Testing Drug Treatments After CAR T-cell Therapy in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma
Purpose
This phase II trial tests whether mosunetuzumab and/or polatuzumab vedotin helps benefit patients who have received chemotherapy (fludarabine and cyclophosphamide) followed by chimeric antigen receptor (CAR) T-cell therapy (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel) for diffuse large B-cell lymphoma that has come back (recurrent) or that does not respond to treatment (refractory) or grade IIIb follicular lymphoma. Mosunetuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Polatuzumab vedotin is a monoclonal antibody, called polatuzumab, linked to a drug called vedotin. Polatuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, and delivers vedotin to kill them. Chemotherapy drugs, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. CAR T-cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving mosunetuzumab and/or polatuzumab vedotin after chemotherapy and CAR T-cell therapy may be more effective at controlling or shrinking the cancer than not giving them.
Conditions
- Diffuse Large B-Cell Lymphoma
- Grade 3b Follicular Lymphoma
- Primary Mediastinal (Thymic) Large B-Cell Lymphoma
- Recurrent Diffuse Large B-Cell Lymphoma
- Refractory Diffuse Large B-Cell Lymphoma
- Transformed Follic Lymph to Diff Large B-Cell Lymphoma
- Transformed Marg Zone Lymph to Diff Large B-Cell Lymphoma
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- STEP 1: REGISTRATION: Participants must have a histologically confirmed diagnosis of
diffuse large B-cell lymphoma or follicular lymphoma grade 3b or primary mediastinal
large B-cell lymphoma (PMBCL)
- STEP 1: REGISTRATION: Participants with transformed DLBCL must have transformed
DLBCL from follicular or marginal zone lymphoma
- STEP 1: REGISTRATION: Participant must have bi-dimensionally measurable systemic
disease (at least one lesion with longest diameter > 1.5 cm)
- STEP 1: REGISTRATION: Participants with secondary central nervous system (CNS)
lymphoma (parenchymal, spinal cord, meningeal, cerebrospinal fluid involvement) must
be asymptomatic from their CNS disease
- STEP 1: REGISTRATION: Participants must be registered for step 1 after they have
signed institutional consent for CAR T-cell leukapheresis but prior to the start of
lymphodepleting (LD) chemotherapy for commercial CAR T-cell product
- STEP 1: REGISTRATION: In the opinion of the enrolling physician, participants must
be felt to be a candidate for CAR T-cell therapy with plans to be treated with Food
and Drug Administration (FDA) approved commercially available CD19 CAR T-cell
construct.
- Participants must qualify for commercially approved CD19 CAR T-cell therapy per
FDA package insert.
- If the CAR T-cell product does not meet parameters to be given as an FDA
approved product (i.e. does not meet specification criteria mandated by FDA and
is infused under an expanded access protocol [EAP] or single participant
investigational new drug [IND]) the participant will be taken off of study and
no longer be eligible for step 2 randomization
- STEP 1: REGISTRATION: Participants are permitted to receive or have received
'bridging therapy' after CAR T-cell leukapheresis. However, participants must not
receive polatuzumab vedotin, and/or mosunetuzumab as part of bridging therapy.
- Bridging therapy is defined as lymphoma directed therapy administered between
leukapheresis and the start of LD chemotherapy. This includes cytotoxic
chemotherapy (e.g.: bendamustine and rituximab [BR], rituximab, gemcitabine and
oxaliplatin [R-gem/ox]), radiation, corticosteroids, as well as novel therapies
such as BTK inhibitors (e.g.: Ibrutinib), immunomodulators (e.g.:
lenalidomide), monoclonal antibodies (e.g.: rituximab, obinutuzumab,
tafasitamab) antibody drug conjugates (e.g: loncastuximab), checkpoint
inhibitors (e.g.: pembrolizumab, nivolumab), clinical trial treatments, etc.
- If a participant receives polatuzumab vedotin or mosunetuzumab as bridging they
will ineligible to continue on step 1 registration portion of the study and be
ineligible for step 2 randomization
- STEP 1: REGISTRATION: PET-CT scan must be planned for completion within 60 days
prior to the start of LD chemotherapy.
- All pre-CAR T-cell therapy disease must be assessed and documented on the
baseline/pre-registration tumor assessment form.
- If receiving bridging therapy, participants must have a PET-CT scan upon
completion of all planned bridging therapy. If the PET-CT scan after completion
of bridging therapy is consistent with complete remission per Lugano criteria
as determined by enrolling physician, that participant will be ineligible for
step 2 randomization.
