Background:
Combination chemotherapy with Rituximab has been the mainstay of treatment for CD20-positive
B-cell lymphomas
Significant advances have been made in curing aggressive B-cell lymphomas with
chemoimmunotherapy but indolent lymphomas and relapsed/refractory aggressive lymphomas remain
mostly incurable with chemotherapy alone
Targeted therapies aimed at disrupting key survival pathways in lymphoid malignancies are
emerging and showing significant activity in NHL in both the relapsed and first-line settings
Mechanistically-based combinations of targeted agents are likely to benefit patients who
cannot tolerate or who relapse after or are refractory to standard chemoimmunotherapy
ViPOR targets major survival pathways in B-cell lymphomas including BCL-2 (apoptosis); BTK
(B-cell receptor signaling and NFKB); Cereblon (NFKB) and CD20.
Objectives:
Phase 1b: To determine the maximum tolerated dose (MTD) and the safety and toxicity profile
of the combination of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab and Revlimid (ViPOR) in
relapsed/refractory B-cell malignancies
Phase 2: To determine the overall response rate (ORR) and complete response (CR) rate of
ViPOR in relapsed/refractory B-cell malignancies
Eligibility:
Women and men greater than or equal 18 years of age
ECOG performance status of less than or equal to 2 [JS([1]
Histologically or cytologically confirmed relapsed and/or refractory B-cell lymphoma,
excluding CLL/SLL. NOTE: untreated MCL is included in the phase 2 MCL expansion.
Adequate organ function unless dysfunction secondary to lymphoma effect
Design:
Open-label, single-center, non-randomized phase 1b/2 study
Phase 1b: Standard 3 + 3 design will be used to determine the MTD of dose-escalated
venetoclax with fixed dose ibrutinib, prednisone, obinutuzumab and Revlimid (ViPOR) in
relapsed/refractory B-cell malignancies
Phase 2: Expansion cohorts of aggressive and indolent non-MCL patients and MCL patients will
be treated at the MTD to determine the ORR and CR rate in these subtypes.
Maximum 6 cycles of combination targeted therapy every 21 days
To explore all dose levels in both non-MCL and MCL patient cohorts in the phase 1b study, and
to assess the ORR and CR rate in aggressive and indolent non-MCL and MCL patient cohorts in a
phase 2 dose expansion at the MTD, the accrual ceiling will be set at 130 patients.
- INCLUSION CRITERIA:
- Patients must have histologically or cytologically confirmed B-cell lymphoma confirmed
by the Laboratory of Pathology, NCI, as follows:
Phase1b
- Aggressive B-cell lymphoma: includes DLBCL and subtypes, transformed lymphoma, Burkitt
lymphoma, as well as High-grade B-cell lymphoma with MYC and/or BCL2 and/or BCL6
rearrangement(s).
-Indolent B-cell lymphoma:
- CLL/SLL is excluded given alternative dosing of FDA-approved venetoclax for relapsed
17p CLL and increased risk of TLS with CLL/SLL compared to other non-Hodgkin
lymphomas.
- NOTE: Patients with known active CNS lymphoma are not eligible.
Phase 2
- Relapsed and/or refractory DLBCL and subtypes, including transformed lymphoma as well
as High grade B-cell lymphoma with MYC and/or BCL2 and/or BCL6 rearrangement(s).
- Relapsed and/or refractory Follicular lymphoma (FL)
- Untreated Mantle cell lymphoma (MCL)
- Relapsed and/or refractory disease on at least 1 prior treatment regimen, as follows:
- Aggressive B-cell lymphoma: relapsed after and/or refractory to at least 1 prior
anthracyclineDoxorubicin-containing regimen
- Indolent B-cell lymphoma: relapsed after and/or refractory to at least 1 prior
anti-CD20 antibodyRituximab-containing regimen.
- NOTE: Patients with untreated MCL will be included in the phase 2 MCL expansion.
