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.

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]

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 .

An open-label study of rovalpituzumab tesirine in patients with DLL3-expressing advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2597-TPS2597 ◽  
Author(s):  
Edward Kavalerchik ◽  
Satwant Lally ◽  
Tae H. Han ◽  
Laura R. Saunders ◽  
Sheila Bheddah ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Solid Tumor ◽  
Phase 1 ◽  
Large Cell ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Notch Receptor ◽  
Antibody Drug Conjugate ◽  
Open Label

TPS2597 Background: Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family. It is highly expressed in high-grade neuroendocrine carcinoma (NEC), such as small cell lung cancer (SCLC) and large cell NEC (LCNEC), but is not expressed in normal tissue. DLL3 is expressed in melanoma, glioblastoma (GBM), neuroendocrine prostate, medullary thyroid carcinoma (MTC), and other solid cancers. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3, composed of a DLL3-specific IgG1 monoclonal antibody joined to a toxic DNA cross-linking agent by a cleavable linker. Rova-T binds to DLL3 on target-expressing cells, is internalized and cleaved, releasing the toxin to induce cell death. A Phase 1 study of Rova-T in SCLC showed encouraging antitumor activity in DLL3-high patients (pts), and was well-tolerated (Rudin et al., Lancet Oncol, 2016). As novel therapies are needed for multiple cancers that express DLL3, Rova-T may be effective in these tumors. Methods: This is a Phase 1/2, open-label, multicenter study (NCT02709889) with 8 cohorts of pts (up to ~318 total, 14 pts enrolled as of 20 January 2017) with melanoma, MTC, GBM, LCNEC, neuroendocrine prostate cancer, gastroenteropancreatic NEC, other NEC, or other solid tumor. In Part A, a 3+3 dose escalation will be used. Rova-T 0.2, 0.3, or 0.4 mg/kg will be given on Day 1 of each 42-day cycle. Dose-limiting toxicities (DLTs) will be assessed over a 21-day period. Dose escalation will proceed within cohort until a maximum tolerated dose is reached. Part B expansion, Stage 1, will explore the recommended dose in 7 pts in disease specific cohorts. Stage 2 will use an adaptive 2-stage design to determine sample size. Pt eligibility: ≥ 18 years; histologically confirmed, measurable, advanced solid tumor; relapsed/refractory to prior standard therapy; ECOG 0-1; no prior exposure to a pyrrolobenzodiazepine-based drug. Primary objective: assess safety and tolerability of Rova-T. Secondary objectives: explore Rova-T antitumor activity, pharmacokinetics, and incidence of anti-therapeutic antibodies. Exploratory objectives: explore the relationship between DLL3 and clinical outcome, and effects on biomarkers and pharmacodynamics. Clinical trial information: NCT02709889.

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

Phase I study of oral S-1 in combination with oxaliplatin (oxali) and bevacizumab (bev) in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4091-4091
Author(s):  
J. Zhang ◽  
K. Chung ◽  
C. Zergebel ◽  
P. Urrea ◽  
M. Quinones ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Cyanuric Acid ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Clinical Pharmacokinetics ◽  
Progression Of Disease ◽  
Recommended Phase Ii Dose

4091 Background: S-1 is a novel oral fluoropyrimidine (tegafur, CDHP and potassium oxonate) designed for enhanced DPD inhibition and reduced GI toxicity. Bev and oxali have demonstrated safety and synergistic anti-tumor activity with oral and IV fluoropyrimidines. The primary objective is to investigate the safety and maximum tolerated dose (MTD) of S-1 combined with bevacizumab and oxaliplatin in patients with advanced solid tumors. Secondary objective is to investigate the clinical pharmacokinetics (PK) of the components of S-1 (FT, CDHP, Oxo), 5-FU, a-fluoro-β-alanine, cyanuric acid, uracil, and oxali and to document any antitumor activity. Methods: ECOG 0/1 patients with advanced or metastatic solid tumors received oral S-1 starting at 20 mg/m2/dose BID x 14 days (classic 3+3 cohort dose escalation by 5mg/m2/dose until MTD), plus fixed doses of bev 7.5 mg/kg IV day 1, and Oxali 130 mg/m2 IV day 1 of every 3 week cycle, with discontinuation of oxali after 4 cycles. Reintroduction of oxali was allowed upon progression of disease. Toxicity, antitumor activity and PKs were assessed. The MTD was defined as the highest dose level at which < 33% of the patients experience a dose- limiting toxicity (DLT) during the first 2 cycles. Results: Of 22 evaluable patients, 3 patients were treated at 20mg/m2 S1 and 13 patients were treated at 25mg/m2 S1 without a DLT. At 30mg/m2, two patients experienced a DLT(Grade 3 diarrhea, Grade 4 mucositis). The MTD and recommended phase II dose of S-1 is 25mg/m2 in combination with oxali and bev. A median of 8 cycles of S-1 were initiated at the 25 mg/m2 dose level. Common MTD level toxicities included fatigue (62%), nausea (62%) and diarrhea (46%), with no grade 4 toxicities observed. Best responses (RECIST): stable disease(16 patients), partial response (2 patients), non-measurable disease (3 patients). The Day 8 AUC(0–8) of 5-FU at 20/25/30 mg/m2 dose level were 230±115 hr*ng/ml, 470±172 hr*ng/ml and 502±169 hr*ng/ml, respectively. Conclusions: The MTD combination of 25mg/m2 S-1, oxali and bev can be given safely. The study will be expanded to test S-1 one week on, one week off schedule in combination with oxali/bev every two weeks. No significant financial relationships to disclose.

