scholarly journals Activity of preclinical and phase I clinical trial of a novel androgen receptor antagonist GT0918 in metastatic breast cancer

2021 ◽  
Author(s):  
Huiping Li ◽  
Guohong Song ◽  
Qiaoxia Zhou ◽  
Ran Ran ◽  
Hanfang Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Xenograft Model ◽  
Metastatic Breast ◽  
Blood Cholesterol ◽  
Breast Cancer Patients ◽  
Dose Escalation Study ◽  
Single Dose Study ◽  
Positive Breast Cancer

Abstract Purpose To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. Methods The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. Results GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. Conclusion GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.

scholarly journals A phase I dose-escalation study of eribulin and S-1 for metastatic breast cancer

2015 ◽  
Vol 112 (5) ◽  
pp. 819-824 ◽  
Author(s):  
T Sakiyama ◽  
J Tsurutani ◽  
T Iwasa ◽  
H Kawakami ◽  
Y Nonagase ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Metastatic Breast ◽  
Dose Escalation Study

scholarly journals A phase I dose-escalation study of a biosimilar trastuzumab in Chinese metastasis breast cancer patients

SpringerPlus ◽  
2015 ◽  
Vol 4 (1) ◽  
Author(s):  
Xinna Zhou ◽  
Jing Yu ◽  
Wenmiao Wang ◽  
Guohong Song ◽  
Xiaoli Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Cancer Patients ◽  
Dose Escalation ◽  
Breast Cancer Patients ◽  
Dose Escalation Study

A phase I dose-escalation study evaluating weekly paclitaxel with neratinib and trastuzumab in women with metastatic HER2-positive breast cancer, NSABP FB-8.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 611-611 ◽  
Author(s):  
Rachel Catherine Jankowitz ◽  
Jame Abraham ◽  
Antoinette R. Tan ◽  
Steven A. Limentani ◽  
Laura M Adamson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Weekly Paclitaxel ◽  
Erbb Receptors ◽  
Her2 Positive ◽  
Dose Escalation Study ◽  
Cancer Trial ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

611 Background: Dual blockade of ErbB receptors combined with chemotherapy compared with single-agent blockade improves efficacy in HER2-positive disease. FB-8 is single arm, Phase I dose-escalation study to determine safety and tolerability of weekly paclitaxel (P), the irreversible tyrosine kinase inhibitor, neratinib (N) and trastuzumab (T) in women with metastatic, HER2-positive breast cancer (MBC). Methods: Women with measurable or non-measurable MBC (ECOG PS 0 - 2) received P (80 mg/m2 IV days 1, 8, 15 of 28-day cycle), T (4 mg/kg IV, then 2 mg/kg IV weekly), and N (oral, daily). N was dose-escalated using 3+3 design at 120 mg, 160 mg, and 240 mg, dose-limiting toxicity (DLT) determined in cycle 1. All patients (pts) received prophylactic anti-diarrheals. Results: All pts were taxane and trastuzumab pre-treated, with mean of 4 prior regimens. At N=120 mg, there was 1 DLT, grade (gr) 3 diarrhea with dehydration. Three more pts were enrolled; none experienced DLT. At N=160 mg, there were no DLTs. At N=240 mg, 2 of 3 pts had DLTs: one gr 3 diarrhea and dehydration, one gr 3 diarrhea, dehydration, and gr 3 mucositis. After de-escalation to N=160 mg, 3 more pts were added. If N=160 mg is well tolerated, a 200 mg cohort is planned. 12 pts completed cycle 1. Efficacy data are available on 10: CR 1, PR 3, SD 1 (8+months). One pt* had resolution of non-target disease (skin and breast mass). 4 pts were off-study before the first scan (DLT 3 and progressive disease 1) and are considered non-responders (NR). The most frequent grade 3-4 adverse event was diarrhea, 3 pts. Conclusions: Dual anti-HER blockade with N, T combined with P is tolerable and highly active in pts pre-treated with anti-HER2 agents and chemotherapy. This combination will be studied in a phase II neoadjuvant breast cancer trial (NSABP FB-7). We thank Pfizer, Inc and Puma Biotechnology, Inc for their support. [Table: see text]

A phase I dose-escalation study of ABT-888 (veliparib) in combination with carboplatin in HER2-negative metastatic breast cancer (MBC).

