Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Acalabrutinib · 20 trials · 35 indications
Progression-free survival (PFS) after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria
To assess whether minimal residual disease (MRD)-driven finite AV treatment is NI to MRD-driven finite VO treatment with respect to PFS. PFS is defined as the time from the date of randomization until date of objective progressive disease per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria as assessed by the investigator or death from any cause in the absence of progression.
PFS was defined as the time from randomization to PD (assessed by BICR according to International Workshop on Chronic Lymphocytic Leukaemia \[iwCLL\] 2018 guideline criteria) or death due to any cause. PD was defined as meeting at least 1 of the below criteria of groups(g) A or B. gA: increase of ≥50% from baseline (BL) or from response in lymph nodes or liver and/or spleen size; any constitutional symptoms; increase of ≥50% over nadir with absolute count ≥ 5×10\^9/liter (L) in circulating lymphocyte count (CLC); gB: decrease of ≥50% from BL secondary to CLL in platelet count; decrease of ≥2 gram per deciliter (g/dL) from BL secondary to CLL in hemoglobin (Hb); increase of CLL cells by ≥50% on successive biopsies in bone marrow (BM). Median PFS was calculated using Kaplan-Meier method and its confidence interval (CI) using Brookmeyer-Crowley method.
To evaluate the safety and tolerability of acalabrutinib monotherapy in participants with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia.
Defined as the time from the date of randomization until disease progression (assessed by the IRC per the Lugano Classification for NHL) or death from any cause, whichever occurs first.
ORR, defined as the proportion of participants who achieve best response of CR, CRi, nPR, or PR per iwCLL criteria as assessed by the investigator.
The cardiac MRI changes that will be assessed include Extracellular volume (ECV), Native T1, and T2, where changes in ECV from baseline to 3-month post acalabrutinib initiation would be the primary endpoint
MRD-negative CR rate is defined as the proportion of participants who achieved MRD-negativity in peripheral blood by NGS at a threshold of 10-5 while in CR per the Lugano Classification for NHL at the end of AVR induction
Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Toxicity as defined by the following: grade \>= 3 cytokine release syndrome, grade \>= 3 neurotoxicity within 30 days of infusion of axicabtagene ciloleucel. Grading will be done in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 for neurotoxicity and the Lee Criteria for cytokine release syndrome, unless otherwise specified.
The RP2D will be defined as the highest dose level for which there are no more than 1/6 DLTs observed.
Complete remission (CR) rate after 7 cycles of treatment with AVO in treatment naïve (TN) transplant ineligible MCL and TN transplant-eligible, TP53 mutated MCL, cohort B. CR rate after 7 cycles of treatment with AVO in TN TP53-mutated MCL, expansion cohort D. Complete remission (CR) is defined radiographically using 2014 Lugano criteria and a negative bone marrow biopsy by histology, immunohistochemistry, and flow cytometry, if bone marrow was initially involved by MCL at screening. CR, a primary endpoint measured after 7 cycles of AVO, does not incorporate minimal residual disease (MRD) testing
Minimal residual disease (MRD) negative (\<1 in 106 cells) CR rate after 7 cycles of treatment with AVO in TN transplant-eligible, TP53 wild type MCL, cohort C
Assessment of AUCinf for acalabrutinib and ACP-5862 (metabolite of acalabrutinib) following administration of capsule with and without rabeprazole.
Assessment of AUClast for acalabrutinib and ACP-5862 following administration of capsule with and without rabeprazole.
Assessment of Cmax for acalabrutinib and ACP-5862 following administration of capsule with and without rabeprazole.
An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. A SAE is an AE occurring during any study phase, that fulfils 1 or more of the following criteria: death, life-threatening, in-participant hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital abnormality or birth defect, and an important medical event that may jeopardize the participant or may require medical treatment to prevent 1 of the outcomes listed above. AEs leading to discontinuation of acalabrutinib were those with action taken was 'Drug Permanently Discontinued' for acalabrutinib.
