Patients must have either failed to achieve a complete remission, or must have relapsed within 2 years after completing first line bendamustine-containing chemoimmunotherapy (including an anti-CD20 monoclonal antibody), as measured from the last dose of bendamustine; relapsed patients must not have received any intervening chemotherapy; patients must have received at least 3 cycles of bendamustine as first line therapy; (note that no minimum dose of bendamustine is required); patients who additionally received any maintenance anti-CD-20 antibody based therapy or consolidative radioimmunotherapy within 2 years of the last dose of the bendamustine therapy are eligible; involved field or involved site radiation is not considered a line of therapy; patients who previously received anthracycline based therapy are excluded; examples of eligible 1st line treatment regimens (note this list is not all inclusive):\r\n* Bendamustine rituximab x 4 cycles\r\n* Bendamustine bortezomib rituximab x 6 cycles followed by rituximab maintenance\r\n* Bendamustine obinutuzumab x 3 cycles
DISEASE CHARACTERISTICS:\n\n          -  Histologically confirmed diagnosis of iNHL (Follicular lymphoma grade 1, 2, 3a;\n             marginal zone lymphoma; small lymphocytic lymphoma or lymphoplasmacytic lymphoma)\n             after treatment with at least 1 or more prior rituximab-containing regimens.\n\n               -  Anti-CD20 mAb-refractory disease is defined as progressive disease while on\n                  rituximab (or another treatment of an anti-CD20 monoclonal antibody) or\n                  progression within 6 months of rituximab-containing (or another treatment of an\n                  anti-CD20 antibody-containing) therapy.\n\n               -  Anti-CD20 mAb-sensitive disease is defined by a response to a prior\n                  rituximab-containing (or another treatment of an anti-CD20 monoclonal antibody)\n                  regimen, and relapse more than 6 months from the last administration of\n                  rituximab-containing (or another treatment of an anti-CD20 antibody-containing)\n                  therapy.\n\n          -  Measurable disease:\n\n               -  At least one lymph node group ? 1.5 cm in longest transverse dimension. Patients\n                  with cutaneous only disease may be enrolled if they have a clearly measurable\n                  skin lesion.\n\n               -  Relapsed or Refractory iNHL that has progressed during or following 1 or more\n                  prior systemic rituximab-containing (or another treatment of an anti-CD20\n                  antibody-containing) regimens for lymphoma\n\n        PRIOR/CONCURRENT THERAPY:\n\n          -  No anti-lymphoma treatments within 28 days before the start of study treatment.\n\n          -  Must have recovered from side effects of prior treatments.\n\n        PATIENT CHARACTERISTICS:\n\n        Performance Status\n\n        • ECOG 0, 1, or 2\n\n        Renal Function • Glomerular Filtration Rate (GFR) > 40mL/min or Serum creatinine ? 1.5 X\n        ULN\n\n        Bone Marrow Reserve\n\n          -  Platelets ?30,000/uL\n\n          -  Hemoglobin ? 8g/dL\n\n          -  Absolute Lymphocytes ?800/uL\n\n          -  ANC/AGC ?750/uL\n\n        Hepatic Function\n\n          -  Total bilirubin ? 2.0 X ULN (unless Gilbert's Syndrome or disease infiltration of\n             liver is present)\n\n          -  AST, ALT ? 3.0 X ULN, or ? 5.0 X ULN (if liver lymphoma is present)\n\n          -  No positive Hep C serology or active Hep B infection\n\n        Cardiovascular\n\n          -  No congestive heart failure < 6 months\n\n          -  No unstable angina pectoris < 6 months\n\n          -  No myocardial infarction < 6 months\n\n          -  No history of ventricular arrhythmias or severe cardiac dysfunction\n\n          -  No history of uncontrollable supraventricular arrhythmias\n\n          -  No NYHA Class > II CHF\n\n          -  No marked baseline prolongation of QT/QTc interval\n\n        Pulmonary\n\n        • Normal clinical assessment of pulmonary function\n\n        Other\n\n          -  Negative serum pregnancy test if female and of childbearing potential\n\n          -  Women who are not pregnant or nursing\n\n          -  Subjects, both females and males, with reproductive potential must agree to use\n             effective contraceptive measures for the duration of the study\n\n          -  No known autoimmune disease other than corrected hypothyroidism\n\n          -  No known prior organ allograft or allogeneic transplantation\n\n          -  Not HIV positive\n\n          -  No active CNS involvement with lymphoma\n\n          -  No psychiatric illness/social situation that would limit compliance\n\n          -  No other illness that in the opinion of the investigator would exclude the subject\n             from participating in the study\n\n          -  Must provide informed consent and HIPPA authorization and agree to comply with all\n             protocol-specified procedures and follow-up evaluations\n\n          -  No active systemic infection requiring parenteral antibiotic therapy\n\n          -  No disease requiring systemic immunosuppressive therapy (inhaled or topical steroids\n             are allowed). Adrenal replacement steroid doses ? 