A Randomized, Multicenter, Open-Label, 3 Arm Phase 3 Study of Obinutuzumab in Combination with Chlorambucil, ACP 196 in Combination with Obinutuzumab, and ACP-196 Monotherapy in Subjects with Previously Untreated Chronic Lymphocytic Leukemia

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

27 Apr 2015 → ongoing

Decision date (initial)

2024-07-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-509348-84-00

EudraCT number

2014-005582-73

ClinicalTrials.gov

NCT02475681

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Pharmacokinetic, Efficacy, Therapy

To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B), based on IRC assessment of PFS per IWCLL 2008 criteria, in subjects with previously untreated CLL.

Secondary objectives 1

1. To evaluate the efficacy of Arm A versus acalabrutinib monotherapy based on IRC assessment of PFS per IWCLL 2008 criteria. To compare Arm A versus Arm B and Arm A versus Arm C in terms of: IRC-assessed objective response rate (ORR) per IWCLL 2008 criteria; Time to next treatment (TTNT) (defined as the time from randomization to institution of non-protocol specified treatment for CLL); Overall survival (OS);

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. "• Men and women ≥ 65 years of age, or > 18 and < 65 years of age provided that they meet at least one of the following criteria: o Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation. o A score higher than 6 on the Cumulative Illness Rating Scale-Geriatric (CIRS-G). • ECOG performance status of 0, 1, or 2. • Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008) • Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: o 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). o Massive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. o Massive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. o Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. 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 subjects 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. o Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. o Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs: - Unintentional weight loss ≥ 10% within the previous 6 months before Screening. - Significant fatigue (ie, ECOG performance status 2; inability to work or perform usual activities). - Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection. - Night sweats for > 1 month before Screening without evidence of infection. • Meet the following laboratory parameters: o Absolute neutrophil count ≥ 750 cells/μL (0.75 x 10^9/L) or ≥ 500 cells/μL (0.50 x 10^9/L) in subjects with documented bone marrow involvement and independent of growth factor support 7 days before assessment. o Platelet count ≥ 50,000 cells/μL (50 x 10^9/L), or ≥ 30,000 cells/μL (30 x 10^9/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. o Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x upper limit of normal (ULN). o Total bilirubin ≤ 1.5 x ULN. o Estimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) ≥ 30 mL/min. • Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations. • Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib or 18 months after the last dose of obinutuzumab in combination with chlorambucil, whichever is longer. • Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. • Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. • Are willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information."
2. • Men and women ≥ 65 years of age, or > 18 and < 65 years of age provided that they meet at least one of the following criteria: o Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation. o A score higher than 6 on the Cumulative Illness Rating Scale-Geriatric (CIRS-G). • ECOG performance status of 0, 1, or 2. • Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008) • Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: o 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). o Massive (ie, ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. o Massive nodes (ie, ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. o Progressive lymphocytosis with an increase of > 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months. 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 subjects 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. o Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. o Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs: - Unintentional weight loss ≥ 10% within the previous 6 months before Screening. - Significant fatigue (ie, ECOG performance status 2; inability to work or perform usual activities). - Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection. - Night sweats for > 1 month before Screening without evidence of infection. • Meet the following laboratory parameters: o Absolute neutrophil count ≥ 750 cells/μL (0.75 x 10^9/L) or ≥ 500 cells/μL (0.50 x 10^9/L) in subjects with documented bone marrow involvement and independent of growth factor support 7 days before assessment. o Platelet count ≥ 50,000 cells/μL (50 x 10^9/L), or ≥ 30,000 cells/μL (30 x 10^9/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. o Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 x upper limit of normal (ULN). o Total bilirubin ≤ 1.5 x ULN. o Estimated creatinine clearance (ie, estimated glomerular filtration rate [eGFR] using Cockcroft-Gault) ≥ 30 mL/min. • Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations. • Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib or 18 months after the last dose of obinutuzumab in combination with chlorambucil, whichever is longer. • Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. • Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. • Are willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information.

Exclusion criteria 1

1. "• Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed). • Known central nervous system (CNS) lymphoma or leukemia. • Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome. • Missing or incomplete documentation of FISH results reflecting the presence or absence of 17p del and the percentage of cells with the deletion in subject records before randomization. • Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic 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 (> 20mg daily of prednisone daily or equivalent). • Corticosteroid use > 20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. For example, subjects requiring steroids at daily doses > 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or white blood cell count (WBC) lowering are excluded"

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the study is PFS as assessed by IRC review per IWCLL 2008 criteria. The primary analysis is a comparison of PFS between Arm A and Arm B.

Secondary endpoints 2

1. "Efficacy: The first secondary endpoint is a comparison of IRC-assessed PFS between Arm A and Arm C. Other secondary endpoints are as follows and compare Arm A versus Arm B and Arm A versus Arm C • OS. Safety: • Frequency, severity, and relatedness of adverse events. • Frequency of adverse events requiring discontinuation of study drug or dose reductions. • Change in laboratory assessments. "
2. Efficacy: The first secondary endpoint is a comparison of IRC-assessed PFS between Arm A and Arm C. Other secondary endpoints are as follows and compare Arm A versus Arm B and Arm A versus Arm C • OS. Safety: • Frequency, severity, and relatedness of adverse events. • Frequency of adverse events requiring discontinuation of study drug or dose reductions. • Change in laboratory assessments.

Investigational products

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

Test 2

Comparator 2

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

Carla Hartman

Public contact point

Organisation

Acerta Pharma B.V.

Contact name

Carla Hartman

Third parties 9

Locations

9 EU/EEA countries · 39 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 81 files

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

Application history

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