A first-in-human phase I study of CZ48, a lactone ring protected oral camptothecin, in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2578-2578
Author(s):  
Devalingam Mahalingam ◽  
Montaser F. Shaheen ◽  
John Sarantopoulos ◽  
Steven Weitman ◽  
Beppino C. Giovanella ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Poor Correlation ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label

2578 Background: CZ48, the 20-O-propionate ester of camptothecin (CPT), is a prodrug of CPT first described by Cao et al. in 1998. The side-chain is enzymatically cleaved in tissues. This gives rise to CPT, a potent inhibitor of topoisomerase I. Methods: An open-label, single-arm, dose-escalation Phase I study was performed to determine the maximum tolerated dose (MTD) of CZ48 in patients with advanced solid tumors. Initial dosing started qd po 80mg/m2, advancing to 2560mg/m2 for 21 consecutive days, followed by 7 days rest. Dosing was restarted in cohorts of 3 patients tid po at 18mg/m2 and escalated to 1g/m2on a 5 days on, 2 days off schedule for 28 days. Patients were prescreened by measuring CPT levels in plasma following a single pilot dose of CZ48. Dose was doubled until occurrence of at least Grade 2 adverse event, at which time 3+3 patient cohorts with a dose escalation of 33%-100% were implemented. DLT in 2/6 patients defined the MTD as the preceding DLT dose. PK parameters were measured prior to dosing, days 1-5, and day 28 of Cycle 1. Results: Poor absorption led to initial qd dosing reaching 2560mg/m2 with no signs of DLT. Subsequent tid dosing showed improved plasma levels and arrival at DLT. 34 patients were treated across 8 dose levels from 18 to 1000 mg/m2. The most frequent study-related adverse effects were cystitis, vomiting, diarrhea and fatigue. Grade IV toxicities observed were febrile neutropenia, anemia, and thrombocytopenia. Preliminary PK data in the qd dosing showed poor correlation between dose and Cmax or AUC, while PK in tid patients showed slightly improved correlation between dose and both CZ48 AUC (Pearson's correlation coefficient ϱ=0.476, p<0.01) and CZ48 Cmax(ϱ =0.51, p<0.01). Evidence of clinical activity with stable disease ≥ 6 months was observed in 2 heavily pre-treated colon and one breast cancer patient. Conclusions: The MTD of tid po CZ48 administered 5 days on, 2 days off of 28-day cycle is between 750 mg/m2 and 576 mg/m2. Overall toxicity is relatively mild, with DLT being cystitis and myelosuppression. Even with tid dosing, PK values correlate poorly to dose. A new formulation with 3-5 fold higher preclinical absorption values is being considered for introduction into the trial. Clinical trial information: NCT00947739.

A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3026-3026 ◽  
Author(s):  
Nicolas Isambert ◽  
Antoine Hollebecque ◽  
Yann Berge ◽  
Hein van Ingen ◽  
Silvano Brienza ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Hsp90 Inhibitor ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study

3026 Background: Debio 0932 is an oral second-generation heat shock protein 90 (HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier penetration, and promising anti-tumor activity both as monotherapy and combination against a broad range of tumors in pre-clinical models. Here we report the results of the dose escalation part of a phase I study in patients with advanced solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, non-randomized, 3 + 3 dose-escalation study to determine the maximum tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 days of treatment in patients with advanced solid tumours or lymphoma resistant to standard therapy. The starting dose in both treatment groups was 50mg. Doses were increased according to an algorithm based on observed toxicity and dose limiting toxicities (DLT). Tumor assessments were performed every 8 weeks. Results: Patient characteristics and results are summarized below. DLTs occurred at 1600mg in both dose groups. Adverse events (AE) were mostly CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac toxicity was observed. The main reason for treatment withdrawal was progressive disease. Investigator-reported cases of SD and PR were observed. Conclusions: Debio 0932 mono-therapy was generally well tolerated and showed promising signs of efficacy in patients with advanced solid tumors. The recommended phase II dose, established at 1000mg QD, will be tested in an additional 30 patients in an ongoing expansion study. A phase I-II study of Debio 0932 in combination with standard of care in the first- and second-line treatment of NSCLC is planned. [Table: see text]

A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Ying Cheng ◽  
Ying Liu ◽  
Jinhua Xu ◽  
Jing Zhu ◽  
Ying Wang ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Renal Cancer ◽  
Phase I Study ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Safety And Efficacy

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3015-3015
Author(s):  
Andrew Eugene Hendifar ◽  
Sant P. Chawla ◽  
Doris Quon ◽  
Victoria S Chua ◽  
Lita Fernandez ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Minor Response ◽  
Grade 3

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.

Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2562-2562 ◽  
Author(s):  
Manish R. Patel ◽  
Gerald Steven Falchook ◽  
Judy Sing-Zan Wang ◽  
Esteban Rodrigo Imedio ◽  
Sanjeev Kumar ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Human Monoclonal Antibody ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Drug Induced ◽  
Recommended Phase Ii Dose

2562 Background: Adavosertib (AZD1775; A) is a highly selective inhibitor of WEE1. This Phase I study (NCT02617277) investigated a range of doses and schedules for oral A plus IV durvalumab (DV), a human monoclonal antibody targeting PD-L1, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Four 28-day schedules (Sch) were evaluated with pts receiving DV 1500 mg on day (d) 1 of each schedule (Table). Patients continued treatment if they showed clinical benefit in the absence of any discontinuation criteria. Pts received A monotherapy for PK analysis prior to the start of combination therapy in Sch B, C (d –7 to –5) and D (d –9 to –5). MTD was determined using a 3+3 dose-escalation cohort design. Predefined dose-limiting toxicities (DLTs) were evaluated during the first cycle of study treatment. Results: 54 pts received A (most common primary tumor sites: colon, 19%; lung, 13%; breast, 11%). The most common grade ≥3 AEs were fatigue (15%), diarrhea (11%) and nausea (9%). DLTs were nausea (n = 2) and diarrhea (n = 1). 7 pts (13%) had A-related SAEs, including reversible and confounded drug-induced liver injury (Sch B 125 mg and Sch C; 1 each). Disease control rate (DCR) for the total cohort was 36%. Preliminary PK at 150 mg BID suggests adequate coverage for cell kill activity and no drug–drug interaction. Conclusions: The MTD/RP2D was A 150 mg BID (3 d on, 4 d off; treatment d 15–17, 22–24) with DV 1500 mg (d 1 Q4W); safety profile was considered acceptable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT02617277. [Table: see text]

scholarly journals A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors

2021 ◽  
Author(s):  
Martina Puglisi ◽  
L Rhoda Molife ◽  
Maja JA de Jonge ◽  
Khurum H Khan ◽  
Leni van Doorn ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Optimal Schedule ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Clinical Trial Registration

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1–5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov)

A five-arm, open-label, phase I/lb study to assess safety and tolerability of the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with chemotherapy or erlotinib in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3023-3023 ◽  
Author(s):  
Carlos Becerra ◽  
Jeffrey R. Infante ◽  
Lawrence E. Garbo ◽  
Michael S. Gordon ◽  
David A. Smith ◽  
...  
Keyword(s):  
Growth Factors ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Single Agent ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Post Dose

3023 Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherapy was given at full recommended doses. Erl was escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts have been enrolled across all arms except trametinib+nab-pac. Preliminary exposure results of trametinib+doc, erl, or pem suggest no PK drug-drug interaction. The predominant DLT for trametinib+doc without growth factors (MTD = 0.5 mg+60 mg/m2) was neutropenia. When administered with growth factors, trametinib+doc has been given up to 1.5 mg+75 mg/m2 with no DLTs. The predominant DLTs for trametinib+erl (MTD = 1 mg+100 mg) were diarrhea and mucositis and for trametinib+pem (MTD = 1.5 mg+500 mg/m2) were mucositis and febrile neutropenia. The MTD for trametinib+pem+carbo has not yet been determined. To date there are 5 PRs in the trametinib+doc group and 2 PRs in the trametinib+pem group. An NSCLC expansion cohort for trametinib+pem is enrolling. Conclusions: Trametinib+doc and trametinib+pem have shown acceptable tolerability and initial evidence of clinical activity.

Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2536-2536 ◽  
Author(s):  
Bojana Milojkovic Kerklaan ◽  
Martijn P. J. K. Lolkema ◽  
Lot A. Devriese ◽  
Emile E. Voest ◽  
A. Nol-Boekel ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Treated Patient ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Oral Topotecan

2536 Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-foot-syndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC0-∞ increased 1.58-fold (90%CI: 1.09–1.29) and Cmax increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n=7). Pazopanib AUC0-24 and Cmax ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC0-∞) and 1.78-fold (Cmax). Clinical trial information: NCT00732420.

