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

Abstract

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. Exposures of pola with R/G-CHP were similar to those in the absence of CHP; exposures of R/G-CHP in the presence of pola were comparable to those in the absence of pola.

CONCLUSIONS:

Pola PK was well characterized with no clinically meaningful DDIs with R/G-CHP. Findings are consistent with previous studies of pola + R/G, and support pola + R/G-CHP use in previously untreated diffuse large B-cell lymphoma.

• Authors: Colby S Shemesh, Priya Agarwal, Tong Lu, Calvin Lee, Randall C Dere, Xiaobin Li, Chunze Li, Jin Y Jin, Sandhya Girish, Dale Miles, Dan Lu
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 85 Issue 5 Pg. 831-842 (05 2020) ISSN: 1432-0843 [Electronic] Germany
• PMID: 32222808 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• Immunoconjugates
• Rituximab
• Vincristine
• Doxorubicin
• Cyclophosphamide
• polatuzumab vedotin
• obinutuzumab
• Prednisone

Topics

• Administration, Intravenous
• Adult
• Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics)
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Agents, Immunological (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Cyclophosphamide (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage, adverse effects, pharmacokinetics)
• Drug Administration Schedule
• Drug Interactions
• Drug Monitoring (methods)
• Female
• Humans
• Immunoconjugates (administration & dosage, adverse effects, pharmacokinetics)
• Lymphoma, B-Cell (drug therapy, pathology)
• Male
• Maximum Tolerated Dose
• Prednisone (administration & dosage, adverse effects, pharmacokinetics)
• Rituximab (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome
• Vincristine (administration & dosage, adverse effects, pharmacokinetics)