10 mg daily prednisone equivalent\n             are permitted in the absence of active autoimmune disease.\n\n          -  No known histologic transformation from iNHL to DLBCL
Patients must have received 4 or more cycles of one of the following prior systemic induction chemotherapy regimens:\r\n* Rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin), prednisone (R-CHOP) (with or without cytarabine-containing cycles, including “Nordic” and European Mantle Cell Lymphoma Network [MCL-NET] protocols) with or without autologous (auto) stem cell transplant (SCT)\r\n* R-Hyper-cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (adriamycin), dexamethasone (CVAD) with or without auto SCT\r\n* Bendamustine + rituximab with or without auto SCT\r\n** Please note:\r\n*** Patients are allowed to receive combinations of the above regimens\r\n*** At the time of registration, patients must be at least 14 days out from last dose of cytotoxic chemotherapy, but no more than 120 days; if a patient underwent auto SCT, he/she must demonstrate engraftment (per treating investigator's discretion) and meet all other hematological requirements as outlined below\r\n*** Patients who progress during induction therapy are not eligible to enroll in this study
For selected higher-risk group B and all group C participants receiving rituximab only (e.g., those with MLBCL, stage III with LDH >= 2 x ULN, and/or bone marrow/central nervous system [CNS] involvement): all participants who will receive rituximab must have hepatitis screening prior to enrollment; participants whose results indicate that they are carrier of hepatitis B can still be treated as per group B or C but will NOT receive rituximab; this screening must be done for eligibility for participants who will receive rituximab, BUT the results are not needed prior to enrollment:\r\n* Hepatitis B immunization status (vaccination yes or no)\r\n* Hepatitis B surface antigen (HBsAg)\r\n* Anti-hepatitis B surface (HBs) antibody\r\n* Anti-hepatitis B core (HBc) antibody
All participants must have screening prior to enrollment; participants whose results indicate that they are carrier of hepatitis B can still be treated per group B and C but will NOT receive rituximab
Treatment failure of rituximab monotherapy (Cohort A) or rituximab plus any concurrent or sequentially administered chemotherapy regimen (Cohort B) for treatment of PTLD. Note: Subjects with CD20 negative disease are eligible to enroll without prior anti-CD20 therapy after failure of first-line treatment (reduction of immunosuppression is not considered first-line therapy) and discussion with the sponsor's medical monitor.
Use of biologic antibody therapy for cGVHD with rituximab, alemtuzumab, or antithymocyte globulin (ATG) within 3 months of starting treatment with abatacept
Patients who have received prior treatment for lymphoma are not eligible\r\n* NOTE: Patients may have received corticosteroids for lymphoma for 10 or fewer days at any dose (no washout period required)\r\n* NOTE: Patients may have received up to 1 prior dose of rituximab before registration; in this case, patients will only receive 3 doses of rituximab on study
Patients who have received chemotherapy (including monoclonal antibodies) or radiotherapy, administered for any condition, within 4 weeks prior to registration are not eligible\r\n* NOTE: Patients may have received one dose of rituximab prior to enrollment; in such cases, patients will only continue with 3 doses of rituximab during induction (4 total doses)
TREATMENT: Patients should have been off conventional therapy for at least 1 week prior to entry in this study, including rituximab
Avoid conceiving for at least 12 months after the last dose of rituximab, or according to the local rituximab Prescribing Information or Summary of Product characteristics (SmPC); at least 28 days after the last dose of any other study drug.
Agree to not donate semen or sperm for at least 12 months following the last dose of rituximab.
