Acalabrutinib in Combination With Anti-CD20 and Venetoclax in Relapsed/Refractory or Untreated CLL/SLL/PLL
- Conditions
- Prolymphocytic LeukemiaChronic Lymphocytic LeukemiaSmall Lymphocytic Lymphoma
- Interventions
- Registration Number
- NCT02296918
- Lead Sponsor
- Acerta Pharma BV
- Brief Summary
To evaluate the safety and preliminary efficacy of acalabrutinib in combination with obinutuzumab in 4 separate cohorts of participants.
- Detailed Description
A Phase 1b Study of ACP-196 in Combination with Obinutuzumab for Participants with Relapsed/Refractory or Untreated chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL)/ prolymphocytic leukemia (PLL).
Study started with two cohorts, on Acalabrutinib and Obinutuzumab, cohort 1 for relapsed or refractory participants and cohort 2 for treatment naïve participants. Then for longer survival data and combination therapy, two new cohorts added to the study, cohort 3 with relapsed or refractory participants on Acalabrutinib, Rituximab and Venetoclax, and cohort 4 with treatment naïve participants on Acalabrutinib, Obinutuzumab and Venetoclax.
Primary endpoints: For Cohorts 1 and 2, the ORR (PR or better) at the 12-month response assessment will be calculated and 95% exact binomial confidence interval (CIs) will be provided. For Cohorts 1 to 4, toxicities will be tabulated by type and grade using NCI-CTCAE (National Cancer Institute - Common Terminology Criteria for Adverse Events) version 4.03 criteria or higher and displayed in summary form.
Currently, study is in maintenance phase and we don't expect a major change in the near future.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 69
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 1: Acalabrutinib+Obinutuzumab (R/R) acalabrutinib Dose-escalation and dose-expansion phases will be conducted for relapsed/refractory (R/R) participants with CLL. In dose-escalation phase, participants will receive oral acalabrutinib Dose 1 once daily (QD), later the dose was switched to Dose 2 twice daily (BID) per Amendment 02. In dose- expansion phase, participants will receive oral acalabrutinib Dose 2 BID in 28-day continuous cycles; and will receive intravenous (IV) infusion of obinutuzumab for total 6 cycles (from Cycles 2 to 7) as on Cycle 2 Day 1 participants will receive Dose 1, on Cycle 2 Day 2 participants will receive Dose 2, on Cycle 2 Days 8 and 15 participants will receive Dose 3, and on Day 1 of Cycles 3 to 7 participants will receive Dose 3. Participants will continue to receive acalabrutinib Dose 2 BID until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Cohort 1: Acalabrutinib+Obinutuzumab (R/R) Obinutuzumab Dose-escalation and dose-expansion phases will be conducted for relapsed/refractory (R/R) participants with CLL. In dose-escalation phase, participants will receive oral acalabrutinib Dose 1 once daily (QD), later the dose was switched to Dose 2 twice daily (BID) per Amendment 02. In dose- expansion phase, participants will receive oral acalabrutinib Dose 2 BID in 28-day continuous cycles; and will receive intravenous (IV) infusion of obinutuzumab for total 6 cycles (from Cycles 2 to 7) as on Cycle 2 Day 1 participants will receive Dose 1, on Cycle 2 Day 2 participants will receive Dose 2, on Cycle 2 Days 8 and 15 participants will receive Dose 3, and on Day 1 of Cycles 3 to 7 participants will receive Dose 3. Participants will continue to receive acalabrutinib Dose 2 BID until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Cohort 2: Acalabrutinib+Obinutuzumab (Treatment-naive) Obinutuzumab Dose-escalation and dose-expansion phases will be conducted for treatment-naïve participants with CLL/ small lymphocytic lymphoma (SLL). In dose-escalation phase, participants will receive oral acalabrutinib Dose 2 BID in first cycle (28-day cycle). In dose- expansion phase, participants will receive oral acalabrutinib Dose 2 BID in 28-day continuous cycles; and will receive IV infusion of obinutuzumab for total 6 cycles (from Cycles 2 to 7) as on Cycle 2 Day 1 participants will receive Dose 1, on Cycle 2 Day 2 participants will receive Dose 2, on Cycle 2 Days 8 and 15 participants will receive Dose 3, and on Day 1 of Cycles 3 to 7 participants will receive Dose 3. Participants will continue to receive acalabrutinib Dose 2 BID until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Cohort 3: Acalabrutinib+Rituximab+Venetoclax (R/R) acalabrutinib The R/R participants with CLL will receive oral acalabrutinib, IV infusion of rituximab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive rituximab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, followed by Dose 1 every 3 weeks (Q3W) for 3 doses, then every 4 weeks (Q4W) for 5 doses (total 9 infusions through the end of Cycle 7). Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15, Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and Dose 5 QD from Cycle 4 Day 1 until completion of Cycle 15. Cohort 2: Acalabrutinib+Obinutuzumab (Treatment-naive) acalabrutinib Dose-escalation and dose-expansion phases will be conducted for treatment-naïve participants with CLL/ small lymphocytic lymphoma (SLL). In dose-escalation phase, participants will receive oral acalabrutinib Dose 2 BID in first cycle (28-day cycle). In dose- expansion phase, participants will receive oral acalabrutinib Dose 2 BID in 28-day continuous cycles; and will receive IV infusion of obinutuzumab for total 6 cycles (from Cycles 2 to 7) as on Cycle 2 Day 1 participants will receive Dose 1, on Cycle 2 Day 2 participants will receive Dose 2, on Cycle 2 Days 8 and 15 participants will receive Dose 3, and on Day 1 of Cycles 3 to 7 participants will receive Dose 3. Participants will continue to receive acalabrutinib Dose 2 BID until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Cohort 3: Acalabrutinib+Rituximab+Venetoclax (R/R) Venetoclax The R/R participants with CLL will receive oral acalabrutinib, IV infusion of rituximab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive rituximab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, followed by Dose 1 every 3 weeks (Q3W) for 3 doses, then every 4 weeks (Q4W) for 5 doses (total 9 infusions through the end of Cycle 7). Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15, Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and Dose 5 QD from Cycle 4 Day 1 until completion of Cycle 15. Cohort 3: Acalabrutinib+Rituximab+Venetoclax (R/R) Rituximab The R/R participants with CLL will receive oral acalabrutinib, IV infusion of rituximab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive rituximab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, followed by Dose 1 every 3 weeks (Q3W) for 3 doses, then every 4 weeks (Q4W) for 5 doses (total 9 infusions through the end of Cycle 7). Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15, Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and Dose 5 QD from Cycle 4 Day 1 until completion of Cycle 15. Cohort 4: Acalabrutinib+Obinutuzumab+Venetoclax (Treatment-naive) acalabrutinib The treatment-naïve participants with CLL will receive oral acalabrutinib, IV infusion of obinutuzumab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive obinutuzumab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, Dose 2 on Cycle 2 Day 2, Dose 3 on Cycle 2 Days 8 and 15, and Dose 3 on Day 1 of Cycles 3 to 7. Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15 as Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and from Cycle 4 Day 1 participants will receive Dose 5 QD until completion of Cycle 15. Cohort 4: Acalabrutinib+Obinutuzumab+Venetoclax (Treatment-naive) Venetoclax The treatment-naïve participants with CLL will receive oral acalabrutinib, IV infusion of obinutuzumab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive obinutuzumab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, Dose 2 on Cycle 2 Day 2, Dose 3 on Cycle 2 Days 8 and 15, and Dose 3 on Day 1 of Cycles 3 to 7. Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15 as Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and from Cycle 4 Day 1 participants will receive Dose 5 QD until completion of Cycle 15. Cohort 4: Acalabrutinib+Obinutuzumab+Venetoclax (Treatment-naive) Obinutuzumab The treatment-naïve participants with CLL will receive oral acalabrutinib, IV infusion of obinutuzumab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive obinutuzumab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, Dose 2 on Cycle 2 Day 2, Dose 3 on Cycle 2 Days 8 and 15, and Dose 3 on Day 1 of Cycles 3 to 7. Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15 as Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and from Cycle 4 Day 1 participants will receive Dose 5 QD until completion of Cycle 15.
- Primary Outcome Measures
Name Time Method Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Percentage of Participants With Objective Response (OR) at 12 Months as Assessed by the Investigator in Cohorts 1 and 2 Day 1 through 12 months The OR is complete remission (CR), incomplete CR (CRi), nodular partial remission (nPR), or partial remission (PR) for at least 2 months. For CLL, CR:lymphocytes (lympho) \<4×10\^9/L, normocellular bone marrow (BM) \<30% lympho, no B-lymphoid nodules, normal lymph nodes (NLN), liver and spleen (L/S), absolute neutrophils (ANC) \>1.5×10\^9/L, platelets \>100×10\^9/L, hemoglobin (Hb) \>11g/dL; CRi: lympho \<4×10\^9/L, hypocellular BM, NLN, L/S, persistent anemia/thrombocytopenia/neutropenia; nPR: CR with present lymphoid nodules (NL); PR: \>=50% reduction in lymphadenopathy and/or enlargement of L/S or lympho (\<5×10\^9/L or \>=50% decrease from baseline), criteria of ANC/platelets/Hb per CR or \>=50% improvement over baseline. Hematology without exogenous growth factors/transfusion. For SLL, CR: no disease/disease-related symptoms, normal/\<=1cm LN, no enlargement of L/S/NL, disease-free BM; PR: \>=50% decrease in dominant masses with no size increase/new lesions, and \>=50% reduction of nodules in S/L.
