This study is being done to test the effectiveness and safety of an investigational drug called acalabrutinib (ACP-196) when taken with already marketed drugs called Venetoclax and Obinutzumab in comparison to chemotherapy that is already in wide use for treatment of patients who have chronic lymphocytic leukemia and who have never been treated before.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Acerta Pharma B.V.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Mar 2019 → ongoing

Decision date (initial)

2024-07-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Acerta Pharma B.V. (a member of the AstraZeneca Group of Companies)

External identifiers

EU CT number

2023-509349-11-00

EudraCT number

2018-002443-28

ClinicalTrials.gov

NCT03836261

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Therapy, Safety

To evaluate the efficacy of acalabrutinib/venetoclax (AV; Arm A) compared with chemoimmunotherapy (fludarabine/cyclophosphamide/rituximab [FCR] or bendamustine/rituximab [BR]; Arm C)

Secondary objectives 1

1. 1.To evaluate the efficacy of AV (Arm A) in comparison with chemo-immunotherapy (FCR/BR [Arm C])” 2. To evaluate the efficacy of acalabrutinib/venetoclax/obinutuzumab (AVG; Arm B) versus FCR/BR (Arm C) 3. To evaluate the efficacy of AV (Arm A) versus FCR/BR (Arm C) and AVG (Arm B) versus FCR/BR (Arm C)

Conditions and MedDRA coding

Previously untreated Chronic Lymphocytic Leukemia Without del(17p) or TP53 Mutation

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests 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. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMa Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 1. Men and women ≥18 years of age. 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. 3. Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018): Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing B-cell marker (CD19, CD20, and CD23) and CD5. Prolymphocytes may comprise <55% of blood lymphocytes. Presence of ≥5x109 B lymphocytes/L (5000/µL) in the peripheral blood (at any point since the initial diagnosis). 4. Active disease per IWCLL 2018 criteria that requires treatment (see Section 4.5.6). 5. Meet the following laboratory parameters: a) Adequate bone marrow function independent of growth factor or transfusion support within 1 week of Screening, as follows: i.ANC ≥750 cells/μL (0.75x109/L); ANC ≥500 cells/μL (0.50x109/L) in subjects with documented bone marrow involvement of CLL ii.Platelet count ≥50,000 cells/μL (50x109/L); platelet count ≥30,000 cells/μL (30x109/L) in subjects with documented bone marrow involvement of CLL b)Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5xULN. c)Total bilirubin ≤2xULN, unless directly attributable to Gilbert’s syndrome d)Estimated creatinine clearance of ≥50 mL/min, calculated using the formula of Cockcroft and Gault (if male, [140Age] x Mass (kg) / [72 x creatinine mg/dL]; multiply by 0.85 if female); estimated creatinine clearance of ≥70 mL/min for subjects selected by investigator to receive FCR in Arm C

Exclusion criteria 1

1. 1. Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisone daily are permitted). 2. Detected del(17p) or TP53 mutation. 3. Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (e.g., Richter’s transformation, PLL, or diffuse large B cell lymphoma [DLBCL]), or central nervous system (CNS) involvement by leukemia. 4. Any comorbidity or organ system impairment rated with a single CIRS score of 4 (excluding the eyes/ears/nose/throat/larynx organ system), or a total CIRS score of >6. 5. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura. 6. History of confirmed progressive multifocal leukoencephalopathy (PML). 7. Received any investigational drug within 30 days before first dose of study drug. 8. Major surgical procedure within 30 days before the first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. 9. History of prior malignancy that could affect compliance with the protocol, or interpretation of results, except for the following: •Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or carcinoma in situ of the prostate at any time prior to study. •Other cancers not specified above which have been curatively treated by surgery and/or radiation therapy from which subject is disease-free for ≥3 years without further treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS), 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.

Secondary endpoints 8

1. 1: Progression-free survival (PFS), 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 investigator assessment.
2. 2: PFS, 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 IRC assessment and investigator assessment
3. 3: Event-free survival (EFS), defined as the time from randomization to the first occurrence of disease progression, initiation of subsequent anti-chronic lymphocytic leukemia (CLL) therapy, or death from any cause per IRC assessment and the investigator assessment
4. - Overall response rate (ORR), defined as the proportion of subjects with a complete response (CR), complete response with incomplete marrow recovery (CRi), nodular partial response (nPR) or partial response (PR) per IRC assessment and investigator assessment
5. - Duration of objective response (DOR), defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause per IRC assessment and investigator assessment
6. - Time to next Therapy (TTNT), defined as the time from randomization to institution of non-protocol specified treatment for CLL
7. - Minimal residual disease (MRD) negativity rate (determined as the proportion of subjects with MRD-negativity) measured in the peripheral blood by flow cytometry (10-4) at the start of Cycle 9 (in Arm A), the start of Cycle 10 (in Arm B), and 12 weeks after the start of Cycle 6 (in Arm C)
8. - Overall survival (OS), defined as the time from randomization to death from any cause.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Acerta Pharma B.V.

Sponsor organisation

Acerta Pharma B.V.

Address

Kloosterstraat 9

City

Oss

Postcode

5349 AB

Country

Netherlands

Scientific contact point

Organisation

Acerta Pharma B.V.

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

Acerta Pharma B.V.

Contact name

AstraZeneca Clinical Study Information Center

Locations

13 EU/EEA countries · 57 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 100 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications