PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The exposure parameters of antibody-conjugated MMAE (acMMAE) and unconjugated MMAE (the cytotoxic component of polatuzumab vedotin-piiq) are summarized in Table 7. The plasma exposure of acMMAE and unconjugated MMAE increased proportionally over polatuzumab vedotin-piiq dose range from 0.1 to 2.4 mg/kg (0.06 to 1.33 times the approved recommended dosage). Cycle acMMAE AUC were predicted to increase by approximately 30% over Cycle AUC, and achieved more than 90% of the Cycle AUC. Unconjugated MMAE plasma exposures were <3% of acMMAE exposures, and the AUC and Cmax were predicted to decrease after repeated every-3-week dosing.Table 7Exposure Parameters of acMMAE and Unconjugated MMAEAfter the first polatuzumab vedotin-piiq dose of 1.8 mg/kg. acMMAEMean (+- SD)Unconjugated MMAEMean (+- SD)Cmax maximum concentration, AUCinf area under the concentration-time curve from time zero to infinity.Cmax (ng/mL)803 (+- 233)6.82 (+- 4.73)AUCinf (dayng/mL)1860 (+- 966)52.3 (+- 18.0). DistributionThe acMMAE central volume of distribution estimated based on population PK analysis is 3.15 L. For humans, MMAE plasma protein binding is 71% to 77% and the blood-to-plasma ratio is 0.79 to 0.98, in vitro.. EliminationThe acMMAE terminal half-life is approximately 12 days (95% CI: 8.1 to 19.5 days) at Cycle with predicted clearance of 0.9 L/day. The unconjugated MMAE terminal half-life is approximately days after the first polatuzumab vedotin-piiq dose.. MetabolismPolatuzumab vedotin-piiq catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. MMAE is substrate for CYP3A4.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of polatuzumab vedotin-piiq were observed based on age (20 to 89 years), sex, or race/ethnicity (Asian and non-Asian). No clinically significant differences in the pharmacokinetics of acMMAE or unconjugated MMAE were observed based on mild to moderate renal impairment (CLcr 30 to 89 mL/min). In mild hepatic impairment (AST or ALT >1.0 to 2.5 ULN or total bilirubin >1.0 to 1.5 ULN), there was 40% increase in MMAE exposure, which was not deemed clinically significant.The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease with or without dialysis, moderate to severe hepatic impairment (AST or ALT >2.5 ULN or total bilirubin >1.5 ULN), or liver transplantation on the pharmacokinetics of acMMAE or unconjugated MMAE is unknown.. Drug Interaction StudiesNo dedicated clinical drug-drug interaction studies with POLIVY in humans have been conducted.. Physiologically-Based Pharmacokinetic (PBPK) Modeling Predictions: Strong CYP3A Inhibitor: Concomitant use of polatuzumab vedotin-piiq with ketoconazole (strong CYP3A inhibitor) is predicted to increase unconjugated MMAE AUC by 45%. Strong CYP3A Inducer: Concomitant use of polatuzumab vedotin-piiq with rifampin (strong CYP3A inducer) is predicted to decrease unconjugated MMAE AUC by 63%.. Sensitive CYP3A Substrate: Concomitant use of polatuzumab vedotin-piiq is predicted not to affect exposure to midazolam (sensitive CYP3A substrate).. Population Pharmacokinetic (popPK) Modeling Predictions:. Bendamustine or Rituximab: No clinically significant differences in the pharmacokinetics of acMMAE or unconjugated MMAE when polatuzumab vedotin-piiq is used concomitantly with bendamustine or rituximab. In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically:. Cytochrome P450 (CYP) Enzymes: MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. MMAE does not induce major CYP enzymes.. Transporter Systems: MMAE does not inhibit P-gp. MMAE is P-gp substrate.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are discussed in greater detail in other sections of the label:Peripheral Neuropathy [see Warnings and Precautions (5.1)] Infusion-Related Reactions [see Warnings and Precautions (5.2)] Myelosuppression [see Warnings and Precautions (5.3)] Serious and Opportunistic Infections [see Warnings and Precautions (5.4)] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.5)] Tumor Lysis Syndrome [see Warnings and Precautions (5.6)] Hepatotoxicity [see Warnings and Precautions (5.7)] Peripheral Neuropathy [see Warnings and Precautions (5.1)] Infusion-Related Reactions [see Warnings and Precautions (5.2)] Myelosuppression [see Warnings and Precautions (5.3)] Serious and Opportunistic Infections [see Warnings and Precautions (5.4)] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.5)] Tumor Lysis Syndrome [see Warnings and Precautions (5.6)] Hepatotoxicity [see Warnings and Precautions (5.7)] The most common adverse reactions (>=20%) included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data described in this section reflect exposure to POLIVY in Study GO29365, multicenter clinical trial for adult patients with relapsed or refractory B-cell lymphomas [see Clinical Studies (14)]. In patients with relapsed or refractory DLBCL, the trial included single-arm safety evaluation of POLIVY in combination with bendamustine and rituximab product (BR) (n 6), followed by an open-label randomization to POLIVY in combination with BR versus BR alone (n 39 treated per arm).Following premedication with an antihistamine and antipyretic, POLIVY 1.8 mg/kg was administered by intravenous infusion on Day of Cycle and on Day of Cycles 2-6, with cycle length of 21 days. Bendamustine 90 mg/m2 daily was administered intravenously on Days and of Cycle and on Days and of Cycles 2-6. rituximab product dosed at 375 mg/m2 was administered intravenously on Day of each cycle. Granulocyte colony-stimulating factor primary prophylaxis was optional and administered to 42% of recipients of POLIVY plus BR.In POLIVY-treated patients (n 45), the median age was 67 years (range 33 86) with 58% being >= age 65, 69% were male, 69% were white, and 87% had an Eastern Cooperative Oncology Group (ECOG) performance status of or 1. The trial required an absolute neutrophil count >=1500/uL, platelet count >=75/uL, creatinine clearance (CLcr) >=40 mL/min, hepatic transaminases <=2.5 times ULN, and bilirubin <1.5 times ULN, unless abnormalities were from the underlying disease. Patients with Grade or higher peripheral neuropathy or prior allogeneic hematopoietic stem cell transplantation (HSCT) were excluded.Patients treated with POLIVY plus BR received median of cycles, with 49% receiving cycles. Patients treated with BR alone received median of cycles, with 23% receiving cycles.Fatal adverse reactions occurred in 7% of recipients of POLIVY plus BR within 90 days of last treatment. Serious adverse reactions occurred in 64%, most often from infection. Serious adverse reactions in >=5% of recipients of POLIVY plus BR included pneumonia (16%), febrile neutropenia (11%), pyrexia (9%), and sepsis (7%).In recipients of POLIVY plus BR, adverse reactions led to dose reduction in 18%, dose interruption in 51%, and permanent discontinuation of all treatment in 31%. The most common adverse reactions leading to treatment discontinuation were thrombocytopenia and/or neutropenia.Table summarizes commonly reported adverse reactions. In recipients of POLIVY plus BR, adverse reactions in >=20% of patients included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.Table Adverse Reactions Occurring in >10% of Patients with Relapsed or Refractory DLBCL and >=5% More in the POLIVY Plus Bendamustine and Rituximab Product GroupAdverse Reactions by Body SystemPOLIVY BRn 45BRn 39All Grades,%Grade or Higher,%All Grades,%Grade or Higher,%The table includes combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.Blood and Lymphatic System Disorders Neutropenia49424436 Thrombocytopenia49403326 Anemia47242818 Lymphopenia131388Nervous System Disorders Peripheral neuropathy40080 Dizziness13080Gastrointestinal Disorders Diarrhea384.4285 Vomiting182.2130General Disorders Infusion-related reaction182.280 Pyrexia332.2230 Decreased appetite272.2210Infections Pneumonia2216Includes events with fatal outcome. 