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N. Shipitofsky
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-012 - Phase 1 Study of the AXL Inhibitor DS-1205c in Combination with Osimertinib in Subjects with Metastatic or Unresectable EGFR-Mutant NSCLC (ID 10172)
09:30 - 09:30 | Author(s): N. Shipitofsky
- Abstract
Background:
In patients with metastatic EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), resistance to EGFR tyrosine kinase inhibition arises from the T790M EGFR mutation in over half of cases; up-regulation of “bypass track” activity in non-EGFR signaling pathways is observed in other cases. Up-regulation of expression of the AXL tyrosine kinase has been observed in EGFRm NSCLC patients experiencing disease progression on erlotinib, and xenograft studies have explored the role of AXL inhibition in combination with EGFR TKI treatment in overcoming such resistance. DS-1205c is a novel, orally administered, specific small molecule inhibitor of AXL.
Method:
Trial Design: This is a multicenter, open-label, Phase 1 study of DS-1205c in combination with osimertinib in metastatic or unresectable EGFR-mutant NSCLC subjects experiencing disease progression during treatment with erlotinib, gefitinib, or afatinib, and without T790M resistance mutation. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, or afatinib, have at least one measurable lesion per RECIST v1.1, do not have spinal cord compression or clinically active brain metastases, and do not have any factors that increase the risk of QTc prolongation. This study includes two parts: Dose Escalation and Dose Expansion. In Dose Escalation, subjects receive DS-1205c during a run-in period, followed by continuous combination treatment with DS-1205c and osimertinib. Escalation of DS-1205c dosing between subjects is determined from dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model (BLRM) following the escalation with overdose control (EWOC) principle. In Dose Expansion, subjects receive DS-1205c at the recommended dose for expansion determined in Dose Escalation, in combination with osimertinib. Primary objectives are to determine the safety, tolerability, and recommended dose for expansion of DS-1205c in combination with osimertinib. Secondary objectives are to assess the pharmacokinetic parameters of DS-1205a (free form of DS-1205c), osimertinib, and osimertinib active metabolites, and to assess antitumor activity (RECIST v1.1).Clinicaltrials.gov identifier: NCT03255083
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.04-013 - Phase 1 Study of the Anti-HER3 Antibody Drug Conjugate U3-1402 in Metastatic or Unresectable EGFR-Mutant NSCLC (ID 10206)
09:30 - 09:30 | Author(s): N. Shipitofsky
- Abstract
Background:
While the treatment of EGFR-mutant NSCLC has significantly improved with the use of EGFR tyrosine kinase inhibitors, there remain limited treatment options for many patients who develop resistance to these agents. The HER3/ERBB3 oncogene is overexpressed in many cancers, including NSCLC, and higher expression is correlated with poorer outcomes. U3-1402 is a novel antibody-drug conjugate (ADC) comprised of a recombinant fully human anti-HER3 antibody (patritumab) covalently conjugated via a cleavable peptide linker to a derivative of the topoisomerase I inhibitor exatecan. After U3-1402 binds to HER3 on the tumor cell surface, it is internalized and leads to apoptosis via inhibition of topoisomerase I. This ADC achieves a high drug-to-antibody ratio of ~8:1.
Method:
Trial Design: This is a multicenter, open-label Phase 1 study of U3-1402 in metastatic or unresectable non-squamous NSCLC subjects harboring EGFR-activating mutation who (a) are T790M mutation-negative after disease progression during treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while on osimertinib. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib, have at least one measurable lesion per RECIST v1.1, have adequate bone marrow and organ function, do not have LVEF < 45% by either ECHO or MUGA scan, do not have mean QTc prolongation to > 470 ms for females and >450 ms for males, and do not have spinal cord compression or clinically active brain metastases. This study includes two parts: Dose Escalation and Dose Expansion. In Dose Escalation, subjects receive U3-1402 via intravenous infusion in 21-day cycles. In Dose Escalation, escalation of U3-1402 dosing between subjects is based on dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM) using a Bayesian logistic regression model (BLRM) following the escalation with overdose control (EWOC) principle. In Dose Expansion, subjects receive U3-1402 at the recommended dose for expansion determined in Dose Escalation. Primary objective is to determine the safety, tolerability, and recommended dose for expansion of U3-1402. Secondary objectives are to assess the pharmacokinetic parameters of U3-1402, total anti-HER3 antibody, and MAAA-1181a (drug payload), and to assess antitumor activity of U3-1402 (RECIST v1.1).Clinicaltrials.gov identifier: NCT03260491
Result:
Section not applicable
Conclusion:
Section not applicable
