Clinical Trials /

Acalabrutinib, Venetoclax, and Obinutuzumab for Initial Therapy of CLL

NCT03580928

Description:

This research study is evaluating the combination of three drugs - acalabrutinib, venetoclax, and obinutuzumab -- as a possible treatment for chronic lymphocytic leukemia (CLL). The drugs involved in this study are: - Acalabrutinib - Venetoclax - Obinutuzmab

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib, Venetoclax, and Obinutuzumab for Initial Therapy of CLL
  • Official Title: A Phase 2 Study of Acalabrutinib, Venetoclax, and Obinutuzumab (AVO) for Initial Therapy of Chronic Lymphocytic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 18-226
  • NCT ID: NCT03580928

Conditions

  • Chronic Lymphocytic Leukemia (CLL)

Interventions

DrugSynonymsArms
VenetoclaxVenclextaAcalabrutinib/Venetoclax/Obinutuzumab
ObinutuzumabGazyvaAcalabrutinib/Venetoclax/Obinutuzumab
AcalabrutinibCalquenceAcalabrutinib/Venetoclax/Obinutuzumab

Purpose

This research study is evaluating the combination of three drugs - acalabrutinib, venetoclax, and obinutuzumab -- as a possible treatment for chronic lymphocytic leukemia (CLL). The drugs involved in this study are: - Acalabrutinib - Venetoclax - Obinutuzmab

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of investigational drugs to learn whether the drugs work in treating a
      specific disease. "Investigational" means that the drugs are being studied. The FDA (the U.S.
      Food and Drug Administration) has not approved acalabrutinib for CLL, although it is
      FDA-approved for patients with relapsed mantle cell lymphoma. The FDA has approved venetoclax
      and obinutuzumab separately for the treatment of patients with CLL. However, the FDA has not
      approved the combination of these three drugs together (acalabrutinb, venetoclax, and
      obinutuzumab) as a treatment for any disease. This combination is investigational. In this
      research study, the investigators are trying to learn if giving the three drugs together can
      safely and effectively treat CLL.

      Acalabrutinib is a type of drug called a kinase inhibitor. It blocks a type of protein called
      Bruton Tyrosine Kinase (BTK) that helps CLL cells live and grow. By blocking BTK,
      acalabrutinib may kill cancer cells or stop them from growing. As of September 2017,
      acalabrutinib has been administered to more than 2,000 people including healthy volunteers,
      patients with cancers, and patients with rheumatoid arthritis. A few hundred patients with
      CLL have been treated with acalabrutinib as a single drug, and some of these patients had
      improvement of their cancer with this treatment.

      Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein on the
      surface of the CLL cell, causing it to die. Obintuzumab has already been shown to be safe and
      effective at treating CLL, and is FDA-approved when given together with chemotherapy.

      Venetoclax is an oral drug that blocks the function of a protein called BCL-2. CLL cancer
      cells are thought to depend on the BCL-2 protein for their survival. By blocking BCL-2,
      venetoclax may kill cancer cells or stop them from growing. Venetoclax has been shown to be
      safe and effective when given alone to treat patients with CLL and is FDA-approved for
      patients with CLL after their disease has worsened after at least 1 prior therapy.

      If, after 15 or 24 cycles of this investigational therapy, participants have a complete
      response to the drugs in this trial -- meaning that the investigators cannot detect any CLL
      using CT scans, bone marrow biopsy and a sensitive test called minimal residual disease (MRD)
      testing -- participants will stop therapy with acalabrutinib and venetoclax. The
      investigators will continue to monitor participants while they are off of therapy, and if the
      CLL comes back participants will be able to restart acalabrutinib and venetoclax. The use of
      MRD testing to identify small amounts of CLL is investigational, meaning that it has not been
      FDA-approved. The use of results from this test to guide the decision to stop and re-start
      therapy, as is done in the trial here, is also investigational.
    

