A phase Ib study of oral Chk1 inhibitor LY2880070 as monotherapy in patients with advanced or metastatic cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3579-3579
Author(s):  
Wilson H. Miller ◽  
Quincy S. Chu ◽  
Nathaniel Bouganim ◽  
Derek J. Jonker ◽  
Gerald Batist ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Competitive Inhibitor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Mitotic Catastrophe ◽  
Total Daily Dose ◽  
Open Label ◽  
Best Response ◽  
Daily Dose ◽  
Anti Tumor Activity

3579 Background: LY2880070 (LY) is an orally-administered, selective adenosine triphosphate-competitive inhibitor of checkpoint kinase 1 (Chk1). LY blocks the checkpoint response, and Chk1 inhibition results in mitotic catastrophe to produce apoptosis. Methods: This 2-part, open-label multi-center study explores the safety, pharmacokinetics (PK) and anti-tumor activity of LY in patients with advanced or metastatic cancers. The primary objective of this study was to determine the maximum tolerated dose (MTD) for multiple escalating oral doses of LY. Secondary objectives were to: 1) Characterize the dose-limiting toxicities (DLTs) and overall safety profile for LY; 2) Evaluate the PK of LY; and 3) Evaluate the anti-tumor activity of LY. Patients received LY orally in 21-day cycles in two treatment arms: 1) A multiple ascending dose (MAD) arm in patients with normal/intermediate CYP2D6 metabolism; or 2) An arm with LY administered as monotherapy to CYP2D6 poor metabolizers. Results: The MTD in normal/intermediate CYP2D6 metabolizers was 200 mg BID daily. A dose of 400 mg QD was not tolerated even with the use of anti-emetics. However, BID administration (same total daily dose) made LY tolerable. Dose-limiting toxicities were predominantly vomiting, nausea, and fatigue, and appeared to be correlated with Cmax. The mean half-life was 5.35 (+/- 2.3) hours. BID dosing provided maintenance of the AUC (3271.4 h∙ng/mL 200 mg BID vs 3377.9 h∙ng/mL 400 mg QD) while lowering Cmax (350.0 ng/mL 200 mg BID vs 691.9 ng/mL 400 mg QD) and increasing Cmin, compared to QD dosing of the same total daily dose. Importantly, BID administration of 200 mg LY resulted in a median Cmin at steady-state that remains above the IC80 for 12 h/day and above the IC50 for 24 h/day. Five patients had a best response of SD for a duration of ≥ 6 cycles. Conclusions: LY was tolerated in a daily BID schedule. The toxicity profile can be modulated by changing the dosing frequency from QD to BID while administering the same daily dose. LY may be a potential combination therapy with DNA damaging agents. Study #: NCT02632448 . This study is sponsored by Esperas Pharma Inc., 1255 boul. Robert-Bourassa #1610, Montreal, Qc, H3B 3X3. Clinical trial information: NCT02632448 .

A phase Ib study of oral Chk1 inhibitor LY2880070 in combination with gemcitabine in patients with advanced or metastatic cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3581-3581 ◽  
Author(s):  
Quincy S. Chu ◽  
Derek J. Jonker ◽  
Diane M. Provencher ◽  
Wilson H. Miller ◽  
Nathaniel Bouganim ◽  
...  
Keyword(s):  
Adverse Events ◽  
Metastatic Cancer ◽  
Competitive Inhibitor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Total Daily Dose ◽  
Open Label ◽  
Daily Dose ◽  
Multi Center Study ◽  
Anti Tumor Activity

