Acalabrutinib, Venetoclax, and Obinutuzumab for Initial Therapy of CLL

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Chronic Lymphocytic Leukemia (CLL)

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Obinutuzumab
* Drug: Acalabrutinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Acalabrutinib/Venetoclax/Obinutuzumab<br>Acalabrutinib 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 | Drug: Venetoclax<br>* 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.<br>* Other names: Venclexta;Drug: Obinutuzumab<br>* Obinutuzumab is a type of drug called a monoclonal antibody. It targets a protein CD20 on the surface of the CLL cell, causing it to die<br>* Other names: Gazyva;Drug: Acalabrutinib<br>* 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<br>* Other names: Calquence;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Partial Response | By 2018 IW-CLL criteria | After 3, 8, 15 and 24 months | 
| Rate of Complete Response | By 2018 IW-CLL criteria | After 15 and 24 months | 
| Progression free survival | By 2018 IW-CLL criteria | At 24 months | 
| Overall survival | Defined as the interval between the first treatment day to death | At 24 and 36 months | 
| Rate of peripheral blood MRD | By flow cytometry | After 8, 15 and 24 months | 
| Time to MRD-positive disease recurrence in the peripheral blood | By flow cytometry | From date of treatment discontinuation until the date of first documented MRD-positive disease in the blood, assessed up to 120 months | 
| Time to clinical disease progression | By 2018 IW-CLL criteria | From date of treatment discontinuation until the date of first documented clinical disease progression, assessed up to 120 months | 
| Rate of infusion related reactions | By CTCAE v4 | After 6 months of obinutuzumab | 
| Rate of tumor lysis syndrome | By Howard criteria | Through study completion, an average of 2 years | 
| Rate of bone marrow MRD | By 4 color flow cytometry | After 8 and after 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Lymphocytic Leukemia (CLL)