- Participants are permitted to receive corticosteroids after leukapheresis
without the need to repeat a PET-CT scan. If steroids are used, they must be
planned to stop no later than 3 days before CAR -T cell infusion.
- If response assessment by central review cannot be completed (I.e., poor
quality of PET-CT scan, PET-CT performed out of window, etc.) this would be
recorded as 'inadequate assessment' and patient would not be eligible for
randomization
- STEP 1: REGISTRATION: Participants that have previously been treated with
polatuzumab vedotin or mosunetuzumab prior to CAR T-cell leukapheresis for either
indolent or aggressive NHL are eligible as long as the participant did not have
refractory disease or progression/relapse within 6 months of the last infusion with
either agent
- STEP 1: REGISTRATION: Participants must be planning to receive CAR T-cell infusion
no earlier than 2 days and no later than 14 days after completion of the last day of
lymphodepleting chemotherapy. Any participant receiving CAR T-cell infusion outside
of this window will be ineligible for step 2 randomization
- STEP 1: REGISTRATION: LD chemotherapy prior to CAR T-cell infusion must be planned
to start within 60 days after step 1 registration
- STEP 1: REGISTRATION: Participants must be >= 18 years of age at the time of
registration
- STEP 1: REGISTRATION: Participants must have Zubrod performance score (PS) of 0, 1,
or 2
- STEP 1: REGISTRATION: Total bilirubin =< 2 x institutional upper limit of normal
(ULN) (within 14 days prior to registration)
- Unless due to Gilbert's disease or lymphomatous involvement of liver
- STEP 1: REGISTRATION: Aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) =< 3 x institutional ULN (within 14 days prior to registration)
- STEP 1: REGISTRATION: Creatinine clearance >= 40 mL/min, as estimated by the
Cockcroft and Gault formula. The creatinine value used in the calculation must have
been obtained within 14 days prior to registration. Estimated creatinine clearance
is based on actual body weight
- STEP 1: REGISTRATION: Participants must have an echocardiogram (ECHO) or multigated
acquisition scan (MUGA) within 60 days prior to registration with a cardiac ejection
fraction >= 40%.
- Participants with current symptoms of cardiac disease must have a clinical risk
assessment of cardiac function using the New York Heart Association Functional
Classification. To be eligible for this trial, participants must be class 2B or
better.
- Participants must not have documented myocardial infarction and percutaneous
coronary intervention (PCI) within 6 months prior to registration or myocardial
infarction without PCI within 3 months of registration, or unstable angina
- STEP 1: REGISTRATION: Participants with peripheral neuropathy must have < grade 2
- STEP 1: REGISTRATION: Participants with hepatitis B virus infection must have
undetectable viral load within 14 days prior to registration, be on suppressive
therapy and have no evidence of hepatitis B virus (HBV) related hepatic damage
- STEP 1: REGISTRATION: Participants with hepatitis C infection must have eradication
therapy completed, have no evidence of hepatitis C infection (HCV) related damage
and have undetectable viral load within 14 days prior to registration
- STEP 1: REGISTRATION: Participants with known human immunodeficiency virus
(HIV)-infection must be on effective anti-retroviral therapy at time of registration
and have undetectable viral load test on the most recent test results obtained
within 6 months prior to registration
- STEP 1: REGISTRATION: Participants must be offered the opportunity to participate in
banking for planned translational medicine and future research. With participant
consent, any residuals from the mandatory tissue submission will also be banked for
future research.
- Note: Streck tubes must be ordered in advance. Please allow 5-7 days for
shipment of the collection kits
- STEP 1: REGISTRATION: NOTE: As a part of the OPEN registration process the treating
institution's identity is provided in order to ensure that the current (within 365
days) date of institutional review board approval for this study has been entered in
the system.
- Participants must be informed of the investigational nature of this study and
must sign and give informed consent in accordance with institutional and
federal guidelines.
- For participants with impaired decision-making capabilities, legally
authorized representatives may sign and give informed consent on behalf of
study participants in accordance with applicable federal, local, and
Central Institutional Review Board (CIRB) regulations
- STEP 2: RANDOMIZATION: Participants must have met all eligibility criteria for step
1 registration
- STEP 2: RANDOMIZATION: Participant's CAR T-cell product must have met specification
parameters to be given as an FDA approved commercial product
- STEP 2: RANDOMIZATION: Participants must have a PET-CT scan between days 25-40 after
CAR T-cell infusion and determined to have a response consistent with stable disease
or partial remission by central review compared to most recent pre-LD chemo/CAR
T-cell PET-CT scan.
