A phase I, dose-escalation, multicenter study of ACT-PFK-158, 2HCl in patients with advanced solid malignancies explores a first-in-human inhibitor of glycolysis.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS494-TPS494 ◽  
Author(s):  
Rebecca Ann Redman ◽  
Paula Raffin Pohlmann ◽  
Michael R. Kurman ◽  
Gilles Tapolsky ◽  
Jason Chesney
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Phase 1 ◽  
Hypoxia Inducible Factor ◽  
Therapeutic Index ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Peripheral Blood Mononuclear ◽  
Activating Mutations ◽  
Dose Limiting Toxicity

TPS494 Background: In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1α, and activation of Ras and AKT converge to increase the activity of a regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). This enzyme synthesizes fructose-2,6-bisphosphate (F2,6BP), which is an activator of 6-phosphofructo-1-kinase, a crucial step of glycolysis that is tightly controlled by multiple metabolic feedback mechanisms and dictates the rate of glycolytic flow. The vast majority of pancreatic ductal adenocarcinomas and approximately 50% of colon adenocarcinomas harbor activating mutations in Ras and these tumors have been reported to be highly glycolytic. PFK158 is a potent small molecule inhibitor of PFKFB3 that is selectively cytotoxic to Ras-transformed epithelial cells and displays broad anti-tumor activity causing ~80% growth inhibition in several mouse models of human-derived tumors and syngeneic murine models of colon cancer. Importantly, IND-enabling safety and toxicity studies have demonstrated that PFK158 is well tolerated in rats and dogs with an expected good therapeutic index, lending support for a phase 1 trial that is now underway. Methods: The primary objective of the study is to describe the dose limiting toxicity and to determine either the maximum tolerated dose or biological effective dose of PFK-158 in a “3+3” cohort-based dose escalation design that follows a modified Fibonacci scheme. Multiple secondary endpoints have been incorporated to assess the effects of PFK-158 on peripheral blood mononuclear cell F2,6BP activity and on glucose uptake using FDG-PET imaging. This trial is currently enrolling at two US sites; Cohort 1 has been completed without dose-limiting toxicity and Cohort 2 is enrolling with two subjects under treatment as of September 2014. In conclusion, PFK158 is the first-in-man and first-in-class PFKFB3 inhibitor to be examined in a phase I trial and may have significant clinical utility either as a monotherapy or when combined with other targeted agents. Clinical trial information: NCT02044861.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

Sequential or combined designs for Phase I/II clinical trials? A simulation study

2019 ◽  
Vol 16 (6) ◽  
pp. 635-644 ◽  
Author(s):  
Caroline Rossoni ◽  
Aurélie Bardet ◽  
Birgit Geoerger ◽  
Xavier Paoletti
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Therapeutic Index ◽  
Maximum Tolerated Dose ◽  
Correct Decision ◽  
Operating Characteristics ◽  
In Series ◽  
Expansion Cohort

Background: Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. Both phases are increasingly combined. For Phase I/II trials, two main types of designs are debated: a dose-escalation stage to select the maximum tolerated dose, followed by an expansion cohort to investigate its activity (dose-escalation followed by an expansion cohort), or a joint modelling to identify the best trade-off between toxicity and activity (efficacy–toxicity). We explore this question in the context of a paediatric Phase I/II platform trial. Methods: In series of simulations, we assessed the operating characteristics of dose-escalation followed by an expansion cohort (DE-EC) designs without and with reassessment of the maximum tolerated dose during the expansion cohort (DE-ECext) and of the efficacy–toxicity (EffTox) design. We investigated the probability to identify an active and tolerable agent, that is, the percentage of correct decision, for various dose-toxicity activity scenarios. Results: For a large therapeutic index, the percentage of correct decision reached 96.0% for efficacy–toxicity versus 76.1% for dose-escalation followed by an expansion cohort versus 79.6% for DE-ECext. Conversely, when all doses were deemed not active, the percentage of correct decision was 47% versus 55.9% versus 69.2%, respectively, for efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Finally, in the case of a narrow therapeutic index, the percentage of correct decision was 48.0% versus 64.3% versus 67.2%, respectively, efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Conclusion: As narrow indexes are common in oncology, according to the present results, the sequential dose-escalation followed by an expansion cohort is recommended. The importance to re-estimate the maximum tolerated dose during the expansion cohort is confirmed. However, despite their theoretical advantages, Phase I/II designs are challenged by the variations in populations between the Phase I and the Phase II parts and by the lagtime in the evaluation of toxicity and activity.

Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: A phase I study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8586-8586
Author(s):  
D. S. Siegel ◽  
D. M. Weber ◽  
C. S. Mitsiades ◽  
M. A. Dimopoulos ◽  
J. L. Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Combination Methods ◽  
Novel Drug

8586 Background: Novel drug combinations may improve patient outcome in relapsed/refractory multiple myeloma (MM), which remains especially challenging to treat. Preclinical studies suggest that the histone deacetylase inhibitor vorinostat may have synergistic potential when combined with lenalidomide and dexamethasone. This phase I, multicenter, open-label study evaluated vorinostat plus lenalidomide and dexamethasone in patients (pts) with relapsed or refractory MM. The primary objective was to determine the maximum tolerated dose (MTD); other endpoints included overall safety and tolerability, as well as activity of the combination. Methods: Pts aged ≥18 years with relapsed or refractory MM were enrolled sequentially into 1 of 5 dosing levels ( Table ) using a standard 3+3 design for ≤8 cycles. Barring dose-limiting toxicities (DLTs) in the first cycle, dose escalation continued until the MTD was established. Response was assessed, and adverse events (AEs) were recorded. Results: Of 12 pts accrued to date, 11 (92%) have experienced ≥1 AE, with drug-related AEs reported by 6 pts (96% ≤Grade 2). The most common drug-related AEs (each in 4 pts) were fatigue and thrombocytopenia. Serious AEs in 2 pts (17%) were not considered drug-related. No pts discontinued due to AEs, and no DLT has been observed to date. Dose escalation to dose level (DL) 4 was achieved as no DLTs were observed in DLs 1–3. The MTD has not yet been reached. Of 11 pts evaluable for efficacy, best responses include: complete response in 1 pt, partial response in 2 pts, minimal response in 2 pts, and stable disease in 3 pts; 3 pts had progressive disease (PD). Currently, 9 pts remain on treatment, with 3 pts discontinuing treatment due to PD. Conclusions: These preliminary data suggest that vorinostat with lenalidomide and dexamethasone represents a well tolerated and active novel oral combination therapy for the treatment of relapsed/refractory MM. [Table: see text] [Table: see text]

Phase I dose escalation of the oral histone deacetylase inhibitor (HDACi) resminostat in combination with FOLFIRI in colorectal cancer (CRC) patients: The SHORE trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3625-3625
Author(s):  
Henning Schulze-Bergkamen ◽  
Dirk Jaeger ◽  
Hans-Georg Kopp ◽  
Frank Mayer ◽  
Michael Bitzer ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Synergistic Effects ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Moderate Intensity ◽  
Hematological Toxicity ◽  
Open Label ◽  
Cancer Models ◽  
Gi Symptoms

3625 Background: Resminostat is a novel oral HDAC inhibitor with broad activity in various cancer models. In CRC models, resminostat revealed synergistic effects with 5-FU and irinotecan/SN-38, indicating its (re-)sensitization potential when applied in combination therapy. Furthermore, resminostat downregulates thymidylate synthase, involved in drug resistance to 5-FU and effectively inhibits HDAC2, one of the target enzymes believed to critically support development of CRC. The phase I/II SHORE trial investigates resminostat in combination with FOLFIRI in patients previously treated with 5-FU. Methods: Patients (pts) with advanced CRC having previously received 5-FU alone or in combination with other agents who were scheduled for FOLFIRI in second or later treatment lines were included. The phase I comprised an open-label, inter-patient, ‘3+3’ dose escalation design with increasing doses of resminostat combined with standard FOLFIRI. Pts received resminostat on 5 consecutive days, followed by a 9-day drug free period (‘5+9’ scheme, i.e. 14-day cycles). On days 3 and 4 of each cycle (C), FOLFIRI was administered. Primary objective of the Phase I part was to determine safety and tolerability, the maximum tolerated dose and pharmacokinetics of the combination. Results: 17 pts (median age 61 yrs; 12 males; 11 ECOG 0; 6 ECOG 1; median therapy line 2 [2-6]) were enrolled in 4 dose levels of resminostat 200, 400, 600 mg QD (3 pts each) and 400 mg BID (6 pts) plus FOLFIRI. Two pts discontinued in C1 and were replaced. No DLT occurred. AEs consisted mainly of GI symptoms of mild and moderate intensity (nausea, vomiting and diarrhea) leading to decreased electrolyte plasma levels in some pts. In the highest dose level tested (400 mg BID) hematological toxicity, mainly neutropenia up to grade 4, was observed leading to dose reductions in 3 pts in C3 and C7. No objective responses were reported, however some pts showed SD for prolonged time (up to 32 w). Results of the completed phase I part will be reported. Conclusions: The combination of resminostat with standard FOLFIRI was safe and well tolerated warranting continuation into the Phase II part of the study. Clinical trial information: NCT01277406.