mAb (including rituximab) within 2 weeks of enrollment
Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent; patients with a prior reaction to rituximab are permitted if the investigator feels that this reaction is manageable with standard supportive care measures and would otherwise be comfortable administering rituximab outside of the clinical trial setting
Part 2: Subjects who have received any amount of rituximab within 365 days of planned dose day 1 must have a serum rituximab level of <500 ng/mg documented by the study's reference laboratory prior to the initiation of dosing. Potential subjects who have received any other anti CD20 MAb therapy (obinutuzumab, ofatumumab, or ibritumomab tiuxetan) must be at least 8 half-lives past their last dose prior to initiation of study drug dosing. Washout periods for these drugs are as follows:
Has insurance coverage or is willing to pay for protocol therapy (rituximab x 4 or Zevalin x 1)
No prior rituximab unless HCLv patient
Patients must have received at least one prior therapy for CLL comprised of the following:\r\n* ? 1 regimen containing an anti-CD20 antibody (e.g., rituximab, obinutuzumab) administered for ? 2 doses\r\n* ? 1 regimen containing ? 1 cytotoxic agent (eg, bendamustine, fludarabine, chlorambucil, cyclophosphamide) administered for ? 2 cycles
Patients must have had at least two prior chemotherapeutic or biologic (e.g. rituximab alone) regimens and not currently eligible for standard curative options; steroids alone and local radiation do not count as regimens
Treatment with rituximab monotherapy within 3 months or rituximab combination therapies (example, with bendamustine, fludarabine, ibrutinib, or cytotoxic drugs) within 6 months prior to enrollment
No prior cytotoxic chemotherapy; prior therapy with single-agent rituximab is permitted; prior involved-field radiotherapy to symptomatic nodal sites of involvement is also permitted
Prior therapy with rituximab is permitted, even in the setting of rituximab-refractory disease
Treatment with rituximab or other anti-B cell specific antibodies within previous 3 months
Use of rituximab and other anti-cluster of differentiation antigen 20 (CD20) antibodies known to have the same epitope as rituximab or anti-cluster of differentiation antigen 20 (CD20) for which the epitope is unknown within 3 months prior to enrollment;
Use of rituximab and other anti-cluster of differentiation 20 (CD20) antibodies known to have the same epitope as rituximab or anti-CD20 for which the epitope is unknown within 3 months prior to start of lymphodepletion
mAb (including rituximab) within 2 weeks of enrollment
Relapsed or refractory to any prior rituximab-containing regimen.
Received rituximab within 4 weeks of study start.
Rituximab within 12 months prior to study registration; only exception will be if rituximab was given for indications other than the treatment of aggressive lymphoma, or for one prior cycle of treatment
Subjects who have had treatments with anti-cancer agents including rituximab or obinutuzumab and/or other monoclonal antibody or radioimmunotherapy within 6 weeks before the starting IP treatment.
Previous treatment with any chemotherapy and/or rituximab or other monoclonal antibody.
Has B-cell lymphoma refractory to or intolerant of established therapy known to provide clinical benefit for their condition and having received rituximab as a single agent or in combination with other therapies.
A known hypersensitivity to rituximab, HH1, Betalutin or murine proteins or any excipient used in rituximab, HH1 or Betalutin.
Patients must have failed at least 1 prior regimen before ibrutinib (not including single agent rituximab or single agent corticosteroids)\r\n* Note: any relapse after prior autologous stem cell transplantation (SCT) will make the patient eligible regardless of other prior therapy
Known hypersensitivity to lenalidomide or thalidomide, ibrutinib, rituximab, etoposide, vincristine,\r\ndoxorubicin, cyclophosphamide, or prednisone
Patients must have relapsed after at least 1 but at most 3 prior lines of therapy, including rituximab-based immunochemotherapy and alkylating agents. A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cyclesof polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to other PI3Ki is acceptable provided there is no resistance.
Rituximab resistance at any line of therapy (resistance defined as lack of response, or progression within 6 months of the last course of treatment with a rituximab containing regimen including rituximab maintenance)
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm; patients must be >= 2 weeks from prior anti-lymphoma therapy; the use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed
Any prior treatment with rituximab or any other anti-CD20 agent must have been > 6 months prior to the first dose of PRTX-100
Planned to receive chemotherapy for 6 cycles which the treating physician plans to utilize for pegfilgrastim to minimize risk for neutropenic fever, including but not limited to rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP), rituximab, etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (R-EPOCH), and rituximab, cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone, administered on a hyperfractionated schedule (R-HyperCVAD), cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP), and dexamethasone, methotrexate, ifosfamide, asparaginase, and etoposide (SMILE)
Patients must have relapsed (recurrence after complete response or presented progression after partial response) after last rituximab-containing therapy (other previous treatment lines after rituximab are allowed). A previous regimen is defined as one of the following: at least 2 months of single-agent therapy (less than 2 months of therapy is allowed for patients who responded to single-agent rituximab); at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to PI3K is acceptable (except to copanlisib) provided there is no resistance. Patients with prior intolerance to PI3K inhibitors other than copanlisib are eligible.
have had a progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing treatment OR
Progression free interval or treatment free interval of less than 12 months since the last rituximab containing treatment (including rituximab maintenance). For patients considered unwilling/unfit to receive chemotherapy : progression free interval or treatment free interval of less than 6 months since the last rituximab containing treatment (including rituximab maintenance), as assessed by the investigator
Able to start the protocol therapy (1st dose of rituximab) between day 28-60 post-transplant
Males must agree to take appropriate precautions to avoid fathering a child (with at least 99% certainty) from screening through 12 months after the last dose of rituximab; (Note: permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed)
Previous severe or life-threatening allergic reaction with rituximab or known allergy to the compounds found in INCB7839
Mantle cell lymphoma\r\n* Beyond 1st CR with relapsed disease, progressive disease during first line rituximab-chemotherapy combination, or persistent disease after first line rituximab-chemotherapy combination and not eligible or appropriate for conventional allogeneic or autologous SCT\r\n* Relapsed after prior autologous SCT
Patients must have received at least 1 prior rituximab-based immunochemotherapy (e.g., R-CHOP, R-EPOCH, etc.)