Blood samples were collected to determine the AUCinf of acalabrutinib and ACP-5862 in plasma. The AUCinf was determined using non-compartmental method.
Blood samples were collected to determine the AUC0-12 of acalabrutinib and ACP-5862 in plasma. The AUC0-12 was determined using non-compartmental method.
Blood samples were collected to determine the AUClast of acalabrutinib and ACP-5862 in plasma. The AUClast was determined using non-compartmental method.
Blood samples were collected to determine the Cmax of acalabrutinib and ACP-5862 in plasma. The Cmax was determined using non-compartmental method.
Blood samples were collected to determine the tmax of acalabrutinib and ACP-5862 in plasma. The tmax was determined using non-compartmental method.
Urine samples were collected to determine the CL/F of acalabrutinib. The CL/F was determined using non-compartmental method.
Blood samples were collected to determine the Vz/F of acalabrutinib in plasma. The Vz/F was determined using non-compartmental method.
Blood samples were collected to determine the λz of acalabrutinib and ACP-5862 in plasma. The λz was determined using non-compartmental method.
Blood samples were collected to determine the t1/2λz of acalabrutinib and ACP-5862 in plasma. The t1/2λz was determined using non-compartmental method.
Blood samples were collected to determine the MRCmax of acalabrutinib and ACP-5862 in plasma. The MRCmax was determined using non-compartmental method.
Blood samples were collected to determine the MRAUCinf of acalabrutinib in plasma. The MRAUCinf was determined using non-compartmental method.
Blood samples were collected to determine the AUCτ of acalabrutinib and ACP-5862 in plasma. The AUCτ was determined using non-compartmental method.
Blood samples were collected to determine the Cmin of acalabrutinib and ACP-5862 in plasma. The Cmin was determined using non-compartmental method.
Blood samples were collected to determine the MRAUCτ of acalabrutinib and ACP-5862 in plasma. The MRAUCτ was determined using non-compartmental method.
Blood samples were collected to determine the TCP of acalabrutinib and ACP-5862 in plasma. The TCP in systemic exposure was calculated as AUCτ (steady state)/AUCinf (first dose). The TCP was determined using non-compartmental method.
Blood samples were collected to determine the Rac AUC of acalabrutinib and ACP-5862 in plasma. The Rac AUC was calculated as AUCτ (steady state)/AUCτ (first dose). The Rac AUC was determined using non-compartmental method.
Blood samples were collected to determine the Rac Cmax of acalabrutinib and ACP-5862 in plasma. The Rac Cmax was calculated as Cmax (steady state)/Cmax (first dose). The Rac Cmax was determined using non-compartmental method.
The ORR \[based on International workshop on chronic lymphocytic leukemia (iwCLL) 2018 criteria as assessed by the BICR\] was defined as the percentage of participants who achieved a complete response (CR), CR with incomplete marrow recovery (CRi), nodular partial response (nPR), and partial response (PR). The ORR and the corresponding 95% 2-sided confidence interval (CI) of ORR were presented based on Clopper-Pearson exact method.
Acalabrutinib is considered as safe and tolerable if ≦1 of 6 patients experiences a DLT.
Treatment-emergent adverse events were used to characterize the safety profile of acalabrutinib alone or in combination with rituximab in participants with relapsed/refractory follicular lymphoma (R/R FL).
The objective response rate (ORR) is used to characterize the activity of acalabrutinib alone or in combination with rituximab in participants with relapsed/refractory marginal zone lymphoma (R/R MZL).
Treatment-emergent adverse events were used to characterize the safety of acalabrutinib in combination with rituximab and lenalidomide in participants with relapsed/refractory follicular lymphoma (R/R FL).
