| Eligibility |
Inclusion Criteria:
- Signed informed consent form.
- Ability and willingness to comply with the requirements of the study protocol.
- Age =18 years.
- Have documented previously untreated chronic lymphocytic leukemia according to iwCLL /
WHO criteria.
- Require treatment of CLL per iwCLL guidelines.
- CIRS score = 6 (patient's CLL diagnosis is not included in CIRS score).
- Eastern Cooperative Oncology Group Performance Status of 0 or 1.
- Adequate hematologic function (unless caused by underlying disease, as established by
extensive bone marrow involvement or as a result of hypersplenism secondary to the
involvement of the spleen by CLL per the investigator) defined as follows:
- Hemoglobin = 8 g/dL without transfusion support, unless anemia is due to marrow
involvement of CLL.
- Absolute neutrophil count = 1.0 x 10^9/L.
- Platelet count = 30 x 10^9/L; in cases of thrombocytopenia clearly due to marrow
involvement of CLL (per the discretion of the investigator), platelet count
should be = 10 x 10^9/L if there is bone marrow involvement.
- Adequate renal function, as indicated by modified Cockcroft-Gault equation (eCCR; with
the use of ideal body mass [IBM] instead of mass) of > 50mL/min
- Adequate liver function, as indicated by:
- AST or ALT = 2.5 x ULN.
- Total bilirubin = 1.5 x ULN (or = 5 x ULN for patients with documented Gilbert
syndrome).
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
per year during the treatment period and for at least 30 days after the last dose of
venetoclax or 18 months after the last dose of obinutuzumab, whichever is longer.
- Women must refrain from donating eggs during this same period.
- A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (> 12 continuous months of amenorrhea with
no identified cause other than menopause), and has not undergone surgical
sterilization (removal of ovaries and/or uterus).
- Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, hormonal contraceptives that
inhibit ovulation, hormone-releasing intrauterine devices, and copper
intrauterine devices.
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of
contraception.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined
below:
- With female partners of childbearing potential, men must remain abstinent or use
a condom plus an additional contraceptive method that together result in a
failure rate of < 1% per year during the treatment period and for at least 90
days after the last dose of venetoclax or 18 months after the last dose of
obinutuzumab, whichever is longer. Men must refrain from donating sperm during
this same period.
- With pregnant female partners, men must remain abstinent or use a condom for the
duration of the pregnancy to avoid exposing the embryo.
- The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of
contraception.
Exclusion Criteria:
- Prior CLL-directed therapy. Patients may have received a brief (=7 days) course of
systemic steroids prior to initiation of study therapy for control of lymphoma-related
symptoms.
- Transformation of CLL to aggressive NHL (Richter's transformation or prolymphocytic
leukemia).
- Known hypersensitivity to any of the study drugs.
- History of prior malignancy, except for conditions as listed below if patients have
recovered from the acute side effects incurred as a result of previous therapy:
- Malignancies treated with curative intent and with no known active disease within
2 years
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease (no time constraint).
- Adequately treated cervical carcinoma in situ without evidence of disease (no
time constraint).
- Surgically/adequately treated low grade, early stage, localized prostate cancer
without evidence of disease (no time constraint).
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection
(excluding fungal infections of nail beds) at study enrollment, or any major episode
of infection requiring treatment with IV antibiotics or hospitalization (relating to
the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1.
- Requires the use of warfarin (because of potential drug-drug interactions that may
potentially increase the exposure of warfarin).
- Received the following agents within 7 days prior to the first dose of venetoclax:
- Strong and moderate CYP3A inhibitors.
- Strong and moderate CYP3A inducers.
- Consumed grapefruit, grapefruit products, Seville oranges (including marmalade
containing Seville oranges), or star fruit within 3 days prior to the first dose
of venetoclax.
- Clinically significant history of liver disease, including active viral or other
hepatitis, current alcohol abuse, or cirrhosis
- Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface
antigen (HBsAg), or hepatitis C (HCV) antibody
- Patients who are positive for HCV antibody must be negative for HCV by polymerase
chain reaction (PCR) to be eligible for study participation
- Patients with occult or prior HBV infection (defined as positive total hepatitis
B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is
undetectable. These patients must be willing to undergo monthly DNA testing and
should consider antiviral prophylaxis as per institutional standards.
- Known infection with HIV or human T-cell leukemia virus 1 (HTLV-1)
- Receipt of live-virus vaccines within 28 days prior to the initiation of study
treatment or need for live-virus vaccines at any time during study treatment
- Pregnant or lactating, or intending to become pregnant during the study
°Women of childbearing potential must have a negative serum pregnancy test result
within 21 days prior to initiation of study drug per institutional standards.
- Recent major surgery (within 4 weeks prior to the start of Cycle 1, Day 1) other than
for diagnosis.
- Inability to swallow a large number of tablets.
- Malabsorption syndrome or other condition that precludes enteral route of
administration. This is subject to investigator discretion.
- Known allergy to both xanthine oxidase inhibitors and rasburicase.
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