Date: 2015-01-11
Type of information: Presentation of results at a congress
phase: 1b
Announcement: presentation of results at the World Conference on Lung Cancer 2015 in Denver
Company: GSK (UK) Five Prime Therapeutics (USA - CA)
Product: FP-1039/GSK3052230
Action
mechanism: protein. FP-1039/GSK3052230 is a protein designed to intervene in fibroblast growth factor (FGF) signaling. FGFs are a family of 22 related extracellular proteins called ligands that normally regulate cell proliferation and survival in humans. In certain tumor types – including some squamous non-small cell lung cancers (sqNSCLC), head and neck cancers, and breast cancers – there is amplification of the gene for FGFR1, which results in over-expression of the FGFR1 protein on the surface of the tumor cell. Approximately half of the 22 known FGFs can activate FGFR1, leading to increased FGF signaling and cancerous cell growth. Another function of FGF proteins and their receptors is to mediate angiogenesis. As a ligand trap, FP-1039/GSK3052230 is thought to bind to FGF ligands circulating in the extracellular space, thereby preventing these signaling proteins from reaching FGFR1 on the surface of tumor cells where they would otherwise stimulate cancer cell division and/or angiogenesis. However, FP-1039/GSK3052230 is not believed to bind to certain \"hormonal\" FGFs, including FGF23, which regulates phosphate levels in the blood. As a result, treatment with FP-1039/GSK3052230 treatment has not been shown to cause hyperphosphatemia, a side effect seen with small molecule inhibitors of FGF receptors, which block the activity of both cancer-associated FGFs and FGF23. Five Prime successfully completed a Phase 1a clinical trial of FP-1039 in 39 patients with solid tumors and licensed the development and commercialization rights for FP-1039/GSK3052230 in the U.S., Europe and Canada to GSK, who now funds clinical development. Five Prime retains rights outside of these regions as well as an option to co-promote FP-1039/GSK3052230 in the U.S. GSK is conducting a Phase 1b trial evaluating the safety and efficacy of FP-1039/GSK3052230 weekly infusion in combination with paclitaxel plus carboplatin in previously untreated FGFR1 gene-amplified metastatic sqNSCLC (Arm A), in combination with docetaxel in FGFR1 gene-amplified metastatic sqNSCLC that has progressed after at least one line of chemotherapy (Arm B), or in combination with pemetrexed plus cisplatin in patients with untreated and unresectable malignant pleural mesothelioma (Arm C), a tumor in which the FGF2 ligand is overexpressed.
Disease: squamous non small cell lung cancer (sqNSCLC), mesothelioma
Therapeutic area: Cancer - Oncology
Country: Belgium, Denmark, France, Netherlands, Russian Federation, Spain, UK, USA
Trial
details: This phase IB trial aims to identify anticancer activity of GSK3052230 in subjects with malignancies with abnormal dependence on FGF pathway signaling. Combination doses of GSK3052230 with standard of care chemotherapy in the first and second line or greater setting of metastatic squamous non-small cell lung cancer (NSCLC) and first line malignant pleural mesothelioma subjects will be studied in the 3+3 dose-escalation design. This will be a multi-arm, multicenter, non-randomized, parallel-group, uncontrolled, open-label Phase IB study designed to evaluate the safety, tolerability and preliminary activity of GSK3052230 in combination with paclitaxel + carboplatin (Arm A), in combination with docetaxel (Arm B), or in combination with pemetrexed + cisplatin (Arm C). Approximately 70 subjects will be enrolled in the study (approximately up to 120 may be enrolled). (NCT01868022)
Latest
