Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma.
| Title: | Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma. |
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| Authors: | Shemesh CS; Department of Clinical Pharmacology Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. shemesh.colby@gene.com.; Agarwal P; Department of Clinical Pharmacology Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Lu T; Department of Clinical Pharmacology Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Lee C; Clinical Science, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Dere RC; Bioanalytical Science, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Li X; Department of Clinical Pharmacology Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Li C; Department of Clinical Pharmacology Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Jin JY; Department of Clinical Pharmacology Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Girish S; Department of Clinical Pharmacology Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Miles D; Department of Clinical Pharmacology Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.; Lu D; Department of Clinical Pharmacology Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. lu.dan@gene.com. |
| Source: | Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2020 May; Vol. 85 (5), pp. 831-842. Date of Electronic Publication: 2020 Mar 28. |
| Publication Type: | Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7806519 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0843 (Electronic) Linking ISSN: 03445704 NLM ISO Abbreviation: Cancer Chemother Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Berlin : Springer Verlag; Original Publication: Berlin, New York, Springer International. |
| MeSH Terms: | Antibodies, Monoclonal*/administration & dosage ; Antibodies, Monoclonal*/adverse effects ; Antibodies, Monoclonal*/pharmacokinetics ; Immunoconjugates*/administration & dosage ; Immunoconjugates*/adverse effects ; Immunoconjugates*/pharmacokinetics ; Lymphoma, B-Cell*/drug therapy ; Lymphoma, B-Cell*/pathology ; Rituximab*/administration & dosage ; Rituximab*/adverse effects ; Rituximab*/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 ; Doxorubicin/administration & dosage ; Doxorubicin/adverse effects ; Doxorubicin/pharmacokinetics ; Drug Monitoring/methods ; Prednisone/administration & dosage ; Prednisone/adverse effects ; Prednisone/pharmacokinetics ; Vincristine/administration & dosage ; Vincristine/adverse effects ; Vincristine/pharmacokinetics ; Administration, Intravenous ; Adult ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Interactions ; Female ; Humans ; Male ; Maximum Tolerated Dose ; Treatment Outcome |
| 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. |
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| Contributed Indexing: | Keywords: B-cell non-Hodgkin lymphoma; Combination therapy; Drug interactions; Pharmacokinetics; Phase Ib/II; Polatuzumab vedotin |
| Substance Nomenclature: | 0 (Antibodies, Monoclonal); 0 (Antibodies, Monoclonal, Humanized); 0 (Antineoplastic Agents, Immunological); 0 (Immunoconjugates); 4F4X42SYQ6 (Rituximab); 5J49Q6B70F (Vincristine); 80168379AG (Doxorubicin); 8N3DW7272P (Cyclophosphamide); KG6VO684Z6 (polatuzumab vedotin); O43472U9X8 (obinutuzumab); VB0R961HZT (Prednisone) |
| SCR Protocol: | CHOP protocol |
| Entry Date(s): | Date Created: 20200331 Date Completed: 20201117 Latest Revision: 20260521 |
| Update Code: | 20260522 |
| PubMed Central ID: | PMC7188703 |
| DOI: | 10.1007/s00280-020-04054-8 |
| PMID: | 32222808 |
| Database: | MEDLINE |
Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't