Venetoclax Ibrutinib Prednisone Obinutuzumab and Revlimid in Combination With Polatuzumab (ViPOR-P) in Relapsed/Refractory B-cell Lymphoma

  • STATUS
    Recruiting
  • End date
    May 1, 2027
  • participants needed
    32
  • sponsor
    National Cancer Institute (NCI)
Updated on 12 September 2021
cancer
lymphoma
flow cytometry
filgrastim
granulocyte colony stimulating factor
prednisone
bone marrow procedure
venetoclax
colony stimulating factor
gm-csf
neutrophil count
g-csf
b-cell lymphoma
ibrutinib
fludeoxyglucose f-18

Summary

Background

Aggressive B-cell lymphomas can be cured but people with disease that resists treatment or that returns after treatment have poor outcomes with standard therapies. Indolent B-cell lymphomas are generally incurable with standard therapy and treatment is aimed at controlling symptoms and achieving a durable remissions. Researchers want to see if a combination of drugs can help patients with both aggressive and indolent B-cell lymphomas.

Objective

To learn if it is safe and effective to give polatuzumab along with venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide to people with certain B-cell lymphomas.

Eligibility

Adults ages 18 and older with relapsed and/or refractory B-cell lymphoma who have had at least one prior cancer treatment.

Design

Participants will be screened with:

Medical history

Physical exam

Assessment of how they do their daily activities

Blood and urine tests

Heart function test

Tissue biopsy (if needed)

Body imaging scans (may get a contrast agent through an intravenous (IV) catheter)

Participants will have a bone marrow aspiration and/or biopsy. A needle will be put into the hipbone. Bone marrow will be removed.

Participants may give blood, tissue, saliva, or cheek swab samples. They may have optional biopsies.

Screening tests will be repeated during the study.

Treatment will be given for up to 6 cycles. Each cycle lasts 21 days.

Participants will take venetoclax and prednisone tablets by mouth. They will take ibrutinib and lenalidomide capsules by mouth. They will get obinutuzumab and polatuzumab by IV infusion. They will keep a medicine diary.

Participants will visit the clinic 30 days after treatment ends. They will have follow-up visits for 5 years. If needed, they can visit their local doctor instead. They may be contacted by phone, mail, etc., for the rest of their life....

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 non-Hodgkin lymphoma (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-P targets major survival pathways in B-cell lymphomas including BCL-2 (apoptosis); BTK (B-cell receptor signaling and NF-kB); Cereblon (NF-kB) and CD20 with additional genotoxic stress from the anti-mitotic antibody-drug conjugate targeting CD79b, polatuzumab.
    Objectives

To determine the maximum tolerated dose (MTD) and the safety and toxicity profile of polatuzumab in combination with venetoclax, ibrutinib, prednisone, obinutuzumab and Revlimid(SqrRoot) (lenalidomide) (ViPOR-P) in relapsed/refractory B-cell lymphomas

Eligibility
  • Women and men greater than or equal to 18 years of age
  • ECOG performance status of less than or equal to 2
  • Histologically or cytologically confirmed relapsed and/or refractory B-cell lymphoma, excluding mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
  • Adequate organ function unless dysfunction secondary to lymphoma
Design
  • Open-label, single-center, non-randomized phase 1 study
  • Standard 3 + 3 design will be used to determine the MTD of polatuzumab in combination with venetoclax, ibrutinib, prednisone, obinutuzumab and Revlimid (lenalidomide) (ViPOR-P) in relapsed/refractory B-cell lymphomas
  • A small expansion cohort will be treated at the MTD in a further analysis of safety and preliminary activity.
  • Maximum 6 cycles of combination targeted therapy every 21 days.
  • To explore all dose levels in the phase 1 study and to allow for the possibility of a few screen failures and inevaluable subjects, the accrual ceiling will be set at 32 patients.