Number of Participants With Treatment-Emergent Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 Abnormalities in Laboratory Parameters in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) Participants with treatment-emergent CTCAE Grade 3 or 4 abnormalities in laboratory parameters are reported. Laboratory analysis included hematology, clinical chemistry, and immunology.
Number of Participants with Shift From Baseline to Worst (Grade 3 and 4) Post-baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status in all Cohorts Baseline (Days -28 to -1) through the final data cutoff date (approximately 6 years 8 months) The ECOG Performance Status assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (\>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair \>50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=death. Shift from baseline (Days -28 to -1) to worst Grade 3 and/4 in EOCG status are reported.
Number of Participants With Abnormal Vital Signs Reported as TEAEs in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) Participants with abnormal vital signs (blood pressure, respiratory rate, heart rate, temperature, and body weight) reported as TEAEs are reported.
- Secondary Outcome Measures
Name Time Method Apparent oral clearance (CL/F) of Administration of Acalabrutinib in Cohorts 1, 3, and 4 Cohort 1: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycle 1. Cohorts 3 and 4: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycles 1, 3, and 5. (each cycle is 28 days) The CL/F of acalabrutinib is reported.
Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib and its Metabolite ACP-5862 in Cohorts 1, 3, and 4 During Cohort 1: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycle 1. Cohorts 3 and 4: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycles 1, 3, and 5. (each cycle is 28 days) The Tmax of acalabrutinib and its metabolite ACP-5862 are reported.
Maximum Observed Plasma Concentration (Cmax) of Venetoclax in Cohorts 3 and 4 Predose and at 0.5, 1, 2, 3, 4, 6, and 24 hours post dose on Cycle 3 Day 1 and Cycle 5 Day 1. (each cycle is 28 days) The Cmax of venetoclax is reported.
Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Venetoclax in Cohorts 3 and 4 Predose and at 0.5, 1, 2, 3, 4, 6, and 24 hours post dose on Cycle 3 Day 1 and Cycle 5 Day 1. (each cycle is 28 days) The AUC0-last of venetoclax is reported.
Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to infinity (AUC0-inf) of Acalabrutinib and its Metabolite ACP-5862 in Cohorts 1, 3, and 4 Cohort 1: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycle 1. Cohorts 3 and 4: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycles 1, 3, and 5. (each cycle is 28 days) The AUC0-inf of acalabrutinib and ACE-5862 are reported.
Terminal Elimination Rate Constant (λz) of Acalabrutinib and its Metabolite ACP-5862 in Cohorts 1, 3, and 4 Cohort 1: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycle 1. Cohorts 3 and 4: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycles 1, 3, and 5. (each cycle is 28 days) The λz of acalabrutinib and ACP-5862 are reported.
Percentage of Participants with CR as Assessed by the Investigator in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) For CLL, CR: lymphocytes \< 4×10\^9/L, normocellular bone marrow \< 30% lymphocytes, no B-lymphoid nodules, normal lymph nodes, liver and spleen, absolute neutrophils \> 1.5×10\^9/L, platelets \> 100×10\^9/L, hemoglobin \> 11g/dL. Hematology without exogenous growth factors/ transfusion. For SLL, CR: no disease/disease-related symptoms, normal/\<=1 cm lymph nodes, no enlargement of liver/spleen/lymphoid nodules, disease-free bone marrow.
Progression Free Survival (PFS) as Assessed by the Investigator in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) The PFS is defined as the time from the date of first dose of study drug to the date of first PD or death due to any cause, whichever occurred first. For CLL, PD is defined as any one of the criteria as: lymphocytes \>=50% increase from baseline, appearance of any new lesion or new appearance of hepatomegaly or splenomegaly or \>= 50% increase in lymphadenopathy/hepatomegaly/splenomegaly, decrease of Hb levels \>2 g/dL or to \<10 g/dL, or decrease of platelets \>50% or to\<100,000/μL. For SLL, PD is defined as any one of the criteria as: appearance of a new lesion \>1.5 cm in any axis; \>=50% increase in the products of at least 2 LNs; \>=50% increase in the longest diameter of a previously identified node \>1 cm in short axis; \>=50% increase in the size of the L and/or S or previously determined nodules in the L/S; or new or recurrent BM involvement. The PFS was estimated using Kaplan-Meier method.
Time to Initial PR or Better Response as Assessed by the Investigator in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) The time to initial PR or better response is defined as the time from the date of first dose of study drug to the date of first PR or better (ie, CRi or CR). For CLL, CR: lymphocytes (lympho) \<4×10\^9/L, normocellular bone marrow (BM) \<30% lympho, no B-lymphoid nodules, normal lymph nodes (NLN), liver and spleen (L/S), absolute neutrophils (ANC) \>1.5×10\^9/L, platelets \>100×10\^9/L, hemoglobin (Hb) \>11g/dL; CRi: lympho \<4×10\^9/L, hypocellular BM, NLN, L/S, persistent anemia/thrombocytopenia/neutropenia; PR: \>=50% reduction in lymphadenopathy and/or enlargement of L/S or lympho (\<5×10\^9/L or \>=50% decrease from baseline), criteria of ANC/platelets/Hb per CR or \>=50% improvement over baseline. Hematology without exogenous growth factors/transfusion. For SLL, CR: no disease/disease-related symptoms, normal/\<=1cm LN, no enlargement of L/S/NL, disease-free BM; PR: \>=50% decrease in dominant masses with no size increase/new lesions, and \>=50% reduction of nodules in S/L.
Percentage of Participants With OR at Cycle 16 as Assessed by the Investigator in Cohorts 3 and 4 Day 1 to the end of Cycle 16 (each cycle is 28 days) The OR is complete remission (CR), incomplete CR (CRi), nodular partial remission (nPR), or partial remission (PR) for at least 2 months. For CLL, CR: lymphocytes \<4×10\^9/L, normocellular bone marrow \<30% lymphocytes, no B-lymphoid nodules, normal lymph nodes (NLN), liver and spleen (L/S), absolute neutrophils (ANC) \>1.5×10\^9/L, platelets \>100×10\^9/L, hemoglobin (Hb) \>11g/dL; CRi: lymphocytes \<4×10\^9/L, hypocellular bone marrow, NLN, L/S, persistent anemia/thrombocytopenia/neutropenia; nPR: CR with present lymphoid nodules; PR: \>=50% reduction in lymphadenopathy and/or enlargement of L/S or lymphocytes (\<5×10\^9/L or \>=50% decrease from baseline), criteria of ANC/platelets/Hb per CR or \>=50% improvement over baseline. Hematology without exogenous growth factors/transfusion.
Time to Next Treatment (TTNT) as Assessed by the Investigator in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) The TTNT is defined as the time from the date of first dose of study drug to the date of institution of subsequent anticancer therapy for CLL or death due to any cause, whichever occurred first. The TTNT was estimated using Kaplan-Meier method.
Time of Maximum Plasma Concentration (Tmax) of Venetoclax in Cohorts 3 and 4 Predose and at 0.5, 1, 2, 3, 4, 6, and 24 hours post dose on Cycle 3 Day 1 and Cycle 5 Day 1. (each cycle is 28 days). The Tmax of venetoclax is reported.
Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib and its Metabolite ACP-5862 in Cohorts 1, 3, and 4 Cohort 1: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycle 1. Cohorts 3 and 4: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycles 1, 3, and 5. (each cycle is 28 days) The Cmax of acalabrutinib and ACP-5862 are reported.
Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib and its Metabolite ACP-5862 in Cohorts 1, 3, and 4 Cohort 1: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycle 1. Cohorts 3 and 4: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycles 1, 3, and 5.(each cycle is 28 days) The AUC0-last of acalabrutinib and ACE-5862 are reported.
Overall Survival (OS) as Assessed by the Investigator in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) The OS is defined as the time from the date of first dose of study drug to death due to any cause or last follow-up. The OS was estimated using Kaplan-Meier method.
