This phase II trial studies how well venetoclax and ibrutinib work in treating patients with
chronic or small lymphocytic leukemia. Venetoclax and ibrutinib may stop the growth of cancer
cells by blocking some of the enzymes needed for cell growth.
- Brief Title: Venetoclax and Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL)
- Official Title: A Phase II Study of Venetoclax and Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL)
Clinical Trial IDs
- ORG STUDY ID:
- SECONDARY ID:
- NCT ID:
- Chronic Lymphocytic Leukemia
- Small Lymphocytic Lymphoma
|Ibrutinib||PCI-32765, Imbruvica||Relapsed/Refractory CLL Group|
|Venetoclax||ABT-199, GDC-0199||Relapsed/Refractory CLL Group|
The goal of this clinical research study is to learn if venetoclax given in combination with ibrutinib can help to control CLL or SLL. The safety of the drug combination will be also studied.
Study Drug Administration:
If you are found to be eligible to take part in this study, you will receive the study drugs in study cycles that are 4 weeks (28 days) long.
You will take 3 capsules of ibrutinib 1 time every day while you are on study with about 1 cup (8 ounces) of water.
If you miss a dose of ibrutinib, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. You should not take extra capsules on the following day to make up the missed dose.
Beginning on Day 1 of Cycle 4, you will also take tablets of venetoclax 1 time every day for the rest of the study. Each dose of venetoclax will be taken at about the same time as ibrutinib with about 1 cup (8 ounces) of water, within 30 minutes after you finish eating a low-fat breakfast.
In order to lower the risk of side effects, you will start taking venetoclax at a low dose and then it will be increased each week as directed by your doctor until you are taking the full dose.
If you vomit within 15 minutes of taking venetoclax and all the tablets are still intact, another dose may be taken. Otherwise, you should not take another dose. In cases where a dose of venetoclax is missed or forgotten, you should take the dose as soon as possible, as long as it is within 8 hours after the dose was planned to have been taken.
You will also be given standard drugs to help decrease the risk of side effects beginning 3 days before your first dose of venetoclax. You may ask the study staff for information about how the drugs are given and their risks.
Tumor Lysis Syndrome Monitoring:
Starting about 3 days before receiving your first dose of venetoclax (and continuing for at least 5 weeks of treatment), you will be given a drug to lower the risk of a serious side effect called Tumor Lysis Syndrome (TLS). TLS happens when cancer cells break down rapidly. The break-down products enter the bloodstream and are not flushed out quickly enough.
You will have blood tests (about 2 tablespoons each time) before your dose and may have blood tests (about 2 tablespoons) 4, 8, 12 and 24 hours after your dose. Based on your test results, your study doctor may have more instructions for you, and you may need to meet with a kidney doctor while you are in the hospital. You will be hospitalized after your first dose of venetoclax to check for or treat TLS. You may need to receive fluids by vein.
Every week during Cycle 1, then every 2 weeks in Cycles 2 and 3, blood (about 2 tablespoons) will be drawn for routine tests.
On Days 1 and 15 of Cycle 1, then on Day 1 of Cycles 2 and 3, you will have a physical exam.
At the end of Cycles 3, 6, 9, 12, 15, 18, 21, and 27, then every 6-12 months after that:
- You will have a bone marrow aspiration/biopsy to check the status of the disease.
- You will have CT or PET scans.
Every week during Cycle 4, then every 2 weeks in Cycles 5 and 6, blood (about 2 tablespoons) will be drawn for routine tests.
Every week during Cycles 4 and 5, then on Days 1 and 15 of Cycle 6, you will have a physical exam.
On Day 1 of Cycles 7 and beyond:
- You will have a physical exam.
- Blood (about 2 tablespoons) will be drawn for routine tests.
Physical exams and blood draws may be done more often if the doctor thinks it is needed.
Length of Treatment:
You may receive venetoclax for up to 2 years. You may continue receiving ibrutinib for as long as the study doctor thinks it is in your best interest. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.
This is an investigational study. Ibrutinib is FDA approved and commercially available for the treatment of patients with mantle cell lymphoma and in patients with CLL who have received at least 1 prior treatment. Its use in this study is investigational. Venetoclax is not FDA approved or commercially available. The combination of venetoclax and ibrutinib is investigational.
The study doctor can describe how the study drugs are designed to work.
