A Phase Ib/II, Open-Label Study Of LJM716 In Combination With BYL719 Compared To Taxane Or Irinotecan In Patients With Previously Treated Esophageal Squamous Cell Carcinoma.
To compare the safety and efficacy of the combination of LJM716 and BYL719 against currently available treatments of physicianâ??s choice (Paclitaxel, Docetaxel or Irinotecan) in previously treated ESCC patients. â?? Phase 1b: To estimate the MTD and/or RP2D of LJM716-BYL719. â?? Phase 2: To compare the anti-tumor activity of LJM716-BYL719 vs physicianâ??s choice of chemotherapy (paclitaxel, docetaxel or irinotecan). â?? To characterize the safety and tolerability of the combination. â?? To further assess the anti-tumor activity of LJM716-BYL719. â?? To characterize the PK profiles of LJM716 and BYL719 when used in combination. The study includes a phase Ib dose escalation portion to define the MTD/RP2D for the combination of LJM716 and BYL719, followed by an open-label randomized phase II study of the LJM716-BYL719 combination vs. physicianâ??s choice of second-line therapy (paclitaxel, docetaxel, irinotecan). Both the phase Ib and the phase II portion of the study will be conducted in patients with recurrent or metastatic ESCC who have previously been treated with platinum-based chemotherapy. No molecular pre-selection will be performed.
Inclusion Criteria: ï¿½ Recurrent or metastatic squamous cell carcinoma of the esophagus ï¿½ No more than one prior chemotherapy regimen (Phase II) ï¿½ Progression during or after platinum-based therapy for recurrent or metastatic ESCC, or recurrence within 6 months of platinum-based chemotherapy or chemoradiotherapy for localized disease ï¿½ Measurable disease as per RECIST (Phase II) Exclusion Criteria: ï¿½ CNS metastatic involvement ï¿½ Prior treatment with a HER3-targeted antibody or a PI3K inhibitor 13.0
Overview of esophageal squamous cell carcinoma (ESCC) pathogenesis, epidemiology and current treatment Esophageal cancer is the eighth most common cancer and the sixth most common cause of death from cancer. Squamous cell carcinoma has been the predominant histologic subtype of esophageal cancer, but has been recently rivaled by the rise of adenocarcinoma. The standard of care for first line treatment of advanced or metastatic esophageal cancer is platinum-based combination chemotherapy. No standard of care exists in second-line treatment, where progression-free survival of 3 months, and overall survival of 5 months, is commonly seen. Targeted agents have not been successful in the treatment of squamous cell carcinoma of the esophagus. Initial reports demonstrated that gefitinib had activity in advanced esophageal cancer. However, in a randomized phase III study of gefitinib vs placebo in second or third line esophageal cancer, including approximately 25% with squamous histology, demonstrated only modest improvement in progression-free survival was seen without any impact on overall survival. The activity of cetuximab as firstline treatment in esophageal cancer including adenocarcinoma and ESCC was not reproduced in a larger first-line study of panitumumab in esophageal adenocarcinoma, which demonstrated shortened overall survival compared to chemotherapy alone. New therapies for advanced metastatic esophageal cancer are therefore needed. Alterations of the HER3/PI3K pathway have been described in ESCC; Novartis, data on file). Overview of LJM716 HER3 is a member of the ErbB family of receptor tyrosine kinases. HER3 itself lacks a functional kinase domain, but can be activated by heterodimerization with either HER2 or EGFR. HER2 heterodimerization occurs in the setting of HER2 overexpression, and HER3 ligand, neuregulin (NRG1) is thought not to play a role in this setting. In contrast, in EGFR driven tumors, HER3 is activated via a neuregulin autocrine loop. HER3 is the only member of the ErbB family which contains docking sites for both PI3K as well as RAS adapter proteins, thus transmitting a potent oncogenic signal through the PI3K/AKT as well as the MAPK pathways . LJM716 is a potent anti-HER3 antagonist mAb with a binding affinity (Kd) towards human HER3 of 32 pM. LJM716 binds a non-linear epitope contained within domains 2 and 4 of HER3. LJM716 binding does not block NRG1 binding to HER3 but prevents the structural rearrangements required for HER3 activation and downstream signaling. Due to its ability to block multiple modes of HER3 signaling, LJM716 displays single-agent anti-tumor activity in a range of xenograft models, both HER2-driven, ligand-independent as well as EGFR-driven, ligand-dependent. Finally, LJM716 displays combination activity with targeted agents that inhibit the ErbB family or PI3K signaling. Overview of BYL719 PI3Ks are lipid kinases that are important in controlling signaling pathways involved in cell proliferation, motility, cell death and cell invasion. There is substantial evidence that in many tumors the PI3K signaling pathway is constitutively activated. This is thought to be a critical step in mediating the transforming potential and growth stimulating activity of various oncogenes (HER2, EGFR, PDGFR, PIK3CA, p53, RAS, SRC etc.) contributing to the onset and growth of solid tumors and tumors of the hematopoietic system in patients. Class I PI3K contains four isoforms, p110Î±, p110Î², p110Î´ and p110Î³ which carry out nonredundant signaling functions. Î± and Î² isoforms are ubiquitously expressed. The Î± isoform is linked upstream mainly to receptor tyrosine kinases, whereas the Î² isoform can mediate signals from both G-protein-coupled receptors and from receptor tyrosine kinases. The Î± isoform is the only isoform for which somatic mutations are found in solid tumors. Therefore the development of a p110Î± specific PI3K inhibitor is expected to reduce the potential for inducing treatment related toxicity and improve the therapeutic window. BYL719 is an oral class I Î±-specific phosphatidylinositol-3-kinase (PI3K) inhibitor belonging to the 2-aminothiazole class of compounds. BYL719 strongly inhibits the PI3KÎ± isoform (p110Î± and p110Î± mutations) and much less strongly the Î², Î´ and Î³ isoforms. BYL719 has demonstrated anti-tumor activity in preclinical in vitro and in vivo tumor models. In vitro, BYL719 has been shown to inhibit the proliferation of cell lines harboring PIK3CA mutations. In vivo, BYL719 has demonstrated dosedependent tumor growth inhibition in various subcutaneous tumor transplant models. BYL719 is currently being investigated as a single agent and as a combination agent in several studies. As a single agent doses up to 450 mg once daily have been administered to cancer patients. On 08 February 2012, the MTD was determied to be 400mg on a once daily schedule.
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