Time to Initial CR as Assessed by the Investigator in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) The time to initial CR is defined as the time from the date of first dose of study drug to the date of first CR. For CLL, CR: lymphocytes \< 4×10\^9/L, normocellular bone marrow \< 30% lymphocytes, no B-lymphoid nodules, normal lymph nodes, liver and spleen, absolute neutrophils \> 1.5×10\^9/L, platelets \> 100×10\^9/L, hemoglobin \> 11g/dL. Hematology without exogenous growth factors/ transfusion. For SLL, CR: no disease/disease-related symptoms, normal/\<=1 cm lymph nodes, no enlargement of liver/spleen/lymphoid nodules, disease-free bone marrow.
Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib in Cohort 1 Pre-dose; 0.5, 1, 2, 3, 4, and 6 hours post-dose for Cycle 1. (each cycle is 28 days) The AUC0-6 of acalabrutinib is reported.
Terminal Elimination Half-life (t1/2) of Acalabrutinib and its Metabolite ACP-5862 in Cohorts 1, 3, and 4 Cohort 1: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycle 1. Cohorts 3 and 4: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycles 1, 3, and 5. (each cycle is 28 days) The t1/2 of acalabrutinib and ACP-5862 are reported.
Percentage of Participants With Minimal Residual Disease (MRD)-negative CR as Assessed by the Investigator in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) For CLL, CR: lymphocytes \<4×10\^9/L, normocellular bone marrow (BM) \<30% lymphocytes, no B-lymphoid nodules, normal lymph nodes, liver, and spleen, absolute neutrophil count \>1.5×10\^9/L, platelets \>100×10\^9/L, hemoglobin \> 11g/dL; CRi: lymphocytes \< 4×10\^9/L, hypocellular BM, normal lymph nodes, liver, and spleen, persistent anemia/thrombocytopenia/neutropenia. Hematology without exogenous growth factors/transfusion. For SLL, CR: no disease/disease-related symptoms, normal/\<=1 cm lymph nodes, no enlargement of liver/spleen/lymphoid nodules, disease-free BM. MRD negativity was determined in bone marrow by flow cytometry.
Duration of Response (DoR) as Assessed by the Investigator in all Cohorts Day 1 through the final data cutoff date (approximately 6 years 8 months) The DoR is defined as the time from the date of achieving the first CR, CRi, nPR, or PR (PR or better) to the date of progressive disease (PD) or death due to any cause, whichever occurred first. The CR, CRi, nPR, and PR are defined in the above outcome measure. For CLL, PD is defined as any one of the criteria: lymphocytes \>=50% increase from baseline, appearance of any new lesion or new hepatomegaly or splenomegaly or \>= 50% increase in lymphadenopathy/hepatomegaly/splenomegaly, decrease of Hb levels \>2 g/dL or to \<10 g/dL, or decrease of platelets \>50% or to\<100,000/μL. For SLL, PD is defined as any one of the criteria: appearance of a new lesion \>1.5 cm in any axis; \>=50% increase in the products of at least 2 LNs; \>=50% increase in the longest diameter of a previously identified node \>1 cm in short axis; \>=50% increase in the size of the L and/or S or previously determined nodules in the L/S; or new or recurrent BM involvement. The DoR was estimated using Kaplan-Meier method.
Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Venetoclax in Cohorts 3 and 4 Predose and at 0.5, 1, 2, 3, 4, 6, and 24 hours post dose on Cycle 3 Day 1 and Cycle 5 Day 1. (each cycle is 28 days) The AUC0-6 of venetoclax is reported.
Apparent Volume of Distribution (Vz/F) of Acalabrutinib in Cohorts 1, 3, and 4 Cohort 1: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycle 1. Cohorts 3 and 4: pre-dose; 0.5, 1, 2, 3, 4, 6, and 24 hours post-dose for Cycles 1, 3, and 5. (each cycle is 28 days) The Vz/F of acalabrutinib is reported.
The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) Scores in Cohorts 3 and 4 At the end of Cycle 2 and Cycle 42 (each cycle is 28 days). The EORTC QLQ-C30 is a 30-item questionnaire designed to assess health related quality of life in cancer participants. It includes a 30-item questionnaire designed to assess health related quality of life in cancer patients. There are 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social); 3 symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale. Several single-item symptom measures are also included (dyspnea, insomnia, appetite, constipation, diarrhea, and financial impact). A linear transformation was applied to the raw scores so that all transformed scores lie between 0 to 100. A high score for a functional scale represents a high (healthy/better) level of functioning, a high score for the global health status represents a high (better) quality of life, but a high score for a symptom scale represents a high (worse) level of symptoms/problems.
Trial Locations
- Locations (1)
Research Site
🇺🇸Columbus, Ohio, United States