3581 Background: LY2880070 (LY) is an oral, selective competitive inhibitor of checkpoint kinase 1 (Chk1). Chk1 inhibitors are known to increase the anti-tumor efficacy of agents such as gemcitabine (GEM), which induce replication stress. Synergy between these two agents has been applied to the clinical setting. Methods: This two-part, open-label multi-center study explores the safety, pharmacokinetics (PK), and anti-tumor activity of LY in patients with advanced or metastatic cancers. The primary objective of this study was to determine the maximum tolerated dose (MTD) for multiple escalating oral doses of LY in combination with GEM. Secondary objectives were to: 1) Characterize the dose-limiting toxicities (DLTs) and overall safety profile for LY; 2) Evaluate the PK of LY; and 3) Evaluate the anti-tumor activity of LY. Patients received LY in a variety of different dose regimens, in combination with GEM (50 to 800 mg/m2) on days 1, 8, and 15 (optional) of a 21-day cycle. Results: The combination of LY with GEM required lower doses of both LY (vs 200 mg BID monotherapy RP2D dose) and GEM (vs approved doses). The dose levels explored ranged from LY:GEM of 10 mg QD:800 mg/m2 to 50 mg BID:100 mg/m2. BID dosing of LY was implemented in order to maximize the total daily dose and avoid the adverse events that appeared to correlate with Cmax. Treatment-emergent adverse events in > 40% of patients included vomiting, nausea, and fatigue. DLTs included reduced platelet count (Gr2), fatigue (Gr3), diarrhea (Gr3), and thrombocytopenia (x2, Gr2). The t1/2 of LY was ~ 5 h, and was not significantly affected by combination with GEM. Two patients had a best overall response of SD for a duration of ≥ 6 cycles, and a confirmed PR was observed in an ovarian cancer patient who had failed multiple regimens. Conclusions: LY was tolerated in combination with lower dose GEM. The toxicity profile can be modulated by changing the dosing frequency from QD to BID while administering the same daily dose. LY may be good candidate for combination therapy with DNA damaging agents. Clinical trial information: NCT02632448 .

First-in-human phase I study of LY2780301, an oral P70S6K/AKT inhibitor, in patients with refractory solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3005-3005 ◽  
Author(s):  
Emiliano Calvo ◽  
Karim Adnane Benhadji ◽  
Analia Azaro ◽  
Ignacio Duran ◽  
Guillem Argiles ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Competitive Inhibitor ◽  
Primary Objective ◽  
Total Daily Dose ◽  
Akt Inhibitor ◽  
Best Response ◽  
Daily Dose ◽  
Number Of Cycles ◽  
Dose Levels ◽  
Study Therapy

3005 Background: LY2780301is an oral potent, highly selective ATP competitive inhibitor against p70S6 kinase and AKT. We report on safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity from the first-in-men study of LY2780301 in solid tumors.  Methods: Eligible pts (ECOG≤1) had relapsed solid tumors, adequate hematologic, renal, and hepatic functions. Using a predictive pre-clinical PK/PD model and non-clinical toxicology data, a total daily dose of 100-1000 mg, was selected.  LY2780301 was given either once or twice daily for 28-day cycle until disease progression. Dose escalation (3+3 design) was based on CTCAE V4 toxicities. The primary objective was to define the recommended phase 2 dose of LY2780301. Secondary objectives were PK, PD (pS6 in skin), and preliminary antitumor activity. Results: 32 patients were treated at dose levels from 100mg – 500mg total daily dose.  LY2780301 was well tolerated at all dose levels   No dose-limiting toxicities were observed in cycle 1.  Common toxicities potentially related to study therapy included:  constipation (7pts), fatigue (5pts), nausea (4pts), diarrhea (3pts), and vomiting (3pts).  Grade 3/4 toxicities potentially related to study therapy were: anemia (3pts), increased ALT/AST (1pt), and increased GGT (1pt).  Average number of cycles received across all dose levels was 2. There were no partial or complete responses; best response observed was prolonged stable disease for 6.5 cycles. Plasma exposures of LY278030 exceeded predicted efficacious dose in all pts (AUC 0-24H >25000 ng*hr/mL). Increase in exposure with dose was observed (QD or BID) with significant inter-pt variability. The exposure increase was less than linear with dose. Preliminary PK parameters are CL/F 4.5L/h and t1/2 of 24 hours. pS6 assessment  in skin showed inhibition in > 50% of pts receiving 400-500 mg per day. Positive correlation with the exposure of the didesmethyl metabolite was observed. Conclusions: LY2780301displayed favorable safety profile, and high PK exposures in the range of efficacious dose. The recommended dose will be defined in the range between 300 and 500 mg. Further exploration of PK/PD effect in mesothelioma is ongoing. 