Phase I study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced-stage ovarian cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 2-2 ◽  
Author(s):  
Premal H. Thaker ◽  
William Hampton Bradley ◽  
Charles A. Leath ◽  
Camille Catherine Gunderson ◽  
Nicholas Borys ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Primary Objective ◽  
Newly Diagnosed ◽  
Peritoneal Cancer ◽  
Interval Debulking Surgery ◽  
Objective Clinical Response ◽  
Dose Levels ◽  
Dose Limiting Toxicity ◽  
Ongoing Phase

2 Background: This study evaluated weekly intraperitoneal (IP) GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine-cholesterol lipopolymer, with intravenous (IV) weekly taxane (T) and carboplatinum (C) every 3 weeks in epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). The primary objective was to evaluate the tolerability and safety of GEN-1 with NAC. Secondary objectives included objective clinical response and pathological response at interval debulking surgery (IDS). Methods: Newly diagnosed EOC patients with no prior therapies were eligible. The trial utilized a 3+3 design with dose escalation in ~30% increments at GEN-1 IP dose levels of 36 mg/m2, 47 mg/m2, 61 mg/m2, and 79 mg/m2 weekly for 8 treatments with concurrent IV T/C. Dose-limiting toxicity (DLT) was based on the first 4 doses of GEN-1 administered. Results: 18 patients were enrolled into the study and 12 of those patients received all 8 treatments with no DLTs. 14 patients underwent IDS. Most common related toxicities were Gr 1 nausea, abdominal pain and fatigue. One patient experienced Gr 2 fevers associated with GEN-1 but responded to acetaminophen and fluids. Conclusions: Adding GEN-1 to T/C is safe and appears to be active in EOC patients receiving NAC. Dose limiting toxicity was not reached and further dose escalation and safety and activity is being evaluated in an ongoing phase I/II study. Clinical trial information: NCT02480374. [Table: see text]

Cefixime Allows Greater Dose Escalation of Oral Irinotecan: A Phase I Study in Pediatric Patients With Refractory Solid Tumors

2006 ◽  
Vol 24 (4) ◽  
pp. 563-570 ◽  
Author(s):  
Wayne L. Furman ◽  
Kristine R. Crews ◽  
Catherine Billups ◽  
Jianrong Wu ◽  
Amar J. Gajjar ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Maximum Tolerated Dose ◽  
Severe Diarrhea ◽  
Dose Limiting Toxicity

PurposeIrinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea.Patients and MethodsIn separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime.ResultsWithout cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ng×h/mL; standard deviation [SD], 6.8 ng × h/mL v 10.4 ng × h/mL; SD, 4.3 ng × h/mL, respectively; P = .030).ConclusionCefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

Phase I, pharmacokinetic (PK), pharmacodynamic study of paricalcitol [19-nor-1 alpha, 25-(OH)2 D2] in combination with gemcitabine [2’,2’ difluorodeoxycytidine] in patients with advanced malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12010-12010
Author(s):  
D. Trump ◽  
M. Javle ◽  
J. Muindi ◽  
L. Pendyala ◽  
W. Yu ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Cytidine Deaminase ◽  
Maximum Tolerated Dose ◽  
Chemotherapeutic Agents ◽  
Fixed Dose ◽  
Unknown Primary ◽  
Peripheral Blood Mononuclear

