Polatuzumab Vedotin, Bendamustine, and Rituximab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma
- Signed informed consent form (ICF)
- Age >= 18 years
- Able to comply with the study protocol, in the investigator’s judgment
- Histologically confirmed DLBCL (obtaining pathology samples is not required prior to enrollment, but confirmation of availability is required prior to enrollment)
- Must have received at least one prior rituximab containing chemotherapy therapy for DLBCL
- Patients must be transplant-eligible and have either relapsed or have become refractory to a prior regimen
- The following DLBCL histologies would be considered eligible for study entry: * DLBCL, not otherwise specified (NOS) (including both germinal center like [GCB] type and activated B-cell-like [ABC] type) * T-cell/histiocyte-rich large B-cell lymphoma * High-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements * High grade B-cell lymphoma, NOS * Primary mediastinal (thymic) large B-cell lymphoma * Epstein Barr virus positive DLBCL, NOS * HHV8-positive DLBCL, NOS * Human immunodeficiency virus (HIV) positive DLBCL
- At least one bi-dimensionally measurable lesion on imaging scan defined as > 1.5 cm in its longest dimension
- Life expectancy of at least 24 weeks
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- Hemoglobin >= 9 g/dL
- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
- Platelet count >= 75 x 10^9/L
- For women who are not postmenopausal (>= 12 months of non-therapy-induced amenorrhea and age > 45 years) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or to use single highly effective or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for >= 12 months after the last dose of rituximab * Abstinence is only acceptable if it is in line with 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. * Examples of highly effective contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide.
- For women of childbearing potential, a negative serum pregnancy test result within 7 days prior to commencement of dosing. Women who are considered not to be of childbearing potential are not required to have a pregnancy test
- For men, agreement to remain abstinent or to 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 6 months after the last dose of study drug and agreement to refrain from donating sperm during this same period * Men with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy. * Abstinence is only acceptable if it is in line with 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 * Male patients considering preservation of fertility should bank sperm before treatment with polatuzumab vedotin
- Contraindication to bendamustine or rituximab
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies (MAbs) (or recombinant antibody-related fusion proteins) or known sensitivity or allergy to murine products
- History of sensitivity to mannitol (mannitol is an excipient in bendamustine)
- Prior use of any monoclonal antibody (MAb), radioimmunoconjugate, or antibody drug conjugate (ADC) within 5 half-lives or 4 weeks, whichever is longer, before cycle 1 day 1
- Treatment with chemotherapy, immunotherapy, immunosuppressive therapy, or any investigational agent for the purposes of treating cancer within 2 weeks prior to cycle 1 day 1. Radiotherapy for palliative relief of symptoms is allowed
- All acute, clinically significant treatment-related toxicity from prior therapy, except for alopecia, must have resolved to grade =< 2 prior to cycle 1 day 1
- Ongoing corticosteroid use > 30 mg/day prednisone or equivalent, for purposes other than lymphoma symptom control. Patients receiving corticosteroid treatment =< 30 mg/day prednisone or equivalent must be documented to be on a stable dose prior to study enrollment and initiation of therapy (cycle 1 day 1)
- Ineligibility for ASCT (determined by investigator per local institutional practice)
- Prior ASCT
- History of transformation of indolent disease to DLBCL
- Active central nervous system (CNS) lymphoma. (Previously treated CNS disease is allowed)
- Current grade > 1 peripheral neuropathy
- History of other malignancy that could affect compliance with the protocol or interpretation of results. Exceptions include, but are not limited to: * Patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix or ductal carcinoma in situ of the breast at any time prior to the study are eligible * A patient with any other malignancy that has been treated with curative intent and the malignancy has been in remission without treatment for > 3 years prior to enrollment is eligible * Patients with low-grade, early-stage prostate cancer with no requirement for systemic therapy at any time prior to study are eligible
- Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
- 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 intravenous (IV) antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to cycle 1 day 1
- Patients with suspected or latent tuberculosis * Latent tuberculosis should be confirmed according to local testing requirements
- Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] serology) * Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody [HBcAb]) may be included if HBV DNA is undetectable, provided that they are willing to undergo DNA testing on day 1 of every cycle and monthly for at least 12 months after the last cycle of study treatment and are willing to get prophylaxis with lamuvidine or entecavir for 6 months post immunosuppressive therapy. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible
- Patients who are positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
- Positive test results for uncontrolled HIV infection * For patients with controlled HIV status (positive HIV antibody, on antiretroviral therapy with stable HIV viral load) are eligible
- Known infection human T-cell leukemia virus 1 (HTLV-1) virus
- Vaccination with a live vaccine within 28 days prior to treatment
- Recent major surgery (within 6 weeks before the start of cycle 1 day 1) other than for diagnosis
- Women who are pregnant or lactating or who intend to become pregnant within a year of the last dose of study treatment in the rituximab cohorts or within 18 months of the last dose of study treatment in the obinutuzumab cohort
- Creatinine > 1.5 x upper limit of normal (ULN) or a measured creatinine clearance < 40 mL/min
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN
- Total bilirubin >= 1.5 x ULN. Patients with documented Gilbert disease may be enrolled if total bilirubin is =< 3 x ULN
- International normalized ratio (INR) or prothrombin time (PT) > 1.5 x ULN in the absence of therapeutic anticoagulation
- Partial thromboplastin time (PTT) or activated (a)PTT > 1.5 x ULN in the absence of a lupus anticoagulant
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
I. To evaluate the efficacy of the combination of polatuzumab vedotin plus bendamustine-rituximab (BR) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) as measured by the positron emission tomography (PET)-defined complete response (CR) rate using Modified Lugano Response Criteria at the time of primary response assessment (3 weeks after cycle 3 day 1 or last dose of study medication) as determined by the investigators.
I. To determine overall response (ORR), partial response (PR), stable disease (SD), progressive disease (PD) rate of combination therapy.
II. To assess safety and tolerability profile of combination therapy.
III. To assess duration of response (DOR) of combination therapy.
IV. To determine number of patients who underwent an autologous stem cell transplant (ASCT).
V. To determine differences in response based on cell of origin (COO) analysis (by HANS method) and Cmyc status (by fluorescence in situ hybridization [FISH])
VI. To assess differences in response rates based on timing of relapse. (< 12 months of front-line R-chemotherapy) versus (> 12 months after front-line R-chemotherapy) and bulky disease prior to ASCT.
VII. To assess 2-year (yr) progression free survival (PFS) and overall survival (OS) of combination therapy.
VIII. To assess stem cell collection failure rate (minimum stem cell collection is 1.5 x 10^6 CD34+ cells).
PATIENT-REPORTED OUTCOME OBJECTIVE:
I. To evaluate peripheral neuropathy symptom severity and interference on daily functioning and to better understand treatment impact, tolerability, and reversibility, as measured by the Therapy-Induced Neuropathy Assessment Scale (TINAS).
I. Pending additional funding the following exploratory biomarkers/testing will be conducted on banked specimens (blood and tissue).
II. Minimal residual disease (MRD) as quantified by measurements of lymphoma-specific markers deoxyribonucleic acid (DNA) extracted from peripheral blood at baseline and end-of therapy.
III. Next-gene sequencing studies will be conducted on stored relapsed tissue samples to assess markers of response.
IV. Biomarkers related to tumor biology and the mechanisms of action of polatuzumab vedotin and rituximab or obinutuzumab.
V. Biomarkers will be assessed retrospectively using a tissue block (preferred) or 15 serial freshly cut, unstained slides plus punch biopsy of the tissue block from the time of relapse diagnosis.
Patients receive polatuzumab vedotin intravenously (IV) over 90 minutes on day 2 of cycle 1 and day 1 of cycles 2 and 3. Patients also receive bendamustine hydrochloride IV over 60 minutes on days 2 and 3 of cycle 1 and days 1 and 2 of cycles 2 and 3 and rituximab IV on day 1 of cycles 1-3. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment patients are followed up every 3 months for up to 2 years.
Trial Phase Phase II
Trial Type Treatment
University of Colorado Hospital
Manali K. Kamdar
- Primary ID 19-1195.cc
- Secondary IDs NCI-2021-02617
- Clinicaltrials.gov ID NCT04535102