lymphocytic leukemia/ Small lymphocytic lymphoma (CLL/SLL) following a lead-in period with idelalisib and rituximab
Detailed description
This phase 1, multicenter, dose-escalation study is designed to find the Recommended Phase 2 Dose (RP2D) of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory CLL/SLL and to assess the clinical activity of the combination with rituximab in patients with relapsed or refractory CLL/SLL and to assess the clinical activity of the combination.
Interventions
DRUGDose combination 1-1
100 mg QD of idelalisib + 100 mg QD of venetoclax
DRUGdose combination 1-2
100 mg QD of idelalisib + 200 mg QD of venetoclax
DRUGDose combination 1-3
100 mg BID of idelalisib + 200 mg QD of venetoclax
DRUGdose combination 1-4
150 mg BID of idelalisib + 200 mg QD of venetoclax
DRUGSub-Trial: Dose combination 2-1
100 mg BID of idelalisib + 100 mg QD of venetoclax
DRUGSub-Trial: Dose combination 2-2
150 mg BID of idelalisib + 100 mg QD of venetoclax
Sponsors
Gilead Sciences
Virginia Commonwealth University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients will start on dose level 1 of venetoclax in combination with rituximab and idelalisib, then escalate or de-escalate (if lower dose is available) based upon the estimated probabilities of toxicity from an extension of the continual reassessment method for 2 agents.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Age ≥ 18 years of age. Relapsed or refractory B-cell CLL or biopsy-proven SLL. Treatment required in the opinion of the investigator Must have had at least one standard treatment with a regimen containing at least one of the following agents/classes of agents; and where specified, must also meet the treatment duration, progression, and/or relapse criteria for that class of agent: * Fludarabine * An alkylator (eg, chlorambucil, bendamustine) * A BTK inhibitor (eg, ibrutinib, acalabrutinib); and must have progressed or relapsed \> 6 months after last BTK inhibitor treatment * An anti-CD20 monoclonal antibody (eg, rituximab, obinutuzumab) * A BCL-2-family protein inhibitor (eg, venetoclax, navitoclax); and * if best response is \< CR with BCL-2-family protein inhibitor treatment * must have had ≥ 1 year of BCL-2-family protein inhibitor treatment; and * must have progressed \> 6 months after last BCL-2-family protein inhibitor treatment * if best response is CR with BCL-2-family protein inhibitor treatment * must have relapsed ≥ 1 year after last BCL-2-family protein inhibitor treatment * A PI3K inhibitor (eg, idelalisib, duvelisib, TGR-1202, copanlisib, buparlisib); and must have progressed or relapsed \> 6 months after last treatment with the PI3K inhibitor (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION) Prior allogeneic stem cell transplant allowed provided the following criteria are met: * ≥ 12 months have elapsed since allogeneic transplant * No current or prior evidence of graft-versus-host disease * No current requirement for immunosuppressive therapy Prior autologous stem cell transplant allowed provided ≥ 6 months have elapsed since autologous transplant. Eastern Cooperative Oncology Group performance status of 0, 1, or 2 Adequate bone marrow function as follows: * Absolute neutrophil count (ANC) ≥ 1,000/mm3 (without support of granulocyte colony stimulating factors) * Platelets ≥ 50,000/mm3 (untransfused) * Hemoglobin ≥ 9.0 g/dL Adequate coagulation, renal, and hepatic function as follows: * aPTT and PT ≤ 1.2 × upper limit of normal (ULN) for the laboratory * Calculated creatinine clearance ≥ 50 mL/min as calculated by the standard Cockcroft-Gault equation using age, actual weight, creatinine, and gender * AST and ALT ≤ 1.5 × ULN for the laboratory * Bilirubin ≤ 1.5 × ULN for the laboratory. For a woman of childbearing potential (WCBP), a negative serum pregnancy test performed within 7 days prior to initiation of study treatment. Note: Postmenopausal is defined as any of the following: * Age ≥ 60 years * Age \< 60 years and amenorrheic for at least 1 year with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range * Bilateral oophorectomy WCBP and male patients must agree to use a medically accepted form of birth control for the duration of study treatment and for at least 1 month following completion of venetoclax and/or idelalisib or 12 months following rituximab, whichever occurs later. Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
A patient who meets any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Find the RP2D of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) | 41 Months | Determine the recommended phase 2 dose of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory CLL/SLL following a lead-in period with idelalisib and rituximab. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determination of cumulative complete response (CR) rate. | 52 Months | Determine the cumulative CR rate to the study regimen at 7 and 13 months using the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. |
| Summarize the objective response rate. | 52 Months | Determine the cumulative overall disease response to the study regimen at 7 and 13 months using the 2008 IWCLL criteria. |
| Minimal residual disease (MRD) rate | 52 Months | Estimate the rate of undetectable minimal residual disease (MRD) status for idelalisib and venetoclax in combination with rituximab using 4-color flow cytometry in peripheral blood and/or bone marrow for responding patients |
| Safety Evaluation: Determine adverse events (AEs) reported using criteria in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 | 63 Months | Observed adverse events of treatment with idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory CLL/ SLL following a lead-in period with idelalisib and rituximab utlizing CTCAE Version 5.0 |
| Progression Free Survival Rate | 63 Months | Determine the progression-free survival (PFS) rate (at 24 months following initiation of venetoclax) for idelalisib and venetoclax in combination with rituximab |
| Pharmacokinetics of the combination of idelalisib and venetoclax. | 7 Years | Determine the idelalisib and venetoclax plasma concentrations measured at designated time points throughout the study: pre-Tx; C1D1; C1D15; C1D22; C1D29; C3D1; C7D22; C13D222; at DLT (if feasible); at relapse (if feasible)\] |
| Overall Survival Rate | 63 Months | determine the OS rate (at 24 months following initiation of venetoclax) for idelalisib and venetoclax in combination with rituximab. |
Outcome results
None listed