- Note: Patients with delayed enrollment > 21 days after 'day +30' PET-CT scan
will necessitate a repeat PET-CT scan if concerning signs or symptoms of
lymphoma progression develop.
- Note: If response assessment by central review cannot be completed (I.e., poor
quality of PET-CT scan, PET-CT performed out of window, etc.) this would be
recorded as 'inadequate assessment' and patient would not be eligible for
randomization
- STEP 2: RANDOMIZATION: Eligible participants must be randomized no later than 60
days after CAR -T infusion
- STEP 2: RANDOMIZATION: Participants must have started LD chemotherapy within 60 days
of signing consent for step 1 registration
- STEP 2: RANDOMIZATION: Participants must have S2114 CAR T-cell therapy form
submitted to Southwest Oncology Group (SWOG) prior to step 2 randomization
- STEP 2: RANDOMIZATION: Participants must have had a PET-CT scan upon completion of
all planned bridging therapy if received, with the exception of up to 7 days of
corticosteroids. If the PET-CT scan after completion of bridging therapy was
consistent with complete remission per Lugano criteria as determined by enrolling
physician, that participant will be ineligible for step 2 randomization.
- If response assessment by central review cannot be completed (I.e., poor
quality of PET-CT scan, PET-CT performed out of window, etc.) this would be
recorded as 'inadequate assessment' and patient would not be eligible for
randomization
- STEP 2: RANDOMIZATION: Participants must have Zubrod PS of 0, 1, or 2
- STEP 2: RANDOMIZATION: Absolute neutrophil count (ANC) >= 1.0 x 10^3/uL and
participants must not have received myeloid growth factor within 72 hours prior to
this lab being drawn (within 7 days prior to step 2 randomization)
- STEP 2: RANDOMIZATION: Platelets >= 75 x 10^3/uL and participants must not have
received platelet transfusion within 72 hours prior to this lab being drawn (within
7 days prior to step 2 randomization)
- STEP 2: RANDOMIZATION: Total bilirubin =< 2 x institutional ULN (within 7 days prior
to step 2 randomization)
- Unless due to Gilbert's disease or lymphomatous involvement of liver
- STEP 2: RANDOMIZATION: AST and ALT =< 3 x institutional ULN (within 7 days prior to
step 2 randomization)
- STEP 2: RANDOMIZATION: Creatinine clearance >= 40 mL/min, as estimated by the
Cockcroft and Gault formula. The creatinine value used in the calculation must have
been obtained within 7 days prior to step 2 randomization. Estimated creatinine
clearance is based on actual body weight (within 7 days prior to step 2
randomization)
- STEP 2: RANDOMIZATION: Participants with peripheral neuropathy must have < grade 2
- STEP 2: RANDOMIZATION: Participants with current symptoms of cardiac disease must
have a clinical risk assessment of cardiac function using the New York Heart
Association Functional Classification. To be eligible for this trial, participants
must be class 2B or better
- STEP 2: RANDOMIZATION: Participants with history of hepatitis B viral infection must
have undetectable viral load within 14 days prior to step 2 randomization and on
suppressive therapy
- STEP 2: RANDOMIZATION: Participants with history of hepatitis C viral infection must
have undetectable viral load within 14 days prior to step 2 randomization
- STEP 2: RANDOMIZATION: Participants with known human immunodeficiency virus
(HIV)-infection must be continuing to receive anti-retroviral therapy and have an
undetectable viral load test within 14 days prior to step 2 randomization
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants must have documented
disease progression while on Arm 4 (observation) on this protocol. The follow-up
tumor assessment form documenting disease progression must be submitted to SWOG
prior to step 3 crossover registration
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants must be registered within
28 days of the date of progression
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants must have imaging that
clearly demonstrates progression compared to day +30 PET-CT scan
- Note: These scans should be performed as standard of care and only performed
between scheduled response assessments required for study if symptoms arise
that are concerning for progression
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants must have Zubrod PS of 0,
1, or 2
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): ANC >= 1.0 x 10^3/uL and participants
must not have received myeloid growth factor within 72 hours prior to this lab being
drawn (within 14 days prior to step 3 crossover registration)
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Platelets >= 75 x 10^3/uL and
participants must not have received platelet transfusion within 72 hours prior to
this lab being drawn (within 14 days prior to step 3 crossover registration)
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Total bilirubin =< 2 x institutional
ULN (within 14 days prior to step 3 crossover registration)
- Unless due to Gilbert's disease or lymphomatous involvement of liver
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): AST and ALT =< 3 x institutional ULN
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Creatinine clearance >= 40 mL/min, as
estimated by the Cockcroft and Gault formula. The creatinine value used in the
