Safety and efficacy of TQ-B3525, a novel and selective oral PI3K α/δ inhibitor, in Chinese patients with advanced malignancies: A phase I dose-escalation and expansion trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8058-8058
Author(s):  
Huaqing Wang ◽  
Wenqi Jiang ◽  
Su Li ◽  
Yu Wang ◽  
Peng Sun ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Dose Escalation ◽  
Solid Tumor ◽  
Geometric Mean ◽  
Chinese Patients ◽  
Advanced Solid Tumor ◽  
Advanced Malignancies ◽  
Anti Cancer ◽  
Grade 3

8058 Background: TQ-B3525 is a novel and selective oral PI3K α/δ inhibitor with activity 41 and 138 folds higher than Buparlisib against PI3K α and PI3K δ in pre-clinical research. This Phase I study (NCT03510767) assessed the safety, tolerability, pharmacokinetics and antitumor activity of TQ-B3525 in Chinese patients with advanced malignancies. Methods: Patients with relapsed or refractory (R/R) lymphoma who have experienced at least two prior systemic anti-cancer treatments, and advanced solid tumor who have failed standard anti-cancer treatment, were enrolled. TQ-B3525 was administered orally from 2mg, 5mg, 10mg, 20mg once daily (qd) to 10mg, 20mg twice daily (bid). DLT was observed in the first cycle (28 days) of dose-escalation phase. Dose-expansion phase started at the dose level which objective response occurs. Results: Between June 2018 and December 2019, a total of 40 patients were enrolled, Including 27 patients with R/R lymphoma and 13 patients with advanced solid tumor. Three DLTs (both grade 3 hyperglycemia) were observed: two in the 20mg bid dose cohort and one in the 10mg bid. The common AEs of all grades were hyperglycemia (65.0%), glycosylated hemoglobin increased (35.0%) and diarrhea (32.5%). Grade 3 or 4 treatment-related AEs occurred in 11 patients (27.5%), with the most common one also being hyperglycemia (10.0%). TQ-B3525 was rapidly absorbed (Tmax: 1-2 h) and moderately eliminated (T1/2: 10-12 h). At steady state, the geometric mean AUC0-24 and Ctrough of TQ-B3525 at 20mg qd were 1060.7 ± 198.6 h*ng/mL and 23.4 ± 9.5 ng/mL, which was above IC50 (4.2 ng/ml). 23 lymphoma patients were evaluable for clinical response per 2014 Lugano Classification. The overall response rate (ORR) was 60.9% (95% CI, 38.5-80.2). The ORR at ≥10mg qd was 70.0% (14/20, [95% CI, 49.9-90.1]). For R/R FL, the ORR was 72.7% (8/11, [95% CI, 46.4-99.1]). At data cut-off (2nd February, 2020), the median PFS for lymphoma was not reached (events rate: 33.3%). The longest duration of response at data cutoff was 11.8 months in a patient with FL. Conclusions: TQ-B3525 is well-tolerated in Chinese patients with advanced malignancies, and demonstrated high promising antitumor activity in R/R lymphoma patients. Recommended phase II dose was established at 20mg qd. A single-arm phase 2 trial of TQ-B3525 in patients with R/R FL is currently underway. Clinical trial information: NCT03510767 .

A Q7D phase I study of TPI 287, a novel taxane, in advanced malignancies: Imaging studies, pharmacokinetics (PK) and circulating tumor cell (CTC) quantitation

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12008-12008 ◽  
Author(s):  
J. J. Hwang ◽  
J. L. Marshall ◽  
S. Malik ◽  
H. Chun ◽  
T. Ahmed ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Advanced Malignancies ◽  
Tumor Measurements ◽  
Grade 3

12008 Background: Taxanes have demonstrated activity across a broad range of cancers, but resistance remains an issue. TPI 287 is a third generation taxane designed to overcome issues of resistance secondary to mdr and mutant tubulin. The purpose of this Phase I study was to determine the maximum tolerated dose and pharmacokinetics of IV TPI 287. Methods: Phase I study: TPI 287 is administered IV on days 1, 8, 15 of a 28 day cycle (Q7D) with at least 3 patients treated per dose escalation, in a typical phase I design. Dosing began at 7 mg/m2 and has advanced to the fifth cohort of patients, who are being treated at a dose of 85 mg/m2. Tumor response is assessed after every second cycle via imaging and tumor measurements. Samples are collected for PK analysis and circulating tumor cell (CTC) quantitation. Results: Sixteen pts have been enrolled (9 males, median years = 60.11; 7 females, median years = 50.71: median number of previous chemotherapies = 4). Diagnoses included colorectal (4), prostate (3), breast, kidney, cervical, brain, lung, osteosarcoma, basal cell, endometrial, ovarian cancers. Of 16 pts, 8 and 5 have completed 1, 2 cycles, respectively. Only one drug related grade 3 adverse event (hypersensitivity reaction) occurred, at 14 mg/m2. No other reported toxicities are related to TPI 287. PK and CTC studies are ongoing. Conclusions: These initial results show that TPI 287 is well tolerated at a dose up to 56 mg/m2 administered Q7D, and dose escalation continues. [Table: see text]