Trial Arms

NameTypeDescriptionInterventions
Acalabrutinib/Venetoclax/ObinutuzumabExperimentalAcalabrutinib will be administered orally twice daily at 100 mg bid Venetoclax will be administered orally once daily, with dose ramp-up from 20 mg up to a final dose of 400 mg Obinutuzumab will be administered as per standard of care for 6 months with dosing at 100 mg on cycle 1 day 1, 900 mg on cycle 1 day 2, and then 1,000 mg on cycle 1 days 8, 15, and day 1 of cycles 2-6
  • Venetoclax
  • Obinutuzumab
  • Acalabrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must have CLL or SLL

          -  In cohort 2, subjects must have TP53-aberrant disease defined as:

               -  Del(17p) detected on karyotype and/or FISH; OR

               -  TP53 mutation

          -  Participants must have measurable disease (lymphocytosis > 5,000 / µl, or palpable or
             CT measurable lymphadenopathy ≥ 1.5 cm, or bone marrow involvement ≥30%).

          -  Subjects must not have received any prior systemic therapy for CLL or SLL due to
             meeting IWCLL 2018 guidelines and must currently have an indication for treatment as
             defined by the IWCLL 2018 guidelines:

               -  Massive or progressive or symptomatic splenomegaly; OR

               -  Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR

               -  Significant fatigue (i.e. ECOG PS 2 or worse; cannot work or unable to perform
                  usual activities); OR

               -  Fever ≥ 100.5°F for 2 or more weeks without evidence of infection; OR

               -  Night sweats for ≥ 1 months without evidence of infection; OR

               -  Presence of weight loss ≥ 10% over the preceding 6 months; OR

               -  Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period or
                  lymphocyte doubling time of less than 6 months; OR

               -  Evidence of progressive marrow failure as manifested by the development of or
                  worsening of anemia and/or thrombocytopenia; OR

               -  Autoimmune anemia and/or thrombocytopenia that is poorly responsive to
                  corticosteroids and another standard therapy such as rituximab; OR

               -  Symptomatic or functional extranodal involvement

          -  Age greater than or equal to 18 years.

          -  ECOG performance status ≤2

          -  Participants must have adequate organ and marrow function as defined below:

               -  total bilirubin ≤1.5 times upper limit of normal, unless there is disease
                  involvement of the liver, hemolysis, or a known history of Gilbert's disease, in
                  which case direct bilirubin must be ≤3 times the upper limit of normal

               -  AST and ALT ≤ 2.5 times the upper limit of normal. If there is hemolysis or
                  documented disease involvement of the liver, then patients with any AST or ALT
                  abnormalities remain eligible.

               -  creatinine clearance (CrCl) ≥ 50 mL/min using 24-hour urine collection for
                  creatinine clearance or calculated CrCl

               -  PT/INR ≤2 times the upper limit of normal and PTT ≤2 times the upper limit of
                  normal

               -  Absolute neutrophil count ≥750 cells/mm3 or ≥500 cells/mm3 in subjects with
                  documented bone marrow involvement

               -  Platelet count without transfusional support must be ≥50,000 cells/mm3 or ≥
                  30,000 cells/mm3 in subjects with documented bone marrow involvement

          -  Pregnant or lactating

        Exclusion Criteria:

          -  Participants who have a history of other malignancies except:

               -  Malignancy treated with curative intent and with no known active disease present
                  and felt to be at low risk for recurrence by treating physician. Current adjuvant
                  hormonal therapy for disease treated with curative intent is permissible.

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease.

               -  Adequately treated carcinoma in situ without evidence of disease.

               -  Low-risk prostate cancer on active surveillance

          -  Participants who are receiving any other investigational agents.

          -  History of severe allergic reactions attributed to compounds of similar chemical or
             biologic composition to obinutuzumab, venetoclax, or acalabrutinib. Patients with
             reactions to other CD20 monoclonal antibodies (e.g. rituximab, ofatumumab) are not
             excluded.

          -  Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV),
             and herpes zoster (VZV) at start of treatment

          -  Known or suspected Richter's transformation or known CNS involvement

          -  Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc.,
             within 28 days of the first dose of study drug or chronic administration of >20 mg/day
             of prednisone within 7 days of the first dose)

          -  Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.

