Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Richter's Syndrome, Small Lymphocytic Lymphoma
Conditions
Keywords
Bruton's tyrosine kinase inhibitor
Brief summary
This study is evaluating the safety and efficacy of a new BTK inhibitor, acalabrutinib, for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Interventions
DRUGAcalabrutinib
Participants will receive acalabrutinib as stated in the arms' description.
Sponsors
Acerta Pharma BV
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men and women ≥ 18 years of age with a confirmed diagnosis of CLL/SLL, which has relapsed after, or been refractory to, ≥ 2 previous treatments for CLL/SLL. 2. Must have measurable CLL/SLL defined as ≥ 1 lymph node ≥ 2 cm as measured in the longest diameter. 3. Active disease meeting ≥ 1 of the following International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for requiring treatment: 1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin \< 10 g/dL) and/or thrombocytopenia (platelets \< 100,000/μL). 2. Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. 3. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. 4. Progressive lymphocytosis with an increase of \> 50% over a 2-month period or a lymphocyte doubling time (LDT) of \< 6 months. The LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In participants with initial blood lymphocyte counts of \< 30 X 10\^9/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections) should be excluded. 5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. 6. Constitutional symptoms documented in the participant's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs: i. Unintentional weight loss ≥ 10% within the previous 6 months before screening. ii. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before screening without evidence of infection. iii. Night sweats for \> 1 month before screening without evidence of infection. 4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 5. Agreement to use highly effective methods of contraception during the study and for 2 days after the last dose of study drug if sexually active and able to bear or beget children (see Section 3.7.9 for list of highly effective methods of contraception). 6. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. 7. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local participant privacy regulations). Inclusion Criteria for Treatment Subgroups 1. Treatment Naive only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL, who require treatment per National Cancer Institute (NCI) or International Working Group guidelines and a) do not want to receive chemoimmunotherapy or b) have comorbidities that would preclude chemoimmunotherapy. 2. Ibrutinib Intolerant only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL who are not tolerating ibrutinib due to ibrutinib-related AEs. 3. Richter's Syndrome/Prolymphocytic Leukemia Transformation only: Men and women ≥ 18 years of age and biopsy proven diffuse large B cell lymphoma (DLBCL) Richter's transformation or prolymphocytic leukemia transformation. 4. Ibrutinib relapsed/refractory (R/R) only: Men and women ≥ 18 years of age with confirmed diagnosis of CLL/SLL whose best response after 2 cycles of ibrutinib therapy was stable disease or nonresponse or who initially responded to ibrutinib therapy and now have signs of clinical progression.
Exclusion criteria
1. Prior malignancy, except for adequately treated basal cell, squamous cell skin cancer or in situ cervical cancer. Participants with other prior malignancies from which the participant has been disease free for ≥ 2 years may be included if approved by the medical monitor. 2. A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk. 3. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or left ventricular ejection fraction (LVEF) ≤ 40%. 4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 5. Any immunotherapy within 4 weeks of first dose of study drug. 6. For participants with recent chemotherapy or experimental therapy the first dose of study drug must occur after 5 times the half-life of the agent(s). 7. Relapsed after, or refractory to, prior BTK inhibitor therapy (Note: Does not apply to Ibrutinib R/R or Richter's Syndrome Group). 8. Any history of Richter's transformation (Note: Does not apply to Richter's Syndrome Group). 10\. Central nervous system (CNS) involvement by lymphoma. 11. Grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation. 12\. Known history of human immunodeficiency virus (HIV) or serologic status indicating active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection or any uncontrolled active systemic infection. Participants with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative polymerase chain reaction (PCR) result before enrollment. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded. 13\. Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenic purpura (ITP) defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (\> 20 mg daily of prednisone daily or equivalent). 14\. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug. 15\. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 16\. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug. 17\. Major surgery within 4 weeks before first dose of study drug. 18. ANC \< 0.75 x 10\^9/L or platelet count \< 50 x 10\^9/L unless there is bone marrow involvement. 19\. Total bilirubin \> 1.5 x upper limit of normal (ULN) (total bilirubin ≤ 2.5 x ULN allowed in participants with autoimmune hemolytic anemia that is otherwise controlled); and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3.0 x ULN unless disease related. 20\. Serum amylase \> 1.5 x ULN or serum lipase \> 1.5 x ULN. 21. Significant screening electrocardiogram (ECG) abnormalities including, 2nd degree AV block type II, 3rd degree block, Grade 2 or higher bradycardia, or QTc ≥ 480 ms. 22\. Cardiac troponin I levels above the limit of normal as specified by the manufacturer. 23\. Breast feeding or pregnant. 24. History of bleeding diathesis (eg, hemophilia, von Willebrand disease). 25. Concurrent participation in another therapeutic clinical trial. 26. Estimated creatinine clearance of \< 30 mL/min, calculated using the formula of Cockcroft and Gault \[(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female\]. 27\. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1 | From Day 1 to Day 28 after first dose of study drug | Participants with DLTs in Phase 1 are reported. The DLT was defined as any of the following events unless the adverse event is clearly related to disease progression or the participant's current medical history and associated comorbidities: (1) Any Grade 3 or greater nonhematologic toxicity with the exceptions of alopecia and Grade 3 nausea, vomiting, and diarrhea that respond to supportive therapy; (2) Hematologic toxicities including Grade 4 neutropenia lasting more than 5 days, Grade 4 or Grade 3 thrombocytopenia with bleeding or any requirement for platelets transfusion, Grade 3 or greater febrile neutropenia (body temperature of 38.5 degrees Celsius or more), or Grade 4 anemia, unexplained by underlying disease; or (3) Dosing delay due to toxicity for \> 7 consecutive days. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Day 1 through the final data cutoff date (approximately 7 years 6 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. |
| Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Day 1 through the final data cutoff date (approximately 7 years 6 months) | The treatment emergent ECI included the events identified based on preclinical findings, emerging data from clinical studies relating to acalabrutinib, and pharmacological effects of approved Bruton's tyrosine kinase (BTK) inhibitors and reported after the first dose of the study drug. |
| Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Day 1 through the final data cutoff date (approximately 7 years 6 months) | Participants with clinically important laboratory abnormalities with CTCAE Grade 3 or more are reported. Laboratory analysis included hematology, clinical chemistry, amylase, lipase, cardiac troponin I, hepatitis B and C testing, and urinalysis. The CTCAE version 4.03 is a descriptive terminology is used for AE reporting. The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 3 as severe AE, Grade 4 as life-threatening or disabling AE, and Grade 5 as death related to AE. |
| Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Day 1 through the final data cutoff date (approximately 7 years 6 months) | Participants with clinically abnormal vital signs (blood pressure, respiratory rate, pulse rate, or body temperature) reported as TEAEs are reported. |
| Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Predose and at 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours postdose on Day 1 and Day 8 | The AUC0-6 of acalabrutinib is reported. |
| Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8 | The AUC0-last of acalabrutinib is reported. |
| Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8 | The AUC0-inf of Acalabrutinib is reported. |
| Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8 | The Cmax of Acalabrutinib is reported. |
| Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8 | The Tmax of Acalabrutinib is reported. |
| Terminal Elimination Half-life (t1/2) of Acalabrutinib | Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8 | The t1/2 of acalabrutinib is reported. |
| Terminal Elimination Rate Constant (λz) of Acalabrutinib | Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8 | The λz of acalabrutinib is reported. |
| Apparent Oral Clearance (CL/F) of Acalabrutinib | Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8 | The CL/F of acalabrutinib is reported. |
| Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8 | The Vz/F of acalabrutinib is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | Day 1 through the final data cutoff date (approximately 7 years 6 months) | For CLL/SLL, OR is defined as complete remission (CR), CR with incomplete marrow recovery (CRi), or partial remission (PR). CR: lymphocytes (lympho) \<4×10\^9/L, normocellular bone marrow (BM), normal lymph nodes (NLN), liver and spleen (L/S), absolute neutrophil count (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, hrombocytopenia, or neutropenia. PR: \>=50% reduction in lymphadenopathy and/or enlargement of L/S or lympho (\<5×10\^9/L or \>=50% decrease from baseline) and criteria of ANC/platelets/Hb per CR or \>=50% improvement over baseline. Hematology result were without exogenous growth factors/transfusion. For RS, OR as CR or PR by Cheson et al. 2014 based on PET/CT scans and bone marrow. CR: disappearance of all detectable clinical evidence of disease and disease-related symptoms and PR: \>=50% decrease in sum of the product diameter of 6 largest nodal masses and no new sites of disease. |
| Duration of Response (DOR) as Assessed by the Investigator | Day 1 through the final data cutoff date (approximately 7 years 6 months) | The DoR is defined as the time from the date of achieving the first CR, CRi, or PR to the date of progressive disease (PD) or death due to any cause, whichever occurred first. The CR, CRi, or PR are defined in the above outcome measure. For CLL/SLL, PD is defined as lympho \>=50% increase from baseline with \>= 5000 B lymphocytes/µL, progressive cytopenias by bone marrow biopsy, appearance of any new lesion or new appearance of hepatomegaly or splenomegaly or \>= 50 % increase in lymphadenopathy/hepatomegaly/splenomegaly, platelets decrease of \>=50% from baseline secondary to CLL or \< 100,000/µL and worsening bone marrow or Hb decrease of \> 2 g/dL from baseline secondary to CLL or decrease to less than 100 g/L and worsening bone marrow. For RS, PD is defined as an increase by 25 % in longest diameter, new lesion or assessable disease progression. The DoR was estimated using Kaplan-Meier method. |
| Progression Free Survival (PFS) as Assessed by the Investigator | Day 1 through the final data cutoff date (approximately 7 years 6 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/SLL, PD is defined as lympho \>= 50 % increase from baseline with \>= 5000 B lymphocytes/µL, progressive cytopenias by bone marrow biopsy, appearance of any new lesion or new appearance of hepatomegaly or splenomegaly or \>= 50 % increase in lymphadenopathy/hepatomegaly/splenomegaly, platelets decrease of \>= 50 % from baseline secondary to CLL or \< 100,000/µL and worsening bone marrow or Hb decrease of \> 2 g/dL from baseline secondary to CLL or decrease to less than 100 g/L and worsening bone marrow. For RS, PD is defined as an increase by 25 % in longest diameter, new lesion or assessable disease progression. The PFS was estimated using Kaplan-Meier method. |
Countries
Italy, United Kingdom, United States
Contacts
STUDY_DIRECTORAcerta Clinical Trials
1-888-292-9613 acertamc@dlss.com
Participant flow
Pre-assignment details
Out of 306 enrolled participates, 5 participants were not treated with the study drug. The data of "All treated population" was collected and analyzed. The results data are reported per the primary completion date (data cut-off date of 15Jul2021). There will be no updated results for all outcome measures at the time of end of study.
Participants by arm
| Arm | Count |
|---|---|
| Relapsed/Refractory Cohort Phase 1 (dose-escalation) and Phase 2 (dose-expansion) were conducted for participants with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In Phase 1, participants received oral once daily (QD) acalabrutinib at Dose 1 (Cohort 1), Dose 2 (Cohort 2a), Dose 3 (Cohort 3), and Dose 4 (Cohort 4a), and twice daily (BID) acalabrutinib at Dose 1 (Cohort 2b) and Dose 5 (Cohort 4b) for 28 days (1 cycle). In Phase 2, participants received oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 continued to receive Dose 1 BID until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. | 134 |
| Treatment-naive Cohort Treatment-naïve participants with confirmed CLL or SLL, received oral acalabrutinib Dose 5 QD (Cohort 7, later switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. | 99 |
| Ibrutinib-intolerant Cohort Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 8a, later switched to Dose 1 BID per protocol amendment 4) or Dose 1 BID (Cohort 8b) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. | 33 |
| Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia transformation (PLL), received oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. | 29 |
| Ibrutinib Relapsed/Refractory Cohort Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, received oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator considered the study treatment to be intolerable or no longer in the participant's best interest. | 6 |
| Total | 301 |
Baseline characteristics
| Characteristic | Relapsed/Refractory Cohort | Treatment-naive Cohort | Ibrutinib-intolerant Cohort | Richters Syndrome/Prolymphocytic Leukemia Transformation Cohort | Ibrutinib Relapsed/Refractory Cohort | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 65.6 Years STANDARD_DEVIATION 9.2 | 63.5 Years STANDARD_DEVIATION 9.7 | 63.9 Years STANDARD_DEVIATION 8.9 | 65.0 Years STANDARD_DEVIATION 9.6 | 62.5 Years STANDARD_DEVIATION 7.9 | 64.6 Years STANDARD_DEVIATION 9.33 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 129 Participants | 94 Participants | 33 Participants | 28 Participants | 6 Participants | 290 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 5 Participants | 2 Participants | 1 Participants | 1 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 11 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) White | 120 Participants | 88 Participants | 31 Participants | 27 Participants | 5 Participants | 271 Participants |
| Sex: Female, Male Female | 35 Participants | 33 Participants | 13 Participants | 14 Participants | 3 Participants | 98 Participants |
| Sex: Female, Male Male | 99 Participants | 66 Participants | 20 Participants | 15 Participants | 3 Participants | 203 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 134 | 2 / 99 | 2 / 33 | 11 / 29 | 2 / 6 |
| other Total, other adverse events | 134 / 134 | 99 / 99 | 33 / 33 | 28 / 29 | 6 / 6 |
| serious Total, serious adverse events | 86 / 134 | 50 / 99 | 20 / 33 | 18 / 29 | 3 / 6 |
Outcome results
Primary
Apparent Oral Clearance (CL/F) of Acalabrutinib
The CL/F of acalabrutinib is reported.