calculation must have been obtained within days prior to step 3 crossover
registration. Estimated creatinine clearance is based on actual body weight (within
14 days prior to step 3 crossover registration)
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with peripheral neuropathy
must have < grade 2
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with current symptoms of
cardiac disease must have a clinical risk assessment of cardiac function using the
New York Heart Association Functional Classification. To be eligible for this trial,
participants must be class 2B or better
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with history of hepatitis
B viral infection must have undetectable viral load within 14 days prior to step 3
crossover registration and on suppressive therapy
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with history of hepatitis
C viral infection must have undetectable viral load within 14 days prior to step 3
crossover registration
- STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with known human
immunodefici
Study Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Experimental Step I (lymphodepleting chemotherapy) |
Patients receive lymphodepleting chemotherapy consisting of fludarabine IV and cyclophosphamide IV on study. Patients then receive tisagenlecleucel IV, axicabtagene ciloleucel IV, or lisocabtagene maraleucel IV on study. |
|
|
Experimental Step II Arm I (mosunetuzumab) |
Patients receive mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. |
|
|
Experimental Step II Arm II (polatuzumab vedotin) |
Patients receive polatuzumab vedotin IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. |
|
|
Experimental Step II Arm III (polatuzumab vedotin, mosunetuzumab) |
Patients receive polatuzumab vedotin IV and mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. |
|
|
Active Comparator Step II Arm IV (observation) |
Patients undergo observation on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. Patients with subsequent progression within 12 months of CAR T-cell therapy may crossover to Arm III. |
|
Recruiting Locations
Westwood, Kansas 66205
Kansas City, Kansas 66160
Overland Park, Kansas 66210
More Details
- Status
- Recruiting
- Sponsor
- SWOG Cancer Research Network
Detailed Description
PRIMARY OBJECTIVES: I. To compare the progression-free survival in participants with relapsed/refractory large B-cell lymphoma or follicular lymphoma grade 3B with stable disease (SD) or partial remission (PR) on first imaging response by central review (day +30 positron emission tomography [PET]/computed tomography [CT] scan) after commercial CD19 CAR T-cell therapy who are randomized to receive each consolidation therapy versus those that receive no consolidation therapy (i.e. control). Ia. Specifically, to compare the progression free survival (PFS) of 1) mosunetuzumab consolidation to no consolidation, 2) polatuzumab vedotin consolidation to no consolidation, 3) mosunetuzumab + polatuzumab vedotin to no consolidation. SECONDARY OBJECTIVES: I. To compare overall survival (OS) in participants randomized to each consolidation treatment arm versus control. II. To compare the complete remission (CR) conversion rate up to one year in participants randomized to each consolidation arm versus control. III. To evaluate the treatment-related adverse events in participants randomized to each consolidation arm. IV. To evaluate the association between total metabolic tumor volume (TMTV), standardized uptake value (SUV) max, and sum product (SPD) of diameters by PET-CT at first imaging response with complete remission conversion up to one year in participants randomized to each consolidation arm as well as those randomized to control. V. To evaluate the overall response rate (ORR), CR rate, PFS, and OS of participants randomized to Arm 4 (observation) who have lymphoma progression within 12 months of CAR T-cell infusion and subsequently 'cross-over' to receive treatment with mosunetuzumab + polatuzumab vedotin. VI. To estimate overall survival for all patients registered to this study. VII. To assess the difference in overall survival between participants who achieved CR at first imaging (day +30) versus those who did not achieve CR at first imaging. BANKING OBJECTIVES: I. To bank specimens for future correlative studies. II. To bank PET-CT images for future correlative studies. OUTLINE: STEP I: Patients receive lymphodepleting chemotherapy consisting of fludarabine intravenously (IV) and cyclophosphamide IV on study. Patients then receive tisagenlecleucel IV, axicabtagene ciloleucel IV, or lisocabtagene maraleucel IV on study. STEP II: Patients are randomized to 1 of 4 arms. ARM I: Patients receive mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. ARM II: Patients receive polatuzumab vedotin IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. ARM III: Patients receive polatuzumab vedotin IV and mosunetuzumab IV on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. ARM IV: Patients undergo observation on study. Patients also undergo PET-CT and/or CT and undergo collection of blood and tissue samples throughout the study. Patients with subsequent progression within 12 months of CAR T-cell therapy may crossover to Arm III.