This is a phase II multicenter, open-label study of polatuzumab vedotin administered by IV infusion in combination with standard doses of bendamustine (B) and rituximab (R) in transplant-eligible patients with relapsed or refractory DLBCL. A total of 22 patients will be enrolled over a period of 2 years through the University of Colorado and additional study sites if applicable. Study treatment will be given in 21-day cycles for patients with DLBCL.
Recruiting
Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Polatuzumab Vedotin | Polatuzumab + BR (minimum 3 cycles) |
The first day of treatment will constitute Cycle 1 Day 1. Patients will be treated with a
minimum of 3 cycles to upto a maximum six cycles to optimize response prior to ASCT per
investigator discretion.
All patients will be evaluated for safety and efficacy according to the schedules of
assessments.
All patients will be assessed for response to treatment by the investigator with the use of
standard criteria according to the Modified Lugano Response Criteria (Cheson et al. 2014; see
Appendix 3) at screening and at the following timepoints:
- At the time of screening
- At the time of primary response assessment, 3 weeks after completion of study treatment
(i.e., 3 weeks after Day 1 of Cycle 3 or after last dose of study medication)) Imaging
at these timepoints must include FDG-PET (18F-fluorodeoxyglucose-positron emission
tomography) and a diagnostic-quality CT scan with both oral and IV contrast. A combined
PET/CT scan is encouraged if feasible. CT scans with oral and IV contrast should include
neck, chest, abdomen, and pelvic scans. In patients for whom contrast is
contraindicated, (e.g., patients with contrast allergy or impaired renal clearance or
patient denial), PET-CT scans without contrast are permitted so long as they permit
consistent and precise measurement of target lesions during the study treatment period.
Patients will also be evaluated every 3 months for 2 years, or until disease progression,
death, withdrawal of consent, or initiation of another anti-cancer therapy. Tumor assessments
should also be performed to confirm clinical suspicion of relapse or disease progression for
documentation. The study will end when all patients enrolled have been followed until death,
have withdrawn consent, have been lost to follow-up, until 2-year follow up, or the Sponsor
decides to end the trial, whichever occurs first.
Once the last patient enrolls and undergoes EOT PET-CT assessment, primary endpoint data and
interim survival analysis will be evaluated and published/presented at meetings. Subsequent
survival analysis will be published post 2-yr follow-up
| Name | Type | Description | Interventions |
|---|---|---|---|
| Polatuzumab + BR (minimum 3 cycles) | Experimental | Patients will be treated with a minimum of 3 cycles up to a maximum six cycles to optimize response prior to ASCT (stem cell transplant) per investigator discretion |
|
Inclusion Criteria:
1. Signed ICF
2. Age ≥ 18 years
3. Able to comply with the study protocol, in the investigator's judgment
4. Histologically confirmed DLBCL (Obtaining pathology samples is not required prior to
enrollment, but confirmation of availability is required prior to enrollment)
5. Must have received at least one prior rituximab containing chemotherapy therapy for
DLBCL.
6. Patients must be transplant-eligible and have either relapsed or have become
refractory to a prior regimen.
7. The following DLBCL histologies would be considered eligible for study entry:
- DLBCL, not otherwise specified (NOS) (including both GCB type and 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
- HIV positive DLBCL
8. At least one bi-dimensionally measurable lesion on imaging scan defined as > 1.5 cm in
its longest dimension
9. Life expectancy of at least 24 weeks
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
11. Adequate hematologic function unless inadequate function is due to underlying disease,
such as extensive bone marrow involvement or hypersplenism secondary to the
involvement of the spleen by lymphoma per the investigator. Adequate hematologic
function is defined as follows:
- Hemoglobin ≥ 9 g/dL o ANC ≥ 1.0 x 109/L
- Platelet count ≥ 75 x 109/L
12. 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.
13. 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.
14. 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.
Exclusion Criteria:
1. History of severe allergic or anaphylactic reactions to humanized or murine MAbs (or
recombinant antibody-related fusion proteins) or known sensitivity or allergy to
murine products
2. Contraindication to bendamustine or rituximab.
3. History of sensitivity to mannitol (mannitol is an excipient in bendamustine).
4. 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.
5. 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.
6. 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.
7. 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).
8. Ineligibility for ASCT (determined by investigator per local institutional practice)
9. Prior ASCT
10. History of transformation of indolent disease to DLBCL
11. Active CNS lymphoma. (Previously treated CNS disease is allowed)
12. Current Grade > 1 peripheral neuropathy
13. 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.
14. 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).
15. 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.
16. Patients with suspected or latent tuberculosis.
• Latent tuberculosis should be confirmed according to local testing requirements.
17. 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.
18. Patients who are positive for Hepatitis C virus (HCV) antibody are eligible only if
PCR is negative for HCV RNA.
19. 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.
20. Known infection human T-cell leukemia virus 1 (HTLV-1) virus. 21. Vaccination with a
live vaccine within 28 days prior to treatment.
22. Recent major surgery (within 6 weeks before the start of Cycle 1 Day 1) other than for
diagnosis.
23. 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
24. Any of the following abnormal laboratory values, unless abnormal laboratory values are
due to underlying lymphoma per the investigator:
• Creatinine > 1.5 x upper limit of normal (ULN) or a measured creatinine clearance < 40
mL/min • AST or 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
- INR or PT > 1.5 x ULN in the absence of therapeutic anticoagulation
- PTT or aPTT > 1.5 x ULN in the absence of a lupus anticoagulant
25. 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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Complete response at primary response |
| Time Frame: | 3 weeks after last dose of study medication |
| Safety Issue: | |
| Description: | The assessment is based on PET/CT, as determined by the investigator |
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | University of Colorado, Denver |
March 22, 2021