No prior cytotoxic chemotherapy for their disease; prior therapy with single-agent rituximab is permitted
Prior therapy with rituximab is permitted, even in the setting of rituximab-refractory disease
Patients will be eligible if the treatment phase consisting in a Rituximab combined with any anthracycline-containing chemotherapy regimen without consolidation with autologous stem cell support (e.g., 6 cycles of CHOP14-21, DA-EPOCH, Mega-CHOP or 12 weeks of VACOP-B or MACOP-B).
At least 6 courses of Rituximab should be administered
History of rituximab or intravenous bevacizumab therapy within six weeks
Received rituximab within 4 months of blood collection for lymphoblastoid cell line (LCL) initiation (unless circulating CD19+ B are >= 2%)
Patients with history of non-response to both pentostatin plus rituximab and to bendamustine plus rituximab
Previous rituximab
Arms A/B – eligible for treatment with ifosfamide, carboplatin, and etoposide (+/- rituximab)
Arm C eligible for treatment with one of the following standard, every 3 week, platinum-based salvage regimens (with or without monoclonal antibody as appropriate for the disease):\r\n* Ifosfamide/carboplatin/etoposide (ICE) or rituximab/ifosfamide/carboplatin/etoposide (RICE);\r\n* Cisplatin, cytarabine (cytosine arabinoside), dexamethasone (DHAP) or rituximab, cisplatin, cytosine arabinoside, dexamethasone (RDHAP);\r\n* Gemcitabine hydrochloride (gemcitabine), dexamethasone, cisplatin (GDP) or rituximab, gemcitabine, dexamethasone, cisplatin (RGDP);\r\n* Gemcitabine and oxaliplatin (GemOx) or rituximab, gemcitabine and oxaliplatin (RGemOx);\r\n* Oxaliplatin, cytosine arabinoside, dexamethasone (OAD) or rituximab, oxaliplatin, cytosine arabinoside, dexamethasone (ROAD)
Treatment with rituximab monotherapy within 3 months or rituximab combination therapies (eg, with bendamustine, fludarabine, ibrutinib, or cytotoxic drugs) within 6 months prior to enrollment
Has receive rituximab
Patients with known hypersensitivity to lenalidomide and/or rituximab
A treatment regimen containing a therapeutic anti-CD20 antibody (e.g., rituximab, ofatumumab, obinutuzumab) AND
Patient who has received previous chemotherapy or radiation therapy in the previous 3 months, except for empiric initial intrathecal administration at diagnosis; rituximab or steroid administration is not an exclusion criterion
Systemic anti-lymphoma therapy given in the previous 30 days before the scheduled therapy dose with the exception of rituximab
Participants who have received more than one (1) prior cycle of chemotherapy similar to cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) or EPOCH with or without rituximab
Rituximab therapy within the 12 months prior to study entry; participants treated with rituximab within 12 months prior to study registration are eligible only if it was given for indications other than the treatment of aggressive lymphoma
Systemic anti-lymphoma therapy given in the previous 30 days before the scheduled therapy dose with the exception of rituximab
Patients who are carriers of hepatitis B will be included in this study; these patients are not eligible to receive rituximab as a component of their chemotherapy mobilization
Previously exposed to rituximab as part of prior lines of treatment.
Histologically confirmed DLBCL at last relapse(by central pathology review before enrolment. .- Relapsed or refractory disease after ?2 lines of chemotherapy including rituximab and anthracycline and either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT
Did not achieve at least a partial response (PR) to a standard salvage regimen (e.g., R-ICE; rituximab, ifosfamide, carboplatin, etoposide, or R-DHAP; rituximab, dexamethasone, cytarabine, cisplatin)
Known hypersensitivity to thalidomide or rituximab
Patient has received other investigational drugs with 14 days before treatment of treatment with bortezomib + rituximab
Prior exposure to either bortezomib or rituximab is not an exclusion criteria
Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of rituximab
Patients with known hypersensitivity to lenalidomide and/or rituximab (CD20+ patients only)
Contraindication to receive any of the individual components of CHOP, rituximab or obinutuzumab
Previously treated with at least one prior systemic chemotherapy, immunotherapy or chemoimmunotherapy and have received at least 2 previous doses of rituximab.
