Abstract CT151: Phase 2 study of TAS-117 in advanced solid tumors harboringphosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog gene aberrations

2021 ◽  
Author(s):  
Jii Bum Lee ◽  
Minkyu Jung ◽  
Seung Hoon Beom ◽  
Gun Min Kim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Viral Oncogene ◽  
Phase 2 Study ◽  
Viral Oncogene Homolog

scholarly journals Phase 2 Study of TAS-117 in Advanced Solid Tumors Harboring Phosphatidylinositol 3-Kinase/v-akt Murine Thymoma Viral Oncogene Homolog Gene Aberrations

2020 ◽  
Author(s):  
Jii Bum Lee ◽  
Minkyu Jung ◽  
Seung Hoon Beom ◽  
Gun Min Kim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Phosphatidylinositol 3 Kinase ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Viral Oncogene Homolog

Abstract Background: TAS-117 is a highly potent and selective allosteric pan-v-akt murine thymoma viral oncogene homolog (Akt) inhibitor. We conducted a single-arm, single-center, phase 2 study of TAS-117 in heavily treated patients with multiple tumors refractory to systemic chemotherapy harboring phosphatidylinositol 3-kinase (PI3K)/Akt mutations using a basket trial design.Methods: Patients with gastrointestinal (GI) cancers were orally administered 16 mg of TAS-117 daily and those with non-GI tumors were administered 24 mg of TAS-117, 4 days on/3-days off. The study was conducted over 21-day treatment cycles. Tumors were assessed by imaging every 6 weeks until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was the overall response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), PFS ratio, and safety and tolerability of TAS-117. Results: Thirteen patients were enrolled; eight with non-GI cancer (breast cancer (31%), ovarian cancer (15%), endometrial cancer (8%), and non-small cell lung cancer (8%)) and five with GI cancer (colon cancer (15%), rectal cancer (8%), gastric cancer (8%), and gallbladder cancer (8%)). The median age was 53 years. The Eastern Cooperative Oncology Group performance status was 0 in eight patients; ten patients were treated with TAS-117 after >4 lines of therapy. Twelve patients showed mutations in PIK3 catalytic subunit alpha (PIK3CA): E542K (15%), E545A (8%), E545K (31%), H1047R (31%), and Q546K (8%). One patient harbored an Akt1E17K mutation. The median treatment duration was 1.4 months; the median number of treatment cycles was 2. The ORR was 8%, and the DCR was 23%. The median PFS and OS were 1.4 and 4.8 months, respectively. Nine patients had disease progression, two experienced adverse events, one withdrew, and one discontinued treatment on the physician’s recommendation. Treatment-related adverse events (AEs) occurred in 85% of patients, and 27% experienced grade 3–4 AEs (grade 3 anorexia, 9%) and hyperglycemia (grade 3, 9%; grade 4, 9%). Conclusions: TAS-117 showed limited antitumor activity and manageable toxicity in patients with advanced solid tumors. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in those with breast cancer harboring PIK3CA H1047R and Akt1E17K mutations. Trial registration: This study was registered with ClinicalTrial.gov (NCT03017521 in January 11, 2017.).

TRIDENT-1: A global, multicenter, open-label Phase II study investigating the activity of repotrectinib in advanced solid tumors harboring ROS1 or NTRK1-3 rearrangements.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9637-TPS9637
Author(s):  
Robert Charles Doebele ◽  
Jessica Jiyeong Lin ◽  
Misako Nagasaka ◽  
Viola Weijia Zhu ◽  
Nashat Y. Gabrail ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Phase 1 ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Resistance Mutations ◽  
Open Label ◽  
Phase 2 Study