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. TPS106-TPS106 ◽  
Author(s):  
S. Viswanathan ◽  
R. Wesolowski ◽  
R. M. Layman ◽  
G. Alejandra ◽  
B. Miller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Metastatic Breast ◽  
Dose Escalation Study

A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 508-508 ◽  
Author(s):  
Ian E. Krop ◽  
Cristina Saura ◽  
Jordi Rodon Ahnert ◽  
Carlos Becerra ◽  
Carolyn D. Britten ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Metastatic Breast ◽  
Pi3k Pathway ◽  
Dose Escalation Study ◽  
Her2 Breast Cancer ◽  
Disease Stabilization

508 Background: Alterations in the PI3K/AKT/mTOR pathway have been implicated in resistance to trastuzumab (T) in HER2+ breast cancer. BEZ235, a potent oral dual PI3K/mTORC1/2 inhibitor, has demonstrated growth inhibition and apoptosis in HER2+ breast cancer models, including those harboring PI3K pathway alterations, and with T resistance. In a Phase I study, BEZ235 was well tolerated as a single agent in pts with advanced solid tumors. The aim of this study was to determine the MTD of BEZ235 in combination with T in pts with T-resistant HER2+ metastatic breast cancer (mBC) with alterations of the PI3K pathway. Methods: Pts with T-resistant HER2+ mBC (i.e. disease progression during adjuvant therapy or metastatic disease on therapy with T) received oral BEZ235 daily, with weekly T (2 mg/kg). Pts were eligible for enrollment if a tumor sample was demonstrated to contain a molecular alteration of PIK3CA and/or PTEN. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: As of 23 Sep 2011, 15 of the 19 enrolled pts were evaluable for dose escalation analysis. BEZ235 was evaluated at 3 dose levels: (1) 400 mg/day (3 pts); (2) 600 mg/day (6 pts); (3) 800 mg/day (10 pts), administered either in capsule form (400 mg) or in sachet form (600 mg and 800 mg). The MTD of BEZ235 in combination with T was estimated to be 600 mg/day. Observed DLTs were G3 nausea at 600 mg/day (1 pt), and G3 nausea, G3 fatigue and G3 skin rash (1 pt each) at 800 mg/day. The most frequent G3/4 adverse events (CTCAE v3.0) suspected to be related to study treatment were diarrhea (4 pts) and nausea (2 pts). No deaths related to study treatment occurred. 1 pt with lung and brain metastases had a partial response. 4 pts had disease stabilization for ≥4 cycles (16 weeks), including 1 pt with liver metastases, in whom BEZ235/T treatment resulted in disease stabilization for more than 21 cycles (84 weeks). Conclusions: BEZ235in combination with T demonstrated an acceptable safety profile in pts with HER2+ mBC and PI3K pathway alterations. Following the Bayesian model recommendation, the MTD for BEZ235 in combination with T was estimated to be 600 mg/day. The safety expansion arm is ongoing at the MTD.

scholarly journals Dose-escalation phase I study in metastatic breast cancer patients with combination of paclitaxel and tegafur·uracil

2010 ◽  
Vol 1 (1) ◽  
pp. 45-49
Author(s):  
AKIHIKO OSAKI ◽  
SHOSHU MITSUYAMA ◽  
JUN-ICHI KUREBAYASHI ◽  
HIROSHI SONOO ◽  
REIKI NISHIMURA ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Cancer Patients ◽  
Dose Escalation ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Breast Cancer Patients
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