152.6Includes event with fatal outcome. Upper respiratory tract infection13080Investigations Weight decreased162.282.6Metabolism and Nutrition Disorders Hypokalemia169102.6 Hypoalbuminemia132.280 Hypocalcemia112.250. Other clinically relevant adverse reactions (<10% or with <5% difference) in recipients of POLIVY plus BR included:Blood and lymphatic system disorders: pancytopenia (7%)Musculoskeletal disorders: arthralgia (7%)Investigations: hypophosphatemia (9%), transaminase elevation (7%), lipase increase (7%)Respiratory disorders: pneumonitis (4.4%)Selected treatment-emergent laboratory abnormalities are summarized in Table 5. In recipients of POLIVY plus BR, >20% of patients developed Grade or neutropenia, leukopenia, or thrombocytopenia, and >10% developed Grade neutropenia (13%) or Grade thrombocytopenia (11%).Table Selected Laboratory Abnormalities Worsening from Baseline in Patients with Relapsed or Refractory DLBCL and >=5% More in the POLIVY Plus Bendamustine and Rituximab Product GroupLaboratory ParameterIncludes laboratory abnormalities that are new or worsening in grade or with worsening from baseline unknown. POLIVY BRn 45BRn 39All Grades,(%)Grade 3-4,(%)All Grades,(%)Grade 3-4,(%)Hematologic Lymphocyte count decreased87879082 Neutrophil count decreased78615633 Hemoglobin decreased78186210 Platelet count decreased76316426Chemistry Creatinine increased874.4775 Calcium decreased449260 SGPT/ALT increased38082.6 SGOT/AST increased360262.6 Lipase increased369135 Phosphorus decreased337288 Amylase increased240182.6 Potassium decreased2411285Safety was also evaluated in 173 adult patients with relapsed or refractory lymphoma who received POLIVY, bendamustine, and either rituximab product or obinutuzumab in Study GO29365, including the 45 patients with DLBCL described above. In the expanded safety population, the median age was 66 years (range 27 86), 57% were male, 91% had an ECOG performance status of 0-1, and 32% had history of peripheral neuropathy at baseline.Fatal adverse reactions occurred in 4.6% of recipients of POLIVY within 90 days of last treatment, with infection as leading cause. Serious adverse reactions occurred in 60%, most often from infection.Table summarizes the most common adverse reactions in the expanded safety population. The overall safety profile was similar to that described above. Adverse reactions in >=20% of patients were diarrhea, neutropenia, peripheral neuropathy, fatigue, thrombocytopenia, pyrexia, decreased appetite, anemia, and vomiting. Infection-related adverse reactions in >10% of patients included upper respiratory tract infection, febrile neutropenia, pneumonia, and herpesvirus infection.Table Most Common Adverse Reactions (>=20% Any Grade or >=5% Grade or Higher) in Recipients of POLIVY and Chemoimmunotherapy for Relapsed or Refractory LymphomaAdverse Reaction by Body System POLIVY Bendamustine Rituximab Product or Obinutuzumabn 173All Grades,%Grade or Higher,%The table includes combination of grouped and ungrouped terms.Blood and Lymphatic System Disorders Neutropenia4439 Thrombocytopenia3123 Anemia2814 Febrile neutropeniaPrimary prophylaxis with granulocyte colony-stimulating factor was given to 46% of all patients. 1313 Leukopenia138 Lymphopenia1212Nervous System Disorders Peripheral neuropathy402.3Gastrointestinal Disorders Diarrhea458 Vomiting272.9General Disorders Fatigue405 Pyrexia302.9 Decreased appetite291.7Infections Pneumonia1310Includes events with fatal outcome. Sepsis66Includes events with fatal outcome. Metabolism and Nutrition Disorders Hypokalemia186. Blood and lymphatic system disorders: pancytopenia (7%). Musculoskeletal disorders: arthralgia (7%). Investigations: hypophosphatemia (9%), transaminase elevation (7%), lipase increase (7%). Respiratory disorders: pneumonitis (4.4%). Other clinically relevant adverse reactions (<20% any grade) included:General disorders: infusion-related reaction (7%)Infection: upper respiratory tract infection (16%), lower respiratory tract infection (10%), herpesvirus infection (12%), cytomegalovirus infection (1.2%)Respiratory: dyspnea (19%), pneumonitis (1.7%)Nervous system disorders: dizziness (10%)Investigations: weight decrease (10%), transaminase elevation (8%), lipase increase (3.5%)Musculoskeletal disorders: arthralgia (7%)Eye disorders: blurred vision (1.2%). General disorders: infusion-related reaction (7%). Infection: upper respiratory tract infection (16%), lower respiratory tract infection (10%), herpesvirus infection (12%), cytomegalovirus infection (1.2%). Respiratory: dyspnea (19%), pneumonitis (1.7%). Nervous system disorders: dizziness (10%). Investigations: weight decrease (10%), transaminase elevation (8%), lipase increase (3.5%). Musculoskeletal disorders: arthralgia (7%). Eye disorders: blurred vision (1.2%). 6.2Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to polatuzumab vedotin-piiq in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.Across all arms of Study GO29365, 8/134 (6%) patients tested positive for antibodies against polatuzumab vedotin-piiq at one or more post-baseline time points. Across clinical trials, 14/536 (2.6%) evaluable POLIVY-treated patients tested positive for such antibodies at one or more post-baseline time points. Due to the limited number of patients with antibodies against polatuzumab vedotin-piiq, no conclusions can be drawn concerning potential effect of immunogenicity on efficacy or safety.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Polatuzumab vedotin-piiq is CD79b-directed antibody-drug conjugate with activity against dividing cells. The small molecule, MMAE, is an anti-mitotic agent covalently attached to the antibody via cleavable linker. The monoclonal antibody binds to CD79b, B-cell specific surface protein, which is component of the B-cell receptor. Upon binding CD79b, polatuzumab vedotin-piiq is internalized, and the linker is cleaved by lysosomal proteases to enable intracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.. 12.2 Pharmacodynamics. Over polatuzumab vedotin-piiq dosages of 0.1 to 2.4 mg/kg (0.06 to 1.33 times the approved recommended dosage), higher exposure was associated with higher incidence of some adverse reactions (e.g., >=Grade peripheral neuropathy, >=Grade anemia) and lower exposure was associated with lower efficacy. Cardiac ElectrophysiologyPolatuzumab vedotin-piiq did not prolong the mean QTc interval to any clinically relevant extent based on ECG data from two open-label studies in patients with previously treated B-cell malignancies at the recommended dosage.. 12.3 Pharmacokinetics. The exposure parameters of antibody-conjugated MMAE (acMMAE) and unconjugated MMAE (the cytotoxic component of polatuzumab vedotin-piiq) are summarized in Table 7. The plasma exposure of acMMAE and unconjugated MMAE increased proportionally over polatuzumab vedotin-piiq dose range from 0.1 to 2.4 mg/kg (0.06 to 1.33 times the approved recommended dosage). Cycle acMMAE AUC were predicted to increase by approximately 30% over Cycle AUC, and achieved more than 90% of the Cycle AUC. Unconjugated MMAE plasma exposures were <3% of acMMAE exposures, and the AUC and Cmax were predicted to decrease after repeated every-3-week dosing.Table 7Exposure Parameters of acMMAE and Unconjugated MMAEAfter the first polatuzumab vedotin-piiq dose of 1.8 mg/kg. acMMAEMean (+- SD)Unconjugated MMAEMean (+- SD)Cmax maximum concentration, AUCinf area under the concentration-time curve from time zero to infinity.Cmax (ng/mL)803 (+- 233)6.82 (+- 4.73)AUCinf (dayng/mL)1860 (+- 966)52.3 (+- 18.0). DistributionThe acMMAE central volume of distribution estimated based on population PK analysis is 3.15 L. For humans, MMAE plasma protein binding is 71% to 77% and the blood-to-plasma ratio is 0.79 to 0.98, in vitro.. EliminationThe acMMAE terminal half-life is approximately 12 days (95% CI: 8.1 to 19.5 days) at Cycle with predicted clearance of 0.9 L/day. The unconjugated MMAE terminal half-life is approximately days after the first polatuzumab vedotin-piiq dose.. MetabolismPolatuzumab vedotin-piiq catabolism has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. MMAE is substrate for CYP3A4.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of polatuzumab vedotin-piiq were observed based on age (20 to 89 years), sex, or race/ethnicity (Asian and non-Asian). No clinically significant differences in the pharmacokinetics of acMMAE or unconjugated MMAE were observed based on mild to moderate renal impairment (CLcr 30 to 89 mL/min). In mild hepatic impairment (AST or ALT >1.0 to 2.5 ULN or total bilirubin >1.0 to 1.5 ULN), there was 40% increase in MMAE exposure, which was not deemed clinically significant.The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease with or without dialysis, moderate to severe hepatic impairment (AST or ALT >2.5 ULN or total bilirubin >1.5 ULN), or liver transplantation on the pharmacokinetics of acMMAE or unconjugated MMAE is unknown.. Drug Interaction StudiesNo dedicated clinical drug-drug interaction studies with POLIVY in humans have been conducted.. Physiologically-Based Pharmacokinetic (PBPK) Modeling Predictions: Strong CYP3A Inhibitor: Concomitant use of polatuzumab vedotin-piiq with ketoconazole (strong CYP3A inhibitor) is predicted to increase unconjugated MMAE AUC by 45%. Strong CYP3A Inducer: Concomitant use of polatuzumab vedotin-piiq with rifampin (strong CYP3A inducer) is predicted to decrease unconjugated MMAE AUC by 63%.. Sensitive CYP3A Substrate: Concomitant use of polatuzumab vedotin-piiq is predicted not to affect exposure to midazolam (sensitive CYP3A substrate).. Population Pharmacokinetic (popPK) Modeling Predictions:. Bendamustine or Rituximab: No clinically significant differences in the pharmacokinetics of acMMAE or unconjugated MMAE when polatuzumab vedotin-piiq is used concomitantly with bendamustine or rituximab. In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically:. Cytochrome P450 (CYP) Enzymes: MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. MMAE does not induce major CYP enzymes.. Transporter Systems: MMAE does not inhibit P-gp. MMAE is P-gp substrate.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Relapsed or Refractory Diffuse Large B-cell Lymphoma. The efficacy of POLIVY was evaluated in Study GO29365 (NCT02257567), an open-label, multicenter clinical trial that included cohort of 80 patients with relapsed or refractory DLBCL after at least one prior regimen. Patients were randomized 1:1 to receive either POLIVY in combination with bendamustine and rituximab product (BR) or BR alone for six 21-day cycles. Randomization was stratified by duration of response (DOR) to last therapy. Eligible patients were not candidates for autologous HSCT at study entry. The study excluded patients with Grade or higher peripheral neuropathy, prior allogeneic HSCT, active central nervous system lymphoma, or transformed lymphoma.Following premedication with an antihistamine and antipyretic, POLIVY was given by intravenous infusion at 1.8 mg/kg on Day of Cycle and on Day of Cycles 2-6. Bendamustine was administered at 90 mg/m2 intravenously daily on Days and of Cycle and on Days and of Cycles 2-6. rituximab product was administered at dose of 375 mg/m2 intravenously on Day of Cycles 1-6. The cycle length was 21 days.Of the 80 patients randomized to receive POLIVY plus BR (n 40) or BR alone (n 40), the median age was 69 years (range: 30-86 years), 66% were male, and 71% were white. Most patients (98%) had DLBCL not otherwise specified. The primary reasons patients were not candidates for HSCT included age (40%), insufficient response to salvage therapy (26%), and prior transplant failure (20%). The median number of prior therapies was (range: 1-7), with 29% receiving one prior therapy, 25% receiving prior therapies, and 46% receiving or more prior therapies. Eighty percent of patients had refractory disease to last therapy.In the POLIVY plus BR arm, patients received median of cycles, with 49% receiving cycles. In the BR arm, patients received median of cycles, with 23% receiving cycles.Efficacy was based on complete response (CR) rate at the end of treatment and DOR, as determined by an independent review committee (IRC). Other efficacy measures included IRC-assessed best overall response.Response rates are summarized in Table 8.Table 8Response Rates in Patients with Relapsed or Refractory DLBCLResponse per IRC, (%)PET-CT based response per modified Lugano 2014 criteria. Bone marrow confirmation of PET-CT CR was required. PET-CT PR required meeting both PET criteria and CT criteria for PR. POLIVY BRn 40BRn 40PR partial remission.Objective Response at End of TreatmentEnd of treatment was defined as 6-8 weeks after Day of Cycle or last study treatment. (95% CI)18 (45)(29, 62)7 (18)(7, 33) CR (95% CI)16 (40)(25, 57)7 (18)(7, 33) Difference in CR rates, (95% CI)Miettinen-Nurminen method. 22 (3, 41)Best Overall Response of CR or PRPET-CT results were prioritized over CT results. (95% CI)25 (63)(46, 77)10 (25)(13, 41) Best Response of CR (95% CI)20 (50)(34, 66)9 (23)(11, 38)In the POLIVY plus BR arm, of the 25 patients who achieved partial or complete response, 16 (64%) had DOR of at least months, and 12 (48%) had DOR of at least 12 months. In the BR arm, of the 10 patients who achieved partial or complete response, (30%) had DOR lasting at least months, and (20%) had DOR lasting at least 12 months.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dose of POLIVY is 1.8 mg/kg as an intravenous infusion over 90 minutes every 21 days for cycles in combination with bendamustine and rituximab product. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated. (2)Premedicate with an antihistamine and antipyretic before POLIVY. (2)See Full Prescribing Information for instructions on preparation and administration. (2.4). The recommended dose of POLIVY is 1.8 mg/kg as an intravenous infusion over 90 minutes every 21 days for cycles in combination with bendamustine and rituximab product. Subsequent infusions may be administered over 30 minutes if the previous infusion is tolerated. (2). Premedicate with an antihistamine and antipyretic before POLIVY. (2). See Full Prescribing Information for instructions on preparation and administration. (2.4). 2.1Recommended Dosage. The recommended dose of POLIVY is 1.8 mg/kg administered as an intravenous infusion every 21 days for cycles in combination with bendamustine and rituximab product. Administer POLIVY, bendamustine, and rituximab product in any order on Day of each cycle. The recommended dose of bendamustine is 90 mg/m2/day on Days and when administered with POLIVY and rituximab product. The recommended dose of rituximab product is 375 mg/m2 intravenously on Day of each cycle.If not already premedicated, administer an antihistamine and antipyretic at least 30 minutes prior to POLIVY. Administer the initial dose of POLIVY over 90 minutes. Monitor patients for infusion-related reactions during the infusion and for minimum of 90 minutes following completion of the initial dose. If the previous infusion was well tolerated, the subsequent dose of POLIVY may be administered as 30-minute infusion and patients should be monitored during the infusion and for at least 30 minutes after completion of the infusion.If planned dose of POLIVY is missed, administer as soon as possible. Adjust the schedule of administration to maintain 21-day interval between doses.. 2.2Management of Adverse Reactions. Table provides management guidelines for peripheral neuropathy, infusion-related reaction, and myelosuppression.Table 1Management of Peripheral Neuropathy, Infusion-Related Reaction, and MyelosuppressionEventDose ModificationGrade 2-3Peripheral NeuropathyHold POLIVY dosing until improvement to Grade or lower.If recovered to Grade or lower on or before Day 14, restart POLIVY with the next cycle at permanently reduced dose of 1.4 mg/kg.If prior dose reduction to 1.4 mg/kg has occurred, discontinue POLIVY.If not recovered to Grade or lower on or before Day 14, discontinue POLIVY.Grade 4Peripheral NeuropathyDiscontinue POLIVY.Grade 1-3Infusion-Related ReactionInterrupt POLIVY infusion and give supportive treatment.For the first instance of Grade wheezing, bronchospasm, or generalized urticaria, permanently discontinue POLIVY.For recurrent Grade wheezing or urticaria, or for recurrence of any Grade symptoms, permanently discontinue POLIVY.Otherwise, upon complete resolution of symptoms, infusion may be resumed at 50% of the rate achieved prior to interruption. In the absence of infusion related symptoms, the rate of infusion may be escalated in increments of 50 mg/hour every 30 minutes.For the next cycle, infuse POLIVY over 90 minutes. If no infusion-related reaction occurs, subsequent infusions may be administered over 30 minutes. Administer premedication for all cycles.Grade 4Infusion-Related ReactionStop POLIVY infusion immediately.Give supportive treatment.Permanently discontinue POLIVY.Grade 3-4 NeutropeniaSeverity on Day of any cycle. If primary cause is due to lymphoma, dose delay or reduction may not be needed. Hold all treatment until ANC recovers to greater than 1000/microliter.If ANC recovers to greater than 1000/microliter on or before Day 7, resume all treatment without any additional dose reductions. Consider granulocyte colony-stimulating factor prophylaxis for subsequent cycles, if not previously given.If ANC recovers to greater than 1000/microliter after Day 7:restart all treatment. Consider granulocyte colony-stimulating factor prophylaxis for subsequent cycles, if not previously given. If prophylaxis was given, consider dose reduction of bendamustine.if dose reduction of bendamustine has already occurred, consider dose reduction of POLIVY to 1.4 mg/kg. Grade 3-4 Thrombocytopenia Hold all treatment until platelets recover to greater than 75,000/microliter.If platelets recover to greater than 75,000/microliter on or before Day 7, resume all treatment without any additional dose reductions.If platelets recover to greater than 75,000/microliter after Day 7:restart all treatment, with dose reduction of bendamustine.if dose reduction of bendamustine has already occurred, consider dose reduction of POLIVY to 1.4 mg/kg. restart all treatment. Consider granulocyte colony-stimulating factor prophylaxis for subsequent cycles, if not previously given. If prophylaxis was given, consider dose reduction of bendamustine.. if dose reduction of bendamustine has already occurred, consider dose reduction of POLIVY to 1.4 mg/kg.. restart all treatment, with dose reduction of bendamustine.. if dose reduction of bendamustine has already occurred, consider dose reduction of POLIVY to 1.4 mg/kg.. 2.3Recommended Prophylactic Medications. If not already premedicated for rituximab product, administer an antihistamine and antipyretic at least 30 to 60 minutes prior to POLIVY for potential infusion-related reactions [see Warnings and Precautions (5.2)].Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus throughout treatment with POLIVY.Consider prophylactic granulocyte colony stimulating factor administration for neutropenia [see Warnings and Precautions (5.3)].Administer tumor lysis syndrome prophylaxis for patients at increased risk of tumor lysis syndrome [see Warnings and Precautions (5.6)].. 2.4Instructions for Preparation and Administration. Reconstitute and further dilute POLIVY prior to intravenous infusion. POLIVY is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.. ReconstitutionReconstitute immediately before dilution.More than one vial may be needed for full dose. Calculate the dose, the total volume of reconstituted POLIVY solution required, and the number of POLIVY vials needed.Using sterile syringe, slowly inject Sterile Water for Injection, USP, using the volume provided in Table 2, into the POLIVY vial, with the stream directed toward the inside wall of the vial to obtain concentration of 20 mg/mL of polatuzumab vedotin-piiq.Table 2Reconstitution VolumesStrengthVolume of Sterile Water for Injection, USP required for reconstitution30 mg vial1.8 mL140 mg vial7.2 mLSwirl the vial gently until completely dissolved. Do not shake.Inspect the reconstituted solution for discoloration and particulate matter. The reconstituted solution should appear colorless to slightly brown, clear to slightly opalescent, and free of visible particulates. Do not use if the reconstituted solution is discolored, is cloudy, or contains visible particulates. Do not freeze or expose to direct sunlight. If needed, store unused reconstituted POLIVY solution refrigerated at 2C to 8C (36F to 46F) for up to 48 hours or at room temperature (9C to 25C, 47F to 77F) up to maximum of hours prior to dilution. Discard vial when cumulative storage time prior to dilution exceeds 48 hours.. Reconstitute immediately before dilution.. More than one vial may be needed for full dose. Calculate the dose, the total volume of reconstituted POLIVY solution required, and the number of POLIVY vials needed.. Using sterile syringe, slowly inject Sterile Water for Injection, USP, using the volume provided in Table 2, into the POLIVY vial, with the stream directed toward the inside wall of the vial to obtain concentration of 20 mg/mL of polatuzumab vedotin-piiq.. Swirl the vial gently until completely dissolved. Do not shake.. Inspect the reconstituted solution for discoloration and particulate matter. The reconstituted solution should appear colorless to slightly brown, clear to slightly opalescent, and free of visible particulates. Do not use if the reconstituted solution is discolored, is cloudy, or contains visible particulates. Do not freeze or expose to direct sunlight. If needed, store unused reconstituted POLIVY solution refrigerated at 2C to 8C (36F to 46F) for up to 48 hours or at room temperature (9C to 25C, 47F to 77F) up to maximum of hours prior to dilution. Discard vial when cumulative storage time prior to dilution exceeds 48 hours.. DilutionDilute polatuzumab vedotin-piiq to final concentration of 0.72-2.7 mg/mL in an intravenous infusion bag with minimum volume of 50 mL containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.Determine the volume of 20 mg/mL reconstituted solution needed based on the required dose.Withdraw the required volume of reconstituted solution from the POLIVY vial using sterile syringe and dilute into the intravenous infusion bag. Discard any unused portion left in the vial.Gently mix the intravenous bag by slowly inverting the bag. Do not shake.Inspect the intravenous bag for particulates and discard if present.If not used immediately, store the diluted POLIVY solution as specified in Table 3. Discard if storage time exceeds these limits. Do not freeze or expose to direct sunlight. Table 3Diluted POLIVY Solution Storage ConditionsDiluent Used to Prepare Solution for InfusionDiluted POLIVY Solution Storage ConditionsTo ensure product stability, do not exceed specified storage durations. 0.9% Sodium Chloride Injection, USPUp to 36 hours at 2C to 8C (36F to 46F) or up to hours at room temperature (9 to 25C, 47 to 77F)0.45% Sodium Chloride Injection, USPUp to 18 hours at 2C to 8C (36F to 46F) or up to hours at room temperature (9 to 25C, 47 to 77F)5% Dextrose Injection, USPUp to 36 hours at 2C to 8C (36F to 46F) or up to hours at room temperature (9 to 25C, 47 to 77F)Limit transportation to 30 minutes at 9C to 25C or 24 hours at 2C to 8C (refer to instructions below). The total storage plus transportation times of the diluted product should not exceed the storage duration specified in Table 3.Agitation stress can result in aggregation. Limit agitation of diluted product during preparation and transportation to administration site. Do not transport diluted product through an automated system (e.g., pneumatic tube or automated cart). If the prepared solution will be transported to separate facility, remove air from the infusion bag to prevent aggregation. If air is removed, an infusion set with vented spike is required to ensure accurate dosing during the infusion.No incompatibilities have been observed between POLIVY and intravenous infusion bags with product-contacting materials of polyvinyl chloride (PVC) or polyolefins (PO) such as polyethylene (PE) and polypropylene (PP). No incompatibilities have been observed with infusion sets or infusion aids with product-contacting materials of PVC, PE, polyurethane (PU), polybutadiene (PBD), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyetherurethane (PEU), fluorinated ethylene propylene (FEP), or polytetrafluorethylene (PTFE), or with filter membranes composed of polyether sulfone (PES) or polysulfone (PSU).. Dilute polatuzumab vedotin-piiq to final concentration of 0.72-2.7 mg/mL in an intravenous infusion bag with minimum volume of 50 mL containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.. Determine the volume of 20 mg/mL reconstituted solution needed based on the required dose.. Withdraw the required volume of reconstituted solution from the POLIVY vial using sterile syringe and dilute into the intravenous infusion bag. Discard any unused portion left in the vial.. Gently mix the intravenous bag by slowly inverting the bag. Do not shake.. Inspect the intravenous bag for particulates and discard if present.. If not used immediately, store the diluted POLIVY solution as specified in Table 3. Discard if storage time exceeds these limits. Do not freeze or expose to direct sunlight. Limit transportation to 30 minutes at 9C to 25C or 24 hours at 2C to 8C (refer to instructions below). The total storage plus transportation times of the diluted product should not exceed the storage duration specified in Table 3.. Agitation stress can result in aggregation. Limit agitation of diluted product during preparation and transportation to administration site. Do not transport diluted product through an automated system (e.g., pneumatic tube or automated cart). If the prepared solution will be transported to separate facility, remove air from the infusion bag to prevent aggregation. If air is removed, an infusion set with vented spike is required to ensure accurate dosing during the infusion.. No incompatibilities have been observed between POLIVY and intravenous infusion bags with product-contacting materials of polyvinyl chloride (PVC) or polyolefins (PO) such as polyethylene (PE) and polypropylene (PP). No incompatibilities have been observed with infusion sets or infusion aids with product-contacting materials of PVC, PE, polyurethane (PU), polybutadiene (PBD), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polyetherurethane (PEU), fluorinated ethylene propylene (FEP), or polytetrafluorethylene (PTFE), or with filter membranes composed of polyether sulfone (PES) or polysulfone (PSU).. AdministrationAdminister POLIVY as an intravenous infusion only.POLIVY must be administered using dedicated infusion line equipped with sterile, non-pyrogenic, low-protein-binding in-line or add-on filter (0.2- or 0.22-micron pore size) and catheter.Do not mix POLIVY with or administer as an infusion with other drugs.. Administer POLIVY as an intravenous infusion only.. POLIVY must be administered using dedicated infusion line equipped with sterile, non-pyrogenic, low-protein-binding in-line or add-on filter (0.2- or 0.22-micron pore size) and catheter.. Do not mix POLIVY with or administer as an infusion with other drugs.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Hepatic impairment has the potential to increase exposure to MMAE. Monitor patients for adverse reactions. (8.6)Lactation: Advise not to breastfeed. (8.2). Hepatic impairment has the potential to increase exposure to MMAE. Monitor patients for adverse reactions. (8.6). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], POLIVY can cause fetal harm. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of the small molecule component of POLIVY, MMAE, to pregnant rats during organogenesis at exposures below the clinical exposure at the recommended dose of 1.8 mg/kg POLIVY every 21 days resulted in embryo-fetal mortality and structural abnormalities (see Data). Advise pregnant woman of the potential risks to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal DataNo embryo-fetal development studies in animals have been performed with polatuzumab vedotin-piiq. In an embryo-fetal developmental study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of POLIVY, on gestational days and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve [AUC] at the recommended dose).. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of polatuzumab vedotin-piiq in human milk, the effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with POLIVY and for at least months after the last dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating POLIVY [see Use in Specific Populations (8.1)].. Contraception. FemalesPOLIVY can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for months after the final dose [see Nonclinical Toxicology (13.1)].. MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for at least months after the final dose [see Nonclinical Toxicity (13.1)].. InfertilityBased on findings from animal studies, POLIVY may impair male fertility. The reversibility of this effect is unknown [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. Safety and effectiveness of POLIVY have not been established in pediatric patients.. 8.5 Geriatric Use. Among 173 patients treated with POLIVY in Study GO29365, 95 (55%) were >=65 years of age. Patients aged >=65 had numerically higher incidence of serious adverse reactions (64%) than patients aged <65 (53%). Clinical studies of POLIVY did not include sufficient numbers of patients aged >=65 to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment. Avoid the administration of POLIVY in patients with moderate or severe hepatic impairment (bilirubin greater than 1.5 ULN). Patients with moderate or severe hepatic impairment are likely to have increased exposure to MMAE, which may increase the risk of adverse reactions. POLIVY has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) and Warnings and Precautions (5.7)]. No adjustment in the starting dose is required when administering POLIVY to patients with mild hepatic impairment (bilirubin greater than ULN to less than or equal to 1.5 ULN or AST greater than ULN).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Peripheral Neuropathy: Monitor patients for peripheral neuropathy and modify or discontinue dose accordingly. (5.1)Infusion-Related Reactions: Premedicate with an antihistamine and antipyretic. Monitor patients closely during infusions. Interrupt or discontinue infusion for reactions. (5.2)Myelosuppression: Monitor complete blood counts. Manage using dose delays or reductions and growth factor support. Monitor for signs of infection. (5.3)Serious and Opportunistic Infections: Closely monitor patients for signs of bacterial, fungal, or viral infections. (5.4)Progressive Multifocal Leukoencephalopathy (PML): Monitor patients for new or worsening neurological, cognitive, or behavioral changes suggestive of PML. (5.5)Tumor Lysis Syndrome: Closely monitor patients with high tumor burden or rapidly proliferative tumors. (5.6)Hepatotoxicity: Monitor liver enzymes and bilirubin. (5.7)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception during treatment and for months after the last dose. (5.8). Peripheral Neuropathy: Monitor patients for peripheral neuropathy and modify or discontinue dose accordingly. (5.1). Infusion-Related Reactions: Premedicate with an antihistamine and antipyretic. Monitor patients closely during infusions. Interrupt or discontinue infusion for reactions. (5.2). Myelosuppression: Monitor complete blood counts. Manage using dose delays or reductions and growth factor support. Monitor for signs of infection. (5.3). Serious and Opportunistic Infections: Closely monitor patients for signs of bacterial, fungal, or viral infections. (5.4). Progressive Multifocal Leukoencephalopathy (PML): Monitor patients for new or worsening neurological, cognitive, or behavioral changes suggestive of PML. (5.5). Tumor Lysis Syndrome: Closely monitor patients with high tumor burden or rapidly proliferative tumors. (5.6). Hepatotoxicity: Monitor liver enzymes and bilirubin. (5.7). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception during treatment and for months after the last dose. (5.8). 5.1Peripheral Neuropathy. POLIVY can cause peripheral neuropathy, including severe cases. Peripheral neuropathy occurs as early as the first cycle of treatment and is cumulative effect [see Adverse Reactions (6.1)]. POLIVY may exacerbate pre-existing peripheral neuropathy.In Study GO29365, of 173 patients treated with POLIVY, 40% reported new or worsening peripheral neuropathy, with median time to onset of 2.1 months. The peripheral neuropathy was Grade in 26% of cases, Grade in 12%, and Grade in 2.3%. Peripheral neuropathy resulted in POLIVY dose reduction in 2.9% of treated patients, dose delay in 1.2%, and permanent discontinuation in 2.9%. Sixty-five percent of patients reported improvement or resolution of peripheral neuropathy after median of month, and 48% reported complete resolution.The peripheral neuropathy is predominantly sensory; however, motor and sensorimotor peripheral neuropathy also occur. Monitor for symptoms of peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, dysesthesia, neuropathic pain, burning sensation, weakness, or gait disturbance. Patients experiencing new or worsening peripheral neuropathy may require delay, dose reduction, or discontinuation of POLIVY [see Dosage and Administration (2.2)].. 5.2Infusion-Related Reactions. POLIVY can cause infusion-related reactions, including severe cases. Delayed infusion-related reactions as late as 24 hours after receiving POLIVY have occurred. With premedication, 7% of patients (12/173) in Study GO29365 reported infusion-related reactions after the administration of POLIVY. The reactions were Grade in 67%, Grade in 25%, and Grade in 8%. Symptoms included fever, chills, flushing, dyspnea, hypotension, and urticaria.Administer an antihistamine and antipyretic prior to the administration of POLIVY, and monitor patients closely throughout the infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management [see Dosage and Administration (2.2)].. 5.3Myelosuppression. Treatment with POLIVY can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia. In patients treated with POLIVY plus BR (n 45), 42% received primary prophylaxis with granulocyte colony-stimulating factor. Grade or higher hematologic adverse reactions included neutropenia (42%), thrombocytopenia (40%), anemia (24%), lymphopenia (13%), and febrile neutropenia (11%) [see Adverse Reactions (6.1)]. Grade hematologic adverse reactions included neutropenia (24%), thrombocytopenia (16%), lymphopenia (9%), and febrile neutropenia (4.4%). Cytopenias were the most common reason for treatment discontinuation (18% of all patients).Monitor complete blood counts throughout treatment. Cytopenias may require delay, dose reduction, or discontinuation of POLIVY [see Dosage and Administration (2.2)]. Consider prophylactic granulocyte colony-stimulating factor administration.. 5.4Serious and Opportunistic Infections. Fatal and/or serious infections, including opportunistic infections such as sepsis, pneumonia (including Pneumocystis jiroveci and other fungal pneumonia), herpesvirus infection, and cytomegalovirus infection have occurred in patients treated with POLIVY [see Adverse Reactions (6.1)].Grade or higher infections occurred in 32% (55/173) of patients treated with POLIVY. Infection-related deaths were reported in 2.9% of patients within 90 days of last treatment.Closely monitor patients during treatment for signs of infection. Administer prophylaxis for Pneumocystis jiroveci pneumonia and herpesvirus.. 5.5Progressive Multifocal Leukoencephalopathy (PML). PML has been reported after treatment with POLIVY (0.6%, 1/173). Monitor for new or worsening neurological, cognitive, or behavioral changes. Hold POLIVY and any concomitant chemotherapy if PML is suspected, and permanently discontinue if the diagnosis is confirmed.. 5.6Tumor Lysis Syndrome. POLIVY may cause tumor lysis syndrome. Patients with high tumor burden and rapidly proliferative tumor may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures, including tumor lysis syndrome prophylaxis.. 5.7Hepatotoxicity. Serious cases of hepatotoxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred in patients treated with POLIVY.In recipients of POLIVY in Study GO29365 (n 173), Grade and transaminase elevations developed in 1.9% and 1.9%, respectively. Laboratory values suggestive of drug-induced liver injury (both an ALT or AST greater than times upper limit of normal [ULN] and total bilirubin greater than times ULN) occurred in 2.3% of patients.Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk of hepatotoxicity. Monitor liver enzymes and bilirubin level.. 5.8Embryo-Fetal Toxicity. Based on the mechanism of action and findings from animal studies, POLIVY can cause fetal harm when administered to pregnant woman. The small molecule component of POLIVY, MMAE, administered to rats caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at exposures below those occurring clinically at the recommended dose.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with POLIVY and for at least months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with POLIVY and for at least months after the last dose [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety data described below reflect exposure to POLIVY 1.8 mg/kg in 480 patients with large B-cell lymphoma (LBCL), including those with previously untreated LBCL (POLARIX) and relapsed or refractory DLBCL (GO29365).. Previously Untreated DLBCL, NOS or HGBL. GO39942 (POLARIX)The safety of POLIVY in combination with R-CHP chemoimmunotherapy was evaluated in POLARIX, randomized double-blind, placebo-controlled, multicenter study of 873 patients with previously untreated large B-cell lymphoma, 435 of whom received POLIVY plus R-CHP [see Clinical Studies (14.1)]. Patients were randomized 1:1 to receive POLIVY plus R-CHP or to receive R-CHOP for six 21-day cycles followed by two additional cycles of rituximab alone in both arms. Granulocyte colony-stimulating factor (G-CSF) primary prophylaxis was required and administered to 90% of patients in the POLIVY plus R-CHP arm and 93% of patients in the R-CHOP arm. Following premedication with an antihistamine and antipyretic, POLIVY was administered intravenously at 1.8 mg/kg on Day of Cycles 1-6. R-CHP was administered starting on Day of Cycles 1-6. Rituximab monotherapy was administered on Day of Cycles 7-8 [see Clinical Studies (14.1)]. The trial required an absolute neutrophil count >=1,000/uL, platelet count >=75,000/uL, creatinine clearance (CLcr) >=40 mL/min, hepatic transaminases <=2.5 times the upper limit of normal (ULN), and bilirubin <1.5 times ULN, unless abnormalities were from the underlying disease. The trial excluded patients having age >80, ECOG performance status above 2, known central nervous system (CNS) lymphoma, and Grade or higher peripheral neuropathy. The median age was 65 years overall (range: 19 to 80 years); 54% of patients were male; 53% were White, 19% were Asian, 2%, Black or African American, and 5% were Hispanic or Latino.In the POLIVY plus R-CHP group, 92% of patients received cycles of POLIVY, and 94% completed cycles of combination therapy.Serious adverse reactions occurred in 34% of patients who received POLIVY plus R-CHP, including febrile neutropenia and pneumonia in >=5% of recipients. Fatal adverse reactions occurred in 3% of recipients of POLIVY plus R-CHP within 90 days of last treatment, primarily from infection including pneumonia (0.9%) and sepsis (0.2%). Adverse reactions led to dose reduction of POLIVY in 6% of patients, mainly from peripheral neuropathy. Adverse reactions lead to dose interruption of POLIVY in 18% of patients, most commonly from pneumonia and neutropenia, and permanent discontinuation of POLIVY in 4.4% of patients.Table summarizes adverse reactions in POLARIX. In recipients of POLIVY plus R-CHP, adverse reactions in >=20% of patients, excluding laboratory abnormalities, were peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis. New or worsening Grade to laboratory abnormalities in >=10% of patients were lymphopenia, neutropenia, hyperuricemia, and anemia.Table 6Select Adverse Reactions Occurring in >=10% of Patients Treated with POLIVY Plus R-CHP in POLARIXAdverse Reactions by Body SystemPOLIVY R-CHPn 435R-CHOPn 438All Grades,%Grade 3-4,%All Grades,%Grade 3-4,%The table includes combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.0.Blood and Lymphatic System DisordersLaboratory values are based on integrated analysis of laboratory and adverse reaction data. Reported investigations exclude electrolytes. Lymphopenia80447744 Anemia68146711 Neutropenia60396042 Thrombocytopenia328336 Febrile neutropeniaFebrile neutropenia includes febrile neutropenia, febrile bone marrow aplasia, and neutropenic sepsis. 151599Investigations Creatinine increased660.7640.9 Aspartate aminotransferase increased260.7231.1 Alanine aminotransferase increased251.4270.5 Alkaline phosphatase increased230220.5 Uric acid increased19181716 Weight decreased130.9120.2Nervous System Disorders Peripheral neuropathyAt last assessment, peripheral neuropathy was unresolved in 42% in the POLIVY R-CHP arm and in 33% in the R-CHOP arm. Peripheral neuropathy includes all terms containing neuropathy, neuralgia, dysesthesia, paresthesia, hypoesthesia, peroneal nerve palsy, hypotonia, hyporeflexia, neuromyopathy, and hyperesthesia. 531.6541.1 Altered taste140160 Headache130.2140.9Gastrointestinal Disorders Nausea421.1370.5 Diarrhea313.9201.8 Constipation291.1290.2 MucositisMucositis includes stomatitis, oropharyngeal pain, mucosal inflammation, mouth ulceration, oral pain, oropharyngeal discomfort, aphthous ulcer, odynophagia, oral discomfort, tongue blistering, and tongue ulceration. 221.4190.5 Abdominal painAbdominal pain includes abdominal pain, abdominal discomfort, gastrointestinal pain, epigastric discomfort, and related terms. 161.1141.6 Vomiting151.1140.7General Disorders Fatigue372.5383.0 Pyrexia161.4130 EdemaEdema includes edema, face edema, swelling face, edema peripheral, fluid overload, fluid retention, pulmonary edema, peripheral swelling, and swelling. 140.5110.2 Infusion-related reactionInfusion related reaction is reflective of the combination regimen due to same-day administration. 131.1161.6Skin and Subcutaneous Tissue Disorders Alopecia240240.2 RashRash includes rash, dermatitis, and related terms. 130.7110Musculoskeletal Disorders Musculoskeletal painMusculoskeletal pain includes musculoskeletal pain, back pain, musculoskeletal chest pain, neck pain, myalgia, and bone pain. 190.5211.8Infections Upper respiratory tract infectionUpper respiratory tract infection incudes sinusitis, laryngitis, pharyngitis, nasopharyngitis, rhinitis, and specific infections. 170.5160.5Metabolism and Nutrition Disorders Decreased appetite171.1140.7Respiratory Disorders Cough150140 Dyspnea130.9100.9. Other clinically relevant adverse reactions in <10% of recipients of POLIVY plus R-CHP included:Infections: pneumonia, herpesvirus infection, sepsis, cytomegalovirus infection Metabolic disorders: tumor lysis syndrome Renal disorders: renal insufficiency Respiratory disorders: pneumonitis Infections: pneumonia, herpesvirus infection, sepsis, cytomegalovirus infection Metabolic disorders: tumor lysis syndrome Renal disorders: renal insufficiency Respiratory disorders: pneumonitis Relapsed or Refractory DLBCL, NOS. GO29365The data described in this section reflect exposure to POLIVY in Study GO29365, multicenter clinical trial for adult patients with relapsed or refractory B-cell lymphomas [see Clinical Studies (14.2)]. In patients with relapsed or refractory DLBCL, the trial included single-arm safety evaluation of POLIVY in combination with bendamustine and rituximab product (BR) (n 6), followed by an open-label randomization to POLIVY in combination with BR versus BR alone (n 39 treated per arm).Following premedication with an antihistamine and antipyretic, POLIVY 1.8 mg/kg was administered by intravenous infusion on Day of Cycle and on Day of Cycles 2-6, with cycle length of 21 days. Bendamustine 90 mg/m2 daily was administered intravenously on Days and of Cycle and on Days and of Cycles 2-6. rituximab product dosed at 375 mg/m2 was administered intravenously on Day of each cycle. Granulocyte colony-stimulating factor primary prophylaxis was optional and administered to 42% of recipients of POLIVY plus BR.In POLIVY-treated patients (n 45), the median age was 67 years (range 33 86) with 58% being >=age 65, 69% were male, 69% were White, and 87% had an Eastern Cooperative Oncology Group (ECOG) performance status of or 1. The trial required an absolute neutrophil count >=1500/uL, platelet count >=75/uL, creatinine clearance (CLcr) >=40 mL/min, hepatic transaminases <=2.5 times ULN, and bilirubin <1.5 times ULN, unless abnormalities were from the underlying disease. Patients with Grade or higher peripheral neuropathy or prior allogeneic hematopoietic stem cell transplantation (HSCT) were excluded.Patients treated with POLIVY plus BR received median of cycles, with 49% receiving cycles. Patients treated with BR alone received median of cycles, with 23% receiving cycles.Fatal adverse reactions occurred in 7% of recipients of POLIVY plus BR within 90 days of last treatment. Serious adverse reactions occurred in 64%, most often from infection. Serious adverse reactions in >=5% of recipients of POLIVY plus BR included pneumonia (16%), febrile neutropenia (11%), pyrexia (9%), and sepsis (7%).In recipients of POLIVY plus BR, adverse reactions led to dose reduction in 18%, dose interruption in 51%, and permanent discontinuation of all treatment in 31%. The most common adverse reactions leading to treatment discontinuation were thrombocytopenia and/or neutropenia.Table summarizes commonly reported adverse reactions. In recipients of POLIVY plus BR, adverse reactions in >=20% of patients included neutropenia, thrombocytopenia, anemia, peripheral neuropathy, fatigue, diarrhea, pyrexia, decreased appetite, and pneumonia.Table Adverse Reactions Occurring in >10% of Patients with Relapsed or Refractory DLBCL and >=5% More in the POLIVY Plus Bendamustine and Rituximab Product Group in Study GO29365Adverse Reactions by Body SystemPOLIVY BRn 45BRn 39All Grades,%Grade or Higher,%All Grades,%Grade or Higher,%The table includes combination of grouped and ungrouped terms. Events were graded using NCI CTCAE version 4.Blood and Lymphatic System Disorders Neutropenia49424436 Thrombocytopenia49403326 Anemia47242818 Lymphopenia131388Nervous System Disorders Peripheral neuropathy40080 Dizziness13080Gastrointestinal Disorders Diarrhea384.4285 Vomiting182.2130General Disorders Infusion-related reaction182.280 Pyrexia332.2230 Decreased appetite272.2210Infections Pneumonia2216Includes fatalities. 152.6Includes fatality. Upper respiratory tract infection13080Investigations Weight decreased162.282.6Metabolism and Nutrition Disorders Hypokalemia169102.6 Hypoalbuminemia132.280 Hypocalcemia112.250. Other clinically relevant adverse reactions (<10% or with <5% difference) in recipients of POLIVY plus BR included:Blood and lymphatic system disorders: pancytopenia (7%)Musculoskeletal disorders: arthralgia (7%)Investigations: hypophosphatemia (9%), transaminase elevation (7%), lipase increased (7%)Respiratory disorders: pneumonitis (4.4%)Selected treatment-emergent laboratory abnormalities are summarized in Table 8. In recipients of POLIVY plus BR, >20% of patients developed Grade or neutropenia, leukopenia, or thrombocytopenia, and >10% developed Grade neutropenia (13%) or Grade thrombocytopenia (11%).Table Select Laboratory Abnormalities Worsening from Baseline in Patients with Relapsed or Refractory DLBCL and >=5% More in the POLIVY Plus Bendamustine and Rituximab Product GroupLaboratory ParameterIncludes laboratory abnormalities that are new or worsening in grade or with worsening from baseline unknown. POLIVY BRn 45BRn 39All Grades,(%)Grade 3-4,(%)All Grades,(%)Grade 3-4,(%)Hematologic Lymphocyte count decreased87879082 Neutrophil count decreased78615633 Hemoglobin decreased78186210 Platelet count decreased76316426Chemistry Creatinine increased874.4775 Calcium decreased449260 SGPT/ALT increased38082.6 SGOT/AST increased360262.6 Lipase increased369135 Phosphorus decreased337288 Amylase increased240182.6 Potassium decreased2411285Safety was also evaluated in 173 adult patients with relapsed or refractory lymphoma who received POLIVY, bendamustine, and either rituximab product or obinutuzumab in Study GO29365, including the 45 patients with DLBCL described above. In the expanded safety population, the median age was 66 years (range 27 86), 57% were male, 91% had an ECOG performance status of 0-1, and 32% had history of peripheral neuropathy at baseline.Fatal adverse reactions occurred in 4.6% of recipients of POLIVY within 90 days of last treatment, with infection as leading cause. Serious adverse reactions occurred in 60%, most often from infection.Table summarizes the most common adverse reactions in the expanded safety population. The overall safety profile was similar to that described above. Adverse reactions in >=20% of patients were diarrhea, neutropenia, peripheral neuropathy, fatigue, thrombocytopenia, pyrexia, decreased appetite, anemia, and vomiting. Infection-related adverse reactions in >10% of patients included upper respiratory tract infection, febrile neutropenia, pneumonia, and herpesvirus infection.Table Most Common Adverse Reactions (>=20% Any Grade or >=5% Grade or Higher) in Recipients of POLIVY and Chemoimmunotherapy for Relapsed or Refractory LymphomaAdverse Reaction by Body System POLIVY Bendamustine Rituximab Product or Obinutuzumabn 173All Grades,%Grade or Higher,%The table includes combination of grouped and ungrouped terms.Blood and Lymphatic System Disorders Neutropenia4439 Thrombocytopenia3123 Anemia2814 Febrile neutropeniaPrimary prophylaxis with granulocyte colony-stimulating factor was given to 46% of all patients. 1313 Leukopenia138 Lymphopenia1212Nervous System Disorders Peripheral neuropathy402.3Gastrointestinal Disorders Diarrhea458 Vomiting272.9General Disorders Fatigue405 Pyrexia302.9 Decreased appetite291.7Infections Pneumonia1310Includes fatalities. Sepsis66Includes fatalities. Metabolism and Nutrition Disorders Hypokalemia186. Blood and lymphatic system disorders: pancytopenia (7%). Musculoskeletal disorders: arthralgia (7%). Investigations: hypophosphatemia (9%), transaminase elevation (7%), lipase increased (7%). Respiratory disorders: pneumonitis (4.4%). Other clinically relevant adverse reactions (<20% any grade) included:General disorders: infusion-related reaction (7%)Infection: upper respiratory tract infection (16%), lower respiratory tract infection (10%), herpesvirus infection (12%), cytomegalovirus infection (1.2%)Respiratory: dyspnea (19%), pneumonitis (1.7%)Nervous system disorders: dizziness (10%)Investigations: weight decrease (10%), transaminase elevation (8%), lipase increase (3.5%)Musculoskeletal disorders: arthralgia (7%)Eye disorders: blurred vision (1.2%). General disorders: infusion-related reaction (7%). Infection: upper respiratory tract infection (16%), lower respiratory tract infection (10%), herpesvirus infection (12%), cytomegalovirus infection (1.2%). Respiratory: dyspnea (19%), pneumonitis (1.7%). Nervous system disorders: dizziness (10%). Investigations: weight decrease (10%), transaminase elevation (8%), lipase increase (3.5%). Musculoskeletal disorders: arthralgia (7%). Eye disorders: blurred vision (1.2%).