Acalabrutinib in Combination With Anti-CD20 and Venetoclax in Relapsed/Refractory or Untreated CLL/SLL/PLL

NCT02296918 | Completed Phase 1 DMC

• 1 other identifier: ACE-CL-003
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 1

Brief Summary

To evaluate the safety and preliminary efficacy of acalabrutinib in combination with obinutuzumab in 4 separate cohorts of participants.

Conditions

Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Prolymphocytic Leukemia

Keywords

CLL; SLL; PLL; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Prolymphocytic Leukemia; ACP-196; acalabrutinib; obinutuzumab; rituximab; venetoclax

Outcome Measures

Primary Outcomes (5)

• Percentage of Participants With Objective Response (OR) at 12 Months as Assessed by the Investigator in Cohorts 1 and 2

  The OR is complete remission (CR), incomplete CR (CRi), nodular partial remission (nPR), or partial remission (PR) for at least 2 months. For CLL, CR:lymphocytes (lympho) \<4×10\^9/L, normocellular bone marrow (BM) \<30% lympho, no B-lymphoid nodules, normal lymph nodes (NLN), liver and spleen (L/S), absolute neutrophils (ANC) \>1.5×10\^9/L, platelets \>100×10\^9/L, hemoglobin (Hb) \>11g/dL; CRi: lympho \<4×10\^9/L, hypocellular BM, NLN, L/S, persistent anemia/thrombocytopenia/neutropenia; nPR: CR with present lymphoid nodules (NL); PR: \>=50% reduction in lymphadenopathy and/or enlargement of L/S or lympho (\<5×10\^9/L or \>=50% decrease from baseline), criteria of ANC/platelets/Hb per CR or \>=50% improvement over baseline. Hematology without exogenous growth factors/transfusion. For SLL, CR: no disease/disease-related symptoms, normal/\<=1cm LN, no enlargement of L/S/NL, disease-free BM; PR: \>=50% decrease in dominant masses with no size increase/new lesions, and \>=50% reduction of nodules in S/L.

  Day 1 through 12 months

• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in all Cohorts

  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.

  Day 1 through the final data cutoff date (approximately 6 years 8 months)

• Number of Participants With Treatment-Emergent Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 Abnormalities in Laboratory Parameters in all Cohorts

  Participants with treatment-emergent CTCAE Grade 3 or 4 abnormalities in laboratory parameters are reported. Laboratory analysis included hematology, clinical chemistry, and immunology.

  Day 1 through the final data cutoff date (approximately 6 years 8 months)

• Number of Participants With Abnormal Vital Signs Reported as TEAEs in all Cohorts

  Participants with abnormal vital signs (blood pressure, respiratory rate, heart rate, temperature, and body weight) reported as TEAEs are reported.

  Day 1 through the final data cutoff date (approximately 6 years 8 months)

• Number of Participants with Shift From Baseline to Worst (Grade 3 and 4) Post-baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status in all Cohorts

  The ECOG Performance Status assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (\>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair \>50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=death. Shift from baseline (Days -28 to -1) to worst Grade 3 and/4 in EOCG status are reported.

  Baseline (Days -28 to -1) through the final data cutoff date (approximately 6 years 8 months)

Secondary Outcomes (23)

• Percentage of Participants with CR as Assessed by the Investigator in all Cohorts

  Day 1 through the final data cutoff date (approximately 6 years 8 months)

• Percentage of Participants With Minimal Residual Disease (MRD)-negative CR as Assessed by the Investigator in all Cohorts

  Day 1 through the final data cutoff date (approximately 6 years 8 months)

• Percentage of Participants With OR at Cycle 16 as Assessed by the Investigator in Cohorts 3 and 4

  Day 1 to the end of Cycle 16 (each cycle is 28 days)

• Duration of Response (DoR) as Assessed by the Investigator in all Cohorts

  Day 1 through the final data cutoff date (approximately 6 years 8 months)

• Progression Free Survival (PFS) as Assessed by the Investigator in all Cohorts

  Day 1 through the final data cutoff date (approximately 6 years 8 months)

Study Arms (4)

Cohort 1: Acalabrutinib+Obinutuzumab (R/R)

EXPERIMENTAL

Dose-escalation and dose-expansion phases will be conducted for relapsed/refractory (R/R) participants with CLL. In dose-escalation phase, participants will receive oral acalabrutinib Dose 1 once daily (QD), later the dose was switched to Dose 2 twice daily (BID) per Amendment 02. In dose- expansion phase, participants will receive oral acalabrutinib Dose 2 BID in 28-day continuous cycles; and will receive intravenous (IV) infusion of obinutuzumab for total 6 cycles (from Cycles 2 to 7) as on Cycle 2 Day 1 participants will receive Dose 1, on Cycle 2 Day 2 participants will receive Dose 2, on Cycle 2 Days 8 and 15 participants will receive Dose 3, and on Day 1 of Cycles 3 to 7 participants will receive Dose 3. Participants will continue to receive acalabrutinib Dose 2 BID until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first.