An open-label, multi-center phase I study of the safety and tolerability of the novel immunomodulatory agent PG545 in subjects with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3083-3083 ◽  
Author(s):  
Keith Dredge ◽  
Todd Brennan ◽  
Michael Paul Brown ◽  
Jason D. Lickliter ◽  
Darryn Bampton ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Nk Cells ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
100Mg Dose ◽  
Immunomodulatory Agent ◽  
Recist 1.1 ◽  
Best Response ◽  
Plasma Cytokines

3083 Background: PG545 (pixatimod, pINN) is a novel immunomodulatory agent which stimulates dendritic cells (DC) via TLR9/IL-12 pathway to activate natural killer (NK) cells. It also inhibits tumour-associated macrophages in cancer models. We report on safety, PK, PD, and antitumor activity of PG545 monotherapy. Methods: In this dose escalation (3+3 design) study, eligible pts (ECOG≤1) with advanced solid malignancies who failed standard therapies received PG545 once weekly as a 1-hour i.v. infusion until disease progression or discontinuation due to intolerability. The primary objective was determination of the maximum tolerated dose (MTD). Secondary objectives evaluated safety, antitumor activity based on RECIST (1.1) criteria, PK and PD (plasmacytoid DC & NKp46+NK cells from PBMC, and plasma cytokines/chemokines). Results: The study recruited 23 subjects across four cohorts (25, 50, 100 & 150 mg). Three dose limiting toxicities (DLTs) - hypertension (2), epistaxis (1) - occurred in the 150 mg cohort, which was identified as a non-tolerated dose level. No DLTs occurred in the 100 mg cohort, which was identified as the MTD. Six SAEs were reported to be possibly or likely related to PG545 treatment. No RECIST 1.1 objective responses were reported; best response was prolonged stable disease up to 24 weeks (mCRC), with disease control rate in evaluable subjects of 38% (6/16) at eight weeks. Exposure (AUC0-last) was proportional up to 100mg and mean half-life was 144 hours. At 50 and 100mg dose levels, two subjects in each cohort exhibited up to 4-fold increased numbers of NKp46+NK cells, IFN-α-producing pDCs, and increases (up to 25-fold) in plasma IFN-γ, TNF-α, IP-10 and MCP-1. Conclusions: PG545 is well tolerated up to 100 mg once-weekly via i.v. infusion. Human exposure data at 50mg and 100mg reach exposures consistent with those required for preclinical efficacy. Preliminary PD data support the proposed mechanism of action, which represents a promising approach to improve the efficacy of existing therapies. These data, and the absence of toxicities associated with chemo- or immunotherapies, support the development of PG545 in combination clinical trials. Clinical trial information: NCT02042781.

Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2574-2574 ◽  
Author(s):  
Jeffrey R. Infante ◽  
Philippe L. Bedard ◽  
Geoffrey Shapiro ◽  
Todd Michael Bauer ◽  
Amy Prawira ◽  
...  
Keyword(s):  
Phase 1 ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
In Vivo Models ◽  
Best Response ◽  
Gastrointestinal Side Effects ◽  
Anti Tumor Activity

2574 Background: PTC596 is an oral investigational new drug that reduces levels of BMI1, a protein required for CSC survival. PTC596 reduced the number of CSCs in preclinical models and slowed growth rates of tumor xenografts in rodent models. The primary objectives of this first-in-human trial of PTC596 were to determine safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives included exploratory assessments of biological efficacy, pharmacodynamic changes and anti-tumor activity. Methods: A Phase I multi-center, open-label study was conducted in patients with advanced solid tumors using a modified 3+3 design, followed by a dose-confirmatory 10-patient expansion. PTC596 was administered using bodyweight-adjusted twice-per-week (biw) oral dosing in 4 week cycles. Dose escalation and MTD were based on observed cycle 1 DLTs. Anti-tumor activity was assessed by RECIST 1.1. Results: A total of 31 patients with a broad range of tumor types were enrolled at dose levels of 0.65 (N = 3), 1.3 (N = 3), 2.6 (N = 3), 5.2 (N = 11), 7 (N = 8) and 10 mg/kg (N = 3). Nausea, vomiting, and diarrhea were the most common all grade adverse events, though usually mild and manageable. At 10 mg/kg one patient experienced DLTs of neutropenia, mucositis, and thrombocytopenia. The other two patients at this dose level also experienced poor tolerability with Grade 2 nausea, vomiting, and diarrhea that may be partially due to the overall pill burden and excipients. The recommended dose for the expansion and further study was 7 mg/kg. Over the dosing range, plasma concentrations of PTC596 increased in an approximately dose-proportional manner and at doses of 2.6 mg/kg and above exceeded those associated with activity in vitro and in vivo models. Best response was stable disease in 5 patients including two with minor radiographic reductions in tumor volume. Conclusions: PTC596 is tolerable with manageable gastrointestinal side effects. At 7 mg/kg biw exposures exceeded those associated with preclinical activity and future clinical studies are planned for this first-in class molecule that targets CSCs. Clinical trial information: NCT02404480.