news: * On January 11, 2016, Five Prime Therapeutics provided an update on GSK ongoing Phase 1b clinical trial of FP-1039/GSK3052230, an FGF ligand trap, in patients with squamous non-small cell lung cancer (sqNSCLC) and mesothelioma. GSK presented preliminary clinical safety and efficacy data from the Phase 1b trial at the World Conference on Lung Cancer on September 9, 2015 (see below). At the time, data from Arm A in treatment-naïve sqNSCLC patients were encouraging, Arm B in second line sqNSCLC had few patients enrolled, and data from Arm C were immature because few mesothelioma patients were then evaluable. Based on preliminary data, GSK and Five Prime have agreed to continue to enroll up to 30 mesothelioma patients at the expansion dose of 15 mg/kg in Arm C of the trial. GSK plans to submit data for presentation at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting in June. The companies have also agreed to stop enrolling the sqNSCLC patient study cohorts given the change in treatment paradigms following approvals of immuno-oncology agents and the increasingly competitive landscape. * On September 9, 2015, Five Prime Therapeutics, a clinical-stage biotechnology company focused on discovering and developing novel protein therapeutics for cancer and inflammatory diseases, announced that initial data from GSK\'s ongoing Phase 1b clinical trial of FP-1039/GSK3052230, an FGF ligand trap, in patients with squamous non small cell lung cancer (sqNSCLC) and mesothelioma were featured in an oral presentation by Dr. Pilar Garrido at the World Conference on Lung Cancer 2015 in Denver. The presentation titled, \"FP1039/GSK3052230 with chemotherapy in patients with fibroblast growth factor (FGF) pathway deregulated squamous NSCLC or MPM,\" included study data through August 5, 2015. The Phase 1b trial being conducted by GSK is evaluating the safety and efficacy of FP-1039/GSK3052230 weekly infusion in combination with paclitaxel plus carboplatin in previously untreated FGFR1 gene-amplified metastatic sqNSCLC (Arm A), in combination with docetaxel in FGFR1 gene-amplified metastatic sqNSCLC that has progressed after at least one line of chemotherapy (Arm B), or in combination with pemetrexed plus cisplatin in patients with untreated and unresectable malignant pleural mesothelioma (Arm C). Each arm involves a dose escalation phase, followed by an expansion phase up to 30 patients. GSK continues to enroll patients in the study. As of August 5, 2015, 176 patients with first-line or previously-treated squamous NSCLC were tested centrally for FGFR1 gene amplification, with a positive rate of approximately 20%. 44 patients had been dosed with FP-1039/GSK3052230 at dose levels ranging from 5mg/kg to 20mg/kg in combination with chemotherapy across the three study arms. In Arm A, a maximum tolerated dose was not identified, therefore a maximum feasible dose (MFD) was determined and expansion of the arm was at 20 mg/kg IV weekly. In Arm B, dose escalation is ongoing, and in Arm C, the maximally tolerated dose was established and expansion of the arm was at 15 mg/kg IV weekly. No dose limiting toxicities (DLTs) have been observed in sqNSCLC patients (Arms A and B), and 3 DLTs were reported in mesothelioma patients (Arm C, 20mg/kg): Grade 5 bowel perforation/ischemia, Grade 3 elevated creatinine level and Grade 3 infusion reaction. The most common adverse events across all three arms were neutropenia, anemia, constipation, diarrhea, nausea, vomiting, decreased appetite, pyrexia, fatigue, asthenia and alopecia. Infusion reactions were seen in 17%, 14%, and 37% of patients treated in Arms A, B, and C, respectively. Toxicities typically associated with small-molecule FGFR kinase inhibitors, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. Preliminary efficacy data as measured by RECIST (Arms A and B) and mRECIST (Arm C) criteria are reported in the following table: Five Prime Therapeutics now expects that full results from the study will be available during 2016. Best Tumor
ResponseArm A
(1L sqNSCLC):
paclitaxel +
carboplatin + FP-
1039 (n=18)Arm B
(2L+ sqNSCLC):
docetaxel + FP-1039
(n=7)Arm C
(1L MPM):
pemetrexed +
cisplatin + FP-
1039 (n=19)Partial response 10* 0 3 Stable disease 3 4 5 Progressive disease 2 1 1 Not evaluable 3 2 10 ORR 55% 0% 16% Disease control rate 72% 57% 42%