An open-label, phase I trial of BI 754091 alone and in combination with BI 754111 in Asian patients (pts) with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3054-3054
Author(s):  
Yoon-Koo Kang ◽  
Kensei Yamaguchi ◽  
Do-Youn Oh ◽  
Shunsuke Kondo ◽  
Yasutoshi Kuboki ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Primary Endpoint ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Objective Response ◽  
Hepatocellular Cancer ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label

3054 Background: Dual blockade of immune checkpoint molecules, PD-1 and LAG-3, may enhance the anti-tumor response versus PD-1 blockade alone. This Phase I trial investigated BI 754091, an anti-PD-1 antibody, as monotherapy and in combination with BI 754111, an anti-LAG-3 antibody, in Asian pts with advanced solid tumors. Methods: This trial comprised 3 parts. Parts 1 and 2 (dose escalation) were in pts with unresectable/metastatic solid tumors. In Part 1, pts received BI 754091 240 mg intravenously (iv), every 3 weeks (q3w); in Part 2, pts received BI 754091 240 mg in combination with BI 754111 (400 mg, 600 mg or 800 mg iv, q3w). Dose escalation was guided by a Bayesian logistic regression model, with overdose control. The primary endpoint in Parts 1 and 2 was maximum tolerated dose (MTD) of BI 754091 alone or in combination with BI 754111, based on dose-limiting toxicities (DLTs) in Cycle 1. In Part 3, BI 754091 240 mg plus BI 754111 600 mg q3w was assessed in 4 expansion cohorts. Cohorts A–C included pts with: A) gastric/esophagogastric junction cancer; B) esophageal cancer; C) hepatocellular cancer; all had received ≥1 line of prior systemic therapy and no prior anti-PD-(L)1 therapy. Cohort D included pts who had received prior anti-PD-(L)1 therapy for the tumor types in Cohorts A–C. The primary endpoint in Part 3 was objective response (confirmed complete response or partial response [PR] per RECIST 1.1). Results: In Part 1, 6 pts received BI 754091 240 mg. In Part 2, 9 pts received BI 754091 240 mg plus BI 754111 (400 mg/600 mg/800 mg; n = 3 per cohort). No DLTs were reported in Parts 1 and 2. In Part 3, 121 pts were treated (97 [80%] male, median age 61 years [range 23–80]); Cohorts A/B/C/D included 33/33/20/35 pts. All-grade adverse events (AEs) and treatment-related AEs (TRAEs) were experienced by 96 (79%) and 47 (39%) pts, respectively. The most commonly reported AEs (all/≥G3) were pyrexia (21%/0%), decreased appetite (17%/2%), anemia (11%/6%), and nausea (9%/0%). 36 (30%) pts reported immune-related AEs, most commonly hypothyroidism, in 7 (6%) pts. Confirmed PR was observed in 6 pts (5%; Cohort A/B, n = 4/2) and 35 (29%) pts had stable disease (Cohort A/B/C/D, n = 9/11/10/5). Conclusions: MTD was not reached for BI 754091 monotherapy or for BI 754091 in combination with BI 754111. The recommended dose for the combination was determined as BI 754091 240 mg plus BI 754111 600 mg q3w. Treatment was well tolerated and consistent with that observed in the global trial. Preliminary anti-tumor activity was seen. Clinical trial information: NCT03433898 .

A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3611-3611
Author(s):  
Ben George ◽  
Donald A. Richards ◽  
William Jeffery Edenfield ◽  
Steven L Warner ◽  
Lars Mouritsen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

3611 Background: TP-1287 is a an orally bioavailable phosphate prodrug of alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a multicenter, Phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .

A First-in-human Phase I Study of TAS0728, an Oral Covalent Binding Inhibitor of HER2, in Patients With Advanced Solid Tumors With HER2 or HER3 Aberrations.

2021 ◽  
Author(s):  
Sarina A Piha-Paul ◽  
Analía Azaro ◽  
Hendrik Tobias Arkenau ◽  
Do-Youn Oh ◽  
Matthew D Galsky ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Covalent Binding ◽  
Temporal Association ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Grade 3

Abstract TAS0728 is an oral covalent binding inhibitor of human epidermal growth factor receptor 2 (HER2). A first-in-human open-label, dose-escalation, phase I study (NCT03410927) was initiated to investigate the safety and dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) and/or recommended phase II dose of TAS0728 in adults with advanced solid tumors with HER2 or HER3 overexpression, amplification or mutation. In total, 19 patients received TAS0728 at escalating doses from 50 to 200 mg BID for 21-day cycles. Following escalation of the dose to 200 mg BID, a total of two DLTs were observed, both cases of Grade 3 diarrhea (lasting >48 hours and not responsive to aggressive antidiarrheal treatment). Following de-escalation of the dose to 150 mg BID, another DLT of Grade 3 diarrhea was observed in one patient. Additionally, at 150 mg BID, one patient had a fatal cardiac arrest after receiving 1 cycle (21 days) of TAS0728. The etiology of the cardiac arrest event was not clear, however causal relationship to TAS0728 could not be excluded due to the temporal association observed. Partial responses were observed in 2 of 14 patients evaluable for TAS0728 treatment response. The study was stopped due to unacceptable toxicity during the dose-escalation as the overall risk-benefit ratio no longer favored the dose level being tested, therefore the MTD was not determined. ClinicalTrials.gov registration number: NCT03410927; registered on January 25, 2018.

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