Time frame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
Population: The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 114 L/hr | Standard Deviation 44.4 |
| Cohort 1 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 176 L/hr | Standard Deviation 62.1 |
| Cohort 2a | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 193 L/hr | Standard Deviation 121 |
| Cohort 2a | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 216 L/hr | Standard Deviation 154 |
| Cohort 2b | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 212 L/hr | Standard Deviation 302 |
| Cohort 2b | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 162 L/hr | Standard Deviation 141 |
| Cohort 3 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 112 L/hr | Standard Deviation 98.4 |
| Cohort 3 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 122 L/hr | Standard Deviation 55.5 |
| Cohort 4a | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 131 L/hr | Standard Deviation 70.3 |
| Cohort 4a | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 265 L/hr | Standard Deviation 263 |
| Cohort 4b | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 344 L/hr | Standard Deviation 242 |
| Cohort 4b | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 169 L/hr | Standard Deviation 123 |
| Cohort 4b | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 108 L/hr | Standard Deviation 32 |
| Cohort 4b | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 191 L/hr | Standard Deviation 180 |
| Cohort 7 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 315 L/hr | Standard Deviation 488 |
| Cohort 7 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 389 L/hr | Standard Deviation 1070 |
| Cohort 8a | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 352 L/hr | Standard Deviation 43.7 |
| Cohort 8a | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 94.5 L/hr | — |
| Cohort 8b | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 336 L/hr | Standard Deviation 258 |
| Cohort 8b | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 311 L/hr | Standard Deviation 166 |
| Cohort 9 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 132 L/hr | Standard Deviation 51.8 |
| Cohort 9 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 142 L/hr | Standard Deviation 88.9 |
| Cohort 10 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 156 L/hr | Standard Deviation 40.3 |
| Cohort 10 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 167 L/hr | Standard Deviation 95.1 |
| Cohort 11 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 8 | 188 L/hr | Standard Deviation 92.5 |
| Cohort 11 | Apparent Oral Clearance (CL/F) of Acalabrutinib | Day 1 | 137 L/hr | Standard Deviation 77.4 |
Primary
Apparent Volume of Distribution (Vz/F) of Acalabrutinib
The Vz/F of acalabrutinib is reported.
Time frame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
Population: The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 286 L | Standard Deviation 150 |
| Cohort 1 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 268 L | Standard Deviation 332 |
| Cohort 2a | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 574 L | Standard Deviation 992 |
| Cohort 2a | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 302 L | Standard Deviation 238 |
| Cohort 2b | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 450 L | Standard Deviation 1250 |
| Cohort 2b | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 333 L | Standard Deviation 729 |
| Cohort 3 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 182 L | Standard Deviation 230 |
| Cohort 3 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 165 L | Standard Deviation 104 |
| Cohort 4a | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 172 L | Standard Deviation 114 |
| Cohort 4a | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 2100 L | Standard Deviation 3290 |
| Cohort 4b | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 739 L | Standard Deviation 745 |
| Cohort 4b | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 1480 L | Standard Deviation 2850 |
| Cohort 4b | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 384 L | Standard Deviation 466 |
| Cohort 4b | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 133 L | Standard Deviation 30 |
| Cohort 7 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 1180 L | Standard Deviation 4940 |
| Cohort 7 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 930 L | Standard Deviation 1750 |
| Cohort 8a | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 2600 L | Standard Deviation 2030 |
| Cohort 8a | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 125 L | — |
| Cohort 8b | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 726 L | Standard Deviation 814 |
| Cohort 8b | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 422 L | Standard Deviation 290 |
| Cohort 9 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 171 L | Standard Deviation 125 |
| Cohort 9 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 179 L | Standard Deviation 134 |
| Cohort 10 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 235 L | Standard Deviation 105 |
| Cohort 10 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 533 L | Standard Deviation 716 |
| Cohort 11 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 1 | 158 L | Standard Deviation 102 |
| Cohort 11 | Apparent Volume of Distribution (Vz/F) of Acalabrutinib | Day 8 | 234 L | Standard Deviation 162 |
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib
The AUC0-6 of acalabrutinib is reported.