Details
Condition Diffuse Large B-Cell Lymphoma, Lymphoma, Lymphoproliferative Disorder, Lymphoma, Burkitt's Lymphoma, B-Cell Lymphoma, Non-Hodgkin's Lymphoma, non-hodgkin's lymphoma (nhl), burkitt lymphoma, lymphomas, diffuse large cell lymphoma, diffuse large b cell lymphoma
Treatment prednisone, Ibrutinib, Obinutuzumab, venetoclax, Revlimid, Polatuzumab
Clinical Study IdentifierNCT04739813
SponsorNational Cancer Institute (NCI)
Last Modified on12 September 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
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: with the following exceptions
MCL is excluded given increased risk of tumor lysis syndrome (TLS) with venetoclax compared to other non-Hodgkin lymphomas and need for venetoclax ramp-up, dose-escalation
CLL/SLL is excluded given alternative dosing of FDA-approved venetoclax for relapsed CLL/SLL and increased risk of TLS with CLL/SLL compared to other non-Hodgkin lymphomas
NOTE: Patients with known active CNS lymphoma are not eligible
Relapsed and/or refractory disease after at least 1 prior treatment regimen, as
follows
Aggressive B-cell lymphoma: relapsed after and/or refractory to at least 1 prior anthracycline-containing regimen
Indolent B-cell lymphoma: relapsed after and/or refractory to at least 1 prior anti- CD20 antibody-containing regimen
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 FDG-avid 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 to18 years
NOTE: Because no dosing or adverse event data are currently available on the
use of polatuzumab in combination with venetoclax, ibrutinib, obinutuzumab
prednisone and Revlimid 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 greater than or equal to 1,000/mcL
hemoglobin 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, or a significant bleeding risk has been ruled out in the absence of a positive Lupus Anticoagulant
total bilirubin less than or equal to 1.5 X institutional ULN (or less than or equal to 3 X institutional ULN for patients with documented Gilberts syndrome identified by an isolated unconjugated hyperbilirubinemia in the absence of other signs of liver dysfunction and/or UGT1A1 mutational testing)
AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional ULN
Serum creatinine less than or equal to 2.0 mg/dL; OR
Creatinine clearance greater than or equal to 30 mL/min/1.73 m2 for patients with creatinine levels above 2 mg/dL
NOTE: Cr Cl will be calculated with the use of the 24-hour creatinine
clearance or eGRF in the clinical lab
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 polatuzumab, 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 less than 1% per year as outlined below
Agreement to refrain from donating eggs during timelines specified 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 post-menarcheal, 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 post-ovulation 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 post-ovulation methods) and withdrawal are not acceptable methods of contraception
Contraception Requirements
Time frame/Study Drug (Pre-Treatment/During Treatment) - Women/Men (Time frame prior to/during dosing)
\--- Pre-Treatment/During Treatment/All drugs; Women - Begins 28 days prior to
treatment; Men - Begins on day 1
Time frame/Study Drug (Post-Treatment) - Women/Men (Time frame after the last dose)
Post-Treatment/Venetoclax; Women - 90 days; Men - 90 days
Post-Treatment/Ibrutinib; Women - 3 months; Men - 3 months
Post-Treatment/Obinutuzumab; Women - 18 months; Men - 6 months
Post-Treatment/Revlimid; Women - 28 days; Men - 28 days
Post-Treatment/Polatuzumab; Women - 3 months; Men - 5 months
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 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 or anti-cancer antibodies within 2 weeks. NOTE: Short courses of corticosteroids or palliative XRT prior to enrollment are permitted within the 2- week washout period
Radio- or toxin-immunoconjugates within 10 weeks
Previous treatment with polatuzumab or more than one of the other 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
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 to the first dose of venetoclax or ibrutinib are excluded, as noted
Strong CYP3A inhibitors within 7 days
Strong CYP3A inducers within 7 days
Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days
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 inves0tigator
Symptomatic congestive heart failure, unstable angina pectoris, or uncontrolled 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
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 (i.e., none detected in copies/mL or IU/mL). 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 intend to become pregnant during the study, are excluded from this study because Revlimid has known teratogenic effects and polatuzumab, 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 who are not receiving active treatment 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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