12010 Background: Calcitriol+ gemcitabine (gem) combination results in synergistic anti-tumor effect in preclinical models. Cytidine deaminase (CDD) inactivates gem into 2’,2’-difluorodeoxyuridine (dFdU) and its overexpression may lead to gem resistance. Calcitriol decreases CDD activity in peripheral blood mononuclear cells (PBM). Paricalcitol is cytotoxic in vitro and synergistic with several chemotherapeutic agents, including gem. We are conducting a phase I study of paricalcitol + fixed-dose gem. Objectives: The primary aim is to determine maximum tolerated dose (MTD) of the combination in patients (pts) with advanced cancer. Secondary aims are to evaluate toxicity, the effect of paricalcitol on gem PK, CDD activity in PBM and clinical outcome. Methods: Each cycle is 4 weeks: Gem 800 mg/m2 (over 80 min) weekly × 3, starting day 1; paricalcitol weekly, 24 h prior to gem, starting day 7. Standard 3+3 dose-escalation schema is used. Planned paricalcitol doses are 0.24, 0.72, 1.20, 1.8, 2.4 μg/kg, and 25% increments till MTD. Gem PK and CDD activity (PBM) are studied on days 1 and 8. Paricalcitol PK studies are obtained on day 7. Results: Fourteen pts with the following cancers: pancreatic (n=3), colon (n=3), lung (n=5), esophageal (n=1), bladder (n=1) and unknown primary (n=1) have been enrolled. No dose limiting toxicities have occurred. Median of 2 cycles were delivered (range 1–9). Grade 3 toxicities: anemia (n=3 pts), neutropenia (n=5), thrombocytopenia (n=3), thrombosis (n=2), anorexia (n=1), hypophosphatemia (n=1), dehydration (n=1), syncope (n=1), pneumonia (n=1) and chills (n=1). Grade 4 toxicities: anemia (n=1) and neutropenia (n=1). Hypercalcemia (> grade 1) did not occur. Stable disease occurred in 2 and progressive disease in 3. Conclusions: MTD was not reached at 1.8 μg/kg of paricalcitol with gem 800 mg/m2/week. Dose escalation is ongoing. PK data will be presented at meeting. Supported by NIH grants CA67267 and CA85142. [Table: see text]

Phase I combination study of trabectedin (T) and capecitabine (C) in patients with advanced malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2079-2079
Author(s):  
L. Gore ◽  
E. Rivera ◽  
K. Lavallee ◽  
S. Holden ◽  
S. Grolnic ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Excision Repair ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Limiting Toxicity

2079 Background: T binds to the minor groove of DNA, synergizes with functional nuclease excision repair and targets inducible transcription. T is active in several tumor types and exhibits preclinical synergy with C. The primary objective of this study is to determine the maximum tolerated dose (MTD) of T in combination with C. Secondary objectives include safety and pharmacokinetic (PK) analyses. Methods: Pts with advanced cancer, performance status 0–1 and adequate organ function are eligible. Pts received T starting at 0.4 mg/m2 over 3 hours on day 1 followed by C on days 2 through 15. The initial dose of C was 2000 mg/m2/day and was reduced to 1600 mg/m2/day due to GI dose-limiting toxicity. Dose escalation of T continued. Cycles are repeated every 3 weeks, with PK sampling included. Standard “3+3” dose escalation design, definitions of dose limiting toxicity (DLT), and dose modification for toxicity are implemented. Results: To date, 30 patients have received 112 cycles (range 1–12, median 4) of treatment at 7 dose levels. Two of 3 pts at dose level 4 (C 2000 mg/m2/d and T 0.9 mg/m2) and 2/6 pts at dose level 3 (C 2000 mg/m2/d and T 0.75 mg/ m2) developed gastrointestinal DLT (emesis, diarrhea, pancreatitis). C was subsequently reduced to 1600 mg/m2/d and a new T dose escalation was initiated at 0.6 mg/m2. Treatment has been well tolerated with C 1600 mg/m2/d and T up to the current dose of 0.9 mg/m2 (dose level 4a), with 1of 6 subjects experiencing grade 1 alkaline phosphatase. The most frequently reported related grade 3–4 adverse events (AEs) are diarrhea (23%), neutropenia (20%), nausea (16.6%), hand-foot syndrome (16.6%) and vomiting (13%). Anti-tumor activity to date includes a confirmed partial response lasting 8 months (m) in a patient with cholangiocarcinoma, and prolonged stable disease in 2 patients with breast cancer (6 and 7m), ovarian cancer (11m) and chondrosarcoma (9m). Conclusions: The combination of C 1600mg/m2/d and T up to 0.9mg/m2 is tolerable and has promising activity in several tumor types. Dose escalation of T continues at 1.1 mg/m2. Biologic and pharmacokinetic analyses will be presented. [Table: see text]

A phase I dose-escalation of trifluridine/tipiracil in combination with oxaliplatin in metastatic colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3626-TPS3626 ◽  
Author(s):  
Antoine Hollebecque ◽  
Guillem Argiles ◽  
Thierry Andre ◽  
Andres Cervantes ◽  
Catherine Leger ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Activity ◽  
Metastatic Colorectal Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Nude Mouse Model

