An open-label expanded-access study to evaluate the safety, tolerability, and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and hepatic impairment.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2559-2559
Author(s):  
Wasif M. Saif ◽  
Lee S. Rosen ◽  
Michelle A. Rudek ◽  
Weijing Sun ◽  
Dale Randall Shepard ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hepatic Impairment ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
Hepatic Function ◽  
Moderate Hepatic Impairment ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Impaired Hepatic Function ◽  
Grade 3

2559 Background: The Phase 3 RECOURSE study showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (Mayer et al. N Engl J Med 2015;372:1909-19). A Phase 1 open-label study evaluated the safety and pharmacokinetics of FTD/TPI in patients with advanced solid tumors and varying degrees of hepatic impairment to inform dosing recommendations for these patients. Methods: Patients aged ≥18 years with advanced solid tumors, an Eastern Cooperative Oncology Group performance status ≤2, normal hepatic function, and mild, moderate, or severe impaired hepatic function according to the National Cancer Institute criteria were enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1-5 and days 8-12 of each 28-day cycle, except for those with severe impaired hepatic function (dose was to be determined). Results: 24 patients were enrolled to normal (n=8), mild (n=10), and moderate (n=6) groups. Study enrollment was stopped as 5/6 patients in the moderate group experienced elevated bilirubin levels (grade ≥3). The other baseline characteristics were similar across groups. Overall, 12 patients (50%) had at least 1 adverse event leading to study discontinuation: 2 in normal, 5 in mild, and 5 in the moderate hepatic impairment groups. Pharmacokinetic results are summarized in the table. Conclusions: The exposure to FTD or TPI was not increased by hepatic impairment and the patients who experienced grade 3 and 4 increased total bilirubin were not overexposed to FTD or TPI. Clinical trial information: NCT02301104. [Table: see text]

scholarly journals Pharmacokinetics and safety of rucaparib in patients with advanced solid tumors and hepatic impairment

2021 ◽  
Author(s):  
Nikolay Grechko ◽  
Viera Skarbova ◽  
Monika Tomaszewska-Kiecana ◽  
Rodryg Ramlau ◽  
Piotr Centkowski ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hepatic Impairment ◽  
Geometric Mean ◽  
Hepatic Function ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Moderate Hepatic Impairment ◽  
Advanced Solid Tumors ◽  
Castration Resistant Prostate Cancer ◽  
Normal Hepatic Function

Abstract Purpose The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors. Methods Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg. Concentrations of rucaparib and its metabolite M324 in plasma and urine were measured. Pharmacokinetic parameters were compared between hepatic function groups, and safety and tolerability were assessed. Results Sixteen patients were enrolled (n = 8 per group). Rucaparib maximum concentration (Cmax) was similar, while the area under the concentration–time curve from time 0 to infinity (AUC0–inf) was mildly higher in the moderate hepatic impairment group than in the normal control group (geometric mean ratio, 1.446 [90% CI 0.668–3.131]); similar trends were observed for M324. Eight (50%) patients experienced ≥ 1 treatment-emergent adverse event (TEAE); 2 had normal hepatic function and 6 had moderate hepatic impairment. Conclusion Patients with moderate hepatic impairment showed mildly increased AUC0–inf for rucaparib compared to patients with normal hepatic function. Although more patients with moderate hepatic impairment experienced TEAEs, only 2 TEAEs were considered treatment related. These results suggest no starting dose adjustment is necessary for patients with moderate hepatic impairment; however, close safety monitoring is warranted.

