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Venetoclax and Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL)

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ClinicalTrials.gov Identifier: NCT02756897
Recruitment Status : Recruiting
First Posted : April 29, 2016
Last Update Posted : May 24, 2018
Sponsor:
Collaborator:
AbbVie
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

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.

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 FDA approved and commercially available for the treatment of patients with CLL who have have received at least 1 prior treatment. The combination of venetoclax and ibrutinib is investigational.

The study doctor can describe how the study drugs are designed to work.

Up to 160 participants will be enrolled in this study. All will take part at MD Anderson.


Condition or disease Intervention/treatment Phase
Leukemia Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Drug: Ibrutinib Drug: Venetoclax Phase 2

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Detailed Description:

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.

If the study doctor thinks it is in your best interest, Cycle 4 may be delayed. In this case, you will continue taking ibrutinib, but you will not start taking venetoclax until the study doctor thinks that it is safe for you to do so.

Tumor Lysis Syndrome Monitoring:

Starting about 3 days before receiving your first dose of venetoclax at the beginning of the study and then at any time that the dose increases (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.

Study Visits:

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 Cycle 4, then on Day 1 of Cycles 5 and 6, you will have a physical exam.

On Day 1 of Cycles 7 and beyond:

  • You will have a physical exam (every 3 cycles only).
  • Blood (about 2 tablespoons) will be drawn for routine tests. After the first year of the study, this can be done every 3 cycles.

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Venetoclax and Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL)
Actual Study Start Date : July 7, 2016
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : July 2025


Arm Intervention/treatment
Experimental: Relapsed/Refractory CLL Group
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.
Drug: Ibrutinib
420 mg by mouth once daily in a 28 day cycle.
Other Names:
  • PCI-32765
  • Imbruvica

Drug: Venetoclax

At the start of cycle 4 Venetoclax taken by mouth as weekly dose escalation:

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
  • GDC-0199

Experimental: High-Risk CLL Participants With No Prior Therapy Group
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.
Drug: Ibrutinib
420 mg by mouth once daily in a 28 day cycle.
Other Names:
  • PCI-32765
  • Imbruvica

Drug: Venetoclax

At the start of cycle 4 Venetoclax taken by mouth as weekly dose escalation:

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
  • GDC-0199




Primary Outcome Measures :
  1. Best Response (CR/CRi)) of Combined Ibrutinib and Venetoclax in Participants with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) [ Time Frame: Start of drug combination up to 2 months after drug combination stopped ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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 (In pts with elevated total bilirubin due to increased indirect bilirubin, pts with direct bilirubin </= 1.5 x ULN are eligible), -- Creatinine clearance >50 mL/min (calculated according to institutional standards or using Cockcroft-Gault , MDRD, or CKD-EPI 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

Exclusion Criteria:

  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 strong (CYP3A) inhibitors or strong CYP3A inducers 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

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): NCT02756897


Contacts
Contact: Nitin Jain, MBBS 713-745-6080

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
AbbVie
Investigators
Principal Investigator: Nitin Jain, MBBS M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02756897     History of Changes
Other Study ID Numbers: 2015-0860
NCI-2016-00797 ( Registry Identifier: NCI CTRP )
First Posted: April 29, 2016    Key Record Dates
Last Update Posted: May 24, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Leukemia
Chronic Lymphocytic Leukemia
CLL
Small Lymphocytic Lymphoma
SLL
Refractory and/or relapsed
Ibrutinib
PCI-32765
Imbruvica
Venetoclax
ABT-199
GDC-0199

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Venetoclax
Antineoplastic Agents