Best response and overall response rate per the criteria investigator uses for each disease histology. Standardized response and progression criteria is based on established criteria for B-cell malignancies, including WM (Cheson 2014; Owen 2013; Hallek 2008; Bladé 1998; and Durie 2006).
| Arm | Type | Description |
|---|---|---|
| Acalabrutinib, Venetoclax | EXPERIMENTAL | Acalabrutinib in combination with Venetoclax |
| Acalabrutinib, Venetoclax, Obinutuzumab | EXPERIMENTAL | Acalabrutinib in combination with Venetoclax with Obinutuzumab |
| Chemoimmunotherapy | ACTIVE_COMPARATOR | Chemoimmunotherapy FCR: Fludarabine, Cyclophosphamide and Rituximab BR: Bendamustine and Rituximab |
| Arm A: Acalabrutinib plus Venetoclax (AV) | EXPERIMENTAL | Participants will receive acalabrutinib and venetoclax orally. |
| Arm B: Venetoclax plus Obinutuzumab (VO) | EXPERIMENTAL | Participants will receive Venetoclax orally and Obinutuzumab via IV infusion. |
| acalabrutinib + R-CHOP | EXPERIMENTAL | Acalabrutinib plus Rituximab, Cyclosphosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) |
| placebo + R-CHOP | PLACEBO_COMPARATOR | Placebo plus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) |
| Acalabrutinib | EXPERIMENTAL | Acalabrutinib will be orally administered until disease progression or unacceptable toxicity |
| Rituximab and Chlorambucil | ACTIVE_COMPARATOR | Chlorambucil orally administered and Rituximab via IV infusion for 6 cycles |
| Acalabrutinib in combination with bendamustine and rituximab | EXPERIMENTAL | Acalabrutinib administered twice per day (BID) orally (PO) plus bendamustine on Days 1 and 2 and rituximab on Day 1; cycles are repeated every 28 days. |
| Placebo in combination with bendamustine and rituximab | PLACEBO_COMPARATOR | Matching placebo administered BID PO plus bendamustine on Days 1 and 2 and rituximab on Day 1; cycles are repeated every 28 days. |
| Acalabrutinib and Venetoclax | EXPERIMENTAL | For Cohort 1, each participant will be in the study for approximately 5 years (60 months) counting from C1D1, starting with 2 cycles of acalabrutinib lead-in treatment, followed by 12 cycles of AV combination treatment, and 4 years of follow-up. For Cohort 2, each participant will be in the study for approximately 5 years (60 months) counting from C1D1 starting with 2 cycles of acalabrutinib lead-in treatment, followed by 22 cycles of AV combination treatment, and 3 years of follow-up. |
| Treatment (acalabrutinib) | EXPERIMENTAL | Patients receive acalabrutinib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CMR, CT, bone marrow aspiration/biopsy, and collection of blood samples throughout the trial. |
| Acalabrutinib and Rituximab | EXPERIMENTAL | Patients will receive Dose A of acalabrutinib orally in X dosing schedule beginning on Cycle 1 Day 1 for a maximum of 28 cycles or until 2014 Lugano Classification for Non-Hodgkin's Lymphoma (NHL)-defined disease progression or another discontinuation criterion is met. Patients will also receive an intravenous (IV) infusion of Dose B rituximab on Cycle 1 Day 15 and Dose C of rituximab as an subcutaneous (SC) injection on Day 1 of Cycle 2 through Cycle 8. |
| Acalabrutinib + Venetoclax + Rituximab | EXPERIMENTAL | Acalabrutinib + Venetoclax + Rituximab (AVR) |
| Arm I (acalabrutinib, venetoclax, obinutuzumab) | ACTIVE_COMPARATOR | Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Beginning cycle 3, patients receive venetoclax PO once a week on days 1-28, then once daily starting cycle 4. Patients who are BM MRD4-positive or in PR also receive obinutuzumab IV over 4-6 hours on days 1, 2, 8, and 15 of cycle 15 and day 1 of cycles 16-20. Treatment repeats every 28 days (or 42 days for cycle 14) for up to 26 cycles in the absence of disease progression or unacceptable toxicity. |
