A phase II open-label study in adult and adolescent patients (pts) with advanced solid tumors harboring fibroblast growth factor receptor (FGFR) gene alterations.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS480-TPS480
Author(s):  
Shubham Pant ◽  
Josep Tabernero ◽  
Christophe Massard ◽  
Gopa Iyer ◽  
Olaf Witt ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Locally Advanced ◽  
Safety Data ◽  
Genetic Alterations ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Gene Alterations

TPS480 Background: The pan- FGFR tyrosine kinase inhibitor erdafitinib is approved by the US Food and Drug Administration for adults with locally advanced or metastatic urothelial carcinoma and susceptible FGFR3/2 genetic alterations who have progressed during or after ≥ 1 line of prior platinum-containing chemotherapy. FGFR gene alterations are potential oncogenic drivers that have been reported in many solid tumors in adult and pediatric pts. Because of limited response to standard of care options in pts failing systemic therapy, there is strong rationale to assess the safety and efficacy of erdafitinib in adolescent and adult pts with advanced solid tumors and FGFR alterations. Methods: This phase 2, open-label study (RAGNAR/42756493CAN2002; NCT04083976) will include pts aged ≥ 12 years with histologically confirmed unresectable, locally advanced, or metastatic solid tumors (except urothelial tumors) harboring predefined FGFR mutations or fusions. Eligibility screening includes molecular screening for FGFR alterations by central or local next-generation sequencing assays, and other clinical criteria. Pts will enroll into either a broad panel cohort (BPC) of target FGFR alterations or an exploratory cohort (EC) for FGFR alterations that do not meet criteria for BPC. Approximately 280 pts (BPC, n = 240; EC, n = 40) will be enrolled. The primary efficacy end point is overall response rate (ORR) as assessed by the independent review committee. Secondary end points include investigator-assessed ORR, duration of response, disease control rate, progression-free survival, overall survival, safety, pharmacokinetics, and health-related quality of life. Safety assessments include adverse events, vital signs, electrocardiograms, physical examinations, laboratory tests, performance status assessment, growth assessments in adolescents, and ophthalmologic examination. As of December 2019, pts are being enrolled at ~158 sites in 15 countries. Results of this study will provide efficacy and safety data for erdafitinib across multiple solid tumors with FGFR alterations and evaluate the potential benefit of targeting the underlying altered biology of FGFR irrespective of tumor histology in adult and adolescent pts. Clinical trial information: NCT04083976.

Phase 1 open-label study evaluating the safety, pharmacokinetics, and preliminary efficacy of dilpacimab in patients with advanced solid tumors

2021 ◽  
pp. molcanther.0985.2020
Author(s):  
Michael S. Gordon ◽  
John Nemunaitis ◽  
Minal Barve ◽  
Zev A. Wainberg ◽  
Erika P. Hamilton ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Open Label Study ◽  
Label Study

PLANETTE: A modular phase IIa multicenter open-label study evaluating the ATR inhibitor ceralasertib (AZD6738) in ATM mutant advanced solid tumors.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS189-TPS189
Author(s):  
Wassim Abida ◽  
Elkhan Sanay ◽  
Natalia Lukashchuk ◽  
Andrew Pierce ◽  
Wessel de Graaf ◽  
...  
Keyword(s):  
Dna Damage ◽  
Solid Tumors ◽  
Ataxia Telangiectasia ◽  
Synthetic Lethality ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Minor Response ◽  
Open Label Study ◽  
Label Study ◽  
Tumor Types

TPS189 Background: Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are kinases that orchestrate cellular responses to DNA damage. ATM is primarily activated by DNA double strand breaks, and ATR is recruited to regions of single stranded DNA that arise due to collapsed or stalled replication forks. Although ATM and ATR are activated by distinct pathways, their downstream targets and effects partially overlap to activate cell cycle checkpoints and DNA damage repair. Ceralasertib is a potent, oral, selective inhibitor of ATR. Pre-clinical studies have consistently demonstrated synthetic lethality of ATR inhibitors, including ceralasertib, in ATM-deficient models across multiple tumor types (Kwok et al 2017, Min et al 2017, Lloyd et al 2020, Hustedt et al 2019). Early clinical evidence of efficacy is from a phase I study of ceralasertib in combination with olaparib in relapsed, refractory cancer (NCT02576444). Amongst 5 participants with a range of solid tumors harboring deleterious ATM mutations, there was 1 complete response, 3 stable diseases (1 with minor response 20-30%) and 1 patient with disease progression. Two participants had clinical benefit ongoing for more than 12 months (Eder et al 2019). ATM deficiency may be detected through genomic testing for loss-of-function alterations in the gene, or through immunohistochemical methods to detect loss of protein expression. Genomic alterations in ATM occur across multiple solid tumor types, including approximately 4% of advanced prostate cancers. Methods: PLANETTE (clinicaltrials.gov identifier (NCT 04564027) is a modular phase 2a multicenter open-label study investigating DNA-damage response agents in patients with advanced cancers that harbor molecular alterations. Module 1 will study the ATR inhibitor ceralasertib in tumors with deleterious or suspected deleterious mutations in ATM. Patients will be identified at cancer centers which routinely perform molecular profiling to detect ATM mutations. Central confirmation of ATM mutation by NGS and ATM IHC testing will be conducted retrospectively. Cohort A will enroll ~25 patients with advanced solid tumors (except NSCLC and prostate cancer), cohort B will include ~27 patients with metastatic CRPC who have previously progressed on a novel hormonal agent. The primary endpoints are investigator assessed ORR in Cohort A and composite response that includes radiographic, PSA, and CTC response per PCWG criteria in Cohort B. Secondary endpoints include duration of response, and progression free survival. Pharmacodynamic and other biomarkers will be explored. Enrolment is planned to start in November 2020. Clinical trial information: 04564027.

A phase I open-label study investigating the disposition of [14C]-cabazitaxel in patients with advanced solid tumors

2015 ◽  
Vol 26 (3) ◽  
pp. 350-358 ◽  
Author(s):  
Laurence Ridoux ◽  
Dorothée R. Sémiond ◽  
Carine Vincent ◽  
Hélène Fontaine ◽  
Christine Mauriac ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Open Label Study ◽  
Label Study

scholarly journals ACT-1 Multicenter investigator-initiated registration-directed Phase 2 study of E7090 in subjects with advanced or recurrent solid tumors with fibroblast growth factor receptor (FGFR) gene alteration: FORTUNE trial

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi9-vi9
Author(s):  
Masamichi Takahashi ◽  
Yohei Chiba ◽  
Kazuki Sudo ◽  
Yuki Kojima ◽  
Hitomi Okuma ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Genetic Alterations ◽  
Precision Oncology ◽  
Functional Evaluation ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Gene Alterations

Abstract Background: Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, 2021), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods: The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043, ClinicalTrials.gov: NCT04962867)

scholarly journals SYST-01. MULTICENTER INVESTIGATOR-INITIATED PHASE 2 STUDY OF E7090 IN SUBJECTS WITH ADVANCED OR RECURRENT SOLID TUMORS WITH FIBROBLAST GROWTH FACTOR RECEPTOR (FGFR) GENE ALTERATION: FORTUNE STUDY

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv8-iv8
Author(s):  
Masamichi Takahashi ◽  
Yohei Chiba ◽  
Kazuki Sudo ◽  
Yuki Kojima ◽  
Hitomi Okuma ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Genetic Alterations ◽  
Precision Oncology ◽  
Functional Evaluation ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Gene Alterations

Abstract Background Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, in press), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043)

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