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

A Phase 1b Study of ACP-196 in Combination With Obinutuzumab for Patients With Relapsed / Refractory or Untreated CLL/SLL/PLL

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

A Phase 1b Study of ACP-196 in Combination with Obinutuzumab for Participants with Relapsed/Refractory or Untreated chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL)/ prolymphocytic leukemia (PLL).

Study started with two cohorts, on Acalabrutinib and Obinutuzumab, cohort 1 for relapsed or refractory participants and cohort 2 for treatment naïve participants. Then for longer survival data and combination therapy, two new cohorts added to the study, cohort 3 with relapsed or refractory participants on Acalabrutinib, Rituximab and Venetoclax, and cohort 4 with treatment naïve participants on Acalabrutinib, Obinutuzumab and Venetoclax.

Primary endpoints: For Cohorts 1 and 2, the ORR (PR or better) at the 12-month response assessment will be calculated and 95% exact binomial confidence interval (CIs) will be provided. For Cohorts 1 to 4, toxicities will be tabulated by type and grade using NCI-CTCAE (National Cancer Institute - Common Terminology Criteria for Adverse Events) version 4.03 criteria or higher and displayed in summary form.

Currently, study is in maintenance phase and we don't expect a major change in the near future.

Inclusion Criteria

1. Participants with a diagnosis of intermediate or high risk CLL (or variant immunophenotype), SLL, or B-cell prolymphocytic leukemia (B-PLL) by International Workshop on Chronic Lymphocytic Leukemia (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. Participants in Cohorts 1 and 3 may have received previous ibrutinib (or another Bruton tyrosine kinase (BTK) inhibitor) as long as discontinuation was for a reason other than on-treatment disease progression.

3. All participants 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 autoimmune hemolytic anemia (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. Participants 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. Participants must have adequate organ function, defined as creatinine ≤2.5 times the upper limit of normal range (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, and bilirubin ≤2.5 x ULN. For Cohorts 3 and 4, participants 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 10^9/L. In participants with CLL involvement of the marrow, >30 x 10^9/L for Cohorts 1 and 2. For Cohorts 3 and 4, participants must have hemoglobin >9 g/dL.

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

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

11. Participant 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. Participants must be ≥18 years of age.

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

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

15. Participant 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 participant'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 participant 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. Participants must be able to swallow whole capsules.

18. Inclusion of women and minorities: Participants 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 participants in a Phase 1b trial precludes any analysis of data to compare participant 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 participants' safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.

3. Female participants who are pregnant or breastfeeding.

4. Participants 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 gastrointestinal (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 autoimmune hemolytic anemia (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. Participants with active infections requiring IV antibiotic/antiviral therapy are not eligible for entry onto the study until resolution of the infection. Participants on prophylactic antibiotics or antivirals are acceptable.

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

15. Participants 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. Participants 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. Participants receiving prophylactic intravenous immunoglobulin (IVIG) may have positive hepatitis serologies. Participants who are on IVIG who have positive hepatitis serologies must have a negative hepatitis B DNA to be eligible.
    3. Participants with a history of HBV infection but negative HBV serologies at screening must also have a negative HBV PCR to be eligible.
    4. Participants with a known history of hepatitis C or who are hepatitis C antibody positive should be tested for HCV RNA during screening. Participants 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. Participants with substance abuse or other medical or psychiatric conditions that, in the opinion of the investigator, would confound study interpretation or affect the participant's ability to tolerate or complete the study.

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

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