Acalabrutinib and Venetoclax Treatment of Newly Diagnosed Patients With CLL at High Risk of Infection or Early Treatment

NCT03868722 | Recruiting Phase 2 DMC

• 1 other identifier: PreVent-ACaLL
• Study Type: interventional
• Target: 212
• Locations: 3 countries
• Sites: 7

Brief Summary

Many patients with CLL have a weakened immune system due to their disease. It increases their risk of developing serious, treatment-requiring infections such as blood poisoning or pneumonia, which in the worst case may end with fatal outcomes. Serious infections due to CLL are responsible for one third of all deaths among CLL patients. PreVent-ACaLL study will investigate whether a combination of two known types of cancer drugs can reduce the risk of infection and thus mortality when given preventively to newly diagnosed CLL patients. A newly developed register-based computer model can predict which patients are at high risk in order to develop infections as a result of their CLL. A preventive treatment might be initiated before patients need chemotherapy. In this way, the cancer disease might be "reset" so that the immune system, which is inhibited by CLL, is restored and the risk of fatal infections is minimized.

Conditions

CLL

Outcome Measures

Primary Outcomes (2)

• Grade 3-Infection-free survival

  Grade 3-Infection-free survival in the treatment arm compared to the observation arm

  12 weeks after finishing treatment

• Event-free survival

  Event-free survival, event being either grade ≥3 infection or CLL treatment

  2 years after enrollment

Secondary Outcomes (5)

• Event-free survival

  12 weeks after treatment initiation,1 year and 2 years after enrollment

• Overall survival

  Assessed at 12 weeks, 1 year and 2 years from treatment/observation initiation

• Treatment free survival

  Assessed at 12 weeks, 1 year and 2 years from treatment/observation initiation

• Rate of infections

  assessed at 12 weeks, 1 year and 2 years from treatment/observation initiation

• Rate of infections grade ≥3

  assessed at 12 weeks, 1 year and 2 years from treatment/observation initiation

Study Arms (2)

Treatment arm

EXPERIMENTAL

Treatment with Acalabrutinib and Venetoclax is initiated within 14 days after randomization.

Drug: Acalabrutinib; Drug: Venetoclax

Observation arm

NO INTERVENTION

Observation period is initiated within 14 days after randomization.

Interventions

Acalabrutinib DRUG

Acalabrutinib 100 mg BID from cycle 1 day 1 for 3 cycles of 28 days.

Also known as: Calquence

Treatment arm

Venetoclax DRUG

Venetoclax, ramp up during the first five weeks starting cycle 1 day 1, 7 days treatment on each dose level (20-50-100-200-400 mg), thereafter 400 mg once daily for a total of 3 cycles of 28 days.

Also known as: Venclexta, Venclyxto

Treatment arm

Eligibility Criteria

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

You may qualify if:

• CLL diagnosed according to IWCLL criteria within one year prior to randomization
• High risk of infection and/or progressive treatment within 2 years according to CLL-TIM
• IWCLL treatment indication not fulfilled
• Life expectancy \> 2 years
• Age at least 18 years
• Ability and willingness to provide written informed consent and adhere to study procedures and treatment
• Adequate bone marrow function as indicated by platelets above 100 x 10E9, hemoglobin above 10 g/dL and neutrophils above 1 x 10E9
• Creatinine clearance above 30 mL/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault
• Adequate liver function as indicated by a total bilirubin≤ 2 x, AST/ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient's CLL or to Gilbert's Syndrome.
• Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration.
• Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.
• Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 2 days after the last dose of investigational drugs.
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information

You may not qualify if:

• Prior CLL treatment (including monoclonal antibodies, chemotherapy, small molecules)
• Transformation of CLL (Richter's transformation)
• Previous autoimmune disease as AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura) treated with immune suppression or uncontrolled AIHA or ITP
• History of PML
• Uncontrolled or active infection
• Malignancies other than CLL requiring systemic therapies (except anti-hormonal therapies) or considered to impact survival
• Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonists
• History of bleeding disorders or current platelet inhibitors or anticoagulant therapy
• History of clinically significant cardiovascular disease such as arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening.
• History of stroke or intracranial hemorrhage within 6 months prior to registration.
• Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
• Vaccination with live vaccines 28 days prior to registration.
• Major surgery less than 30 days before start of treatment.
• Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
• Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly).