| Arm II (acalabrutinib, venetoclax, early obinutuzumab) | EXPERIMENTAL | Patients receive acalabrutinib PO BID on days 1-28 beginning cycle 2 and venetoclax PO once a week on days 1-28, then once daily starting cycle 4. Patients also receive obinutuzumab IV over 4-6 hours on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2-6. Patients who are BM MRD4-positive or in PR receive obinutuzumab IV over 4-6 hours on day 1 cycles 15-20. Treatment repeats every 28 days (or 42 days for cycle 14) for up to 26 cycles in the absence of disease progression or unacceptable toxicity. |
| Arm 1 | EXPERIMENTAL | Acalabrutinib+ Best Supportive Care |
| Arm 2 | NO_INTERVENTION | Best Supportive Care |
| Treatment (acalabrutinib, axicabtagene ciloleucel) | EXPERIMENTAL | Beginning up to 3 weeks and at least 24 hours prior to leukapheresis, patients receive acalabrutinib PO every 12 hours. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients also receive axicabtagene ciloleucel IV at 36-96 hours after completion of lymphodepleting chemotherapy. |
| Acalabrutinib, Venetoclax, and Obinutuzumab | EXPERIMENTAL | The study will consist of 4 parts (Parts A, B, C, and D). In the relapsed/refractory (R/R) MCL setting (Part A), the phase 1 portion consists of a dose finding stage to determine the recommended phase 2 dose (RP2D). It will follow a 3+3 dose finding schema with a minimum of 6 participants. 11 participants will be enrolled in the Part A expansion cohort. Part B will enroll 24 participants with untreated mantle cell lymphoma who are transplant ineligible and/or TP53 mutated. Part C will enroll 12 participants with untreated mantle cell lymphoma who are transplant eligible and TP53 wild type. Part D will enroll 16 participants with untreated mantle cell lymphoma with a TP53 mutation determined by next generation sequencing, regardless of transplant eligibility. Each study drug is given according to a different schedule. Each treatment cycle lasts 28 days (4 weeks). * Acalabrutinib: * Obinutuzumab: * Venetoclax: |
| Arm A | EXPERIMENTAL | Participants will receive single oral dose of acalabrutinib capsule with 100 mL of water. |
| Arm B | EXPERIMENTAL | Participants will receive single oral dose of acalabrutinib capsule taken with 100 mL of COCA-COLA along with 20 mg rabeprazole. |
| Part 1 / Part 2 | EXPERIMENTAL | Acalabrutinib |
| Part 3 | EXPERIMENTAL | Acalabrutinib in combination with Obinutuzumab |
| Part 1: acalabrutinib Regimen 1 | EXPERIMENTAL | acalabrutinib Regimen 1 for relapsed, refractory Follicular Lymphoma subjects |
| Part 1: acalabrutinib Regimen 2 | EXPERIMENTAL | acalabrutinib Regimen 2 + rituximab for relapsed, refractory, or treatment naive Follicular Lymphoma subjects |
| Part 2: acalabrutinib Regimen 1 | EXPERIMENTAL | acalabrutinib Regimen 1 for relapsed, refractory Marginal Zone Lymphoma subjects |
| Part 2: acalabrutinib Regimen 2 | EXPERIMENTAL | acalabrutinib Regimen 2 + rituximab for relapsed, refractory Marginal Zone Lymphoma subjects |
| Part 3: acalabrutinib Regimen 1 | EXPERIMENTAL | acalabrutinib Regimen + lenalidomide + rituximab for relapsed, refractory Follicular Lymphoma subjects |
| Dose Escalation and Expansion | EXPERIMENTAL | The acalabrutinib dose will be fixed and the ACP-319 dose will be escalated in each of three cohorts, and each cohort will take both study drugs by mouth, twice per day (BID) at approximately 12 hour intervals. Expansion groups of up to 12 subjects for Germinal center B-cell (GCB) DLBCL and Non-GCB DLBCL to take a fixed dose of acalabrutinib and ACP-319. Each disease group will take both study drugs by mouth, twice per day (BID) at approximately 12 hour intervals. |