          -  Ongoing or recent infection requiring intravenous antimicrobials at time of screening.

          -  Known bleeding disorders (e.g. von Willebrand's disease) or hemophilia.

          -  Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
             screening.

          -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment.

          -  Major surgery within 4 weeks of first dose of study drug. If a subject had major
             surgery greater than 4 weeks prior to the first dose, they must have recovered
             adequately from any toxicity and/or complications from the intervention before the
             first dose of study drug.

          -  Currently active, clinically significant cardiovascular disease, such as uncontrolled
             arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart
             Association Functional Classification; or a history of myocardial infarction, unstable
             angina, or acute coronary syndrome within 6 months prior to randomization.

          -  Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left
             bundle branch block.

          -  Patients who require warfarin or other vitamin K antagonists for anticoagulation
             (other anticoagulants are allowed).

          -  Patients who require treatment with proton pump inhibitors (see Appendix F). Subjects
             receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are
             eligible for enrollment on this study.

          -  Patients who require concurrent treatment with strong CYP3A inhibitors or strong CYP3A
             inducers are excluded from the study. If patients are receiving strong CYP3A
             inhibitors/inducers at time of screening but do not require continuous administration
             of these agents, these patients are eligible if there is a 3-day washout period
             between discontinuation of the strong CYP3A inhibitor/inducer and initiation of the
             first study drug, acalabrutinib.

          -  Patients who require concurrent treatment with P-gp inhibitors or narrow therapeutic
             index P-gp substrates are excluded from the study. If patients are receiving P-gp
             inhibitors or narrow therapeutic index P-gp substrates at time of screening but do not
             require continuous administration of these agents, these patients are eligible if
             there is a 3-day washout period between discontinuation of the P-gp inhibitor and
             initiation of acalabrutinib.

          -  Unable to swallow capsules or malabsorption syndrome, disease significantly affecting
             gastrointestinal function, or resection of the stomach or small bowel if thought by
             the investigator to compromise systemic absorption, active, symptomatic inflammatory
             bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

          -  Patients with human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or
             hepatitis B virus (HBV) infection.

          -  Significant co-morbid condition or disease which in the judgment of the Principal
             Investigator would place the patient at undue risk or interfere with the study

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements, compromise the subject's safety, or put the study outcomes at
             undue risk.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The rate of bone marrow minimal residual disease (MRD) negative complete response
Time Frame:After 15 months
Safety Issue:
Description:By 4 color flow cytometry

Secondary Outcome Measures

Measure:Rate of Partial Response
Time Frame:After 3, 8, 15 and 24 months
Safety Issue:
Description:By 2018 IW-CLL criteria
Measure:Rate of Complete Response
Time Frame:After 15 and 24 months
Safety Issue:
Description:By 2018 IW-CLL criteria
Measure:Progression free survival
Time Frame:At 24 months
Safety Issue:
Description:By 2018 IW-CLL criteria
Measure:Overall survival
Time Frame:At 24 months
Safety Issue:
Description:
Measure:Rate of peripheral blood MRD
Time Frame:After 8, 15 and 24 months
Safety Issue:
Description:By flow cytometry
Measure:Time to MRD-positive disease recurrence in the peripheral blood
Time Frame:From date of treatment discontinuation until the date of first documented MRD-positive disease in the blood, assessed up to 120 months
Safety Issue:
Description:By flow cytometry
Measure:Time to clinical disease progression
Time Frame:From date of treatment discontinuation until the date of first documented clinical disease progression, assessed up to 120 months
Safety Issue:
Description:By 2018 IW-CLL criteria
Measure:Rate of infusion related reactions
Time Frame:After 6 months of obinutuzumab
Safety Issue:
Description:By CTCAE v4
Measure:Rate of tumor lysis syndrome
Time Frame:Through study completion, an average of 2 years
Safety Issue:
Description:By Howard criteria
Measure:Rate of bone marrow MRD
Time Frame:After 8 and after 24 months
Safety Issue:
Description:By 4 color flow cytometry

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Chronic Lymphocytic Leukemia (CLL)

Last Updated

December 11, 2019