Drug: acalabrutinib; Drug: Obinutuzumab

Cohort 2: Acalabrutinib+Obinutuzumab (Treatment-naive)

EXPERIMENTAL

Dose-escalation and dose-expansion phases will be conducted for treatment-naïve participants with CLL/ small lymphocytic lymphoma (SLL). In dose-escalation phase, participants will receive oral acalabrutinib Dose 2 BID in first cycle (28-day cycle). In dose- expansion phase, participants will receive oral acalabrutinib Dose 2 BID in 28-day continuous cycles; and will receive IV infusion of obinutuzumab for total 6 cycles (from Cycles 2 to 7) as on Cycle 2 Day 1 participants will receive Dose 1, on Cycle 2 Day 2 participants will receive Dose 2, on Cycle 2 Days 8 and 15 participants will receive Dose 3, and on Day 1 of Cycles 3 to 7 participants will receive Dose 3. Participants will continue to receive acalabrutinib Dose 2 BID until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first.

Drug: acalabrutinib; Drug: Obinutuzumab

Cohort 3: Acalabrutinib+Rituximab+Venetoclax (R/R)

EXPERIMENTAL

The R/R participants with CLL will receive oral acalabrutinib, IV infusion of rituximab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive rituximab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, followed by Dose 1 every 3 weeks (Q3W) for 3 doses, then every 4 weeks (Q4W) for 5 doses (total 9 infusions through the end of Cycle 7). Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15, Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and Dose 5 QD from Cycle 4 Day 1 until completion of Cycle 15.

Drug: acalabrutinib; Drug: Venetoclax; Drug: Rituximab

Cohort 4: Acalabrutinib+Obinutuzumab+Venetoclax (Treatment-naive)

EXPERIMENTAL

The treatment-naïve participants with CLL will receive oral acalabrutinib, IV infusion of obinutuzumab, and oral venetoclax. Participants will receive acalabrutinib Dose 2 BID in 28-day continuous cycles until disease progression, an unacceptable drug-related toxicity, or per the investigator the study treatment is intolerable or no longer in participant's best interest, whichever occurs first. Participants will receive obinutuzumab for total 6 cycles (from Cycles 2 to 7) as Dose 1 on Cycle 2 Day 1, Dose 2 on Cycle 2 Day 2, Dose 3 on Cycle 2 Days 8 and 15, and Dose 3 on Day 1 of Cycles 3 to 7. Participants will receive venetoclax weekly ramp-up schedule over 5 weeks from Cycles 3 to 15 as Dose 1 QD for 1 week on Cycle 3 Day 1, Dose 2 QD for 1 week on Cycle 3 Day 8, Dose 3 QD for 1 week on Cycle 3 Day 15, Dose 4 QD for 1 week on Cycle 3 Day 22, and from Cycle 4 Day 1 participants will receive Dose 5 QD until completion of Cycle 15.

Drug: acalabrutinib; Drug: Obinutuzumab; Drug: Venetoclax

Interventions

acalabrutinib DRUG

Participants will receive oral acalabrutinib in Cohorts 1, 2, 3, and 4. The details are mentioned in the cohort description.

Also known as: ACP-196

Cohort 1: Acalabrutinib+Obinutuzumab (R/R); Cohort 2: Acalabrutinib+Obinutuzumab (Treatment-naive); Cohort 3: Acalabrutinib+Rituximab+Venetoclax (R/R); Cohort 4: Acalabrutinib+Obinutuzumab+Venetoclax (Treatment-naive)

Obinutuzumab DRUG

Participants will receive intravenous obinutuzumab in Cohorts 1, 2, and 4. The details are mentioned in the cohort description.

Also known as: Gazyvaro

Cohort 1: Acalabrutinib+Obinutuzumab (R/R); Cohort 2: Acalabrutinib+Obinutuzumab (Treatment-naive); Cohort 4: Acalabrutinib+Obinutuzumab+Venetoclax (Treatment-naive)

Venetoclax DRUG

Participants will receive oral venetoclax in Cohorts 3 and 4. The details are mentioned in the cohort description.

Also known as: ABT-199, Venclexta, GDC-0199

Cohort 3: Acalabrutinib+Rituximab+Venetoclax (R/R); Cohort 4: Acalabrutinib+Obinutuzumab+Venetoclax (Treatment-naive)

Rituximab DRUG

Participants will receive intravenous rituximab in Cohort 3. The details are mentioned in the cohort description.