| Name | Type | Description |
|---|---|---|
| Acalabrutinib | DRUG | Acalabrutinib, |
| Venetoclax | DRUG | Venetoclax |
| Chemoimmunotherapy | DRUG | fludarabine/cyclophosphamide/rituximab (FCR), bendamustine/rituximab (BR) |
| Obinutuzumab | DRUG | Obinutuzumab |
| placebo | DRUG | Placebo comparator |
| Prednisone | DRUG | Investigational Product |
| Rituximab | DRUG | Investigational Product |
| Cyclophosphamide | DRUG | Investigational Product |
| Vincristine | DRUG | Investigational Product |
| Doxorubicin | DRUG | Investigational Product |
| Chlorambucil | DRUG | Chlorambucil: 0.5 mg/kg body weight orally on Day 1 and Day 15 of Cycles 1-6 |
| Bendamustine | DRUG | Administered intravenously (IV) |
| Biospecimen Collection | PROCEDURE | Undergo collection of blood samples |
| Bone Marrow Aspiration | PROCEDURE | Undergo bone marrow aspiration |
| Bone Marrow Biopsy | PROCEDURE | Undergo bone marrow biopsy |
| Computed Tomography | PROCEDURE | Undergo CT |
| Magnetic Resonance Imaging of the Heart | PROCEDURE | Undergo CMR |
| Axicabtagene Ciloleucel | BIOLOGICAL | Given IV |
| Rabeprazole | DRUG | Participants will receive twice daily oral dose of 20 mg rabeprazole on days -3, -2, and -1. |
| rituximab (IV) | DRUG | - |
| Lenalidomide | DRUG | - |
| ACP-319 | DRUG | Oral |
Inclusion Criteria: * Men and women ≥18 years of age. * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. * Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018) * Active disease per IWCLL 2018 criteria that requires treatment. * Participants must use hig...
Acalabrutinib is a small molecule BTK inhibitor being developed by AstraZeneca PLC (AZN) for chronic lymphocytic leukemia, small lymphocytic lymphoma, recurrent chronic lymphocytic leukemia, and other B-cell malignancies. It is also being studied in infectious disease, including COVID-19. The drug is currently in Phase 1 clinical development.
Acalabrutinib targets Bruton's tyrosine kinase (BTK), an enzyme involved in B-cell receptor signaling. As a BTK inhibitor, it blocks this pathway, which is relevant in B-cell malignancies. This mechanism is being investigated across multiple oncology indications, including chronic lymphocytic leukemia and diffuse large B-cell lymphoma.
Acalabrutinib is developed by AstraZeneca PLC, a biopharmaceutical company listed on the stock exchange under the ticker AZN. The drug is an investigational small molecule BTK inhibitor currently in Phase 1 clinical trials for oncology and infectious disease indications.
Acalabrutinib is in Phase 1 clinical development. It is an investigational drug and has not been approved by the FDA. The FDA has granted it priority review designation, but it remains in clinical trials for conditions such as chronic lymphocytic leukemia and B-cell lymphoma.
Acalabrutinib is being studied in multiple clinical trials, including NCT02328014, a Phase 1 study combining it with ACP-319 for B-cell malignancies, and NCT04257578, a Phase 1 trial with anti-CD19 CAR T-cell therapy for B-cell lymphoma. Additional trials include NCT04529772 and NCT07029737.
Acalabrutinib is also known as Acalabrutinib in combination with BR and Acalabrutinib + R-CHOP standard of care. These names refer to the drug when used in combination regimens, such as with BR (bendamustine and rituximab) or R-CHOP chemotherapy, for treating B-cell malignancies.