Phase I trial of micronized formulation carboxyamidotriazole in patients with refractory solid tumors: pharmacokinetics, clinical outcome, and comparison of formulations.

1997 ◽  
Vol 15 (5) ◽  
pp. 1985-1993 ◽  
Author(s):  
E C Kohn ◽  
W D Figg ◽  
G A Sarosy ◽  
K S Bauer ◽  
P A Davis ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Performance Status ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Response Analysis ◽  
Minor Response ◽  
Similar Frequency ◽  
Disease Stabilization ◽  
Dose Limiting Toxicity

PURPOSE Cytostatic agents targeted against angiogenesis and tumor cell invasive potential form a new class of investigational drugs. Orally administered carboxyamidotriazole (CAI) (NSC609974) is both antiangiogenic and antimetastatic. An encapsulated micronized powder formulation has been developed to optimize CAI administration. A phase I dose escalation trial with pharmacokinetic analysis has been performed. PATIENTS AND METHODS Twenty-one patients with refractory solid tumors and good end organ function and performance status were enrolled onto the study. Patients received a test dose followed 1 week later by daily administration of CAI in the encapsulated micronized formulation at doses of 100 to 350 mg/m2. Patients remained on CAI until disease progression or dose-limiting toxicity. Plasma samples were taken to characterize the pharmacokinetic parameters of this formulation of CAI. RESULTS All patients were assessable for toxicity and 18 were assessable for pharmacokinetics and response analysis. Grade 1 and 2 gastrointestinal side effects were observed in up to 50% of patients. Dose-limiting toxicity was observed in both patients treated at 350 mg/m2/d, consisting of reversible grade 2 to 3 cerebellar ataxia (n = 1) and confusion (n = 1). One minor response (MR) was observed in a patient with renal cell carcinoma and another nine patients had disease stabilization (MR + SD = 47%). Pharmacokinetic analysis demonstrated reduced bioavailability (58% reduction) compared with the PEG-400 liquid formulation previously reported. CONCLUSION The better toxicity profile of encapsulated micronized CAI with similar frequency of disease stabilization and ease of administration compared with the liquid or gelatin capsule, suggests that the micronized formulation is a preferable formulation for subsequent studies. A dose of 300 mg/m2/d is proposed for phase II investigations.

Phase I and Pharmacokinetic Study of Oral Irinotecan Given Once Daily for 5 Days Every 3 Weeks in Combination With Capecitabine in Patients With Solid Tumors

2005 ◽  
Vol 23 (4) ◽  
pp. 889-898 ◽  
Author(s):  
Otto Soepenberg ◽  
Herlinde Dumez ◽  
Jaap Verweij ◽  
Dorothee Semiond ◽  
Maja J.A. deJonge ◽  
...  
Keyword(s):  
Side Effects ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Variability ◽  
Once Daily ◽  
Disease Stabilization ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Purpose To assess the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary antitumor activity of oral irinotecan given in combination with capecitabine to patients with advanced, refractory solid tumors. Patients and Methods Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days. Results Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 × 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 × 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients. Conclusion The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 × 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.

Phase I and Pharmacokinetic Study of the Camptothecin Analog DX-8951f Administered as a 30-Minute Infusion Every 3 Weeks in Patients With Advanced Cancer

2000 ◽  
Vol 18 (23) ◽  
pp. 3986-3992 ◽  
Author(s):  
Valérie Boige ◽  
Eric Raymond ◽  
Sandrine Faivre ◽  
Michel Gatineau ◽  
Kathleen Meely ◽  
...  
Keyword(s):  
Phase I ◽  
Intravenous Infusion ◽  
Topoisomerase I ◽  
High Performance ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Phase Ii Studies ◽  
Heavily Pretreated ◽  
Dose Limiting Toxicity

PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks. PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m2. All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography. RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h·m2. The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m2. CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m2 every 3 weeks in patients previously treated with chemotherapy.

scholarly journals Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low Cmax and improved tolerability, in patients with solid tumors

2020 ◽  
Vol 38 (6) ◽  
pp. 1763-1773
Author(s):  
Jaffer A. Ajani ◽  
Milind Javle ◽  
Cathy Eng ◽  
David Fogelman ◽  
Jackie Smith ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Stable Disease ◽  
Phase I Study ◽  
Potent Inhibitor ◽  
Pharmacokinetic Analysis ◽  
Gastrointestinal Cancers ◽  
Chemotherapy Treatment ◽  
Favorable Safety ◽  
Combination Regimens

Summary 5-fluorouracil (5-FU) and 5-FU derivatives, such as capecitabine, UFT, and S-1, are the mainstay of chemotherapy treatment for gastrointestinal cancers, and other solid tumors. Compared with other cytotoxic chemotherapies, these drugs generally have a favorable safety profile, but hematologic and gastrointestinal toxicities remain common. DFP-11207 is a novel oral cytotoxic agent that combines a 5-FU pro-drug with a reversible DPD inhibitor and a potent inhibitor of OPRT, resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicities. In this Phase I study (NCT02171221), DFP-11207 was administered orally daily, in doses escalating from 40 mg/m2/day to 400 mg/m2/day in patients with esophageal, colorectal, gastric, pancreatic or gallbladder cancer (n = 23). It was determined that DFP-11207 at the dose of 330 mg/m2/day administered every 12 hours was well-tolerated with mild myelosuppressive and gastrointestinal toxicities. The pharmacokinetic analysis determined that the 5-FU levels were in the therapeutic range at this dose. In addition, fasted or fed states had no influence on the 5-FU levels (patients serving as their own controls). Among 21 efficacy evaluable patients, 7 patients had stable disease (33.3%), of which two had prolonged stable disease of >6 months duration. DFP-11207 can be explored as monotherapy or easily substitute 5-FU, capecitabine, or S-1 in combination regimens.

Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors.

1997 ◽  
Vol 15 (2) ◽  
pp. 773-780 ◽  
Author(s):  
C A Johnson ◽  
D Kilpatrick ◽  
R von Roemeling ◽  
C Langer ◽  
M A Graham ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Maximum Plasma ◽  
Time Curve ◽  
Minor Response ◽  
Heavily Pretreated ◽  
Previously Treated ◽  
A Minor

PURPOSE AND METHODS Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer. RESULTS The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine. CONCLUSION This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.

Phase I Clinical and Pharmacokinetic Study of Rebeccamycin Analog NSC 655649 Given Daily for Five Consecutive Days

2001 ◽  
Vol 19 (8) ◽  
pp. 2309-2318 ◽  
Author(s):  
Afshin Dowlati ◽  
Charles L. Hoppel ◽  
Stephen T. Ingalls ◽  
Susan Majka ◽  
Xiaolin Li ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Enterohepatic Circulation ◽  
Central Venous Access ◽  
Area Under The Curve ◽  
Venous Access ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
High Concentration ◽  
Minor Response

PURPOSE: Rebeccamycin analog (NSC 655649) is active against a variety of both solid and nonsolid tumor cell lines. We performed a phase I trial to determine the maximum-tolerated dose (MTD) of rebeccamycin analog when given on a daily × 5 schedule repeated every 3 weeks, characterize the toxicity profile using this schedule, observe patients for antitumor response, and determine the pharmacokinetics of the agent and pharmacodynamic interactions. PATIENTS AND METHODS: Thirty assessable patients received a total of 153 cycles according to the following dose escalation schema: 60, 80, 106, 141, and 188 mg/m2/d × 5 days. RESULTS: Grade 2 phlebitis occurred in all patients before the use of central venous access, placed at dose level 4 and higher. Dose-limiting toxicity (DLT), grade 4 neutropenia, occurred at 188 mg/m2/d × 5 days in both previously treated and chemotherapy-naive patients. Pharmacokinetic analysis revealed a three-compartmental model of drug elimination and a long terminal half-life (154 ± 55 hours). The percentage drop in absolute neutrophil count correlates with the area under the curve∞. The presence of a second peak during the elimination phase as well as a high concentration of NSC 655649 in biliary fluid compared with the corresponding plasma measurement (one patient) is suggestive of enterohepatic circulation. Two partial responses, two minor responses, and six prolonged (> 6 months) cases of stable disease were observed. Of these, three patients with gallbladder cancer and one patient with cholangiocarcinoma experienced either a minor response or a significant period of freedom from progression. CONCLUSION: The recommended phase II dose for NSC 665649 on a daily × 5 every 3 weeks schedule is 141 and 165 mg/m2/d for patients with prior and no prior therapy, respectively, with DLT being neutropenia. During this phase I trial, encouraging antitumor activity was been observed.

A phase I dose escalation trial of ispinesib (SB-715992) administered days 1–3 of a 21-day cycle in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2026-2026 ◽  
Author(s):  
E. I. Heath ◽  
A. Alousi ◽  
J. P. Eder ◽  
M. Valdivieso ◽  
L. S. Vasist ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Advanced Solid Tumors ◽  
Minor Response ◽  
Level 3 ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Limiting Toxicity