Time frame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours postdose on Day 1 and Day 8
Population: Pharmacokinetic (PK) population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 971 hr*ng/mL | Standard Deviation 564 |
| Cohort 1 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 631 hr*ng/mL | Standard Deviation 193 |
| Cohort 2a | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 1250 hr*ng/mL | Standard Deviation 836 |
| Cohort 2a | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 1180 hr*ng/mL | Standard Deviation 859 |
| Cohort 2b | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 819 hr*ng/mL | Standard Deviation 493 |
| Cohort 2b | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 858 hr*ng/mL | Standard Deviation 419 |
| Cohort 3 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 2170 hr*ng/mL | Standard Deviation 1180 |
| Cohort 3 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 1660 hr*ng/mL | Standard Deviation 554 |
| Cohort 4a | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 1750 hr*ng/mL | Standard Deviation 518 |
| Cohort 4a | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 1880 hr*ng/mL | Standard Deviation 1810 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 1630 hr*ng/mL | Standard Deviation 1050 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 2960 hr*ng/mL | Standard Deviation 1570 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 1950 hr*ng/mL | Standard Deviation 487 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 1690 hr*ng/mL | Standard Deviation 1090 |
| Cohort 7 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 1740 hr*ng/mL | Standard Deviation 1540 |
| Cohort 7 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 1480 hr*ng/mL | Standard Deviation 986 |
| Cohort 8a | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 362 hr*ng/mL | Standard Deviation 221 |
| Cohort 8a | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 2080 hr*ng/mL | — |
| Cohort 8b | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 834 hr*ng/mL | Standard Deviation 713 |
| Cohort 8b | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 670 hr*ng/mL | Standard Deviation 471 |
| Cohort 9 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 1860 hr*ng/mL | Standard Deviation 786 |
| Cohort 9 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 1690 hr*ng/mL | Standard Deviation 849 |
| Cohort 10 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 1100 hr*ng/mL | Standard Deviation 590 |
| Cohort 10 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 1250 hr*ng/mL | Standard Deviation 1050 |
| Cohort 11 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 8 | 642 hr*ng/mL | Standard Deviation 310 |
| Cohort 11 | Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib | Day 1 | 789 hr*ng/mL | Standard Deviation 398 |
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib
The AUC0-inf of Acalabrutinib is reported.
Time frame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
Population: The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 1040 hr*ng/mL | Standard Deviation 534 |
| Cohort 1 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 621 hr*ng/mL | Standard Deviation 187 |
| Cohort 2a | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 1320 hr*ng/mL | Standard Deviation 827 |
| Cohort 2a | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 1200 hr*ng/mL | Standard Deviation 865 |
| Cohort 2b | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 855 hr*ng/mL | Standard Deviation 517 |
| Cohort 2b | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 956 hr*ng/mL | Standard Deviation 665 |
| Cohort 3 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 2440 hr*ng/mL | Standard Deviation 1010 |
| Cohort 3 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 1990 hr*ng/mL | Standard Deviation 1020 |
| Cohort 4a | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 2360 hr*ng/mL | Standard Deviation 1210 |
| Cohort 4a | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 2050 hr*ng/mL | Standard Deviation 1680 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 1750 hr*ng/mL | Standard Deviation 1140 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 3250 hr*ng/mL | Standard Deviation 1630 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 1970 hr*ng/mL | Standard Deviation 495 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 1780 hr*ng/mL | Standard Deviation 1230 |
| Cohort 7 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 1910 hr*ng/mL | Standard Deviation 1530 |
| Cohort 7 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 1540 hr*ng/mL | Standard Deviation 973 |
| Cohort 8a | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 574 hr*ng/mL | Standard Deviation 76.3 |
| Cohort 8a | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 2120 hr*ng/mL | — |
| Cohort 8b | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 963 hr*ng/mL | Standard Deviation 728 |
| Cohort 8b | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 801 hr*ng/mL | Standard Deviation 410 |
| Cohort 9 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 1750 hr*ng/mL | Standard Deviation 701 |
| Cohort 9 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 1770 hr*ng/mL | Standard Deviation 776 |
| Cohort 10 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 1350 hr*ng/mL | Standard Deviation 373 |
| Cohort 10 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 1580 hr*ng/mL | Standard Deviation 1030 |
| Cohort 11 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 8 | 652 hr*ng/mL | Standard Deviation 298 |
| Cohort 11 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib | Day 1 | 940 hr*ng/mL | Standard Deviation 430 |
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib
The AUC0-last of acalabrutinib is reported.
Time frame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
Population: The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 1030 hr*ng/mL | Standard Deviation 529 |
| Cohort 1 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 729 hr*ng/mL | Standard Deviation 380 |
| Cohort 2a | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 1270 hr*ng/mL | Standard Deviation 775 |
| Cohort 2a | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 1180 hr*ng/mL | Standard Deviation 861 |
| Cohort 2b | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 795 hr*ng/mL | Standard Deviation 502 |
| Cohort 2b | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 850 hr*ng/mL | Standard Deviation 660 |
| Cohort 3 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 2280 hr*ng/mL | Standard Deviation 1060 |
| Cohort 3 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 1850 hr*ng/mL | Standard Deviation 882 |
| Cohort 4a | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 2020 hr*ng/mL | Standard Deviation 1170 |
| Cohort 4a | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 2030 hr*ng/mL | Standard Deviation 1670 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 1750 hr*ng/mL | Standard Deviation 979 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 3430 hr*ng/mL | Standard Deviation 1640 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 1950 hr*ng/mL | Standard Deviation 487 |
| Cohort 4b | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 1560 hr*ng/mL | Standard Deviation 1020 |
| Cohort 7 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 1790 hr*ng/mL | Standard Deviation 1470 |
| Cohort 7 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 1400 hr*ng/mL | Standard Deviation 929 |
| Cohort 8a | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 539 hr*ng/mL | Standard Deviation 106 |
| Cohort 8a | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 1180 hr*ng/mL | — |
| Cohort 8b | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 748 hr*ng/mL | Standard Deviation 701 |
| Cohort 8b | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 570 hr*ng/mL | Standard Deviation 451 |
| Cohort 9 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 1710 hr*ng/mL | Standard Deviation 669 |
| Cohort 9 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 1860 hr*ng/mL | Standard Deviation 1570 |
| Cohort 10 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 1100 hr*ng/mL | Standard Deviation 590 |
| Cohort 10 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 1260 hr*ng/mL | Standard Deviation 1060 |
| Cohort 11 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 8 | 660 hr*ng/mL | Standard Deviation 294 |
| Cohort 11 | Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib | Day 1 | 850 hr*ng/mL | Standard Deviation 462 |
Primary
Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib
The Cmax of Acalabrutinib is reported.