- Patients must have evaluable disease by clinical exam (i.e. palpable lymphadenopathy,
measurable skin lesions, etc.), laboratory assessment (i.e. lymphoma involvement of
bone marrow or peripheral blood by morphology, cytology or flow cytometry), and/or
imaging (measurable lymph nodes or masses on CT or MRI and/or evaluable FDGavid
lesions on PET).
- NOTE: Lesions that have been irradiated cannot be included in the tumor assessment
unless unequivocal tumor progression has been documented in these lesions after
radiation therapy.
- Age greater than or equal to 18 years
- NOTE: Because no dosing or adverse event data are currently available on the use of
venetoclax in combination with ibrutinib, obinutuzumab, prednisone and Revlimid(R) in
patients <18 years of age, children are excluded from this study, but will be eligible
for future pediatric trials.
- ECOG performance status less than or equal to 2
- Adequate organ and marrow function as defined below unless dysfunction is secondary to
lymphoma:
- absolute neutrophil count* (*RBC transfusions and use of G-CSF will be allowed in
order to meet eligibility parameters): greater than or equal to 1,000/mcL
- hemoglobin* (*RBC transfusions and use of G-CSF will be allowed in order to meet
eligibility parameters): greater than or equal to 8 g/dL
- platelets greater than or equal to 75,000/mcL
- INR: less than or equal to 1.5 X institutional upper limit of normal (ULN) for
patients not receiving therapeutic anticoagulation
- PTT/aPTT: less than or equal to 1.5 X institutional ULN normal except if, in the
opinion of the investigator, the aPTT is elevated because of a positive Lupus
Anticoagulant
- Total Bilirubin: less than or equal to 1.5 X institutional ULN (or <3 X
institutional ULN for patients with documented Gilberts syndrome)
- AST(SGOT)/ALT(SGPT): less than or equal to 2.5 X institutional ULN
- Serum Creatinine: less than or equal to 2.0mg/dL OR
- Creatinine Clearance: greater than or equal to 60 mL/min/1.73 m2 for patients
with creatinine levels above 2 mg/dL
Cr Cl will be calculated with the use of the 24-hour creatinine clearance or modified
Cockcroft-Gault equation (eCCR; with the use of ideal body mass [IBM] instead of mass):
(140 Age) x IBM (kg) x [0.85 if female]/ 72 x serum creatinine (mg/dL)
*RBC transfusions and use of G-CSF will be allowed in order to meet eligibility parameters.
- Immune-modulating drugs (IMiDs) including Revlimid are known to be teratogenic and
potential embryo-fetal harm can be seen with use of venetoclax and ibrutinib. The
effects of obinutuzumab on the developing human fetus is unknown. For these reasons,
women of child-bearing potential and men must agree to use adequate contraception as
described below. Should a woman become pregnant or suspect she is pregnant while she
or her partner is participating in this study, she should inform her treating
physician immediately.
- 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 as outlined below.
- Female subjects of childbearing potential (FCBP) must have a negative serum or
urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 14 days
and again within 24 hours prior to prescribing Revlimid for Cycle 1
(prescriptions must be filled within 7 days as required by Revlimid REMSTM) and
must either commit to continued abstinence from heterosexual intercourse or begin
TWO acceptable methods of birth control, one highly effective method and one
additional effective method AT THE SAME TIME, at least 28 days before she starts
taking Revlimid. FCBP must also agree to ongoing pregnancy testing.
- A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (greater than or equal to 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 less than 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 less than 1% per year as noted below. Men must refrain from
donating sperm during this same period.
- With pregnant female partners, men must remain abstinent or use a condom as noted
below 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.