Also known as: Rituxan

Cohort 3: Acalabrutinib+Rituximab+Venetoclax (R/R)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants with a diagnosis of intermediate or high risk CLL (or variant immunophenotype), SLL, or B-cell prolymphocytic leukemia (B-PLL) by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Hallek et al. 2008) who have:
• Cohorts 1 and 3: Previously received at least 1 therapy for their disease (Cohort 3 enrollment limited to CLL).
• Cohort 2: Previously untreated disease and ≥65 years old OR under 65 years old and refuse or are ineligible for chemoimmunotherapy.
• Cohort 4: Previously untreated disease; Cohort 4 enrollment limited to CLL.
• Participants in Cohorts 1 and 3 may have received previous ibrutinib (or another Bruton tyrosine kinase (BTK) inhibitor) as long as discontinuation was for a reason other than on-treatment disease progression.
• All participants must satisfy one of the following criteria for active disease requiring therapy:
• Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia (AIHA) or thrombocytopenia)
• Massive (≥6 cm below the costal margin), progressive or symptomatic splenomegaly
• Massive nodes (≥10 cm) or progressive or symptomatic lymphadenopathy
• Constitutional symptoms, which include any of the following:
• Unintentional weight loss of 10% or more within 6 months Significant fatigue limiting activity Fevers ≥100.5°F for 2 weeks or more without evidence of infection Night sweats \>1 month without evidence of infection
• This criterion was removed with Amendment 5.
• Participants with a history of Richter's syndrome are eligible if they now have evidence of CLL only, with \<10% large cells in the bone marrow.
• Participants must have adequate organ function, defined as creatinine ≤2.5 times the upper limit of normal range (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, and bilirubin ≤2.5 x ULN. For Cohorts 3 and 4, participants must have creatinine clearance ≥50 mL/min using modified Cockcroft-Gault equation (using Ideal Body Mass \[IBM\] instead of mass):
• IBM (kg) = \[(height cm - 154) ● 0.9\] + (50 if male, 45.5 if female).

You may not qualify if:

• For Cohorts 2 and 4, received previous therapy for CLL. Treatment of autoimmune complications of CLL with steroids or rituximab is allowed, however, CD20 must have returned on 10% of the CLL cells if rituximab was recently administered. Palliative steroids are acceptable at doses ≤20 mg prednisone equivalent daily.
• Any life-threatening illness, medical condition, or organ dysfunction, which in the investigator's opinion, could compromise the participants' safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.
• Female participants who are pregnant or breastfeeding.
• Participants with active cardiovascular disease not medically controlled or those who have had myocardial infarction in the past 6 months, or corrected QT interval (QTc) ≥480 ms.
• Malabsorption syndrome, disease significantly affecting gastrointestinal (GI) function, or resection of the stomach or small bowel or gastric bypass, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
• Grade \>=2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.
• Major surgery within 4 weeks before first dose of study drug.
• History of a bleeding diathesis (e.g., hemophilia, Von Willebrand disease).
• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura.
• History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug.
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 28 days of first dose of study drug.
• Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
• Participants with active infections requiring IV antibiotic/antiviral therapy are not eligible for entry onto the study until resolution of the infection. Participants on prophylactic antibiotics or antivirals are acceptable.
• Participants with history of or ongoing drug-induced pneumonitis.
• Participants with human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection.

Sponsors & Collaborators

• Acerta Pharma BV: lead

Study Sites (1)

Research Site

Columbus, Ohio, 43210, United States

Location

Related Publications (2)

• Woyach JA, Blachly JS, Rogers KA, Bhat SA, Jianfar M, Lozanski G, Weiss DM, Andersen BL, Gulrajani M, Frigault MM, Hamdy A, Izumi R, Munugalavadla V, Quah C, Wang MH, Byrd JC. Acalabrutinib plus Obinutuzumab in Treatment-Naive and Relapsed/Refractory Chronic Lymphocytic Leukemia. Cancer Discov. 2020 Mar;10(3):394-405. doi: 10.1158/2159-8290.CD-19-1130. Epub 2020 Jan 8.

  PMID: 31915195 RESULT

• Arrato NA, Valentine TR, Byrd JC, Jones JA, Maddocks KJ, Woyach JA, Andersen BL. Illness representations and psychological outcomes in chronic lymphocytic leukaemia. Br J Health Psychol. 2022 May;27(2):553-570. doi: 10.1111/bjhp.12562. Epub 2021 Oct 4.

  PMID: 34608724 DERIVED

Related Links

• CSR Synopsis

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic

Interventions

acalabrutinib; obinutuzumab; venetoclax; Rituximab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• AstraZeneca Study Information Center

  1-877-240-9479; information.center@astrazeneca.com

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2014
• First Posted: November 21, 2014
• Study Start: December 22, 2014
• Primary Completion: August 20, 2021
• Study Completion: October 22, 2025
• Last Updated: December 19, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

US (1)