Documented relapsed, refractory or progressive disease after treatment with systemic therapy and must not be Rituximab-refractory.
Investigator considers rituximab monotherapy appropriate.
Systemic anti-lymphoma therapy given in the previous 30 days before the scheduled therapy dose with the exception of rituximab
Patients must not have prior significant hypersensitivity to rituximab (not including infusion reactions)
Immunosuppressants (e.g. Cyclosporin, Rapamycin, Tacrolimus, Rituximab, Alemtuzumab, Natalizumab, etc.).
Histological confirmation of relapsed/refractory diffuse large B-cell lymphoma after prior rituximab and anthracycline-containing systemic treatment regimen such as rituximab-cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine (oncovin), and prednisone (R-CHOP), rituximab-etoposide, vincristine, and doxorubicin (R-EPOCH), rituximab-hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (R-HyperCVAD), etc; a biopsy immediately before enrollment is not required
Subjects must have received no more than 2 prior systemic therapies for lymphoma; prior therapy with systemic rituximab monotherapy or conventional chemotherapy (i.e. bendamustine, cyclophosphamide, vincristine, and prednisone [CVP] or other) +/- rituximab for indolent non-Hodgkin lymphoma (NHL) +/- maintenance/extended-use rituximab will count as 1 line of systemic therapy
Prior use of ibrutinib or other BTK inhibitors, rituximab or lenalidomide
Known anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine proteins or to any component of rituximab
Previously completed anthracycline-based induction chemotherapy with standard regimens including rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP), dose adjusted (DA)-etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide (EPOCH), and rituximab (R), and R-hyper cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine (CVAD); patients need a minimum of 6 cycles of treatment; initial treatment with pidilizumab must be administered between 30-90 days from last dose of induction chemotherapy
Appropriate candidate for systemic immune-chemotherapy such as the standard rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (RCHOP)21 6 cycles as determined by the treating physician
For cohort 1: Male or female subjects with histologic proof of follicular lymphoma grade 1, 2, or 3a relapsing after at least one prior systemic therapy that included rituximab (or other monoclonal CD20 antibody); patients should have rituximab-sensitive disease defined as a documented complete or partial response lasting at least 6 months after the last rituximab containing therapy or rituximab-refractory disease defined as stable or progressive disease within 6 months of the last rituximab-containing therapy
For cohort 2: Male or female subjects with histologic proof of follicular lymphoma grade 1, 2, or 3a relapsing after at least two prior systemic therapies, one of which must include rituximab (or other monoclonal CD20 antibody) or histologic proof of DLBCL relapsing after at least two prior systemic therapies, one of which must include rituximab (or other monoclonal CD20 antibody) and are considered ineligible for high dose therapy/autologous stem cell transplant
Prior therapy must include rituximab and alkylating agents.Prior exposure to idelalisib or other PI3K inhibitors is acceptable (except to copanlisib) provided that there is no resistance.
Patients must be refractory to the last rituximab-based treatment, defined as no response or response lasting < 6 months after completion of treatment. Time interval to assess refractoriness will be calculated between the end date (last day) of the last rituximab-containing regimen and the day of diagnosis confirmation of the subsequent relapse.
Extra-corporeal photopheresis (ECP) or rituximab therapy within 4 weeks prior to enrollment
Cohort B-3: 1) Histologically-confirmed DLBCL 2) Prior standard rituximab + anthracyclin containing regimen, received or not eligible or considered candidate of HD-ASCT 3) Measurable disease (IWG -Lugano 2014)
Participants with new immunosuppressive medication, extra-corporeal photopheresis or rituximab therapy initiated in the 4 weeks prior
Patients must have previously treated relapsed and/or refractory MCL with at least 2 prior lines of therapy (prior carfilzomib, ibrutinib, bortezomib, anthracycline, rituximab or stem cell transplant are acceptable); there is no upper limit for prior lines of therapy
Disease that is refractory to the last prior rituximab-containing therapy defined as either
Relapse after the last rituximab-containing therapy <12 months since last dose of rituximab, OR
Failure to achieve at least a MR after the last rituximab-containing therapy. If the subject meets this exclusion criterion and therefore is excluded from the main randomized study, participation in the non randomized substudy (Arm C) may be considered
Rituximab treatment within the last 12 months before the first dose of study drug.
Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of rituximab.
Relapse after the last rituximab-containing therapy <12 months since last dose of rituximab, OR
Failure to achieve at least a MR after the last rituximab-containing therapy.