Time frame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
Population: The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 685 ng/mL | Standard Deviation 475 |
| Cohort 1 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 521 ng/mL | Standard Deviation 308 |
| Cohort 2a | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 754 ng/mL | Standard Deviation 540 |
| Cohort 2a | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 805 ng/mL | Standard Deviation 757 |
| Cohort 2b | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 706 ng/mL | Standard Deviation 499 |
| Cohort 2b | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 812 ng/mL | Standard Deviation 829 |
| Cohort 3 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 1950 ng/mL | Standard Deviation 1460 |
| Cohort 3 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 1350 ng/mL | Standard Deviation 809 |
| Cohort 4a | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 1350 ng/mL | Standard Deviation 933 |
| Cohort 4a | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 1350 ng/mL | Standard Deviation 1170 |
| Cohort 4b | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 902 ng/mL | Standard Deviation 638 |
| Cohort 4b | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 1550 ng/mL | Standard Deviation 1230 |
| Cohort 4b | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 1600 ng/mL | Standard Deviation 291 |
| Cohort 4b | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 1320 ng/mL | Standard Deviation 1540 |
| Cohort 7 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 1390 ng/mL | Standard Deviation 1260 |
| Cohort 7 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 1020 ng/mL | Standard Deviation 747 |
| Cohort 8a | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 206 ng/mL | Standard Deviation 240 |
| Cohort 8a | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 939 ng/mL | — |
| Cohort 8b | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 616 ng/mL | Standard Deviation 660 |
| Cohort 8b | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 554 ng/mL | Standard Deviation 500 |
| Cohort 9 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 1460 ng/mL | Standard Deviation 913 |
| Cohort 9 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 1190 ng/mL | Standard Deviation 925 |
| Cohort 10 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 727 ng/mL | Standard Deviation 436 |
| Cohort 10 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 610 ng/mL | Standard Deviation 751 |
| Cohort 11 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 8 | 633 ng/mL | Standard Deviation 449 |
| Cohort 11 | Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib | Day 1 | 930 ng/mL | Standard Deviation 595 |
Primary
Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs
Participants with clinically abnormal vital signs (blood pressure, respiratory rate, pulse rate, or body temperature) reported as TEAEs are reported.
Time frame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
Population: All-treated population included all enrolled participants who received 1 or more doses of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hyperpyrexia | 0 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea | 27 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Tachycardia | 3 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Bradycardia | 6 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Pyrexia | 39 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypothermia | 0 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Procedural hypotension | 0 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Blood pressure increased | 0 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea exertional | 5 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertension | 30 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypotension | 7 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Orthostatic hypotension | 0 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Essential hypertension | 0 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertensive crisis | 1 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Malignant hypertension | 0 Participants |
| Cohort 1 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Palpitations | 13 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Bradycardia | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea | 18 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypotension | 12 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Essential hypertension | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Orthostatic hypotension | 5 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Pyrexia | 14 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Palpitations | 4 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypothermia | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Procedural hypotension | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hyperpyrexia | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Malignant hypertension | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Blood pressure increased | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Tachycardia | 8 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea exertional | 5 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertensive crisis | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertension | 28 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Bradycardia | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Tachycardia | 2 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Palpitations | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea exertional | 1 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypotension | 5 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypothermia | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Essential hypertension | 1 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Pyrexia | 10 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Blood pressure increased | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Orthostatic hypotension | 1 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hyperpyrexia | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea | 6 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertensive crisis | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertension | 6 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Malignant hypertension | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Procedural hypotension | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertensive crisis | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Pyrexia | 6 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hyperpyrexia | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypothermia | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Palpitations | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Procedural hypotension | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Blood pressure increased | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea exertional | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Malignant hypertension | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertension | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypotension | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Orthostatic hypotension | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Essential hypertension | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea | 3 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Tachycardia | 3 Participants |
| Cohort 3 | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Bradycardia | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Essential hypertension | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Blood pressure increased | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Malignant hypertension | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertension | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Pyrexia | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea exertional | 1 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Dyspnoea | 2 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Procedural hypotension | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Bradycardia | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Tachycardia | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypothermia | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypertensive crisis | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Orthostatic hypotension | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Palpitations | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hypotension | 2 Participants |
| Cohort 4a | Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs | Hyperpyrexia | 0 Participants |
Primary
Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More
Participants with clinically important laboratory abnormalities with CTCAE Grade 3 or more are reported. Laboratory analysis included hematology, clinical chemistry, amylase, lipase, cardiac troponin I, hepatitis B and C testing, and urinalysis. The CTCAE version 4.03 is a descriptive terminology is used for AE reporting. The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 3 as severe AE, Grade 4 as life-threatening or disabling AE, and Grade 5 as death related to AE.