Up to 78 participants will be enrolled in this study. All will take part at MD Anderson.
|Relapsed/Refractory CLL Group||Experimental||Participants receive Ibrutinib monotherapy for 3 cycles. Each cycle is 4 weeks. At the start of cycle 4, Venetoclax added as a weekly dose escalation. The combination of Venetoclax and Ibrutinib continues for an additional 24 cycles for a total of 27 cycles of treatment.|
|High-Risk CLL Participants With No Prior Therapy Group||Experimental||Participants receive Ibrutinib monotherapy for 3 cycles. Each cycle is 4 weeks. At the start of cycle 4, Venetoclax added as a weekly dose escalation. The combination of Venetoclax and Ibrutinib continues for an additional 24 cycles for a total of 27 cycles of treatment.|
1. Patients with a diagnosis of CLL/SLL who are refractory to and/or relapsed after at least one prior therapy will be eligible (Cohort 1). Untreated patients with high-risk features (del(17p), or mutated TP53, or del(11q), or unmutated IGHV, or >/= 65 years of age) are eligible (Cohort 2) provided they have active disease requiring treatment as defined by the International Working Group for CLL (IWCLL)
2. Age 18 years or older
3. Eastern Cooperative Oncology Group (ECOG) Performance Status </=2
4. Patients must have adequate renal and hepatic function: -- Total bilirubin </=1.5 x upper limit of normal (ULN) or </=3 x ULN for patients with Gilbert's disease, -- Creatinine clearance >50 mL/min (calculated according to institutional standards or using Cockcroft-Gault formula), -- alanine aminotransferase (ALT) and alanine aminotransferase (AST) </=3.0 x ULN, unless clearly due to disease involvement
5. Platelet count of greater than 20,000/mul, with no platelet transfusion in 2 weeks prior to registration. This criteria is waived if the thrombocytopenia is due to bone marrow involvement with the disease
6. Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (Beta-hCG) pregnancy test result within 7 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug. Women of non- childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. Men who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug
7. Free of prior malignancies for 2 years with exception of patients diagnosed with basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast, who are eligible even if they are currently treated or have been treated and/or diagnosed in the past 2 years prior to study enrolment. If patients have another malignancy that was treated within the last 2 years, such patients may be enrolled if the likelihood of requiring systemic therapy for this other malignancy within 2 years is less than 10%, as determined by an expert in that particular malignancy at MD Anderson Cancer Center, and after consultation with the Principal Investigator.
8. Patients or their legally authorized representative must provide written informed consent
1. Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, investigational therapy within 3 weeks prior to the first dose of the study drugs
2. Uncontrolled active systemic infection (viral, bacterial, and fungal)
3. Known positive serology for human immunodeficiency virus (HIV), due to potential drug-drug interactions between anti-retroviral medications and the study drugs
4. Active hepatitis B infection (defined as the presence of detectable HBV DNA, HBe antigen or HBs antigen). Subjects with serologic evidence of prior vaccination (HBsAg negative, anti-HBs antibody positive, anti-HBc antibody negative) are eligible. Patients who are HBsAg negative/HBsAb positive but HBcAb positive are eligible, provided HBV DNA is negative. NOTE - definitions for abbreviations: HBV - hepatitis B virus; DNA - deoxyribonucleic acid; HBe - hepatitis B e; anti-HBs - hepatitis B surface antibody; anti-HBc - hepatitis B core antibody; HBsAg - hepatitis B surface antigen; HBsAb - hepatitis B surface antibody; HBcAb - hepatitis B core antibody
5. Active hepatitis C, defined by the detectable hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR)
6. Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy with >20mg daily of prednisone dose or equivalent
7. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 2 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
8. Patient is pregnant or breast-feeding
9. Concurrent use of warfarin
10. Received Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors (such as fluconazole, ketoconazole, voriconazole, and clarithromycin) within 7 days of starting study drugs; received strong CYP3A inducers (such as rifampin, rifabutin, phenytoin, carbamazepine, and St. John's Wort) within 7 days of starting study drugs
11. Consumed grapefruit, grapefruit products, Seville oranges, or star fruit within 7 days of starting study drugs
12. Prior treatment with venetoclax or ibrutinib
13. Malabsorption syndrome or other condition that precludes enteral route of administration
14. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
|Maximum Eligible Age:||N/A|
|Minimum Eligible Age:||18 Years|
Primary Outcome Measures
|Measure:||Best Response (CR/CRi)) of Combined Ibrutinib and Venetoclax in Participants with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL)|
|Time Frame:||At the end of 6, 28 day cycles|
|Description:||Response defined as a complete response (CR) or partial response (PR) (or CR with incomplete marrow recovery) as determined by investigator assessment using CLL response criteria.|
Secondary Outcome Measures
|Lead Sponsor:||M.D. Anderson Cancer Center|
- Chronic Lymphocytic Leukemia
- Small Lymphocytic Lymphoma
- Refractory and/or relapsed
March 3, 2017