Patients who have been previously treated with bendamustine plus rituximab (BR) are eligible, provided they did not progress during or within 6 months of completing BR treatment
Subjects must have rituximab-refractory disease, defined as lack of CR or PR or PD within 6 months of last dose.
Agrees to protocol-defined use of effective contraception (for women, these restrictions apply for 12 months after the last dose of rituximab or 1 month after the last dose of study drug, whichever is later; for men, these restrictions apply for 12 months after the last dose of rituximab or 3 months after the last dose of study drug, whichever is later)
Patients may have received prior ibrutinib, lenalidomide, rituximab, and/or bortezomib either alone or in combination
Patients must have received prior rituximab therapy and must have recovered from all non-hematologic toxicities; (previous radiation is allowed as long as patients have recovered from all treatment related toxicities)
Having received rituximab within the prior 2 months
Have had chemotherapy (including purine analogs, rituximab, and other investigational agents) within six weeks prior to entering the study
Patients' NHL must have progressed after at least 1 prior rituximab containing regimen.
discontinued previous monoclonal antibody therapy (except rituximab) or radioimmunotherapy administration for at least 60 days before study drug administration.
off rituximab for at least 14 days before the screening visit and be confirmed to have either no response or have disease progression after rituximab treatment.
Prior exposure to rituximab
Subject with diffuse large B-cell lymphoma must have relapsed diffuse large B-cell lymphoma or must have progressed after salvage therapy (with or without standard chemotherapy) for diffuse large B-cell lymphoma. The subject must have received first line therapy with Rituximab-Cyclophosphamide, Hydroxydaunomycin, Vincristine (Oncovin), Prednisone (R-CHOP) [or a similar standard rituximab-containing front-line chemoimmunotherapy regimen including, but not limited to Etoposide, Prednisone, Vincristine (Oncovin), Cyclophosphamide, Doxorubicin (Hydrochloride) + Rituximab (EPOCH + R); Rituximab, Cyclophosphamide, Etoposide, Procarbazine, Prednisone (RCEPP); Rituximab, Cyclophosphamide, Mitoxantrone (Novantrone), Vincristine (Oncovin), Prednisone (RCNOP); Dose-adjusted-Etoposide, Prednisone, Vincristine(Oncovin), Cyclophosphamide, Doxorubicin (Hydrocloride) (DA-EPOCH); and Rituximab, Cyclophosphamide, Etoposide, Vincristine (Oncovin), Prednisone (RCEOP)].
Subject progressed during or within 3 months of completion of a planned course of first-line therapy with Rituximab-Cyclophosphamide, Hydroxydaunomycin, Vincristine (Oncovin), Prednisone (R-CHOP) or an equivalent regimen;
Refractory to or relapse following a rituximab/anthracycline first-line regimen
Intravenous rituximab within 30 days of starting treatment
Prior exposure to rituximab.
Received rituximab containing a multi-agent therapy for the treatment of NHL.
Completion of at least 4 cycles of a rituximab-containing, anthracycline-based combination chemotherapy regimen no sooner than 3 weeks and no longer than 8 weeks prior to the start of radiation therapy
Completion of a full course of first line immunochemotherapy including rituximab OR completion of 4 cycles of first line immunochemotherapy including rituximab if intolerant of treatment (e.g. which include, but are not limited to, rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine sulfate (Oncovin) and prednisone [R-CHOP], rituximab, cyclophosphamide, vincristine sulfate, and prednisone [R-CVP], bendamustine- R)
Indolent B-cell NHL that remains stable or unresponsive during or within 6 months of treatment with rituximab or a rituximab-containing regimen
Refractory to any previous regimen containing rituximab (defined by participants who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen)
Histologically confirmed B-cell NHL (FL or DLBCL): Relapsed from or refractory to ? 1 prior regimen containing rituximab, either alone or in combination, and not be a candidate for hematopoietic SCT or BM transplant
B-cell CLL: Relapsed from or refractory to ? 2 prior lines of treatment, ? 1 of which must have contained rituximab
Arm B: Relapsed from or refractory to ? 2 prior chemotherapy regimens with ? 1 regimen containing rituximab
Arm C: Relapsed from or refractory to ? 2 prior chemotherapy regimens with ? 1 regimen containing rituximab or failed 1 prior rituximab-containing regimen and unable to tolerate additional multiagent chemotherapy
Arm D: Refractory to ? 1 regimen containing any anti-CD20-based therapy, including salvage regimens and maintenance rituximab. Refractory subjects are defined as any subject with less than a PR to any prior anti-CD20-based therapies or progressed within 6 months after completing therapy with any anti-CD20-based regimens, including maintenance rituximab. These subjects must not be eligible for hematopoietic SCT or BM transplant
All patients with untreated Rai stage III-IV are eligible for this protocol; prior treatment with single-agent rituximab permitted; OR patients with untreated Rai stage 0-II who meet one or more criteria for active disease as defined by the International Working Group for CLL (IWCLL); prior treatment with single-agent rituximab permitted
Received previous treatment with rituximab that was not effective.