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• Stichting Hemato-Oncologie voor Volwassenen Nederland: collaborator
• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): collaborator
• Karolinska Institutet: collaborator

Study Sites (7)

Rigshospitalet

Copenhagen, 2100, Denmark

RECRUITING

Herlev og Gentofte Hospital

Herlev, 2730, Denmark

RECRUITING

Sjællands Universitetshospital Roskilde

Roskilde, 4000, Denmark

RECRUITING

Albert Schweitzer Hospital

Dordrecht, 3318, Netherlands

RECRUITING

Ikazia Hospital (Ikazia Ziekenhuis)

Rotterdam, 3083, Netherlands

RECRUITING

Örebro University Hospital

Örebro, 701 85, Sweden

RECRUITING

Karolinska University Hospital

Stockholm, 171 76, Sweden

RECRUITING

Related Publications (10)

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  PMID: 28882879 BACKGROUND

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  PMID: 20206686 BACKGROUND

• de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012 Mar 15;119(11):2590-4. doi: 10.1182/blood-2011-11-390989. Epub 2012 Jan 25.

  PMID: 22279054 BACKGROUND

• Khan WN. Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. Immunol Res. 2001;23(2-3):147-56. doi: 10.1385/IR:23:2-3:147.

  PMID: 11444380 BACKGROUND

• Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, Christensson B, Berglof A, Vihinen M, Nore BF, Smith CI. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009 Mar;228(1):58-73. doi: 10.1111/j.1600-065X.2008.00741.x.

  PMID: 19290921 BACKGROUND

• Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O'Brien S, Chiorazzi N, Burger JA. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012 Feb 2;119(5):1182-9. doi: 10.1182/blood-2011-10-386417. Epub 2011 Dec 16.

  PMID: 22180443 BACKGROUND

• Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff AC. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006 Jul 1;24(19):3187-205. doi: 10.1200/JCO.2006.06.4451. Epub 2006 May 8.

  PMID: 16682719 BACKGROUND

• Soucek L, Buggy JJ, Kortlever R, Adimoolam S, Monclus HA, Allende MT, Swigart LB, Evan GI. Modeling pharmacological inhibition of mast cell degranulation as a therapy for insulinoma. Neoplasia. 2011 Nov;13(11):1093-100. doi: 10.1593/neo.11980.

  PMID: 22131884 BACKGROUND

• Svanberg Teglgaard R, Marquart HV, Hartling HJ, Bay JT, da Cunha-Bang C, Brieghel C, Faitova T, Enggaard L, Kater AP, Levin MD, Kersting S, Ostrowski SR, Niemann CU. Improved Innate Immune Function in Patients with Chronic Lymphocytic Leukemia Treated with Targeted Therapy in Clinical Trials. Clin Cancer Res. 2024 May 1;30(9):1959-1971. doi: 10.1158/1078-0432.CCR-23-2522.

  PMID: 38393694 DERIVED

• Gargiulo E, Teglgaard RS, Faitova T, Niemann CU. Immune Dysfunction and Infection - Interaction between CLL and Treatment: A Reflection on Current Treatment Paradigms and Unmet Needs. Acta Haematol. 2024;147(1):84-98. doi: 10.1159/000533234. Epub 2023 Jul 27.

  PMID: 37497921 DERIVED

MeSH Terms

Interventions

acalabrutinib; venetoclax

Study Officials

• Carsten U Niemann, MD, PhD

  Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Carsten U Niemann, MD, PhD

CONTACT

+45 35457830; carsten.utoft.niemann@regionh.dk

Bitten Aagaard, RN

CONTACT

+45 35455791; bitten.aagaard@regionh.dk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD, Associate Professor

Model Details: Randomization has to occur within 42 days after the first tests for screening were performed. Patients will be randomly assigned to treatment vs observation through 1:1 randomization process with stratification according to country, TP53 aberration status and IGHV mutational status. Treatment or observation period has to be initiated within 14 days after randomization.

Study Record Dates

• First Submitted: February 26, 2019
• First Posted: March 11, 2019
• Study Start: October 11, 2019
• Primary Completion (Estimated): July 31, 2029
• Study Completion (Estimated): July 31, 2030
• Last Updated: December 4, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

DK (3); NL (2); SE (2)