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

scholarly journals 134 Long-Term Deutetrabenazine Treatment Is Associated with Sustained Treatment Response in Tardive Dyskinesia: Results from an Open-Label Extension Study

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 284-285 ◽  
Author(s):  
Robert A. Hauser ◽  
Hadas Barkay ◽  
Hubert H. Fernandez ◽  
Stewart A. Factor ◽  
Joohi Jimenez-Shahed ◽  
...  
Keyword(s):  
Adverse Events ◽  
Percentage Change ◽  
Extension Study ◽  
Total Daily Dose ◽  
Open Label ◽  
Daily Dose ◽  
Open Label Extension ◽  
The Mean ◽  
Over Time

Abstract:Background:In the 12-week ARM-TD and AIM-TD studies evaluating deutetrabenazine for the treatment of tardive dyskinesia (TD), the percentage of patients achieving ≥50% response was higher in the deutetrabenazine-treated group than in the placebo group. These studies also showed low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The current open-label study evaluated the long-term efficacy and safety of deutetrabenazine in patients with TD.Methods:Patients with TD who completed ARM-TD or AIM-TD could enroll in this open-label, single-arm extension study, titrating up over 6 weeks to a maximum total daily dose of deutetrabenazine 48 mg/day on the basis of dyskinesia control and tolerability. The proportion of Abnormal Involuntary Movement Scale (AIMS; items 1-7) responders was assessed based on response rates for achieving ≥50% improvement from baseline in the open-label extension study. AlMS score was assessed by local site raters for this analysis.Results:343 patients enrolled in the extension study. At Week 54 (n=249; total daily dose [mean ± standard error]: 38.6±0.66 mg), the mean percentage change from baseline in AIMS score was –40%; 48% of patients achieved a ≥50% response and 59% of those had already achieved a ≥50% response at Week 15. Further, 34% of those who had not achieved a ≥50% response at Week 15 achieved a ≥50% response at Week 54. At Week 106 (n=169; total daily dose: 39.6±0.77 mg), the mean percentage change from baseline in AIMS score was –45%; 55% of patients achieved a ≥50% response, 59% of those patients had already achieved a ≥50% response at Week 15, and 41% of those who had not achieved a ≥50% response at Week 15 but who reached Week 106 achieved a ≥50% response. At Week 132 (n=109; total daily dose: 39.7±0.97 mg), the mean percentage change from baseline in AIMS score was –61%; 55% of patients achieved a ≥50% response, 61% of those patients had already achieved a ≥50% response at Week 15, and 43% of those who had not achieved a ≥50% response at Week 15 but who reached Week 132 achieved a ≥50% response. Completer analysis suggests that long-term efficacy was not due to dose increases over time. Treatment with deutetrabenazine was generally well tolerated. There were 623 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) of adverse events of special interest were 0.01 for akathisia and restlessness, 0.07 for somnolence and sedation, 0.04 for parkinsonism, and 0.05 for depression.Conclusions:Patients who received long-term treatment with deutetrabenazine achieved response rates that were indicative of clinically meaningful long-term benefit. Results from this open-label trial suggest the possibility of increasing benefit over time with individual dose titration of deutetrabenazine.Funding Acknowledgements:This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.

Pemetrexed in combination with paclitaxel: A phase I clinical and pharmacokinetic trial in patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2051-2051 ◽  
Author(s):  
T. Graefe ◽  
C. Bolling ◽  
C. Lubbing ◽  
J. Latz ◽  
J. Blatter ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Thyroid Carcinoma ◽  
Phase Ii ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Recommended Dose ◽  
Clinical Activity ◽  
Best Response ◽  
Recommended Phase Ii Dose

