Acalabrutinib in Combination With Anti-CD20 and Venetoclax in Relapsed/Refractory or Untreated CLL/SLL/PLL

• Status: Active, not recruiting
• Trial end date: 2026-08-20
• Target enrollment: 0
• Participant gender: All

Summary

To evaluate the safety and preliminary efficacy of acalabrutinib in combination with obinutuzumab in 4 separate cohorts of patients.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Acerta Pharma BV
• Treatments: Acalabrutinib; Obinutuzumab; Rituximab; Venetoclax

Criteria

Inclusion Criteria

1. Subjects with a diagnosis of intermediate or high risk CLL (or variant immunophenotype), SLL, or B-cell prolymphocytic leukemia (B-PLL) by IWCLL 2008 criteria (Hallek et al. 2008) who have:

• Cohorts 1 and 3: Previously received at least 1 therapy for their disease (Cohort 3 enrollment limited to CLL).

• Cohort 2: Previously untreated disease and ≥65 years old OR under 65 years old and refuse or are ineligible for chemoimmunotherapy.

• Cohort 4: Previously untreated disease; Cohort 4 enrollment limited to CLL.

2. Subjects in Cohorts 1 and 3 may have received previous ibrutinib (or another BTK inhibitor) as long as discontinuation was for a reason other than on-treatment disease progression.

3. All subjects must satisfy one of the following criteria for active disease requiring therapy:

• Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia (not attributable to AIHA or thrombocytopenia)

• Massive (≥6 cm below the costal margin), progressive or symptomatic splenomegaly

• Massive nodes (≥10 cm) or progressive or symptomatic lymphadenopathy

• Constitutional symptoms, which include any of the following:

Unintentional weight loss of 10% or more within 6 months Significant fatigue limiting activity Fevers ≥100.5°F for 2 weeks or more without evidence of infection Night sweats >1 month without evidence of infection

4. This criterion was removed with Amendment 5.

5. Subjects with a history of Richter's syndrome are eligible if they now have evidence of CLL only, with <10% large cells in the bone marrow.

6. Subjects must have adequate organ function, defined as creatinine ≤2.5 times the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, and bilirubin ≤2.5 x ULN. For Cohorts 3 and 4, subjects must have creatinine clearance ≥50 mL/min using modified Cockcroft-Gault equation (using Ideal Body Mass [IBM] instead of mass):

7. IBM (kg) = [(height cm - 154) ● 0.9] + (50 if male, 45.5 if female).

8. Platelets >50 x 109/L. In subjects with CLL involvement of the marrow, >30 x 109/L for Cohorts 1 and 2. For Cohorts 3 and 4, subjects must have hemoglobin >9 g/dL.

9. Absolute neutrophil count (ANC) ≥750/mm3. In subjects with CLL involvement of the marrow, ANC ≥500/mm3. For Cohorts 3 and 4, subjects must have ANC ≥1000/mm3.

10. Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2.

11. Subject must not have secondary cancers that result in a life expectancy of <2 years or that would confound assessment of toxicity in this study.

12. Subjects must be ≥18 years of age.

13. Subject must provide written informed consent. A signed copy of the consent form will be retained in the subject's chart.

14. Subject must be able to receive outpatient treatment and follow-up at the treating institution.

15. Subject must have completed all CLL therapies ≥4 weeks prior to first study dose. Palliative steroids are allowed but must be at a dose equivalent of ≤20 mg prednisone daily for at least 1 week prior to treatment initiation.

16. 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, 30 days after the last dose of venetoclax, 12 months the last dose of rituximab, or 18 months after the last dose of obinutuzumab, whichever is the longest period following the subject's study drug discontinuation. Men who are sexually active and able to have children must agree to use highly effective methods of contraception during the study and use a barrier method (condom; even if the subject had a vasectomy) for 2 days after the last dose of acalabrutinib, 18 months after the last dose of obinutuzumab, or 12 months after the last dose of rituximab, or 30 days after the last dose of venetoclax, whichever is longer. Highly effective forms of contraception are defined in Section 6.4.3. Additionally, men must agree to refrain from sperm donation during the study and for 18 months after the last dose of obinutuzumab, or 12 months after the last dose of rituximab, or 30 days after the last dose of venetoclax, whichever is longer.

17. Subjects must be able to swallow whole capsules.

18. Inclusion of women and minorities: Subjects of both genders and all racial/ethnic groups are eligible for the study if they meet eligibility criteria outlined. To date, there is no information that suggests that differences in drug metabolism or disease response would be expected in one group compared with another. The small number of subjects in a Phase 1b trial precludes any analysis of data to compare subject subgroups based on gender or race/ethnicity.

Exclusion Criteria

1. For Cohorts 2 and 4, received previous therapy for CLL. Treatment of autoimmune complications of CLL with steroids or rituximab is allowed, however, CD20 must have returned on 10% of the CLL cells if rituximab was recently administered. Palliative steroids are acceptable at doses ≤20 mg prednisone equivalent daily.

2. Any life-threatening illness, medical condition, or organ dysfunction, which in the investigator's opinion, could compromise the subjects' safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.

3. Female subjects who are pregnant or breastfeeding.

4. Subjects with active cardiovascular disease not medically controlled or those who have had myocardial infarction in the past 6 months, or corrected QT interval (QTc) ≥480 ms.

5. Malabsorption syndrome, disease significantly affecting GI function, or resection of the stomach or small bowel or gastric bypass, ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

6. Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.

7. Major surgery within 4 weeks before first dose of study drug.

8. History of a bleeding diathesis (e.g., hemophilia, Von Willebrand disease).

9. Uncontrolled AIHA or idiopathic thrombocytopenia purpura.

10. History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug.

11. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 28 days of first dose of study drug.

12. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

13. Subjects with active infections requiring intravenous (IV) antibiotic/antiviral therapy are not eligible for entry onto the study until resolution of the infection. Subjects on prophylactic antibiotics or antivirals are acceptable.

14. Subjects with history of or ongoing drug-induced pneumonitis.

15. Subjects with human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) or any uncontrolled active systemic infection.

16. Serologic status reflecting active hepatitis B or C infection.

1. Subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative hepatitis B DNA result by polymerase chain reaction (PCR) before randomization. Those who are HBsAg-positive and/or hepatitis B PCR positive will be excluded.

2. Subjects receiving prophylactic intravenous immunoglobulin (IVIG) may have positive hepatitis serologies. Subjects who are on IVIG who have positive hepatitis serologies must have a negative hepatitis B DNA to be eligible.

3. Subjects with a history of HBV infection but negative HBV serologies at screening must also have a negative HBV PCR to be eligible.

4. Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be tested for HCV RNA during screening. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded. No further testing beyond screening is necessary if PCR results are negative. However, in the setting of rising transaminase and/or bilirubin levels, HCV PCR testing should be performed when clinically indicated.

17. Subjects with substance abuse or other medical or psychiatric conditions that, in the opinion of the investigator, would confound study interpretation or affect the subject's ability to tolerate or complete the study.

18. Subjects cannot concurrently participate in another therapeutic clinical trial.

19. Subject who have received a live virus vaccination within 1 month of starting study drug.