Time frame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
Population: All-treated population included all enrolled participants who received 1 or more doses of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Sodium (decreased) | 12 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (increased) | 5 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Urate (increased) | 24 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Bilirubin (increased) | 2 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (decreased) | 2 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alanine aminotransferase (increased) | 3 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (increased) | 29 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Albumin (decreased) | 2 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (increased) | 29 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute neutrophil count (decreased) | 57 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Creatinine (increased) | 2 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (decreased) | 20 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Lipase (increased) | 1 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (increased) | 3 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin, platelets or neutrophils decreased | 72 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Platelets (decreased) | 20 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Phosphate (decreased) | 9 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alkaline phosphatase (increased) | 1 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin (decreased) | 17 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Glucose (increased) | 3 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (decreased) | 2 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Magnesium (increased) | 2 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Amylase (increased) | 2 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Aspartate aminotransferase (increased) | 2 Participants |
| Cohort 1 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (decreased) | 12 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Glucose (increased) | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (decreased) | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (increased) | 5 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Urate (increased) | 15 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Albumin (decreased) | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Sodium (decreased) | 5 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Amylase (increased) | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alkaline phosphatase (increased) | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Phosphate (decreased) | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Platelets (decreased) | 3 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (decreased) | 2 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (increased) | 8 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Creatinine (increased) | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (increased) | 21 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (decreased) | 7 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin, platelets or neutrophils decreased | 30 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Lipase (increased) | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Bilirubin (increased) | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alanine aminotransferase (increased) | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute neutrophil count (decreased) | 23 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (increased) | 0 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Aspartate aminotransferase (increased) | 2 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Magnesium (increased) | 2 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (decreased) | 1 Participants |
| Cohort 2a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin (decreased) | 5 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alanine aminotransferase (increased) | 1 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin (decreased) | 3 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (increased) | 7 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (decreased) | 3 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (decreased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (increased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute neutrophil count (decreased) | 11 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Amylase (increased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Creatinine (increased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Urate (increased) | 8 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Aspartate aminotransferase (increased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (increased) | 1 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Albumin (decreased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Platelets (decreased) | 4 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Glucose (increased) | 3 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Magnesium (increased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin, platelets or neutrophils decreased | 14 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Lipase (increased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (decreased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Bilirubin (increased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (decreased) | 2 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alkaline phosphatase (increased) | 0 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Sodium (decreased) | 2 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (increased) | 7 Participants |
| Cohort 2b | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Phosphate (decreased) | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alkaline phosphatase (increased) | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Glucose (increased) | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute neutrophil count (decreased) | 13 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin (decreased) | 8 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Platelets (decreased) | 5 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (decreased) | 6 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (increased) | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin, platelets or neutrophils decreased | 19 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Phosphate (decreased) | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (decreased) | 6 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alanine aminotransferase (increased) | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (increased) | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Aspartate aminotransferase (increased) | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Magnesium (increased) | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (decreased) | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Albumin (decreased) | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (increased) | 3 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Urate (increased) | 5 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Sodium (decreased) | 3 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (decreased) | 1 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (increased) | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Amylase (increased) | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Bilirubin (increased) | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Creatinine (increased) | 0 Participants |
| Cohort 3 | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Lipase (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (increased) | 1 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Albumin (decreased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (decreased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Glucose (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Magnesium (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Aspartate aminotransferase (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin, platelets or neutrophils decreased | 4 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Amylase (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alanine aminotransferase (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute lymphocyte count (decreased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Phosphate (decreased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Alkaline phosphatase (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Bilirubin (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (increased) | 2 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Leukocytes (decreased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Platelets (decreased) | 1 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Hemoglobin (decreased) | 3 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Lipase (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Creatinine (increased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Sodium (decreased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Calcium (decreased) | 0 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Urate (increased) | 2 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Absolute neutrophil count (decreased) | 3 Participants |
| Cohort 4a | Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More | Potassium (increased) | 0 Participants |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1
Participants with DLTs in Phase 1 are reported. The DLT was defined as any of the following events unless the adverse event is clearly related to disease progression or the participant's current medical history and associated comorbidities: (1) Any Grade 3 or greater nonhematologic toxicity with the exceptions of alopecia and Grade 3 nausea, vomiting, and diarrhea that respond to supportive therapy; (2) Hematologic toxicities including Grade 4 neutropenia lasting more than 5 days, Grade 4 or Grade 3 thrombocytopenia with bleeding or any requirement for platelets transfusion, Grade 3 or greater febrile neutropenia (body temperature of 38.5 degrees Celsius or more), or Grade 4 anemia, unexplained by underlying disease; or (3) Dosing delay due to toxicity for \> 7 consecutive days.
Time frame: From Day 1 to Day 28 after first dose of study drug
Population: All-treated population included all participants enrolled in Phase 1 (dose-escalation) of the study, received 1 or more doses of study drug, and observed from Day 1 to Day 28 after first dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1 | 0 Participants |
| Cohort 2a | Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1 | 0 Participants |
| Cohort 2b | Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1 | 0 Participants |
| Cohort 3 | Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1 | 0 Participants |
| Cohort 4a | Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1 | 0 Participants |
| Cohort 4b | Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1 | 0 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
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.
Time frame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
Population: All-treated population included all enrolled participants who received 1 or more doses of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 134 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 86 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 99 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 50 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 33 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 20 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 18 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 28 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 6 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 3 Participants |
Primary
Number of Participants With Treatment Emergent Events of Clinical Interest (ECI)
The treatment emergent ECI included the events identified based on preclinical findings, emerging data from clinical studies relating to acalabrutinib, and pharmacological effects of approved Bruton's tyrosine kinase (BTK) inhibitors and reported after the first dose of the study drug.
Time frame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
Population: All-treated population included all enrolled participants who received 1 or more doses of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hepatotoxicity | 4 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Interstitial lung disease/Pneumonitis | 1 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Tumor lysis syndrome | 1 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Neutropenia | 26 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Second primary malignancies, excluding non-melanoma skin | 23 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Atrial fibrillation | 12 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Infections | 118 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Major hemorrhage | 11 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Other Leukopenia | 2 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Anemia | 22 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Ventricular tachyarrhythmias | 2 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hypertension | 31 Participants |
| Cohort 1 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Thrombocytopenia | 10 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hepatotoxicity | 4 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Thrombocytopenia | 1 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Major hemorrhage | 8 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Ventricular tachyarrhythmias | 0 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Second primary malignancies, excluding non-melanoma skin | 14 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Interstitial lung disease/Pneumonitis | 3 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Anemia | 10 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Atrial fibrillation | 6 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Infections | 86 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Neutropenia | 9 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hypertension | 29 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Other Leukopenia | 1 Participants |
| Cohort 2a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Tumor lysis syndrome | 0 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Ventricular tachyarrhythmias | 0 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Atrial fibrillation | 4 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Anemia | 4 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Neutropenia | 5 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Other Leukopenia | 1 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Thrombocytopenia | 4 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Major hemorrhage | 4 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hepatotoxicity | 1 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hypertension | 7 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Infections | 25 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Interstitial lung disease/Pneumonitis | 0 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Second primary malignancies, excluding non-melanoma skin | 3 Participants |
| Cohort 2b | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Tumor lysis syndrome | 0 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hepatotoxicity | 3 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Other Leukopenia | 0 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hypertension | 2 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Neutropenia | 13 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Infections | 18 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Anemia | 10 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Atrial fibrillation | 3 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Interstitial lung disease/Pneumonitis | 0 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Ventricular tachyarrhythmias | 0 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Tumor lysis syndrome | 0 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Major hemorrhage | 0 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Thrombocytopenia | 4 Participants |
| Cohort 3 | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Second primary malignancies, excluding non-melanoma skin | 1 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Ventricular tachyarrhythmias | 0 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hepatotoxicity | 0 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Thrombocytopenia | 0 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Neutropenia | 1 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Second primary malignancies, excluding non-melanoma skin | 0 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Major hemorrhage | 1 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Hypertension | 0 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Interstitial lung disease/Pneumonitis | 0 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Anemia | 1 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Atrial fibrillation | 0 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Other Leukopenia | 0 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Infections | 4 Participants |
| Cohort 4a | Number of Participants With Treatment Emergent Events of Clinical Interest (ECI) | Tumor lysis syndrome | 0 Participants |
Primary
Terminal Elimination Half-life (t1/2) of Acalabrutinib
The t1/2 of acalabrutinib is reported.