2051 Background: Pemetrexed (Alimta [AL]) and paclitaxel (P) are clinically active in a variety of tumors. The primary objective of this trial was to determine the maximum tolerated dose (MTD) of the ALP combination; secondary objectives were: determination of dose-limiting toxicities (DLTs), definition of a recommended phase II dose, pharmacokinetic (PK) characterization and the anecdotal collection of antitumor activity. Methods: Escalating doses of P (3h infusion, d1 and d8) and AL (10 min infusion, d8 prior to P) were given in a 21d cycle. Results: 59 patients (pts) were enrolled. DLTs occurred at the following ALP (mg/m2) doses: 400/30 [G3 bilirubin (b), G3 and G4 thrombocytopenia (plts)]; 500/30 (G4 plts); 500/40 (G3 b); 500/75 (G4 ANC); 500/100 (G4 leukopenia, G4 ANC). With G4 leukopenia and G4 ANC in 4/6 pts and febrile neutropenia in 1 pt, the MTD was reached at the ALP (mg/m2) dose of 500/120. To confirm safety at the recommended dose-level, another 6 patients were treated at the ALP (mg/m2) dose of 500/100. 18 pts [mesothelioma (3), esophagus (2), lung (1), liver (1), renal (1), stomach (1), thyroid (9)] showed stable disease as best response. 4/14 (29%) pts with thyroid carcinoma showed long lasting partial responses [duration (months) 29+, 22, 18, 15]. One additional PR (2) was observed in a pt with penile carcinoma. AL PK when administered with P were consistent with those for AL administered as a single-agent. Conclusions: The ALP combination is safe and shows broad clinical activity. 500/100 mg/m2 is the recommended dose for further studies. Promising antitumor activity was observed in thyroid cancer. A phase II trial in thyroid carcinoma will be conducted. [Table: see text]

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.

First-in-human, dose-escalation, phase (ph) I trial to evaluate safety of anti-Axl antibody-drug conjugate (ADC) enapotamab vedotin (EnaV) in solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2525-2525
Author(s):  
Malaka Ameratunga ◽  
R Donald Harvey ◽  
Morten Mau-Sørensen ◽  
Fiona Thistlethwaite ◽  
Ulf Forssmann ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Metastatic Cancer ◽  
Single Agent ◽  
Treatment Resistance ◽  
Maximum Tolerated Dose ◽  
Antibody Drug Conjugate ◽  
Human Dose ◽  
Elimination Half ◽  
Infusion Reactions ◽  
Anti Tumor Activity

2525 Background: Axl, a transmembrane receptor tyrosine kinase, is aberrantly overexpressed in various human cancers and associated with poor prognosis and treatment resistance. EnaV, a novel ADC of anti-Axl human IgG1 and monomethyl auristatin E, demonstrated potent anti-tumor activity in xenograft models. Methods: In a ph1 trial (NCT02988817), patients (pts) with relapsed/refractory cancer received single agent EnaV, 0.3–2.8 mg/kg once every 3 wks (1Q3W) or 0.45–1.4 mg/kg 3 times over 4 wks (3Q4W). Endpoints included dose-limiting toxicities (DLTs), adverse events (AEs) and pharmacokinetics (PK). DLTs were classed as hematological (e.g. Grade [G] 3/4 febrile neutropenia; G4 neutropenia or anemia) or non-hematological (e.g. severe skin toxicities; G3/4 neuropathy or infusion reactions; ≥G3 treatment-related AEs in first treatment cycle). Upon determining maximum tolerated dose (MTD) per arm and recommended ph2 dose (RP2D), ph2a (dose expansion) will enroll ≤297 pre-treated pts with advanced/metastatic cancer in 7 cohorts. Results: 47 pts with NSCLC (n=8), melanoma (n=9), ovarian (n=22), cervical (n=3) and endometrial (n=5) cancer enrolled in ph1 (1Q3W n=32; 3Q4W n=15). Most pts were female (87%), White (94%) and aged <65 y (66%). MTD was 2.2 mg/kg in 1Q3W arm and 1.0 mg/kg in 3Q4W arm; RP2D was 2.2 mg/kg 1Q3W. EnaV median elimination half-life: 0.9–2.2 d across doses/schedules. In 47 enrolled pts, there were 6 DLTs (Table). Most common AEs (any G; ≥40% pts) were fatigue (64%), nausea (57%), constipation (57%), diarrhea (47%), vomiting (45%) and decreased appetite (43%). 3 pts (1Q3W arm) had partial response (1 NSCLC [2.2 mg/kg dose]; 2 ovarian [1.5 and 2.4 mg/kg dose levels]). Conclusions: The RP2D of single agent EnaV in pre-treated pts with solid tumors was 2.2 mg/kg 1Q3W. EnaV had encouraging preliminary anti-tumor activity and will be evaluated in 7 ph2a expansion cohorts to further assess safety, tolerability, PK, anti-tumor activity and Axl expression. Funding: Genmab A/S. Clinical trial information: NCT02988817. [Table: see text]

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