TPS9637 Background: Repotrectinib is a next-generation ROS1/TRK inhibitor with > 90-fold greater potency than crizotinib against ROS1 and > 100-fold greater potency than larotrectinib against TRK. Preclinical studies demonstrated inhibitory activity of repotrectinib against ROS1 resistance mutations, including the solvent-front mutation (SFM) G2032R. In the phase 1 portion of the study, repotrectinib was found to be well tolerated with encouraging antitumor activity including a 91% confirmed overall response (cORR) in TKI-naïve ROS1+ NSCLC pts. In ROS1+ NSCLC pts who received 1 prior chemo and 1 prior TKI, the cORR was 57% at the clinical dose of 160 mg QD or above. Intra-cranial (IC) activity was observed in ROS1+ NSCLC pts with measurable CNS disease (100% IC-ORR in TKI-naïve and 75% IC-ORR in patients with 1 prior TKI). Encouraging antitumor activity was observed in pts with NTRK+ solid tumors. Methods: A global phase 2 study was initiated and is actively enrolling. The primary endpoint for the Phase 2 study is cORR assessed by BICR (Blinded Independent Central Review) using RECIST v1.1, in each expansion cohort in pts with advanced solid tumors that harbor a ROS1 or NTRK1/2/3 gene fusion. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), IC-ORR, IC-PFS, and quality of life assessments. All pts need to have RECIST 1.1 measurable disease confirmed by BICR and ECOG performance score ≤1. Repotrectinib is administered at 160 mg QD for 14 days and, if tolerated, the dose can be increased to 160 mg BID. Approximately 320 pts (≥12 years old) will be enrolled into 6 defined expansion cohorts, depending on the status of previous treatment with TKIs and cancer types (see table below). Clinical trial information: NCT03093116 . [Table: see text]

Eltrombopag for thrombocytopenia in patients with advanced solid tumors receiving gemcitabine-based chemotherapy: a randomized, placebo-controlled phase 2 study

2017 ◽  
Vol 106 (6) ◽  
pp. 765-776 ◽  
Author(s):  
Eric S. Winer ◽  
Howard Safran ◽  
Boguslawa Karaszewska ◽  
Sebastian Bauer ◽  
Dilawar Khan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Phase 2 Study

scholarly journals Phase 2 study of TAS-117, an allosteric akt inhibitor in advanced solid tumors harboring phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog gene mutations

2021 ◽  
Author(s):  
Jii Bum Lee ◽  
Minkyu Jung ◽  
Seung Hoon Beom ◽  
Gun Min Kim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Adverse Events ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Inhibitor ◽  
Viral Oncogene ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Viral Oncogene Homolog ◽  
Phosphatidylinositol 3

SummaryTAS-117 is a potent and selective allosteric pan-v-akt murine thymoma viral oncogene homolog (Akt) inhibitor. We conducted a single-arm single-center phase 2 study of TAS-117 in heavily treated patients with tumors refractory to systemic chemotherapy and harboring phosphatidylinositol 3-kinase (PI3K)/Akt mutations. Patients with gastrointestinal (GI) cancers were orally administered 16 mg TAS-117 daily, and those with non-GI tumors were administered 24 mg on a 4 days on/3 days off schedule. The primary endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), PFS ratio, safety, and tolerability. Thirteen patients were enrolled: eight with non-GI (breast, ovarian, endometrial, and non-small cell lung) and five with GI (colon, rectal, gastric, and gallbladder) cancers. Ten patients were treated with TAS-117 after ≥ 4 lines of therapy. Twelve patients showed PIK3 catalytic subunit alpha (PIK3CA) mutations; one harbored an Akt1E17K mutation. The median treatment duration was 1.4 months; the median number of treatment cycles was 2. The ORR was 8 %, and DCR was 23 %. The median PFS and OS were 1.4 and 4.8 months, respectively. Grade 3–4 treatment-related adverse events were anorexia (grade 3, 8 %) and hyperglycemia (grade 3, 8 %; grade 4, 8 %).Grade 3–4 treatment-related adverse events occurred in 27 % of grade 3 anorexia (9 %) and hyperglycemia (grade 3, 8 %; grade 4, 9\%). TAS-117 showed limited antitumor activity and manageable toxicity. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in patients with breast cancer harboring PIK3CA H1047R and Akt1E17K mutations.Trial registration: This study was retrospectively registered with ClinicalTrial.gov (NCT03017521 on January 11, 2017).

scholarly journals P86.08 Phase 2 Study of Zenocutuzumab (MCLA-128), a Bispecific HER2/HER3 Antibody in NRG1 Fusion-Positive Advanced Solid Tumors