Time frame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
Population: The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 1.48 Hours | Standard Deviation 1.5 |
| Cohort 1 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 1.09 Hours | Standard Deviation 0.216 |
| Cohort 2a | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 1.44 Hours | Standard Deviation 1.6 |
| Cohort 2a | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 0.942 Hours | Standard Deviation 0.107 |
| Cohort 2b | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 0.914 Hours | Standard Deviation 0.452 |
| Cohort 2b | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 0.995 Hours | Standard Deviation 0.621 |
| Cohort 3 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 0.993 Hours | Standard Deviation 0.303 |
| Cohort 3 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 0.902 Hours | Standard Deviation 0.187 |
| Cohort 4a | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 0.886 Hours | Standard Deviation 0.131 |
| Cohort 4a | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 2.89 Hours | Standard Deviation 3.12 |
| Cohort 4b | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 1.38 Hours | Standard Deviation 0.546 |
| Cohort 4b | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 3.52 Hours | Standard Deviation 4.93 |
| Cohort 4b | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 0.869 Hours | Standard Deviation 0.0811 |
| Cohort 4b | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 1.13 Hours | Standard Deviation 0.408 |
| Cohort 7 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 1.41 Hours | Standard Deviation 1.73 |
| Cohort 7 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 1.02 Hours | Standard Deviation 0.454 |
| Cohort 8a | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 4.83 Hours | Standard Deviation 3.69 |
| Cohort 8a | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 0.914 Hours | — |
| Cohort 8b | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 1.25 Hours | Standard Deviation 0.494 |
| Cohort 8b | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 0.900 Hours | Standard Deviation 0.14 |
| Cohort 9 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 0.867 Hours | Standard Deviation 0.289 |
| Cohort 9 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 0.798 Hours | Standard Deviation 0.0973 |
| Cohort 10 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 1.01 Hours | Standard Deviation 0.209 |
| Cohort 10 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 1.67 Hours | Standard Deviation 1.41 |
| Cohort 11 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 8 | 0.811 Hours | Standard Deviation 0.174 |
| Cohort 11 | Terminal Elimination Half-life (t1/2) of Acalabrutinib | Day 1 | 0.781 Hours | Standard Deviation 0.137 |
Primary
Terminal Elimination Rate Constant (λz) of Acalabrutinib
The λz of acalabrutinib is reported.
Time frame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
Population: The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.679 1/hr | Standard Deviation 0.276 |
| Cohort 1 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.655 1/hr | Standard Deviation 0.132 |
| Cohort 2a | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.750 1/hr | Standard Deviation 0.307 |
| Cohort 2a | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.744 1/hr | Standard Deviation 0.0866 |
| Cohort 2b | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.848 1/hr | Standard Deviation 0.214 |
| Cohort 2b | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.793 1/hr | Standard Deviation 0.191 |
| Cohort 3 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.755 1/hr | Standard Deviation 0.209 |
| Cohort 3 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.798 1/hr | Standard Deviation 0.161 |
| Cohort 4a | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.797 1/hr | Standard Deviation 0.128 |
| Cohort 4a | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.502 1/hr | Standard Deviation 0.3 |
| Cohort 4b | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.578 1/hr | Standard Deviation 0.243 |
| Cohort 4b | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.557 1/hr | Standard Deviation 0.386 |
| Cohort 4b | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.804 1/hr | Standard Deviation 0.0793 |
| Cohort 4b | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.679 1/hr | Standard Deviation 0.251 |
| Cohort 7 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.756 1/hr | Standard Deviation 0.292 |
| Cohort 7 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.745 1/hr | Standard Deviation 0.174 |
| Cohort 8a | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.373 1/hr | Standard Deviation 0.468 |
| Cohort 8a | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.758 1/hr | — |
| Cohort 8b | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.623 1/hr | Standard Deviation 0.218 |
| Cohort 8b | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.784 1/hr | Standard Deviation 0.112 |
| Cohort 9 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.857 1/hr | Standard Deviation 0.209 |
| Cohort 9 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.880 1/hr | Standard Deviation 0.114 |
| Cohort 10 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.706 1/hr | Standard Deviation 0.144 |
| Cohort 10 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.603 1/hr | Standard Deviation 0.324 |
| Cohort 11 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 8 | 0.894 1/hr | Standard Deviation 0.204 |
| Cohort 11 | Terminal Elimination Rate Constant (λz) of Acalabrutinib | Day 1 | 0.916 1/hr | Standard Deviation 0.177 |
Primary
Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib
The Tmax of Acalabrutinib is reported.