A phase I study to evaluate safety and antitumor activity of biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in patients with RCC and other advanced refractory malignancies.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 331-331 ◽  
Author(s):  
D. F. McDermott ◽  
C. G. Drake ◽  
M. Sznol ◽  
J. A. Sosman ◽  
D. C. Smith ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Median Duration ◽  
Dose Escalation ◽  
Tumor Type ◽  
Duration Of Treatment ◽  
Open Label ◽  
Cell Renal Cell Carcinoma ◽  
Dose Escalation Study ◽  
Grade 3

331 Background: Programmed death-1 (PD-1), a T-cell inhibitory receptor, may suppress antitumor immunity. BMS-936558, a fully human PD-1 blocking antibody, has shown antitumor activity and manageable toxicity after biweekly dosing (Sznol, ASCO 2010, #2506). This report provides an update on safety and antitumor activity with special emphasis on RCC. Methods: An open-label phase I dose escalation study of BMS-936558 was conducted in patients (pts) with treatment refractory metastatic clear-cell renal cell carcinoma (RCC), castrate-resistant prostate cancer (CRPC), melanoma (MEL), non-small cell lung cancer, or colorectal cancer (CRC). Dose escalation continued to 10 mg/kg when an expansion cohort for pts (16) with each tumor type was opened for additional safety and efficacy information. Tumor response (RECIST) was evaluated every 8 weeks. Clinically stable pts with early PD could continue until further PD or clinical deterioration. Results: 126 pts (18 RCC) were treated with 1, 3, or 10 mg/kg. MTD was not reached. Across all doses, the most common AEs (Any/grade 3-4) were fatigue (45.2%/6.3%) and diarrhea (30.2%/0.8%) while the most common drug-related AEs (Any/grade 3-4) were fatigue (20.6%/0.8%), rash (11.9%/0%), pruritus (11.3%/0%), and diarrhea (10.3%/0.8%). There was no apparent relationship between dose and frequency of AEs. One pt died with sepsis while being treated for drug-related grade 4 pneumonitis. The median number of prior treatment regimens in the RCC cohort was 2 (range 1-6). Of the 18 RCC pts, 16 were treated with 10 mg/kg. The median duration of treatment was 7.6+mo. ORR was 5/16 (31.2%) and SD>4mo was 6/16 (37.5%). The median duration of response was 4.0+ mo (3.7-7.4+ mo). Of the 2 RCC pts treated with 1 mg/kg, 1 obtained a CR (12+ mo) and 1 had SD (21+ mo). For evaluable CRPC pts, 1/15 pts (6.7%) obtained a PR (2+ mo) and 3/15 (20%) had SD>4mo. Conclusions: BMS-936558 administered biweekly is tolerable and has encouraging antitumor activity in a previously treated patients with RCC. Data on baseline characteristics, long-term toxicity and response duration will be updated at the meeting. [Table: see text]

Vorolanib (CM082) in Chinese patients with advanced solid tumor: A phase 1, open-label, dose escalation study.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 2580-2580 ◽  
Author(s):  
Yan Song ◽  
Jinwan Wang ◽  
Ai-Ping Zhou ◽  
Wen Zhang ◽  
Chris Liang ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Solid Tumor ◽  
Phase 1 ◽  
Chinese Patients ◽  
Advanced Solid Tumor ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

BPI-9016M, a novel c-Met inhibitor, in pretreated advanced solid tumor: Results from a first-in-human, phase I, dose-escalation study.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e21108-e21108
Author(s):  
Xingsheng Hu ◽  
Xin Zheng ◽  
Hongnan Mo ◽  
Xinge Cui ◽  
Lieming Ding ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Solid Tumor ◽  
Advanced Solid Tumor ◽  
Dose Escalation Study ◽  
Met Inhibitor

A phase I dose escalation trial of pulsatile high dose gefitinib and docetaxel in patients with an advanced solid tumor

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 3132-3132 ◽  
Author(s):  
M. G. Fury ◽  
M. Kris ◽  
D. Solit ◽  
D. G. Pfister ◽  
C. G. Azzoli ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Solid Tumor ◽  
High Dose ◽  
Advanced Solid Tumor

Phase I trial of bortezomib in combination with topotecan in advanced solid tumor malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12004-12004
Author(s):  
R. Morgan ◽  
F. Valdes-Albini ◽  
T. Synold ◽  
G. Somlo ◽  
S. Shibata ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
Weekly Schedule ◽  
Clinical Testing ◽  
Advanced Solid Tumor ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Tumor Types