2021 ◽  
Vol 16 (3) ◽  
pp. S675
Author(s):  
A. Schram ◽  
T. Macarulla ◽  
E. O’Reilly ◽  
J. Rodon ◽  
B. Wolpin ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Phase 2 Study

423 Safety and preliminary efficacy of intratumoral cavrotolimod (AST-008), a spherical nucleic acid TLR9 agonist, in combination with pembrolizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A449-A449
Author(s):  
Steven O’Day ◽  
Cesar Perez ◽  
Trisha Wise-Draper ◽  
Glenn Hanna ◽  
Shailender Bhatia ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Solid Tumors ◽  
San Francisco ◽  
Institutional Review Boards ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
Tlr9 Agonist ◽  
Phase 1B ◽  
Spherical Nucleic Acids

BackgroundSpherical nucleic acids (SNAs) are nanostructures consisting of radially oriented, densely packed oligonucleotides arranged in a spherical 3D architecture. SNAs have different properties than linear oligonucleotides, including increased cellular uptake, which may enhance efficacy. Cavrotolimod (AST-008) is an SNA toll-like receptor 9 (TLR9) agonist designed to robustly activate innate and adaptive immune responses. Cavrotolimod is in development for the treatment of advanced solid tumors in combination with PD-1 blockade. Prior studies demonstrated that cavrotolimod, alone and in combination with PD-1 blockade, increased circulating levels of Th1-type cytokines and activated peripheral T cells and NK cells.MethodsAST-008-102 is an ongoing Phase 1b/2 study (NCT03684785). The Phase 1b dose escalation stage examined intratumoral (IT) cavrotolimod at doses of 2, 4, 8, 16, and 32 mg in combination with pembrolizumab in patients with advanced solid tumors. Cavrotolimod was dosed once weekly for 8 weeks and once every 3 weeks thereafter. The Phase 2 dose expansion stage is examining cavrotolimod 32 mg IT in combination with IV pembrolizumab for the treatment of advanced Merkel cell carcinoma (MCC) and in combination with IV cemiplimab for the treatment of advanced cutaneous squamous cell carcinoma (CSCC). Both cohorts are enrolling patients with documented progression of disease on PD-(L)1 blockade. This analysis provides interim results of the Phase 1b stage.ResultsIn the Phase 1b stage, 20 patients were enrolled across all planned dose levels. No dose-limiting toxicities, grade (G)4 toxicities, or treatment-related serious adverse events (AEs) were observed. The most common AEs were injection site reactions (ISRs) and flu-like symptoms. All treatment-related AEs were < G3 except agitation and ISR (1 each). At data cutoff, ORR is 21% (4 of 19 evaluable patients) in a heterogeneous population with solid tumors. All 4 responders (2 melanoma and 2 MCC patients) have ongoing responses, with duration of response exceeding 52 weeks in 2 patients. Three of 4 responders had disease progression on PD-1 blockade at the time of enrollment, and one patient had a prior response to PD-1 blockade, but subsequently relapsed off therapy. Regression of both injected and noninjected lesions was observed. Gene expression analyses demonstrated increased IT infiltration by cytotoxic immune cells in both injected and noninjected tumors. The highest dose (32 mg) was selected for the Phase 2 stage.ConclusionsIT administration of cavrotolimod appears to be safe and well tolerated in combination with pembrolizumab. Durable responses have occurred in patients previously experiencing progressive disease on PD-1 blockade.Trial RegistrationNCT03684785Ethics ApprovalThe study was approved by Institutional Review Boards of Dana-Farber Cancer Institute (IRB #18-584), John Wayne Cancer Institute (WIRB #20183064), University of Miami (IRB #20180957), University of Iowa (IRB #201810763), University of Cincinnati (WIRB #20183064), University of Washington (WIRB #20183064), MSKCC (IRB #20-174), UC San Francisco (WIRB #20183064), U Colorado (WIRB #20183064), Northwestern (IRB #STU00211083), U Arizona (WIRB #20183064), UC Irvine (WIRB #20183064), U Pitt (WIRB #20183064), and Washington University (WIRB #20183064).

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