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.
Keywords:
B-cell non-Hodgkin lymphoma; Combination therapy; Drug interactions; Pharmacokinetics; Phase Ib/II; Polatuzumab vedotin.
Publication types
-
Clinical Trial
-
Clinical Trial, Phase I
-
Clinical Trial, Phase II
-
Multicenter Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Administration, Intravenous
-
Adult
-
Antibodies, Monoclonal* / administration & dosage
-
Antibodies, Monoclonal* / adverse effects
-
Antibodies, Monoclonal* / pharmacokinetics
-
Antibodies, Monoclonal, Humanized / administration & dosage*
-
Antibodies, Monoclonal, Humanized / adverse effects
-
Antibodies, Monoclonal, Humanized / pharmacokinetics
-
Antineoplastic Agents, Immunological / administration & dosage
-
Antineoplastic Agents, Immunological / adverse effects
-
Antineoplastic Agents, Immunological / pharmacokinetics
-
Antineoplastic Combined Chemotherapy Protocols / administration & dosage
-
Antineoplastic Combined Chemotherapy Protocols / adverse effects
-
Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
-
Cyclophosphamide / administration & dosage
-
Cyclophosphamide / adverse effects
-
Cyclophosphamide / pharmacokinetics
-
Dose-Response Relationship, Drug
-
Doxorubicin / administration & dosage
-
Doxorubicin / adverse effects
-
Doxorubicin / pharmacokinetics
-
Drug Administration Schedule
-
Drug Interactions
-
Drug Monitoring / methods
-
Female
-
Humans
-
Immunoconjugates* / administration & dosage
-
Immunoconjugates* / adverse effects
-
Immunoconjugates* / pharmacokinetics
-
Lymphoma, B-Cell* / drug therapy
-
Lymphoma, B-Cell* / pathology
-
Male
-
Maximum Tolerated Dose
-
Prednisone / administration & dosage
-
Prednisone / adverse effects
-
Prednisone / pharmacokinetics
-
Rituximab* / administration & dosage
-
Rituximab* / adverse effects
-
Rituximab* / pharmacokinetics
-
Treatment Outcome
-
Vincristine / administration & dosage
-
Vincristine / adverse effects
-
Vincristine / pharmacokinetics
Substances
-
Antibodies, Monoclonal
-
Antibodies, Monoclonal, Humanized
-
Antineoplastic Agents, Immunological
-
Immunoconjugates
-
Rituximab
-
Vincristine
-
Doxorubicin
-
Cyclophosphamide
-
polatuzumab vedotin
-
obinutuzumab
-
Prednisone