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.

A study of rovalpituzumab tesirine in frontline treatment of patients with DLL3 expressing extensive small cell lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2598-TPS2598 ◽  
Author(s):  
Christine L. Hann ◽  
Daniel Morgensztern ◽  
Afshin Dowlati ◽  
Timothy Francis Burns ◽  
Robert M. Jotte ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Initial Therapy ◽  
Primary Objective ◽  
Notch Receptor ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Frontline Treatment ◽  
Novel Target

TPS2598 Background: Treatment and survival of SCLC patients (pts) has remained mostly unchanged over past decades with high response rates to initial therapy (cisplatin/carboplatin + etoposide), but relapse is near universal with median survival < 1 year in extensive disease. Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family identified as a novel target in high-grade neuroendocrine tumors, and is highly expressed in SCLC but not in normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3. A Phase I study of Rova-T monotherapy in 2nd and 3rd line SCLC pts demonstrated encouraging antitumor activity with an ORR of 18% in all pts, and an ORR of 38% in DLL3-high pts (Rudin et al., Lancet Oncol, 2016.). Methods: This is a Phase I, open-label, multicenter study (NCT02819999; no pts enrolled as of 7 February 2017).In Phase Ia (escalation), 15-34 previously untreated DLL3-high pts will be enrolled and randomized to 1 of 4 cohorts. The primary objective of the Phase Ia portion is assessment of safety and dose-limiting toxicities (DLTs). Phase Ib (expansion) will enroll up to 2 cohorts of 30 pts each, and its primary objective is to characterize antitumor activity of the selected cohort(s). Secondary objectives (Phase Ia/b) include assessment of pharmacokinetics and anti-therapeutic antibodies against Rova-T, and characterization of antitumor activity (Phase Ia). Eligible pts: adults with histologically or cytologically confirmed extensive DLL3-high SCLC based on immunohistochemistry; ECOG 0-1; and life expectancy ≥ 12 weeks. Clinical trial information: NCT02819999. [Table: see text]

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 .

Phase I evaluation of tipifarnib in combination with low-dose Ara-C (LDAC) in high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Interim results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14014-14014
Author(s):  
J. E. Cortes ◽  
E. J. Feldman ◽  
D. Douer ◽  
A. Raza ◽  
S. Fruchtman
Keyword(s):  
Phase I ◽  
Dose Level ◽  
The Elderly ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Finding ◽  
Clinical Activity ◽  
Open Label ◽  
Entire Cohort ◽  
Investigational Agent

14014 Background: Tipifarnib (T) is a farnesyltransferase inhibitor with clinical activity in MDS and AML. LDAC has utility in the elderly with MDS/AML; hence its use in combination with the investigational agent T to improve outcomes is warranted. Methods: The primary objective of this ongoing phase I, dose finding, multicenter, open-label study was to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT) of T+LDAC observed during the first 28 day cycle. MDS (IPSS Int 1, 2 or High) and untreated AML pts (age =75y or =65y with preceding MDS) or relapsed/refractory AML (age >18y) were included. Planned sample size was up to 57 pts with a traditional 3+3 dose escalation and a minimum of 3 pts enrolled per cohort. T (Dose Level 0) was administered initially at 200mg PO BID x 21 days in combination with LDAC 10mg SC BID x 10 days; both repeated every 28 days. Efficacy will be assessed by bone marrow and peripheral blood count studies. Results: 15 pts have been enrolled to date: 2 MDS (Int 1 n=1, High n=1) and 13 AML (7/13 pts with no previous therapy); all 15 pts were evaluable. Mean baseline characteristics for the entire cohort were: age 76.2y, 67% men, Hb 9.4 ± 0.9 g/dL, WBC 8.7 ± 11.3 x 103/μL, platelets 96.8 ± 96.6 x 103/μL. The observed DLT for T+LDAC was generalized rash seen at Dose Level 3. The MTD was therefore determined to be T 300mg and LDAC 15mg. The most common grade 3/4 adverse events were neutropenia, thrombocytopenia, anemia, and rash. Conclusions: These interim findings show the combination of T at 300mg PO BID x 21 days and LDAC at 15mg SC BID x 10 days to be the MTD in this study. Assessment for efficacy is ongoing. [Table: see text] No significant financial relationships to disclose.

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