Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Revlimid (ViPOR) in Relapsed/Refractory B-cell Lymphoma

  • STATUS
    Recruiting
  • End date
    Mar 1, 2023
  • participants needed
    130
  • sponsor
    National Cancer Institute (NCI)
Updated on 16 December 2021
cancer
chronic lymphocytic leukemia
lymphoma
flow cytometry
filgrastim
absolute neutrophil count
granulocyte colony stimulating factor
prednisone
bone marrow procedure
gilbert's syndrome
venetoclax
lenalidomide
colony stimulating factor
white blood cells
gm-csf
neutrophil count
g-csf
follicular lymphoma
diffuse large b-cell lymphoma
b-cell lymphoma
mantle cell lymphoma
revlimid
ibrutinib
high grade b-cell lymphoma
obinutuzumab
transformed lymphoma

Summary

Background

B-cell lymphoma is a cancer of white blood cells found in the lymph nodes. It affects the system that fights infections and disease. Researchers want to learn how certain drugs work together to treat B-cell lymphomas. The drugs are venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR).

Objective

To study the safety of ViPOR for people with B-cell lymphoma.

Eligibility

People ages 18 and older with B-cell lymphoma whose cancer has returned or not improved after treatment

Design

Participants will be screened with:

  • Medical history
  • Physical exam
  • Blood, urine, and heart tests
  • Tissue sample from previous procedure
  • Imaging scans
  • Registration for counseling on the risks of lenalidomide. They must get counseling at least every 28 days.

Participants will have a bone marrow aspiration before treatment.

Participants may have tumor samples taken.

Participants will get ViPOR in 21-day cycles. For up to 6 cycles:

  • Participants will get one drug by IV on days 1 and 2.
  • Participants will take the other four drugs by mouth on most days. After their first dose of venetoclax, they will stay in the clinic for at least 8 hours and return the next day for monitoring. They may be admitted for more drugs or monitoring.

Participants will keep a drug diary.

Participants will have a physical exam and blood and urine tests at least once per cycle. They will have scans 4 times over 6 cycles.

Participants will have a visit about 1 month after their last dose of study drug. They will then have visits every few months for 3 years, and once a year for years 4 and 5. Visits include a physical exam, blood tests, and scans.

Description

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 and relapsed and/or refraactory MCL are 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.

Details
Condition Lymphoma, Non-Hodgkin Lymphoma, Diffuse Large B-Cell Lymphoma, Burkitt Lymphoma
Treatment prednisone, Ibrutinib, Obinutuzumab, venetoclax, Revlimid (lenalidomide)
Clinical Study IdentifierNCT03223610
SponsorNational Cancer Institute (NCI)
Last Modified on16 December 2021

Eligibility

Yes No Not Sure

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)
Relapsed and/or refractory and 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 and relapsed and/or refractory MCL will be included in
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)
the phase 2 MCL expansion
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
For women of childbearing potential
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 men
Agreement to remain abstinent (refrain from heterosexual intercourse) or use a
below
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
Contraception Requirements
(prescriptions must be filled within 7 days as required by Revlimid REMSTM) and
Pre-Treatment/During Treatment
must either commit to continued abstinence from heterosexual intercourse or begin
TWO acceptable methods of birth control, one highly effective method and one
Post-Treatment
additional effective method AT THE SAME TIME, at least 28 days before she starts
Venetoclax- Women- 90 days; Men 90 days
taking Revlimid. FCBP must also agree to ongoing pregnancy testing
Ibrutinib- Women- 3 months; Men- 3 months
A woman is considered to be of childbearing potential if she is postmenarcheal
Obinutuzumab- Women- 18 months; Men- 6 months
has not reached a postmenopausal state (greater than or equal to 12 continuous
Revlimid- Women-28 days; Men- 28 days
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
Agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm, as defined
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
-All Drugs- Women- begins 28 days prior to treatment; Men- Begins on day 1
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

Patients who are actively receiving any other investigational agents
Radio- or toxin-immunoconjugates within 10 weeks prior to the first dose of study drug
Strong CYP3A inhibitors
Strong CYP3A inducers
Uncontrolled and/or symptomatic thyroid disease
Known infection with human T-cell leukemia virus 1 (HTLV-1)
Evidence of active tumor lysis syndrome based on laboratory assessment
The following restrictions apply to current or prior anti-cancer treatment, prior to the
first dose of study drug
Any chemotherapy, external beam radiation therapy, or anti-cancer antibodies within 2
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
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
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
weeks prior to Cycle 1, Day 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
History of recent major surgery within 6 weeks prior to the start of Cycle 1, Day 1
other than for diagnosis
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
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