Acalabrutinib and Venetoclax Treatment of Newly Diagnosed Patients With CLL at High Risk of Infection or Early Treatment
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03868722|
Recruitment Status : Recruiting
First Posted : March 11, 2019
Last Update Posted : February 12, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|CLL||Drug: Acalabrutinib Drug: Venetoclax||Phase 2 Phase 3|
OBJECTIVE AND HYPOTHESIS Phase 2, randomized study of short-term, combined venetoclax and acalabrutinib treatment of newly diagnosed patients with CLL. For patients identified by CLL-TIM (the Machine Learning predictive algorithm, Treatment Infection Model) at high risk of infection and/or early CLL treatment, it is tested whether grade 3-Infection-free, treatment-free survival can be improved by three months of venetoclax+acalabrutinib treatment. Changes in immune dysfunction are measured by an extensive translational program for correlation with changes in infection.
BACKGROUND Infection and immune dysfunction in patients diagnosed with CLL leads to significant morbidity and mortality, as exemplified by the constant rate of infectious deaths in CLL over the last three decades, despite significant improvement in all other causes of death. This also affects patients who do not need treatment according to IWCLL criteria, thus infections are the leading cause of death among patients with CLL. Based on a novel machine learning algorithm, CLL-TIM, patients at high risk (>65% 2-years risk) of severe infection and/or CLL treatment can be identified at diagnosis. By a short period of preemptive treatment for these patients, the aim is to change the natural history of CLL and immune dysfunction.
METHODS The study is an intergroup study between the HOVON (Belgium, the Netherlands) and the Nordic (Denmark, Norway, Sweden, Finland) CLL study groups. For the phase 2 study, 4-8 sites with the capacity of the extensive translational immune phenotyping and/or timely shipment of samples will be selected. Patients are randomized between venetoclax+acalabrutinib treatment for three months or observation. For each treatment arm, 25 patients are needed (50 in total). Thorough assessment of immune function before, during and after treatment as well as detailed reporting on infectious complications, the proof of concept of the PreVent-ACaLL study's capacity to change the natural history of immune dysfunction in CLL by short-term venetoclax-acalabrutinib treatment will be made.
PERSPECTIVES By addressing the unmet need of improving immune function for newly diagnosed CLL patients with high risk of infections and/or early CLL treatment, the aim is to change the paradigm for CLL treatment and the natural history of the disease.
If the phase 2 trial demonstrates a clear signal for safety with indication of benefit for patients in the treatment arm, an extension phase 3 study is planned with the potential to change the future management of CLL.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||212 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||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.|
|Masking:||None (Open Label)|
|Official Title:||Short-term Combined Acalabrutinib and Venetoclax Treatment of Newly Diagnosed Patients With CLL at High Risk of Infection and/or Early Treatment, Who do Not Fulfil IWCLL Treatment Criteria.|
|Actual Study Start Date :||October 11, 2019|
|Estimated Primary Completion Date :||July 31, 2029|
|Estimated Study Completion Date :||July 31, 2030|
Experimental: Treatment arm
Treatment with Acalabrutinib and Venetoclax is initiated within 14 days after randomization.
Acalabrutinib 100 mg BID from cycle 1 day 1 for 3 cycles of 28 days.
Other Name: Calquence
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.
No Intervention: Observation arm
Observation period is initiated within 14 days after randomization.
- Grade 3-Infection-free survival [ Time Frame: 12 weeks after finishing treatment ]Grade 3-Infection-free survival in the treatment arm compared to the observation arm
- Event-free survival [ Time Frame: 2 years after enrollment ]Event-free survival, event being either grade ≥3 infection or CLL treatment
- Event-free survival [ Time Frame: 12 weeks after treatment initiation,1 year and 2 years after enrollment ]Event-free survival, event being either grade ≥3 infection or CLL treatment
- Overall survival [ Time Frame: Assessed at 12 weeks, 1 year and 2 years from treatment/observation initiation ]Overall survival
- Treatment free survival [ Time Frame: Assessed at 12 weeks, 1 year and 2 years from treatment/observation initiation ]Treatment free survival
- Rate of infections [ Time Frame: assessed at 12 weeks, 1 year and 2 years from treatment/observation initiation ]Rate of infections
- Rate of infections grade ≥3 [ Time Frame: assessed at 12 weeks, 1 year and 2 years from treatment/observation initiation ]Rate of infections
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03868722
|Contact: Carsten U Niemann, MD, PhD||+45 email@example.com|
|Contact: Bitten Aagaard, RN||+45 firstname.lastname@example.org|
|Copenhagen, Denmark, 2100|
|Contact: Carsten U Niemann, MD, PhD +45 3545 7830 email@example.com|
|Principal Investigator: Carsten U Niemann, MD, PhD|
|Herlev og Gentofte Hospital||Recruiting|
|Herlev, Denmark, 2730|
|Contact: Lisbeth Enggaard, MD +45 3868 9118 firstname.lastname@example.org|
|Principal Investigator: Lisbeth Enggaard, MD|
|Sjællands Universitetshospital Roskilde||Recruiting|
|Roskilde, Denmark, 4000|
|Contact: Christian B Poulsen, MD +4547324809 email@example.com|
|Principal Investigator: Christian B Poulsen, MD|
|Principal Investigator:||Carsten U Niemann, MD, PhD||Rigshospitalet, Denmark|