Time frame: Predose and at 0.25, 0.5, 0.75, 1, 2, 4, 6, and 24 hours postdose on Day 1 and Day 8
Population: The PK population included all participants who complied with the protocol sufficiently and displayed an evaluable PK profile (e.g. exposure to treatment, availability and integrity of measurements, and absence of major protocol violations). 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 1.01 Hours |
| Cohort 1 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 1.05 Hours |
| Cohort 2a | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 0.917 Hours |
| Cohort 2a | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 0.517 Hours |
| Cohort 2b | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 0.750 Hours |
| Cohort 2b | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 0.750 Hours |
| Cohort 3 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 1.00 Hours |
| Cohort 3 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 1.03 Hours |
| Cohort 4a | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 1.00 Hours |
| Cohort 4a | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 1.00 Hours |
| Cohort 4b | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 0.700 Hours |
| Cohort 4b | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 1.00 Hours |
| Cohort 4b | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 0.758 Hours |
| Cohort 4b | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 0.758 Hours |
| Cohort 7 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 0.783 Hours |
| Cohort 7 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 0.750 Hours |
| Cohort 8a | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 1.30 Hours |
| Cohort 8a | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 1.49 Hours |
| Cohort 8b | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 0.908 Hours |
| Cohort 8b | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 0.783 Hours |
| Cohort 9 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 1.00 Hours |
| Cohort 9 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 0.992 Hours |
| Cohort 10 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 1.00 Hours |
| Cohort 10 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 1.58 Hours |
| Cohort 11 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 8 | 0.533 Hours |
| Cohort 11 | Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib | Day 1 | 0.642 Hours |
Secondary
Duration of Response (DOR) as Assessed by the Investigator
The DoR is defined as the time from the date of achieving the first CR, CRi, or PR to the date of progressive disease (PD) or death due to any cause, whichever occurred first. The CR, CRi, or PR are defined in the above outcome measure. For CLL/SLL, PD is defined as lympho \>=50% increase from baseline with \>= 5000 B lymphocytes/µL, progressive cytopenias by bone marrow biopsy, appearance of any new lesion or new appearance of hepatomegaly or splenomegaly or \>= 50 % increase in lymphadenopathy/hepatomegaly/splenomegaly, platelets decrease of \>=50% from baseline secondary to CLL or \< 100,000/µL and worsening bone marrow or Hb decrease of \> 2 g/dL from baseline secondary to CLL or decrease to less than 100 g/L and worsening bone marrow. For RS, PD is defined as an increase by 25 % in longest diameter, new lesion or assessable disease progression. The DoR was estimated using Kaplan-Meier method.
Time frame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
Population: Efficacy evaluable population included all enrolled participants who received 1 or more doses of study drug and had 1 or more response assessments after the first dose of study drug. The DoR was analyzed for participants who achieved OR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Duration of Response (DOR) as Assessed by the Investigator | 33.3 Months |
| Cohort 2a | Duration of Response (DOR) as Assessed by the Investigator | 26.7 Months |
| Cohort 2b | Duration of Response (DOR) as Assessed by the Investigator | 77.3 Months |
| Cohort 3 | Duration of Response (DOR) as Assessed by the Investigator | 43.0 Months |
| Cohort 4a | Duration of Response (DOR) as Assessed by the Investigator | NA Months |
| Cohort 4b | Duration of Response (DOR) as Assessed by the Investigator | 64.1 Months |
| Cohort 4b | Duration of Response (DOR) as Assessed by the Investigator | NA Months |
| Cohort 7 | Duration of Response (DOR) as Assessed by the Investigator | NA Months |
| Cohort 8a | Duration of Response (DOR) as Assessed by the Investigator | NA Months |
Secondary
Percentage of Participants With Objective Response (OR) as Assessed by the Investigator
For CLL/SLL, OR is defined as complete remission (CR), CR with incomplete marrow recovery (CRi), or partial remission (PR). CR: lymphocytes (lympho) \<4×10\^9/L, normocellular bone marrow (BM), normal lymph nodes (NLN), liver and spleen (L/S), absolute neutrophil count (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, hrombocytopenia, or neutropenia. PR: \>=50% reduction in lymphadenopathy and/or enlargement of L/S or lympho (\<5×10\^9/L or \>=50% decrease from baseline) and criteria of ANC/platelets/Hb per CR or \>=50% improvement over baseline. Hematology result were without exogenous growth factors/transfusion. For RS, OR as CR or PR by Cheson et al. 2014 based on PET/CT scans and bone marrow. CR: disappearance of all detectable clinical evidence of disease and disease-related symptoms and PR: \>=50% decrease in sum of the product diameter of 6 largest nodal masses and no new sites of disease.
Time frame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
Population: Efficacy evaluable population included all enrolled participants who received 1 or more doses of study drug and had 1 or more response assessments after the first dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | 100.0 Percentage of participants |
| Cohort 2a | Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | 75 Percentage of participants |
| Cohort 2b | Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | 92.1 Percentage of participants |
| Cohort 3 | Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | 93.8 Percentage of participants |
| Cohort 4a | Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | 100.0 Percentage of participants |
| Cohort 4b | Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | 100.0 Percentage of participants |
| Cohort 4b | Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | 100.0 Percentage of participants |
| Cohort 7 | Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | 97.3 Percentage of participants |
| Cohort 8a | Percentage of Participants With Objective Response (OR) as Assessed by the Investigator | 100.0 Percentage of participants |
Secondary
Progression Free Survival (PFS) as Assessed by the Investigator
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/SLL, PD is defined as lympho \>= 50 % increase from baseline with \>= 5000 B lymphocytes/µL, progressive cytopenias by bone marrow biopsy, appearance of any new lesion or new appearance of hepatomegaly or splenomegaly or \>= 50 % increase in lymphadenopathy/hepatomegaly/splenomegaly, platelets decrease of \>= 50 % from baseline secondary to CLL or \< 100,000/µL and worsening bone marrow or Hb decrease of \> 2 g/dL from baseline secondary to CLL or decrease to less than 100 g/L and worsening bone marrow. For RS, PD is defined as an increase by 25 % in longest diameter, new lesion or assessable disease progression. The PFS was estimated using Kaplan-Meier method.
Time frame: Day 1 through the final data cutoff date (approximately 7 years 6 months)
Population: Efficacy evaluable population included all enrolled participants who received 1 or more doses of study drug and had 1 or more response assessments after the first dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Progression Free Survival (PFS) as Assessed by the Investigator | 38.3 Months |
| Cohort 2a | Progression Free Survival (PFS) as Assessed by the Investigator | 33.1 Months |
| Cohort 2b | Progression Free Survival (PFS) as Assessed by the Investigator | 79.1 Months |
| Cohort 3 | Progression Free Survival (PFS) as Assessed by the Investigator | 46.6 Months |
| Cohort 4a | Progression Free Survival (PFS) as Assessed by the Investigator | NA Months |
| Cohort 4b | Progression Free Survival (PFS) as Assessed by the Investigator | 67.8 Months |
| Cohort 4b | Progression Free Survival (PFS) as Assessed by the Investigator | NA Months |
| Cohort 7 | Progression Free Survival (PFS) as Assessed by the Investigator | NA Months |
| Cohort 8a | Progression Free Survival (PFS) as Assessed by the Investigator | NA Months |