The primary objectives of the Phase Ib portion of the study are as follows:* To assess the safety and tolerability of the combination of polatuzumab vedotin with bendamustine and rituximab (BR) or bendamustine and obinutuzumab (BG) when administered…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy Outcome Measures:
Response assessment will be determined according to Modified Lugano Response
Criteria for Malignant Lymphoma (Lugano Classification; Cheson et al. 2014; see
Appendix 4 in the protocol).
* CR at primary response assessment (6*8 weeks after Cycle 6, Day 1, or last
dose of study drug) based on PET/CT, as determined by the investigator and IRC
* OR (CR or PR) at primary response assessment based on PET/CT, as determined
by the investigator and IRC
* CR at primary response assessment based on CT only, as determined by the
investigator and IRC
* OR (CR or PR) at primary response assessment based on CT only, as determined
by the investigator and IRC
* BOR (CR or PR) while on study based on PET/CT or CT only, as determined by
the investigator
* NF cohort only: OS and EFS based on PET-CT or CT only, as determined by the
investigator
Secondary outcome
PK outcome measures:
* Serum and plasma concentrations of polatuzumab vedotin, bendamustine and
rituximab versus time
* PK parameters based on concentration*time data for polatuzumab vedotin,
bendamustine and rituximab when these drugs are given in combination
Patient reported outcome measures:
* PROs of peripheral neuropathy symptom severity and symptom interference, as
measured by the TINAS (Thomas et al. 2012; see Appendix 8)
Exploratory biomarker outcome measures:
* Biomarkers related to tumor biology and the mechanisms of action of
polatuzumab vedotin and rituximab. These include but are not limited to the
assessment of CD79b expression levels, apoptotic regulators (e.g., Bcl-2),
markers of immune infiltration and immune regulation (e.g., CD3, CD8, PD-L1),
and identification of other potential prognostic factors.
* 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 initial diagnosis and, if possible, at the time of
disease progression.
* For quantitative assessment of MRD levels of the lymphoma clone in
circulation, blood will be collected at baseline, between Cycle 3 Day 15 and
Cycle 4 Day 1, and at end of treatment corresponding to tumor assessments
Background summary
Non-Hodgkin*s lymphoma (NHL) is the most common hematologic malignancy in
adults.
NHL can be divided into indolent and aggressive lymphomas. Follicular lymphoma
(FL) is the most common subtype of indolent NHL in the Western hemisphere.
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive NHL.
B-cell NHL, including FL and DLBCL, express the CD20 antigen, and anti-CD20
therapy (rituximab) has been demonstrated to provide enhanced anti-tumor
activity in combination with other agents targeting the disease leading to
increased response rates, PFS and OS, which led to acceptance of rituximab as a
standard component in initial therapy. Progress has been made in the treatment
of FL and DLBCL; however, a significant number of patients will not be cured of
the disease. There is a need for the continued development of safe and
effective therapies for patients with disease that relapses or for those who
develop refractory disease during or after first-line therapy.
Bendamustine with and without rituximab has demonstrated efficacy in patients
with R/R iNHL.
BR is recommended as a second-line therapy for patients with FL who either
received alternative therapy in first line or who previously received
bendamustine-based therapy and had a DOR of * 1 year. Commonly used regimens
used to treat transplant eligible patients with R/R DLBCL are also used to
treat transplant-ineligible patients.
Polatuzumab vedotin is an ADC designed for the targeted delivery of MMAE, a
potent microtubule inhibitor to lymphoma cells expressing CD79b.
To date, Phase I data suggest that polatuzumab vedotin in combination with
rituximab has activity in R/R FL and DLBCL with a generally acceptable safety
and tolerability profile. Nonclinical data from murine xenograft models support
the combination of bendamustine, rituximab, and polatuzumab vedotin and
demonstrate significantly improved anti-lymphoma activity of the combination
over BR alone. Obinutuzumab ([G] also known as RO5072759, GA101, and GazyvaTM),
a novel Type II and glycoengineered anti-CD20 antibody, has shown superiority
over rituximab in a Phase III trial in first-line CLL.
