RESUMO
OBJECTIVE: This study investigated the safety and tolerability of lifastuzumab vedotin (DNIB0600A) (LIFA), an antibody-drug conjugate, in patients with recurrent platinum-sensitive ovarian cancer (PSOC). METHODS: In this open-label, multicenter phase 1b study, LIFA was administered intravenously once every 3 weeks (Q3W) with starting dose 1.2 mg/kg in a 3 + 3 dose-escalation scheme. All patients received carboplatin at dose AUC 6 mg/mL·min (AUC6) Q3W for up to 6 cycles. Dose expansion cohorts were enrolled ± bevacizumab 15 mg/kg Q3W. RESULTS: Patients received LIFA at 1.2, 1.8, and 2.4 mg (n = 4, 5, and 20, respectively) with carboplatin. The maximum tolerated dose was not reached. The recommended phase 2 dose (RP2D) was LIFA 2.4 mg/kg + carboplatin AUC6 (cycles 1-6), with or without bevacizumab 15 mg/kg. Twelve patients received RP2D with bevacizumab. All patients experienced ≥1 adverse event (AE). The most common treatment-related AEs were neutropenia, peripheral neuropathy, thrombocytopenia, nausea, fatigue, anemia, diarrhea, vomiting, hypomagnesaemia, aspartate aminotransferase increased, alanine aminotransferase increased, and alopecia. Thirty-four (83%) patients experienced grade ≥ 3 AEs, the most frequent of which were neutropenia and thrombocytopenia. Nine (22%) patients experienced serious AEs. Pulmonary toxicities (34%), considered a potential risk of LIFA, included one patient who discontinued study treatment due to grade 2 pneumonitis. The median duration of progression-free survival was 10.71 months (95% CI: 8.54, 13.86) with confirmed complete/partial responses in 24 (59%) patients. Pharmacokinetics of mono-therapy LIFA was similar in combination therapy. CONCLUSION: LIFA in combination with carboplatin ± bevacizumab demonstrated acceptable safety and encouraging activity in PSOC patients.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carcinoma Epitelial do Ovário/metabolismo , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Neoplasias Ovarianas/metabolismo , Intervalo Livre de ProgressãoRESUMO
PURPOSE: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). PATIENTS AND METHODS: LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). RESULTS: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). CONCLUSIONS: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIb/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacocinética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Epitelial do Ovário/patologia , Feminino , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Segurança do Paciente , Distribuição Tecidual , Resultado do TratamentoRESUMO
Background Endothelin B receptor (ETBR) is involved in melanoma pathogenesis and is overexpressed in metastatic melanoma. The antibody-drug conjugate DEDN6526A targets ETBR and is comprised of the humanized anti-ETBR monoclonal antibody conjugated to the anti-mitotic agent monomethyl auristatin E (MMAE). Methods This Phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of DEDN6526A (0.3-2.8 mg/kg) given every 3 weeks (q3w) in patients with metastatic or unresectable cutaneous, mucosal, or uveal melanoma. Results Fifty-three patients received a median of 6 doses of DEDN6526A (range 1-49). The most common drug-related adverse events (>25% across dose levels) were fatigue, peripheral neuropathy, nausea, diarrhea, alopecia, and chills. Three patients in dose-escalation experienced a dose-limiting toxicity (infusion-related reaction, increased ALT/AST, and drug-induced liver injury). Based on cumulative safety data across all dose levels, the recommended Phase II dose (RP2D) for DEDN6526A was 2.4 mg/kg intravenous (IV) q3w. The pharmacokinetics of antibody-conjugated MMAE and total antibody were dose-proportional at doses ranging from 1.8-2.8 mg/kg. A trend toward faster clearance was observed at doses of 0.3-1.2 mg/kg. There were 6 partial responses (11%) in patients with metastatic cutaneous or mucosal melanoma, and 17 patients (32%) had prolonged stable disease ≥6 months. Responses were independent of BRAF mutation status but did correlate with ETBR expression. Conclusion DEDN6526A administered at the RP2D of 2.4 mg/kg q3w had an acceptable safety profile and showed evidence of anti-tumor activity in patients with cutaneous, mucosal, and uveal melanoma. ClinicalTrials.gov identifier: NCT01522664.