Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Syndrome

Lymphoma

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Leukemia, Prolymphocytic

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Lymphosarcoma

Chronic Lymphocytic Leukemia

Richter Syndrome

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Acalabrutinib

Tyrosine Kinase Inhibitors

Ibrutinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Phase 1 (dose-escalation) and Phase 2 (dose-expansion) will be conducted for participants with relapsed/refractory CLL or SLL. In Phase 1, participants will receive 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 will receive oral acalabrutinib at Dose 1 BID (Cohort 2b) or Dose 5 QD (Cohort 2c, later will be switched to Dose 1 BID per protocol amendment 6) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest. Participants from Phase 1 will be continued to receive Dose 1 BID until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Treatment-naïve participants with confirmed CLL or SLL, will receive oral acalabrutinib Dose 5 QD (Cohort 7, later will be switched to Dose 1 BID per protocol amendment 6) or Dose 1 BID (Cohort 11) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Participants with confirmed CLL or SLL and were not tolerating ibrutinib treatment, will receive 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 will consider the study treatment to be intolerable or no longer in the participant's best interest.

Participants with diffuse large B-cell lymphoma (DLBCL) Richter's transformation (RS) or prolymphocytic leukemia (PLL) transformation, will receive oral acalabrutinib Dose 5 BID (Cohort 9) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Participants with confirmed CLL/SLL and had relapsed/refractory to ibrutinib treatment, will receive oral acalabrutinib Dose 5 QD (Cohort 10) until disease progression or until the investigator will consider the study treatment to be intolerable or no longer in the participant's best interest.

Participants will receive acalabrutinib as stated in the arms' description.

Acerta Clinical Trials

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).

ACP-196 (Acalabrutinib), a Novel Bruton Tyrosine Kinase (BTK) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia, Richter's Syndrome or Prolymphocytic Leukemia

A Phase 1/2, Multicenter, Open-label, and Dose-escalation Study of ACP-196 in Subjects With Chronic Lymphocytic Leukemia, Richter's Syndrome or Prolymphocytic Leukemia

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

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.

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.

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.

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.

Participants with clinically abnormal vital signs (blood pressure, respiratory rate, pulse rate, or body temperature) reported as TEAEs are reported.

The AUC0-last of acalabrutinib is reported.

The AUC0-inf of Acalabrutinib is reported.

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.

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.

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.

Acerta Pharma BV

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.

Relapsed/Refractory 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.

Treatment-naive 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.

Ibrutinib-intolerant 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.

Richters Syndrome/Prolymphocytic Leukemia Transformation 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.

Ibrutinib Relapsed/Refractory Cohort

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

All-treated population included all enrolled participants who received 1 or more doses of study drug.

The Phase 2 dose was chosen on the basis of the pharmacodynamics data.

Global Clinical Lead

Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days.

Cohort 1

Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days.

Cohort 2a

Participants with CLL/SLL received oral acalabrutinib Dose 2 BID for 28 days.

Cohort 2b

Participants with CLL/SLL received oral acalabrutinib Dose 3 QD for 28 days.

Cohort 3

Participants with CLL/SLL received oral acalabrutinib Dose 4 QD for 28 days.

Cohort 4a

Cohort 4b

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.

Number of Participants With Dose Limiting Toxicities (DLTs) in Phase 1

Any TEAEs

Any TESAEs

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Atrial fibrillation

Ventricular tachyarrhythmias

Anemia

Neutropenia

Other Leukopenia

Thrombocytopenia

Major hemorrhage

Hepatotoxicity

Hypertension

Infections

Interstitial lung disease/Pneumonitis

Second primary malignancies, excluding non-melanoma skin

Tumor lysis syndrome

Number of Participants With Treatment Emergent Events of Clinical Interest (ECI)

Hemoglobin, platelets or neutrophils decreased

Absolute neutrophil count (decreased)

Hemoglobin (decreased)

Platelets (decreased)

Leukocytes (decreased)

Leukocytes (increased)

Absolute lymphocyte count (decreased)

Absolute lymphocyte count (increased)

Urate (increased)

Sodium (decreased)

Phosphate (decreased)

Potassium (increased)

Glucose (increased)

Alanine aminotransferase (increased)

Calcium (increased)

Aspartate aminotransferase (increased)

Magnesium (increased)

Potassium (decreased)

Albumin (decreased)

Calcium (decreased)

Alkaline phosphatase (increased)

Amylase (increased)

Bilirubin (increased)

Creatinine (increased)

Lipase (increased)

Number of Participants With Clinically Important Laboratory Abnormalities With Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or More

Tachycardia

Bradycardia

Pyrexia

Hyperpyrexia

Hypothermia

Procedural hypotension

Blood pressure increased

Dyspnoea

Dyspnoea exertional

Hypotension

Orthostatic hypotension

Essential hypertension

Hypertensive crisis

Malignant hypertension

Palpitations

Number of Participants With Clinically Abnormal Vital Signs Reported as TEAEs

Day 1

Day 8

Participants with CLL/SLL received oral acalabrutinib Dose 1 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Participants with CLL/SLL received oral acalabrutinib Dose 2 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Participants with CLL received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Participants with CLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Cohort 2c

Participants with CLL received oral acalabrutinib Dose 3 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Participants with CLL received oral acalabrutinib Dose 4 QD for 28 days and later switched to acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Participants with CLL received oral acalabrutinib Dose 5 BID (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Treatment-naïve participants with CLL or SLL received oral acalabrutinib Dose 5 QD (later switched to Dose 1 BID per protocol amendment 6) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Cohort 7

Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 5 QD (which switched to Dose 1 BID per protocol amendment 4) until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Cohort 8a

Participants with CLL or SLL and were not tolerating ibrutinib treatment, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Cohort 8b

Participants with DLBCLRS or PLL transformation, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Cohort 9

Participants with CLL/SLL and had relapsed/refractory ibrutinib treatment, received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Cohort 10

Treatment-naïve participants with CLL/SLL, received oral acalabrutinib Dose 1 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Cohort 11

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.

Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours (AUC0-6) of Acalabrutinib

Participants with CLL/SLL received oral acalabrutinib Dose 5 BID until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

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.

Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Acalabrutinib

Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Acalabrutinib

Maximum Observed Plasma Concentration (Cmax) of Acalabrutinib

Time of Maximum Plasma Concentration (Tmax) of Acalabrutinib

Terminal Elimination Half-life (t1/2) of Acalabrutinib

Participants with CLL received oral acalabrutinib Dose 1 twice daily until disease progression or per the investigator considered the study treatment to be intolerable or no longer in the participant's best interest.

Terminal Elimination Rate Constant (λz) of Acalabrutinib

Apparent Oral Clearance (CL/F) of Acalabrutinib

Apparent Volume of Distribution (Vz/F) of Acalabrutinib

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.

Percentage of Participants With Objective Response (OR) as Assessed by the Investigator

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.

Spots Global Cancer Trial Database for ACP-196 (Acalabrutinib), a Novel Bruton Tyrosine Kinase (BTK) Inhibitor, for Treatment of Chronic Lymphocytic Leukemia, Richter's Syndrome or Prolymphocytic Leukemia

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

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