Absence of interaction of cabazitaxel on the pharmacokinetics of midazolam: Results of a drug–drug interaction study in patients with advanced solid tumors.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 126-126 ◽  
Author(s):  
Olivier Rixe ◽  
John Sarantopoulos ◽  
Chung-Tsen Hsueh ◽  
A. Craig Lockhart ◽  
Sharona Ross ◽  
...  
Keyword(s):  
Single Dose ◽  
Solid Tumors ◽  
Locally Advanced ◽  
Hepatic Function ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Fixed Sequence ◽  
Normal Hepatic Function ◽  
Grade 3

126 Background: Cabazitaxel (Cbz) is approved in combination with prednisone/prednisolone for the treatment of men with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen. In vitro studies showed that Cbz is mainly metabolized through CYP3A, resulting in inhibition of this family of enzymes. Midazolam (Mdz) is primarily metabolized by CYP3A4. We aimed to determine the effect of Cbz on CYP3A activity by comparing the pharmacokinetic (PK) properties of Mdz when administered alone and following co-administration with Cbz. Methods: An ongoing safety and PK study of Cbz in patients with metastatic or locally advanced solid tumors and varying degrees of hepatic impairment (NCT01140607) included a cohort with normal hepatic function to assess the effect of a single Cbz dose on the PK profile of a single dose of Mdz. This was an open-label, two-period, fixed-sequence study in patients aged between 45 and 60 years with advanced solid tumors and normal hepatic function. A single dose of Mdz (2 mg) was administered orally alone (Day –1) and at the end of a 1-hour infusion of Cbz (25 mg/m2) (Day 1), with a 24-hour interval between the two administrations of Mdz. Endpoints included AUC and AUClastof Mdz with and without Cbz administration, and safety evaluations. Results: Of the 13 patients enrolled and treated in the cohort, 11 patients were included in the PK analysis. Exposure (AUC and AUClast) and other PK parameters after a single administration of Mdz alone and in combination with Cbz (Day 1) were similar. The AUC ratio for Mdz administered alone or with Cbz was 0.97 (90% CI: 0.76–1.23). The AUClast ratio for Mdz administered alone or with Cbz was 1.04 (90% CI: 0.81–1.34). All 13 patients had ≥1 adverse event (AE), 11 (84.6%) experienced a Grade 3–4 AE, and 4 (30.8%) experienced a serious AE. The majority of Grade 3–4 AEs were haematological and no new or unexpected safety findings were observed. Conclusions: In this study, Cbz did not increase the plasma exposure of Mdz. This indicates that Cbz is not a CYP3A inhibitor in the clinical setting and can be administered in combination with drugs metabolized by CYP3A. Clinical trial information: NCT01140607.

scholarly journals Pharmacokinetics of Temsavir, the Active Moiety of the Prodrug Fostemsavir, in Subjects with Hepatic Impairment

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S430-S430 ◽  
Author(s):  
Heather Sevinsky ◽  
Mindy Magee ◽  
Peter Ackerman ◽  
Robert Adamczyk ◽  
Jennifer Karkas ◽  
...  
Keyword(s):  
Hepatic Impairment ◽  
Geometric Mean ◽  
Hepatic Function ◽  
Open Label ◽  
Post Dose ◽  
Viral Attachment ◽  
Linear Mixed Effects ◽  
Active Moiety ◽  
Impaired Hepatic Function ◽  
Hiv 1