The combination of obinutuzumab with bendamustine is being evaluated in several
ongoing studies. Clinical trials with BR and BG have demonstrated efficacy but
have been associated with neutropenia.
The goals of this Phase Ib/II study are to assess the safety, tolerability, and
potential biologic and clinical activity of escalating doses of polatuzumab
vedotin in combination with a standard regimen of an anti-CD20 antibody plus
chemotherapy (rituximab plus bendamustine [BR] or obinutuzumab plus
bendamustine [BG]) in patients with R/R FL or DLBCL.
Study objective
The primary objectives of the Phase Ib portion of the study are as follows:
* To assess the safety and tolerability of the combination of polatuzumab
vedotin with bendamustine and rituximab (BR) or bendamustine and obinutuzumab
(BG) when administered to patients with R/R FL or DLBCL
* To identify the Recommended Phase II Dose (RP2D) for polatuzumab vedotin
given in combination with BR or with BG in patients with R/R FL or DLBCL
The primary objective of the Phase II portion of the study is as follows:
* To evaluate the efficacy of the combination of polatuzumab vedotin plus BR
compared with BR alone in patients with R/R FL or DLBCL as measured by positron
emission tomography (PET)-defined CR rate using Modified Lugano Response
Criteria ((PET-computed tomography [CT] criteria) at the time of primary
response assessment (6*8 weeks after Cycle 6, Day 1 or last dose of study drug)
and as defined by the Independent Review Committee (IRC)
Secondary objectives:
Safety Objectives:
* To assess the safety and tolerability of the combination of polatuzumab
vedotin with BR or BG when administered to patients with R/R FL or DLBCL during
the Phase II portion of the study
* To assess the immunogenicity of polatuzumab vedotin and obinutuzumab, as
measured by the formation of anti-drug antibodies (ADAs)
* To assess the potential relationships of such ADAs (anti-polatuzumab vedotin
and anti-obinutuzumab) formation with other outcome measures (e.g., PK,
efficacy, safety)
Pharmacokinetic Objectives
* To characterize the pharmacokinetics of polatuzumab vedotin in combination
with BR or BG in patients with R/R FL or DLBCL
* To assess potential PK interactions between polatuzumab vedotin and BR or BG
* To evaluate the PK exposure response (e.g., efficacy, safety) relationship
Secondary efficacy objectives (Main study):
To evaluate the efficacy of the combination of polatuzumab vedotin and BR
compared with BR alone according to Modified Lugano 2014 response criteria as
measured by:
* Complete response (CR) at the time of Primary Response Assessment based on
PET-CT, as determined by the investigator
* Objective response (OR; CR or partial response [PR]) at the time of Primary
Response Assessment, based on PET-CT, as determined by the investigator and IRC
* CR at the time of Primary Response Assessment based on CT only, as determined
by the investigator and IRC
* OR at the time of Primary Response Assessment based on CT only, as determined
by the investigator and IRC
* Best objective response (BOR; CR or PR) while on study either by PET-CT or CT
only,as determined by the investigator
* DLBCL cohorts only: BOR, DOR and PFS based on PET-CT or CT, as determined by
IRC
To evaluate the efficacy of the combination of polatuzumab vedotin plus BG
according to Modified Lugano 2014 response criteria as measured by:
* CR at the time of Primary Response Assessment based on PET-CT, as determined
by the investigator and IRC
* OR (CR or PR) at the time of Primary Response Assessment, based on PET-CT, as
determined by the investigator and IRC
* CR at the time of Primary Response Assessment based on CT only, as determined
by the investigator and IRC
* OR at the time of Primary Response Assessment based on CT only, as determined
by the investigator and IRC
* BOR (BOR, CR, or PR) while on study either by PET-CT or CT only as determined
by the investigator
* DLBCL cohorts only: BOR, DOR, and PFS while on study by either PET-CT or CT
only,as determined by IRC
* Patient-reported outcome (PRO) objective:
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).
