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

• ClinicalTrials.gov Identifier: NCT02296918
• Recruitment Status: Active, not recruiting
• First Posted: November 21, 2014
• Last Update Posted: September 18, 2019
• Sponsor: Acerta Pharma BV
• Information provided by (Responsible Party): Acerta Pharma BV

Tracking Information

• First Submitted Date: November 19, 2014
• First Posted Date: November 21, 2014
• Last Update Posted Date: September 18, 2019
• Study Start Date: November 2014
• Estimated Primary Completion Date: January 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 31, 2017)

• Overall Response Rate (ORR) in cohort 1 and cohort 2 [ Time Frame: 12 Months ]
  To determine the overall response rate (ORR) at 12 months with the combination of acalabrutinib plus obinutuzumab in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL)
• Evaluating safety in combination with acalabrutinib [ Time Frame: 24 Months ]
  To establish the safety of the combination of acalabrutinib, rituximab and venetoclax in relapsed and refractory subjects and acalabrutinib, obintuzumab and venetoclax in the previously untreated subjects by evaluating Treatment Emergent Adverse Events as assessed by CTCAE v4.03

• Original Primary Outcome Measures (submitted: November 20, 2014): The overall response rate (ORR) at 12 months with the combination of ACP-196 + obinutuzumab in patients [ Time Frame: 12 Months ]

Current Secondary Outcome Measures (submitted: October 31, 2017)

ORR for treatment with ventoclax [ Time Frame: 16 Months ]

To evaluate the ORR of the combination therapy of acalabrutinib plus venetoclax plus an anti-CD20 antibody at Cycle 16

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Acalabrutinib in Combination With Anti-CD20 and Venetoclax in Relapsed/Refractory or Untreated CLL/SLL/PLL
• Official Title: A Phase 1b Study of ACP-196 in Combination With Obinutuzumab for Patients With Relapsed / Refractory or Untreated CLL/SLL/PLL
• Brief Summary: To evaluate the safety and preliminary efficacy of acalabrutinib in combination with obinutuzumab in 4 separate cohorts of patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chronic Lymphocytic Leukemia
• Small Lymphocytic Lymphoma
• Prolymphocytic Leukemia

Intervention

• Drug: acalabrutinib
  100 mg twice daily continuous
  Other Name: ACP-196
• Drug: Obinutuzumab
  Cycle 2 Day 1, 100 mg IV will be administered. Then on Cycle 2 Day 2, 900 mg administered. On Cycle 2 Days 8 and 15, 1000 mg IV will be administered. On Cycles 3-7, 1000 mg on Day 1 of each cycle will be administered.
  Other Name: Gazyva
• Drug: Venetoclax
  20 mg daily for 1 week, 50 mg daily for 1 week, 100 mg daily for 1 week, 200 mg daily for 1 week, then 400 mg daily for duration of treatment.
  Other Names:

  • ABT-199
  • Venclexta
• Drug: Rituximab
  Rituximab will be given at a starting dose of 375 mg/m2 on Day 1 of Cycle 2, followed by 375 mg/m2 every week for 3 doses and then every 4 weeks for 5 doses for a total of 9 infusions
  Other Name: Rituxan

Study Arms

• Experimental: Double combo with acalabutinib in RR
  For Relapse Refractory subjects, acalabrutinib starting at Cycle 1 as monotherapy then combine with obinutuzumab starting at Cycle 2 for 6 cycles.
  Interventions:

  • Drug: acalabrutinib
  • Drug: Obinutuzumab
• Experimental: Double combo with acalabutinib in TN
  For previously untreated subjects, acalabrutinib starting at Cycle 1 as monotherapy then combine with obinutuzumab starting at Cycle 2 for 6 cycles.
  Interventions:

  • Drug: acalabrutinib
  • Drug: Obinutuzumab
• Experimental: Triplet combo with acalabutinib in RR
  For Relapse Refractory subjects, acalabrutinib starting at Cycle 1 as monotherapy then combine with rituximab starting at Cycle 2 for 6 cycles. Venetoclax, starting at Cycle 3 taken up to 12 cycles
  Interventions:

  • Drug: acalabrutinib
  • Drug: Venetoclax
  • Drug: Rituximab
• Experimental: Triplet combo with acalabutinib in TN
  For previously untreated subjects, acalabrutinib starting at Cycle 1 as monotherapy then combine with obinutuzumab starting at Cycle 2 for 6 cycles. Venetoclax, starting at Cycle 3 taken up to 12 cycles
  Interventions:

  • Drug: acalabrutinib
  • Drug: Obinutuzumab
  • Drug: Venetoclax

• Publications *: Woyach JA, Blachly JS, Rogers KA, Bhat SA, Jianfar M, Lozanski G, Weiss DM, Andersen BL, Gulrajani M, Frigault MM, Hamdy A, Izumi R, Munugalavadla V, Quah C, Wang MH, Byrd JC. Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia. Cancer Discov. 2020 Mar;10(3):394-405. doi: 10.1158/2159-8290.CD-19-1130. Epub 2020 Jan 8.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 1, 2019): 69
• Original Estimated Enrollment (submitted: November 20, 2014): 45
• Estimated Study Completion Date: January 2022
• Estimated Primary Completion Date: January 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Patients with a diagnosis of intermediate or high risk CLL (or variant immunophenotype), SLL, or B-PLL by IWCLL 2008 criteria (48) who have:

• Previously received at least one therapy for their disease.
• Previously untreated disease and 65 years old OR under 65 years old and or refuse or are ineligible for chemoimmunotherapy

All patients 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
• 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 degrees F for 2 weeks or more without evidence of infection
  • Night sweats >1 month without evidence of infection
• Patients with a history of Richter's transformation are eligible if they now have evidence of CLL only, with <10% large cells in the bone marrow.
• ECOG performance status ≤ 2
• Life expectancy of < 2 years or that would confound assessment of toxicity in this study
• Must be ≥ 18 years of age

Exclusion Criteria:

• 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.
• 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.
• 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.
• Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.
• History of a bleeding diathesis (eg, hemophilia, Von Willebrand disease).
• Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenia purpura.
• History of stroke or intracranial hemorrhage within 6 months before the first dose of study drug.
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 28 days of first dose of study drug.
• Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).
• Subjects with history of or ongoing drug-induced pneumonitis.
• 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.
• Subjects who are known to have hepatitis B infection or who are hepatitis B core antibody or surface antigen positive.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02296918
• Other Study ID Numbers: ACE-CL-003
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Acerta Pharma BV
• Study Sponsor: Acerta Pharma BV
• Collaborators: Not Provided

Investigators

• Study Director: Acerta Clinical Trials; 1-888-292-9613; acertamc@dlss.com

• PRS Account: Acerta Pharma BV
• Verification Date: September 2019