Abstract Background Fostemsavir (FTR) is a prodrug of temsavir (TMR), a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells. TMR is primarily metabolized via hydrolytic and oxidative pathways; impaired hepatic function may alter TMR pharmacokinetics (PK). Methods AI438053 (NCT02467335) was an open-label, nonrandomized study in healthy subjects (HS) and subjects with hepatic impairment (HI), defined by Child-Pugh (CP) score: mild (CPA), moderate (CPB), or severe (CPC). HS were matched for age, body weight, and sex. Subjects received a single oral dose of FTR 600 mg fasted and serial PK samples for TMR were collected up to 96 hours post-dose. Unbound TMR at 1 and 3 hours post-dose was determined. Total and unbound PK parameters were derived by noncompartmental methods. Geometric mean ratios (GMR) and 90% confidence intervals (CI) for HI vs.. HS were derived using linear mixed-effects models. Subjects were monitored for adverse events (AEs). Results 18 subjects with HI (N = 6/CP group) and 12 HS received FTR and completed the study. Total and unbound TMR exposures increased with increasing HI severity (see Table). Total and unbound TMR CLT/F decreased with increasing HI severity. Mean % protein binding of TMR was 81.0% in HS and 79.9%, 81.9%, and 76.5% in CPA, CPB, and CPC HI, respectively, and was independent of TMR concentration. There were no deaths, serious AEs, or discontinuations during the treatment period. Conclusion TMR exposures increase with increasing severity of HI. The increase in TMR exposures in patients with mild or moderate HI is not expected to alter the safety profile of FTR. The risk/benefit of higher TMR exposures in severe HI is under evaluation. Disclosures H. Sevinsky, ViiV Healthcare: Employee, Salary; M. Magee, GlaxoSmithKline: Employee and Shareholder, Salary; P. Ackerman, ViiV Healthcare/GSK: Employee and Shareholder, Salary and Stock; R. Adamczyk, Bristol-Myers Squibb: Employee, Salary; J. Karkas, Bristol Myers Squibb: Employee and Shareholder, Salary; S. Lubin, Bristol-Myers Squibb: Employee, Salary; P. Ravindran, Bristol-Myers Squibb: Employee, Salary; C. Llamoso, ViiV Healthcare: Employee, Salary; T. Eley, Bristol-Myers Squibb: Former Employee during study conduct, Salary; K. Moore, ViiV Healthcare: Employee, Salary

A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Igor Puzanov ◽  
Patricia LoRusso ◽  
Kyriakos P. Papadopoulos ◽  
Christopher T. Chen ◽  
Yvan LeBruchec ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Single Agent ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

EAGLE: A phase 3, randomized, open-label study of durvalumab (D) with or without tremelimumab (T) in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6012-6012 ◽  
Author(s):  
Lisa F. Licitra ◽  
Robert I. Haddad ◽  
Caroline Even ◽  
Makoto Tahara ◽  
Mikhail Dvorkin ◽  
...  
Keyword(s):  
Group Performance ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Standard Of Care ◽  
Open Label ◽  
Phase 3 ◽  
Risk Of Death ◽  
Grade 3

6012 Background: EAGLE is a phase 3 study evaluating efficacy of D (anti-PD-L1 mAb) monotherapy and D+T (anti-CTLA-4 mAb) vs standard of care (SOC) in pts with R/M HNSCC who progressed following platinum-based therapy (NCT02369874). Methods: Pts were randomized 1:1:1 to D 10 mg/kg IV every 2 weeks (Q2W), D+T (D 20 mg/kg IV Q4W + T 1 mg/kg IV Q4W for 4 doses, then D 10 mg/kg IV Q2W), or SOC (investigator’s choice: cetuximab, taxane, methotrexate, or fluoropyrimidine-based regimen). The primary endpoint was overall survival (OS) with dual primary objectives of D+T vs SOC and D vs SOC. Additional endpoints included objective response rate (ORR), duration of response (DoR), and adverse events (AEs). Results: 240 pts were randomized to D, 247 to D+T and 249 to SOC. An imbalance for Eastern Cooperative Oncology Group performance status (ECOG PS) was seen in favor of the SOC arm (D, PS 0 = 26%, PS 1 = 74%; D+T, PS 0 = 26%, PS 1 = 74%; SOC, PS 0 = 32%, PS 1 = 68%). The risk of death was not statistically significantly different for D compared with SOC (HR: 0.88; 95% CI: 0.72–1.08; P = 0.20) or D+T vs SOC (HR: 1.04; 95% CI: 0.85–1.26; P = 0.76). Efficacy data are provided in the table. Treatment-related AEs Grade ≥3 were reported in 10.1% of pts (regardless of causality Grade ≥3 AEs were 41.4%) in the D arm, 16.3% (51.2%) for D+T, and 24.2% (44.2%) for SOC. Following treatment, 2% of pts in D, 5% in D+T and 15% in SOC received immunotherapy. Conclusions: D and D+T did not demonstrate a statistically significant improvement in OS compared to standard chemotherapy in pts with R/M HNSCC. Median OS and ORR of D arm were similar to other studies with checkpoint inhibitors. The SOC arm outperformed what has been seen for SOC arms in previous studies; subsequent immunotherapy may have confounded the OS analyses. The safety profile for D and D + T in R/M HNSCC is consistent with previous trials. Clinical trial information: NCT02369874. [Table: see text]