Previously untreated or who received a maximum of one cycle of combination chemotherapy (i.e. rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisone [R-CHOP], R-EPOCH, or rituximab, hyperfractionated cyclophosphamide, vincristine sulfate adriamycin dexamethasone [R-hyperCVAD]) within 4 weeks of study entry except patients who require dose reduction after the first cycle of off-study R-EPOCH
Known hypersensitivity to rituximab
Patient should preferably have received a pre-transplant conditioning with rituximab and carmustine/etoposide/cytarabine/melphalan/Rituxan (BEAM/R); other regimens which are similar may be accepted at the discretion of the principal investigator (PI)
First or subsequent relapse following at least one induction therapy regimen containing rituximab in combination with an anthracycline or rituximab in combination with an alkylating agent
Refractory to rituximab: defined as disease progression while receiving or within 6 months of completing either weekly rituximab induction therapy, or rituximab-based chemoimmunotherapy induction
Previous treatment with rituximab or other monoclonal antibodies, or temozolomide.
Previously untreated patients who have been counseled on approved alternative therapeutic options. Not a candidate for fludarabine/cyclophosphamide/rituximab (FCR) or has preference to not receive chemotherapy.
Other CHOP variants: substitution allowed for 1 component with a drug of the same mechanism of action. Additional components, except alemtuzumab, are allowed. Rituximab may be added if not given within 3 cycles of randomization.
For rituximab + polatuzumab vedotin + venetoclax treatment group, relapsed or refractory DLBCL after treatment with at least one prior chemoimmunotherapy regimen that included an anti-CD20 mAb and for which no curative option exists as determined by the investigator
Subjects with histologically confirmed relapsed or refractory DLBCL who have received at least 1 prior rituximab containing chemotherapy regimen but no more than 5 prior lines of therapy
Intolerable toxicity to prior rituximab therapy.
Not a candidate for treatment with rituximab as a single-agent
Any prior treatment with rituximab
Patients must have received prior Rituximab-containing therapy.
Has, at the initiation of study drug, received cytotoxic chemotherapy or a Bruton's tyrosine kinase (BTK)-inhibitor (e.g. ibrutinib) within the past 3 weeks or rituximab within the past 2 months
Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of rituximab (Rituxan®)
Prior treatment with rituximab and with an alkylating agent (eg, bendamustine, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, nitrosoureas) for iNHL
Lymphoma that is refractory to rituximab and to an alkylating agent
A) Dose Escalation Stage: Confirmed diagnosis of relapsed or refractory Non-Hodgkin Lymphoma (NHL) treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens (or autologous stem cell transplant) , or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician
Expansion Cohort A: Relapsed or refractory DLBCL treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician
Expansion Cohort B: Diagnosis of relapsed or refractory B-cell NHL (other than DLBCL) treated with prior treatment for lymphoid malignancy comprising of at least 1 regimen containing a therapeutic anti-CD20 antibody (eg, rituximab, ofatumumab, GA-101) and at least 2 prior combination chemotherapy regimens or autologous stem cell transplant, or treated with 1 prior combination chemotherapy regimen in patients without an approved second-line therapy option, requiring treatment in the opinion of the treating physician
Autologous transplant eligible patients must have histologically or cytologically confirmed cluster of differentiation (CD)20 positive relapsed or refractory DLBCL by biopsy within 45 days prior to subject enrollment and must have been previously treated with an anthracycline and rituximab-containing regimen
Patient must have been previously treated for B cell non-Hodgkin lymphoma with any of the allowable below:\r\n* First-line treatment with rituximab and an anthracycline-based chemotherapy\r\n* Monotherapy rituximab, dosed prior to first-line rituximab combined with anthracycline containing chemotherapy, or as maintenance therapy\r\n* Radiotherapy as part of the first-line treatment plan including anthracycline and rituximab
If rituximab previously given, lymphoma must have relapsed >= 12 months after last rituximab dose
Patients must have received prior rituximab-containing therapy.