12004 Background: Bortezomib (B) and topotecan (T) have been shown in pre-clinical testing to be synergistic. Based on this data we have performed a phase I study to determine the maximally tolerated dose and toxicities (tox) of B and T delivered sequentially. Methods: 24 pts (KPS<ECOG 3) with advanced malignancies were treated with T (2.0, 2.5, 3.0 or 3.5 mg/m2 in sequential cohorts) IV on days 1 and 8 of each three week cycle. B 1.3 mg/m2 iv was administered six hours following T on days 1 and 8, and alone on days 4 and 12. Pts were treated in cohorts of 3, the MTD dose was expanded to include 10 additional pts for PK analysis. There was no limit on prior therapies. DLT was defined as any gr 3 or 4 non-hematologic toxicity not reversible in 48h or any gr 3 thrombocytopenia lasting >7 days or associated with bleeding or any gr 4. Results: Tumor types included: breast (4), ovary (5), lung (3), others (12). 24 pts were entered (11M 13F). The median age was 55 (range: 34–83). DLT was thrombocytopenia, observed in two pts at 3.5 mg/m2 and one pt at 3.0 mg/m2 (MTD). Other grade 3 or 4 tox included fatigue, lymphopenia, hypomagnesemia, and hypertriglyceridemia. Of the 24 enrolled pts, stable disease was observed in 4 (4 or 5 cycles), 9 progressed, 5 were inevaluable and 6 are too early. PK analysis is pending. Conclusions: T and B delivered sequentially are well tolerated on a weekly schedule. DLT is thrombocytopenia. PK will be presented.(Supported by NCI Grant CA33572). [Table: see text]

A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3016-3016
Author(s):  
Patricia LoRusso ◽  
Mrinal M. Gounder ◽  
Manish R. Patel ◽  
Noboru Yamamoto ◽  
Todd Michael Bauer ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Geometric Mean ◽  
Dose Range ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

3016 Background: BI 907828, a highly potent and orally administered MDM2-p53 antagonist, showed antitumor efficacy in vivo, especially in TP53 wild-type MDM2-amplified de-differentiated liposarcoma (DDLPS) patient-derived xenografts and syngeneic models. Methods: NCT03449381 is a phase I study of BI 907828 in pts with solid tumors. The objectives of the dose-escalation part were to determine the maximum tolerated dose (MTD) based on the frequency of pts with dose-limiting toxicities (DLTs) during cycle 1, determine the recommended dose for expansion, and evaluate the safety and tolerability of two dosing schedules: BI 907828 given on day 1 of 21-day cycles (Arm A) or days 1 and 8 of 28-day cycles (Arm B). Dose escalation was guided by a Bayesian logistic regression model. The secondary objectives include pharmacokinetics (PK), pharmacodynamics and antitumor activity. Results: At January 15, 2021, 54 pts with advanced solid tumors (median of 2 lines of prior systemic therapies; range 0–11) were treated with BI 907828 (Arm A, 29 pts, dose range 10–80 mg; Arm B, 25 pts, dose range 5–60 mg). In Arm A, 5 pts experienced DLTs in cycle 1, including one Grade (Gr) 3 Nausea and one Gr 3 Thrombocytopenia at 45 mg, one Gr 3 Enterocolitis at 60 mg, and one Gr 4 Neutropenia and one Gr 4 Thrombocytopenia at 80 mg. In Arm B, 3 DLTs were reported: one Gr 4 Thrombocytopenia at 45 mg, one Gr 4 Neutropenia associated with Gr 4 Thrombocytopenia, and one Gr 3 Neutropenia at 60 mg. The most common Gr 3/4 treatment-related adverse events (AEs) were Thrombocytopenia (28.6%), Neutropenia (10.7%) and Nausea (10.7%) in Arm A, and Thrombocytopenia (16.6%) and Neutropenia (12.5%) in Arm B. Preliminary PK data indicate that BI 907828 reaches Tmax at 4–6 h. Mean plasma exposures (Cmax and AUC0-inf) increased with dose. The geometric mean (gMean) Clearance/F was 5–19 mL/min and the gMean apparent volume of distribution was 23–57 L. The gMean half-lives estimated after the 1st dose were 26–55 h. Inter-patient variability in exposure was moderate. An increase in the target engagement biomarker GDF-15 in plasma was observed. The mean fold-change from baseline ranged from 8 to 49. Antitumor activity was seen in both schedules. In Arm A, a confirmed PR was seen in 2 pts with MDM2-amplified LPS (one PR lasted > 2 years) and SD in 17 pts. In Arm B, 2 pts had PR (one confirmed in MDM2-amplified LPS and one not yet confirmed in MDM2-amplified pancreatic adenocarcinoma) and 14 had SD. Of note, 5 of 10 pts with DDLPS were progression-free for ≥9 months. Conclusions: BI 907828 showed a manageable safety profile, favorable PK properties and early signs of efficacy, especially in MDM2-amplified tumors. With both dosing regimens, DLTs were Neutropenia and Thrombocytopenia. Non-hematologic AEs, mainly gastrointestinal, were mostly low-grade and not dose-limiting. The MTD of 60 mg in Arm A (day 1 of 21-day cycles) and 45 mg in Arm B (days 1 and 8 of 28-day cycles) are awaiting confirmation. Clinical trial information: NCT03449381.

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