Safety of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3063-3063
Author(s):  
Melissa Lynne Johnson ◽  
Manish R. Patel ◽  
Mohamad Cherry ◽  
Yoon-Koo Kang ◽  
Kensei Yamaguchi ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
T Cell Response ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Median Treatment

3063 Background: LAG-3, an immune checkpoint receptor involved in T-cell regulation, is frequently co-expressed with PD-1. LAG-3 and PD-1 signaling contributes to immune cell exhaustion and reduces the immune response to tumor cells. Dual inhibition of PD-1 and LAG-3 may reactivate the T-cell response better than blockade of either individual pathway. Here, we report combined safety data from 4 trials investigating BI 754111, an anti-LAG-3 mAb, in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: Data from 2 phase I dose-escalation/expansion trials, 1 phase I imaging trial, and 1 phase II trial were included. Eligible patients had advanced and/or metastatic solid tumors with measurable disease and an Eastern Cooperative Oncology Group performance status ≤1. Patients received BI 754111 (intravenously [iv], 4–800 mg) in combination with BI 754091 (iv, 240 mg fixed dose) every 3 weeks (q3w). Patients remained on treatment until progressive disease or unacceptable toxicity. In each trial, safety was assessed by incidence and severity of adverse events (AEs), and graded according to Common Terminology Criteria for AEs, version 5. Results: Overall, 321 patients were treated with BI 754111 in combination with BI 754091 (200 [62%] male; median age, 63 years [range 18–88]). Median treatment exposure was 85 days (range 9–625). Of these patients, 282 (87.9%) had any AE (G≥3 in 99 [30.8%]). 285 patients received the 600 mg recommended phase II dose of BI 754111 plus BI 754091 240 mg q3w. Median treatment exposure in these patients was 74 days (range, 8–590). The table shows the 3 most common AEs and 4 most common immune-related AEs, and their frequency. 21 (7.4%) patients had AEs leading to study drug discontinuation, most commonly infusion-related reactions (IRRs) in 6 (2.1%) patients. Serious AEs (all-cause) occurred in 77 patients (27.0%), most commonly pleural effusion in 6 (2.1%) and deep vein thrombosis in 4 (1.4%) patients. 2 patients (0.7%) experienced an AE resulting in death (cardiac tamponade and acute kidney injury, both related to underlying diseases). Conclusions: The combination of BI 754111 and BI 754091 had a manageable safety profile, similar to other checkpoint inhibitors. Clinical trial information: NCT03156114, NCT03433898, NCT03697304, NCT03780725 . [Table: see text]

scholarly journals Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

2020 ◽  
Author(s):  
Yanshuo Cao ◽  
Ming Lu ◽  
Yu Sun ◽  
Jifang Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Trial ◽  
Open Label Phase ◽  
Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

scholarly journals Safety, efficacy and patient-reported outcomes with trifluridine/tipiracil in pretreated metastatic colorectal cancer: results of the PRECONNECT study

ESMO Open ◽  
2020 ◽  
Vol 5 (3) ◽  
pp. e000698
Author(s):  
Jean-Baptiste Bachet ◽  
Lucjan Wyrwicz ◽  
Timothy Price ◽  
Chiara Cremolini ◽  
Jean-Marc Phelip ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Progression Free Survival ◽  
Open Label ◽  
Patient Reported ◽  
Registration Number ◽  
Grade 3