- Contraception Requirements:
Pre-Treatment/During Treatment:
--All Drugs- Women- begins 28 days prior to treatment; Men- Begins on day 1
Post-Treatment:
- Venetoclax- Women- 90 days; Men 90 days
- Ibrutinib- Women- 3 months; Men- 3 months
- Obinutuzumab- Women- 18 months; Men- 6 months
- Revlimid- Women-28 days; Men- 28 days
- All study participants must be registered into the mandatory Revlimid REMSTM
program and be willing and able to comply with the requirements of Revlimid
REMSTM. NOTE: Females of reproductive potential must adhere to the scheduled
pregnancy testing as required in the Revlimid REMSTM program
- Ability of subject or Legally Authorized Representative (LAR) to understand and
the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
The following restrictions apply to current or prior anti-cancer treatment, prior to the
first dose of study drug:
- Patients who are actively receiving any other investigational agents.
- Any chemotherapy, external beam radiation therapy, or anti-cancer antibodies within 2
weeks prior to the first dose of study drug
- Radio- or toxin-immunoconjugates within 10 weeks prior to the first dose of study drug
- Previous treatment with greater than one of the study agents (i.e., venetoclax,
Ibrutinib or Revlimid), excluding prior prednisone or anti-CD20 antibody treatment
- Prior allogeneic stem cell (or other organ) transplant within 6 months or any evidence
of active graft-versus-host disease or requirement for immunosuppressants within 28
days prior to first dose of study drug
- Not recovered (i.e., less than or equal to Grade 1 or baseline) from adverse events
due to previously administered anti-cancer treatment, surgery, or procedure. NOTE:
Exceptions to this include events not considered to place the subject at unacceptable
risk of participation in the opinion of the PI (e.g., alopecia).
- Patients requiring the use of warfarin are excluded because of potential
drug-drug interactions that may potentially increase the exposure of warfarin.
- Patients requiring the following agents within 7 days prior to the first dose of
venetoclax are excluded:
- Steroid therapy for anti-neoplastic intent
- Strong CYP3A inhibitors
- Strong 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
NOTE: Moderate CYP3A inhibitors and inducers should be used with caution and an alternative
medication used, whenever possible.
- Uncontrolled intercurrent illness including, but not limited to the following that may
limit interpretation of results or that could increase risk to the patient at the
discretion of the investigator:
- Symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia
- Uncontrolled and/or symptomatic thyroid disease
- 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
2 weeks prior to Cycle 1, Day 1;
- Known infection with human T-cell leukemia virus 1 (HTLV-1)
- Clinically significant history of liver disease, including viral or other
hepatitis, current alcohol abuse, or cirrhosis; as well as active infection with
HBV or HCV:
- 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 during treatment and for at least 12 months after completion of
study therapy.
- Malabsorption syndrome or other condition that precludes enteral route of
administration
- Psychiatric illness/social situations that would limit compliance with study
requirements
- Pregnant women, or women who intent to become pregnant during the study, are excluded
from this study because Revlimid has known teratogenic effects and venetoclax,
ibrutinib and obinutuzumab are agents with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with these agents,
breastfeeding should be discontinued if the mother is treated on study.
- HIV-positive patients are ineligible because of the potential for pharmacokinetic
interactions with venetoclax, ibrutinib and Revlimid and combination antiretroviral
therapy. In addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy. Appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated.
- Evidence of active tumor lysis syndrome based on laboratory assessment
- History of recent major surgery within 6 weeks prior to the start of Cycle 1, Day 1
other than for diagnosis
- Receipt of live-virus vaccines within 28 days prior to the initiation of study
treatment
- History of other active malignancy that could affect compliance with the protocol or
interpretation of results
- Patients with a history of curatively treated basal or squamous cell carcinoma or
stage 1 melanoma of the skin as well as any in situ carcinoma are eligible.
- Patients with a malignancy that has been treated with curative intent will also
be eligible. Individuals in documented remission without treatment for greater
than or equal to 2 years prior to enrollment may be included at the discretion of
the investigator.
- Known allergy to both xanthine oxidase inhibitors and rasburicase; or, known
hypersensitivity to any of the study drugs
