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

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ClinicalTrials.gov Identifier: NCT02296918
Recruitment Status : Active, not recruiting
First Posted : November 21, 2014
Last Update Posted : April 1, 2021
Sponsor:
Information provided by (Responsible Party):
Acerta Pharma BV

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

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Prolymphocytic Leukemia Drug: acalabrutinib Drug: Obinutuzumab Drug: Venetoclax Drug: Rituximab Phase 1

Detailed Description:

A Phase 1b Study of ACP-196 in Combination with Obinutuzumab for Patients with Relapsed/Refractory or Untreated CLL/SLL/PLL Study started with two cohorts, on Acalabrutinib and Obinutuzumab, cohort 1 for relapsed or refractory patients and cohort two for treatment naïve subjects. Then for longer survival data and combination therapy, two new cohorts added to the study, cohort 3 with relapsed or refractory subjects on Acalabrutinib, Rituximab and Venetoclax, and cohort 4 with treatment naïve subjects 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 CIs will be provided. For Cohorts 1 to 4, toxicities will be tabulated by type and grade using NCI-CTCAE 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 69 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study of ACP-196 in Combination With Obinutuzumab for Patients With Relapsed / Refractory or Untreated CLL/SLL/PLL
Actual Study Start Date : December 22, 2014
Estimated Primary Completion Date : October 25, 2021
Estimated Study Completion Date : October 25, 2021


Arm Intervention/treatment
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.
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

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.
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

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
Drug: acalabrutinib
100 mg twice daily continuous
Other Name: ACP-196

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

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
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




Primary Outcome Measures :
  1. 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)

  2. 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


Secondary Outcome Measures :
  1. ORR for treatment with venetoclax [ Time Frame: 16 Months ]
    To evaluate the ORR of the combination therapy of acalabrutinib plus venetoclax plus an anti-CD20 antibody at Cycle 16

  2. DOR [ Time Frame: 16 months ]
    DOR

  3. PFS [ Time Frame: 16 months ]
    PFS

  4. TTNT [ Time Frame: 16 months ]
    TTNT

  5. OS [ Time Frame: 16 months ]
    OS

  6. development of BTK mutations [ Time Frame: 16 months ]
    To assess for serial development of resistance by baseline and longitudinal assessment of mutations of Bruton tyrosine kinase (BTK) and phospholipase C gamma 2 (PLCG2) at regular follow-up intervals and by examining diagnosis to relapse samples by whole exome sequencing (all cohorts)

  7. PK: Plasma Concentration of Acalabrutinib and Metabolite ACP-5862 [ Time Frame: 4 months ]
    To determine the plasma concentration of acalabrutinib and its metabolite ACP-5862 over time (first 8 subjects accrued to the Phase 1b expansion of Cohort 1 and subjects in Cohorts 3 and 4 who have not previously participated in PK analysis).

  8. PK: Plasma Concentration of Venetoclax [ Time Frame: 4 months ]
    To determine the plasma concentration of venetoclax over time (subjects in Cohorts 3 and 4 who have not previously participated in PK analysis).



Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02296918


Locations
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United States, Ohio
Research Site
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Acerta Pharma BV
Investigators
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Study Director: AstraZeneca Study Information Center 1-877-240-9479; information.center@astrazeneca.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Acerta Pharma BV
ClinicalTrials.gov Identifier: NCT02296918    
Other Study ID Numbers: ACE-CL-003
First Posted: November 21, 2014    Key Record Dates
Last Update Posted: April 1, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Keywords provided by Acerta Pharma BV:
CLL
SLL
PLL
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Prolymphocytic Leukemia
ACP-196
acalabrutinib
obinutuzumab
rituximab
venetoclax
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Prolymphocytic
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Rituximab
Obinutuzumab
Venetoclax
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents