Polatuzumab Vedotin Combined with Obinutuzumab for Patients with Relapsed or Refractory Non-Hodgkin Lymphoma: Preliminary Safety and Clinical Activity of a Phase Ib/II Study

Phillips, Tycel; Brunvand, Mark W.; Chen, Andy; Press, Oliver W.; Essell, James; Chiappella, Annalisa; Diefenbach, Catherine; Jones, Surai; Hirata, Jamie; Flinn, Ian W.

doi:10.1182/blood.v128.22.622.622

Cited by 30 publications

(31 citation statements)

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“…Patient demographics and baseline characteristics for each study are reported elsewhere [8,9,[19][20][21][22][23]; they were generally similar across treatment arms and ethnic subgroups. The numbers of Asian and non-Asian patients by race and region for the five studies are shown in Supplementary Table 1 (Online Resource 1).…”

Section: Demographicsmentioning

confidence: 99%

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Shi¹,

Tong²,

Ku³

et al. 2020

Cancer Chemother Pharmacol

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Purpose The CD79b-targeted antibody–drug conjugate polatuzumab vedotin (pola), alone and with chemoimmunotherapy, has clinical efficacy and a tolerable safety profile in B-cell non-Hodgkin lymphoma (B-NHL). We assessed (a) whether exposure from global studies of pola is comparable to Asian patients, and (b) if the recommended pola dose is appropriate in Asian patients based on exposure. Methods The pharmacokinetics (PK) of pola in Asian and global populations was characterized for three analytes (antibody-conjugated monomethyl auristatin E (MMAE) [acMMAE], total antibody, and unconjugated MMAE) in five phase 1b/2 single-agent and combination studies in B-NHL patients (JO29138 [JAPICCTI‐142580], DCS4968g [NCT01290549], GO27834 [NCT01691898], GO29044 [NCT01992653], and GO29365 [NCT02257567]). PK data were compared between Japanese phase 1 JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies and between Asian and non-Asian patients in the randomized relapsed/refractory B-NHL cohorts of the phase 1b/2 study GO29365 (NCT02257567). A population PK (popPK) model was used to assess the effects of Asian race and region on acMMAE and unconjugated MMAE exposure. Results PK non-compartmental analysis (NCA) parameters for the key analyte acMMAE in the Japanese JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies were similar. In GO29365 (NCT02257567), the phase 1b/2 combination study, mean exposure to the analytes was generally lower in Asian patients (by ~ 9.9 to 17.5%), but not to a clinically meaningful extent. Overall, the popPK model further suggested comparable PK in Asian patients with B-NHL (race or region) versus non-Asian patients. Conclusion Race has no clinically meaningful effect on pola PK. These results (and observations from efficacy/safety exposure–response analyses) support no pola dose adjustments are warranted for Asian patients with DLBCL.

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Section: Demographicsmentioning

confidence: 99%

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Shi¹,

Tong²,

Ku³

et al. 2020

Cancer Chemother Pharmacol

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“…The potential for PK DDI between CHP and pola was evaluated using exposure comparisons between patients receiving pola + R/G-CHP and those with R/R DLBCL or FL receiving pola with R/G in a phase II study [17,35]. Exposure comparisons included cycle 1 C max and AUC of each pola analyte including acMMAE and unconjugated MMAE.…”

Section: Potential Pk Drug-drug Interaction Of Pola and R/g-chpmentioning

confidence: 99%

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

Shemesh¹,

Agarwal²,

Tong³

et al. 2020

Cancer Chemother Pharmacol

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Purpose The phase Ib/II open-label study (NCT01992653) evaluated the antibody-drug conjugate polatuzumab vedotin (pola) plus rituximab/obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (R/G-CHP) as first-line therapy for B-cell non-Hodgkin lymphoma (B-NHL). We report the pharmacokinetics (PK) and drug-drug interaction (DDI) for pola. Methods Six or eight cycles of pola 1.0-1.8 mg/kg were administered intravenously every 3 weeks (q3w) with R/G-CHP. Exposures of pola [including antibody-conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE] and R/G-CHP were assessed by non-compartmental analysis and/or descriptive statistics with cross-cycle comparisons to cycle 1 and/or after multiple cycles. Pola was evaluated as a potential victim and perpetrator of a PK drug-drug interaction with R/G-CHP. Population PK (popPK) analysis assessed the impact of prior treatment status (naïve vs. relapsed/refractory) on pola PK. Results Pola PK was similar between treatment arms and independent of line of therapy. Pola PK was dose proportional from 1.0 to 1.8 mg/kg with R/G-CHP. Geometric mean volume of distribution and clearance of acMMAE ranged from 57.3 to 95.6 mL/kg and 12.7 to 18.2 mL/kg/day, respectively. acMMAE exhibited multi-exponential decay (elimination half-life ~ 1 week). Unconjugated MMAE exhibited formation rate-limited kinetics.

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“…43 In the adult phase I trial of 25 patients with R/R DLBCL treated at the recommended phase II dosing, there were 4 CRs and 10 PRs. 56 Polatuzumab vedotin has subsequently been combined with rituximab, 56 obinutuzumab, 57 and bendamustine and rituximab or obinutuzumab 58 for patients with R/R DLBCL. In the latter study, 58 with a mean follow-up of 30 months, 9 of 19 responders remained event-free.…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Novel Therapies Potentially Available for Pediatric B-Cell Non-Hodgkin Lymphoma

Harker‐Murray

Pommert

Barth

2020

Journal of the National Comprehensive Cancer Network

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Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma are the most common aggressive pediatric mature B-cell non-Hodgkin lymphomas (B-NHLs). Despite excellent survival with current chemotherapy regimens, therapy for Burkitt lymphoma and DLBCL has a high incidence of short- and long-term toxicities. Patients who experience relapse generally have a very poor prognosis. Therefore, novel approaches using targeted therapies to reduce toxicities and improve outcomes in the relapse setting are needed. The addition of rituximab, a monoclonal antibody against CD20, to upfront therapy has improved survival outcomes for high-risk patients and may allow decreased total chemotherapy in those with low-risk disease. Antibody–drug conjugates have been combined with chemotherapy in relapsed/refractory (R/R) NHL, and multiple antibody–drug conjugates are in development. Additionally, bispecific T-cell–engaging antibody constructs and autologous CAR T-cells have been successful in the treatment of R/R acute leukemias and are now being applied to R/R B-NHL with some successes. PD-L1 and PD-L2 on tumor cells can be targeted with checkpoint inhibitors, which restore T-cell–mediated immunity and antitumor responses and can be added to conventional chemotherapy and immune-directed therapies to augment responses. Lastly, trials of small molecule inhibitors targeting cell signaling pathways in NHL subtypes are underway. This article reviews many of the targeted therapies under development that could be considered for future trials in R/R pediatric mature B-NHL.

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Polatuzumab Vedotin Combined with Obinutuzumab for Patients with Relapsed or Refractory Non-Hodgkin Lymphoma: Preliminary Safety and Clinical Activity of a Phase Ib/II Study

Cited by 30 publications

References 0 publications

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

Novel Therapies Potentially Available for Pediatric B-Cell Non-Hodgkin Lymphoma

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