BackgroundIn RECOURSE (, trifluridine/tipiracil significantly improved overall survival and progression-free survival (PFS) versus placebo in patients with pretreated metastatic colorectal cancer (mCRC). PRECONNECT was designed to further characterise safety and clinical use of trifluridine/tipiracil.MethodsIn this ongoing, international, multicentre, open-label trial, patients with pretreated mCRC received oral trifluridine/tipiracil 35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle. The primary endpoint was safety; secondary endpoints included PFS and quality of life (QoL).Results793 patients (median age 62 years) from 13 countries received trifluridine/tipiracil for a median of 2.84 months (IQR 2.64). Adverse events (AEs) were experienced by 96.7%; the most common (≥20% of patients) were neutropaenia, asthenia/fatigue, nausea, anaemia and diarrhoea. Grade ≥3 AEs occurred in 73.9% of patients, with the most common being neutropaenia (39.1% of patients), anaemia (9.8%) and asthenia/fatigue (5.0%). Median PFS was 2.8 months (95% CI 2.7 to 2.9). Median time to Eastern Cooperative Oncology Group performance status deterioration (≥2) was 8.9 months (range 0.03–14.72). There was no clinically relevant change from baseline in QoL.ConclusionsPRECONNECT showed consistent results with the previously demonstrated safety and efficacy profile of trifluridine/tipiracil, with no new safety concerns identified. QoL was maintained during treatment.Trial registration numberNCT03306394.

Phase I dose-escalating study of PM02734 in a 24-hour infusion schedule every 21 days in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2511-2511
Author(s):  
T. R. Evans ◽  
A. Oaknin ◽  
R. J. Jones ◽  
A. Vandermeeren ◽  
C. Coronado ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase Ii Studies ◽  
Flat Dose ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Escalating

2511 Background: PM02734 is a chemically synthesized depsipeptide with a broad spectrum of activity against solid tumors in vitro (breast, colon, lung, neuroblastoma, prostate, sarcoma and thyroid) and in vivo (breast, prostate, melanoma); as well as an acceptable non-clinical toxicology profile. Methods: Patients (pts) with metastatic or advanced solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT) and recommended dose (RD) of PM02734 infused over 24 hours every 21 days (d). The starting dose was 0.48 mg/m2. Cohorts of 1–6 pts were treated at different dose levels. Results: Thirty seven pts were treated in this study. The median age was 55 years (40–75), sex: males/females 20/19. The median PS was 1 (range 0–2). The most frequent cancer types were colon/ gastric/ sarcoma (n=8/5/5). Most patients were heavily pretreated, with a median of prior therapy lines of 4 (1–12). Patients were treated at 8 dose levels (0.48, 0.72, 1.0, 1.6, 2.4, 3.6, 5.4, and 6.8 mg/m2), the MTD was 6.8 mg/m2 and the RD was 5.4 mg/m2 (10 mg flat dose).Common toxicities grade ≤ 2 included asthenia, nausea/emesis, lymphopenia, injection site reactions and asymptomatic elevated transaminases (TAs). DLT were grade 3 asymptomatic, reversible TA elevations at 6.8 mg/m2. Preliminary PK data is characterized by long half life (>100 h), a wide distribution and high inter-patient variability. Clearance was not correlated with dose or body surface area (BSA), therefore, flat dose was implemented and the RD was explored with this schedule. Efficacy data showed one complete response (CR) of +28 months observed in a pt with metastatic large cell esophageal carcinoma, and five more showed stable disease (SD) for more than 3 months in different histologies. Conclusions: PM02734 shows to be safe, well tolerated and with evidence of activity (1 CR and 5 SD > 3 months) in pts with advanced solid tumors. The DLT was grade 3 asymptomatic and reversible TA elevations, and the RD for further phase II studies is 10 mg. [Table: see text]

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