* The exploratory objectives for this study are as follows:
To make a preliminary assessment of biomarkers related to the drug targets and
mechanism of action of polatuzumab vedotin and/or rituximab or obinutuzumab,
and/or of biomarkers related to disease biology and/or assessments that inform
the improvement of diagnostic tools, and that might predict disease response or
resistance to treatment with polatuzumab vedotin in combination with BR or BG
in R/R FL or DLBCL.
The exploratory efficacy objectives for this study are to evaluate longer-term
outcomes for patients treated with using the Lugano 2014 response criteria
Study design
This design is a Phase Ib/II, multicenter, open-label study of polatuzumab
vedotin administered by IV infusion in combination with standard doses of
bendamustine (B) and rituximab (R) in patients with relapsed or refractory FL
or DLBCL.
The Netherlands will only participate in the Phase II stage: randomization and
expansion phase.
Study treatment will be given in 28-day cycles for patients with FL and in
21-day cycles for patients with DLBCL. The first day of treatment will
constitute Study Day 1. Patients will be treated up to a total of six cycles.
All patients will be evaluated for safety and efficacy according to the
schedules of assessments (Appendix 1).
All patients will be assessed for response to treatment by the investigator
with the use of standard criteria according to the Lugano Response Criteria
(Cheson et al. 2014; see Appendix 4) at screening and at the following
timepoints: Interim response assessment (between Cycle 3 Day 15 and Cycle 4 Day
1) Primary response assessment: 6*8 weeks after completion of study treatment
(i.e., Day 1 of Cycle 6 or after last dose of study medication.
For more information, including a figure of the study design, see pages 67-69
of the protocol.
Intervention
The treatment consists of 6 cycli of infusions with one or a combination of
more of the following treatments:
De cycle in the FL population is 28 days.
De cycle in the DLBCL population is 21 days.
The following tretaments are used in this trial:
Polatuzumab Vedotin (PV): 1,8 mg/kg IV infusion
Rituximab (MabThera®/Rituxan®) (R): 375 mg/m2 IV infusion
Bendamustine (Levact®) (B): 90 mg/m2 IV infusion
In one of the following combinations:
Bendamustine + Rituxumab
Schedule of Cycle 1 day 1: Rituxumab, day 2+3: Bendamustine
Cycle 2 - 6 day 1: Rituxumab + Bendamustine, day 2: Bendamustine
OR
Polatuzumab Vedotin + Bendamustine + Rituxumab
Schedule cycle 1 day 1: Rituxumab, day 2: Polatuzumab Vedotin + Bendamustine,
day 3: Bendamustine
Schedule cycle 2 - 6 day 1: Rituxumab + Polatuzumab Vedotin + Bendamustine, day
2: Bendamustine
Study burden and risks
This information is stated in sections E4, E6 and E9.
The subject may get side effects from the drugs or procedures used in this
study. Side effects can vary from mild to sever and can vary from person to
person. In some cases, side effects can be severe, long persisting or never
disappear. There is also a ery small risk of death.
Side effects associated with Polatuzumab Vedotin
-There is a risk that use of Polatuzumab Vedotin resulting in an inability to
get full doses and cycles of Rituximab + Bendamustine.
-Neutropenia
-Peripheral sensory and / or motor neuropathy
Potential side effects of Polatuzumab:
-Possible side effects on reproduction and fertility.
-It is possible that it has effect on the control of blood sugar levels.
-Small possibility that the immune system produces special antibodies that will
bind to the studied drugs. This may affect the response of the body to similar
medicines.
-There may occur infusion-related reactions such as: fever, chills, rash,
nausea, vomiting, head-ache, cold-like symptoms,difficulty with breathing,
shortness of breath.