Type I hypersensitivity or anaphylactic reactions to murine proteins or to previous infusion of rituximab
Circulating levels of rituximab > 75.0 µg/ml
Rituximab within six weeks
Contraindication to bendamustine, rituximab, or obinutuzumab
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 cohort or within 18 months of last dose in the obinutuzumab cohort
Failure of rituximab for first-line treatment of PTLD. Note: Subjects with CD20 negative disease are eligible to enroll without prior anti-CD20 therapy after failure of first-line treatment (reduction of immunosuppression is not considered first-line therapy) and discussion with the sponsor's medical monitor.
At least 1 prior specific therapeutic regimen, one of which should have included rituximab (patients previously eligible for transplantation: the salvage treatment followed by intensification and Autologous Stem Cell Transplant (ASCT) will be considered one regimen).
Relapsed from or refractory to at least one treatment containing rituximab or another anti-CD20 based immunotherapy combined with anthracycline- or anthracenedione-based chemotherapy
Rituximab-sensitive disease, defined as a Partial Remission (PR) or Complete Remission (CR) to the last rituximab-containing therapy lasting at least 6 months following completion of therapy. Last rituximab-containing therapy is defined as the last therapy regimen containing at least one full dose of rituximab.
Relapse or disease progression following response to prior rituximab-based therapy, requiring treatment by 2007 Revised Response Criteria for Malignant Lymphoma (RRCML) guidelines.
Rituximab-refractory disease, defined as failure to respond to or progression within 6 months of completing rituximab or rituximab-containing combination therapy.
Rituximab-sensitive iNHL, defined as a partial or complete response to their last prior treatment with rituximab or a rituximab-containing regimen lasting at least 6 months following completion of rituximab treatment.
Relapse or disease progression following response to prior rituximab-based therapy, as defined by 2007 RRCML criteria, which requires therapy.
Previous anti-CD20 radioimmunotherapy (RIT) or non-rituximab anti-CD20 therapy (such as obinutuzumab) within 6 months prior to randomization. Patients who have received previous anti-CD20 RIT or non-rituximab anti-CD20 therapy (such as obinutuzumab) must have attained a partial or complete response lasting at least 6 months, and must have recovered from any hematologic or other toxicity.
By standard clinical criteria, be medically appropriate to receive rituximab and anthracycline-containing induction therapy and high-dose chemotherapy with AHCT
In addition to the above, subjects meeting the following criteria will be enrolled in the pre-phase arm of the study, until the accrual target for that arm is reached:\r\n* Age >= 70 years OR KPS =< 70\r\n* Pathologically confirmed diagnosis of DLBCL, with or without simultaneous or antecedent indolent lymphoma\r\n* Previously untreated for DLBCL\r\n* Intended initial treatment to include >= 2 cycles of R-CHOP; rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride (R-EPOCH); or rituximab, cyclophosphamide, etoposide, procarbazine, and prednisone (R-CEPP) using standard doses and schedule; R-CHOP chemoimmunotherapy may be given every 14 days or every 21 days
Subjects meeting the following criteria will be excluded from enrollment in the pre-phase arm of the study, but may be included in the GA only arm\r\n* Contraindication to use rituximab or prednisone including:\r\n** Uncontrolled diabetes mellitus\r\n** Systemic fungal infection\r\n** Evidence of active hepatitis B infection (i.e. patients testing positive for hepatitis B surface antigen or viral deoxyribonucleic acid [DNA] by polymerase chain reaction [PCR] analysis) will be excluded; patients with evidence of past infection without active viremia (i.e. positive hepatitis B DNA PCR) will be treated with entecavir as per institutional guidelines and may be included in the study\r\n** History of any serious adverse reaction to either a corticosteroid or rituximab not including rituximab infusion reactions =< grade 3
Both men and women in the rituximab combination arm (Cohort B) must practice contraception as described above from the time of signing of the informed consent form (ICF) through 12 months after the last dose of study drug.
New chronic GVHD therapies (e.g. gleevec, extracorporeal photopheresis, rituximab, immunosuppressive medications) in the 4 weeks prior
Patients with Burkitt lymphoma or any patient receiving rituximab-cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate / ifosfamide, etoposide, high-dose cytarabine (R- CODOXM/IVAC)
Patient must have histologic or cytological diagnosis of de novo diffuse large B-cell lymphoma (DLBCL) (including lymphomas/leukemias newly transformed to DLBCL) and be scheduled to receive first line chemotherapy with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) or rituximab, etoposide, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride (R-EPOCH); OR patient who will undergo consolidative external radiotherapy after completion of chemotherapy are eligible
Relapsed from or refractory to at least one treatment containing rituximab combined with anthracycline-based chemotherapy
Receiving any other investigational agent that would be considered as a treatment for the lymphoma; NOTE: rituximab maintenance and patients participating on Mayo Clinic vitamin D study are allowed
Had prior exposure to rituximab, natalizumab, vedolizumab, or alemtuzumab.