TPS3626 Background: Trifluridine/tipiracil, also known as TAS‐102, is a combination of an antineoplastic thymidine‐based nucleoside analogue (trifluridine) and a thymidine phosphorylase inhibitor (tipiracil hydrochloride). The antitumor activity of combined trifluridine/tipiracil and oxaliplatin has been studied in gastrointestinal tumor xenografts, including a 5‐FU resistant subline, using a nude mouse model. This study demonstrated increased antitumor activity for the combination compared to trifluridine/tipiracil or oxaliplatin alone (p < 0.001) (Nukatsuka et al., Anticancer Res 2015). These data support the rationale for clinical use of the combination. We describe a phase 1, international, dose-escalation study of the combination in metastatic colorectal cancer (mCRC). Methods: This trial includes mCRC patients pretreated with at least one line of standard chemotherapy. The 14‐day administration schedule of trifluridine/tipiracil differs from current clinical practice to avoid overlapping toxicity, notably decreased neutrophils due to oxaliplatin or trifluridine/tipiracil. Trifluridine/tipiracil is administered orally (cohort 1: 25 mg/m² bid; cohort 2: 30 mg/m² bid; cohort 3: 35 mg/m² bid) from day 1 to 5; and oxaliplatin at 85 mg/m² (with a possibility to reduce to 65 mg/m²) on day 1. The primary objective is to determine the maximum tolerated dose (MTD) through a 3+3 design. Secondary objectives include safety, pharmacokinetics, and preliminary efficacy (overall survival, progression‐free survival, overall response rate and biomarkers). As of December 2016, no dose‐limiting toxicities had been reported in cohorts 1 or 2. The MTD has not yet been reached and dose‐escalation continues with enrollment in cohort 3 at full dose for both drugs (trifluridine/tipiracil 35 mg/m² bid and oxaliplatin 85 mg/m²). Once established, the MTD will be confirmed in 6 additional patients to define the recommended dose to be used in the expansion part of the study planned in the same patient population. The results of the dose‐escalation part are expected in 2017. (NCT02848443). Clinical trial information: NCT02848443.

Final report: A phase I trial of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and metastatic pancreatic cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 398-398
Author(s):  
Heloisa P. Soares ◽  
Taymeyah E. Al-Toubah ◽  
Richard D. Kim ◽  
Jongphil Kim ◽  
Neron K Lewis ◽  
...  
Keyword(s):  
Phase I ◽  
Phase 1 ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Therapeutic Window ◽  
Final Report ◽  
Gene Encoding ◽  
Grade 3

398 Background: The PI3K/mTOR pathway has emerged as a potential target for anticancer therapy. Considerable evidence suggests that targeting a single isoform of PI3K (p110α) would have sufficient antitumor activity and improved therapeutic window. Further, PI3KCA mutations, gene encoding isoform p110α, are described in pancreatic adenocarcinoma (PAC). BYL719 is an oral class I α-specific PI3K inhibitor that showed preclinical anti-tumor activity. The first in human phase 1 trial of BYL719 defined the maximum tolerated dose (MTD) at 400mg QD. Methods: This was a phase I, single center study (standard 3+3 design). The primary objective was to determine the MTD of BYL719 in combination with gemcitabine (G) and nab-paclitaxel (nabP) as frontline therapy in locally advanced or metastatic PAC. BYL719 was given orally daily (Table). Patients (pts) were restaged q2 cycles. The study was closed prematurely due to slow accrual. Results: Fifteen pts were enrolled (median age was 58 years). Three pts each participated in cohorts 1 and 2. Nine pts were enrolled in cohort 3, but 4 were replaced (3 pts withdrew consent prior to evaluation and 1 missed > 10 days of treatment). One pt in cohort 3 had DLT related to grade 3 nausea and vomiting. A total of 19 grade 3 and 4 adverse events were records as probably or possibly associated with BYL719. The most common ones were hyperglycemia, anemia, and neutrophil count decreased. One pt developed Posterior reversible encephalopathy syndrome (PRES) during cycle 7. Although we could not completely exclude BYL719 as a cause, PRES was attributed to G. One pt had sudden death during cycle 4 that was attributed to progression. Only 8 pts were evaluable for response. Two had stable disease, 5 had partial responses and 1 had progression. The median progression-free survival and overall survival were 5.36 months (1.6 to 10 months) and 8.74 months (3.8 to 21.2 months) respectively. Conclusions: The combination of full doses of G + nabP and BYL719 can be safely administered up to BYL dose of 250 mg/day. Clinical trial information: NCT02155088. [Table: see text]

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