-An allergic reaction can occur.
-It can affect the liver: abnormal liverfunction tests or changes on scans. It
is unclear whether this is temporary or permanent.
-Possibility of tumor lysis syndrome.
-Other side effects reported in studies, but which has not been known to be
caused by Polatuzumab: fatigue, nausea, vomiting, diarhea, loss of appetite,
weight loss, anemia, fever, rash, cold, diziness, upper-respiratory infection,
shortness of breath, hair loss, joint pain, back pain, weakness, abdominal
pain, changed liver function, higher blood levels, constipation, mild visual
symptoms.
The adverse reactions of all treatment drugs in this trial are described in the
protocol as well as the risks of all study procedures.
Beneluxlaan 2A
Woerden 3446 GR
NL
Beneluxlaan 2A
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
- Age * 18 years
- Histologically confirmed FL (Grade 1, 2, or 3a) or DLBCL
- Must have received at least one prior therapy for FL or DLBCL. Patients must
have either relapsed or have become refractory to a prior regimen as defined in
the protocol.
- If the patient has received prior bendamustine, response duration must have
been > 1 year (for patients who have relapse disease after a prior regimen)
- At least one bi-dimensionally measurable lesion on imaging scan defined as >
1.5 cm in its longest dimension
- Confirmed availability of archival or freshly collected tumor tissue prior
to study enrollment
- Life expectancy of at least 24 weeks
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- Adequate hematologic function unless inadequate function is due to
underlying disease.
- For women who are not postmenopausal (* 12 months of non*therapy*induced
amenorrhea and age > 45 years) or surgically sterile: 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 or for * 18 months after the
last dose of obinutuzumab, and agreement to refrain from donating eggs.
- For women of childbearing potential, a negative serum pregnancy test result
within 7 days prior to commencement of dosing.
- 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
Exclusion criteria
- 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
- Contraindication to bendamustine, rituximab, or obinutuzumab
- History of sensitivity to mannitol (mannitol is an excipient in bendamustine)
- Prior use of any MAb, radioimmunoconjugate, or ADC within 5 half-lives or 4
weeks, whichever is longer before Cycle 1 Day 1
- Treatment with radiotherapy, chemotherapy, immunotherapy, immunosuppressive
therapy, or any investigational agent for the purposes of treating cancer
within 2 weeks prior to Cycle 1 Day 1
- Ongoing corticosteroid use > 30 mg/day prednisone or equivalent, for
purposes other than lymphoma symptom control
- Treatment with chimeric antigen receptor T-cell therapy within 100 days prior
to Cycle 1 Day 1
- Completion of autologous stem cell transplant within 100 days prior to Cycle
1 Day 1
- Prior allogeneic stem cell transplant
- Eligibility for autologous SCT
- Grade 3b follicular lymphoma
- History of transformation of indolent disease to DLBCL
- Primary or secondary CNS lymphoma
- Current Grade > 1 peripheral neuropathy
- History of other malignancy that could affect compliance with the protocol
or interpretation of results.
- Evidence of significant, uncontrolled concomitant diseases that could affect
compliance with the protocol or interpretation of results, including
significant cardiovascular disease or significant pulmonary disease
- Known active bacterial, viral, fungal, mycobacterial, parasitic, or other
infection at study enrollment or any major episode of infection requiring
treatment with intravenous (IV) antibiotics or hospitalization within 4 weeks
prior to Cycle 1 Day 1
- Patients with suspected or latent tuberculosis,
- Positive test results for chronic hepatitis B virus infection or for
hepatitis C virus antibody
- Known history of HIV seropositive status
- Known infection of human T-cell leukemia virus 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
- Any abnormal laboratory values as defined in the protocol, unless abnormal
laboratory values are due to underlying lymphoma per the investigator
- 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001361-28-NL |
| ClinicalTrials.gov | NCT02257567 |
| CCMO | NL53976.091.15 |