2026 Background: Ispinesib, a novel cytotoxic agent inhibiting the kinesin spindle protein (KSP) has demonstrated significant antitumor activity in multiple murine tumor models. The primary objectives of the study were to assess the safety and tolerability of SB-715992, to determine the dose limiting toxicity (DLT), and the maximum tolerated dose (MTD). Methods: Ispinesib was administered days 1–3 intravenously over 1 hour every 21 days, starting at a dose of 1 mg/m2/day. Traditional 3-patient cohort trial design was utilized with dose levels of 2, 4, 6, 8 mg/m2/day. Results: Twenty-seven patients (24 Caucasians, 3 African-Americans, 16 males, 11 females) with various tumor types were enrolled; colorectal (7), renal (5), bladder (2), lung (2), pharynx (2), pancreas (2), others (7). Grade 3/4 toxicities were noted starting at the 4 mg/m2 dose level with two patients developing grade 4 neutropenia; one for < 5 days, one for > 5 days (with grade 3 leukopenia). At the 6 mg/m2 dose level, grade 3 neutropenia and leukopenia were reported. At the 8 mg/m2 dose level, 3 of 3 patients had grade 4 neutropenia and leukopenia. The 6 mg/m2 dose level was declared the MTD. Toxicities seen in the additional 6 patients included grade 1 fatigue (1/6), grade 1 infusion- related flushing (1/6), grade 3 febrile neutropenia (1/6), and grade 4 neutropenia and leukopenia (1/6). The MTD cohort has been expanded to 10 evaluable patients for confirmation of tolerability and pharmacodynamic endpoints including phosphohistone 3 (PH3), cyclin E, and TUNEL assay on serial tumor biopsies. Preliminary pharmacokinetic data appear linear, but not dose proportional. As predicted, between days 1 and 3, accumulation ranged from 40 to 106%. Exposures appear comparable between cycles 1 and 2. Stable disease in 2 patients with renal cell carcinoma (4 and 5 cycles) and minor response in one patient with bladder cancer were seen. Conclusions: Treatment with ispinesib at the MTD of 6 mg/m2/day x 3 days in patients with advanced solid tumors was well tolerated with consistent dose limiting toxicity of myelosuppression. No significant financial relationships to disclose.

Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3034-3034 ◽  
Author(s):  
P. M. Lorusso ◽  
E. Heath ◽  
M. Valdivieso ◽  
M. Pilat ◽  
A. Wozniak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Selective Inhibitor ◽  
Minor Response ◽  
Heavily Pretreated ◽  
Grade 3

3034 Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2 q2 weeks; Arm 1); irinotecan 300 mg/m2 q3 week (Arm 2); docetaxel 75 mg/m2 (Arm 3) and pemetrexed 500 mg/m2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 & 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome & grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses. [Table: see text]

Phase I study of erlotinib (E) for solid tumors in patients with hepatic or renal dysfunction (HD or RD): CALGB 60101

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3026-3026
Author(s):  
A. A. Miller ◽  
D. J. Murry ◽  
D. R. Hollis ◽  
K. Owzar ◽  
L. D. Lewis ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Progressive Disease ◽  
Performance Status ◽  
Direct Bilirubin ◽  
Hematologic Toxicity ◽  
Renal Obstruction ◽  
Reduced Dose ◽  
Grade 3 ◽  
Tolerable Dose ◽  
Dose Limiting Toxicity

3026 Background: We sought to determine a tolerable dose and characterize the pharmacokinetics (PK) of E in patients with HD or RD. Methods: Patients with biopsy-proven solid tumors that commonly express EGFR, refractory to or without available standard therapy, performance status 0–2, and without biliary or renal obstruction were assigned to one of 3 cohorts (C): C1, AST ≥ 3 × ULN but no RD; C2, direct bilirubin 1–7 mg/dl but no RD; C3, creatinine 1.6–5.0 mg/dl but no HD. After slow accrual of 3 patients, an amended C1 for albumin < 2.5 g/dl accrued 3 additional patients. E was administered po daily in groups of at least 3 evaluable patients in escalating doses of 50, 75, 100, 150 mg starting with 50 mg in HD and 75 mg in RD. Patients had to take E for at least 4 weeks to be considered evaluable for toxicity unless dose-limiting toxicity (DLT) occurred sooner. DLT was defined as: grade 4 neutrophils or platelets; bilirubin ≥ 1.5 × baseline in C1/2 and ≥ 2.5 × ULN in C3; creatinine ≥ 2 × ULN in C1/2 and ≥ 2.5 × baseline in C3; grade ≥ 3 nausea,vomiting,diarrhea despite optimal supportive care; or any other grade ≥ 3 non-hematologic toxicity. Blood samples were obtained before and 1, 2, 3, 4, 6, 24 hrs after the first dose. Plasma E concentrations were measured by HPLC. A 2-compartment PK model was used to estimate total clearance of E. Results: Between 12/01 and 5/05, 55 patients were accrued but 1 never started therapy: male/female, 34/20; white/black, 46/8; median age 56 (range, 39–78); PS 0/1/2, 12/25/17. The distribution of treated/evaluable patients was: 6/5 in C1, 30/16 (attrition due to progressive disease) in C2, and 18/18 in C3. DLT consisted of both total and direct bilirubin ≥ 1.5 × baseline in 3 patients: C1, 1 of 5 at 50 mg; C2, 2 of 6 at 100 mg. In C2, 1 of 7 patients had grade 4 diarrhea/dehydration and grade 3 hypotension at 75 mg. No DLT was encountered in C3 with 12 patients at 150 mg. Clearance (mean ± SD) was cohort-dependent: 1.51 ± 0.64 (C1), 2.36 ± 1.17 (C2), 4.34 ± 2.53 (C3) l/hr; 2-sided exact Kruskal-Wallis p < 0.0006. Conclusions: Patients with RD tolerate 150 mg and appear to have normal clearance of E. Patients with HD should be treated at a reduced dose (i.e. 75 mg) consistent with their reduced clearance. [Table: see text]

A phase I trial of TAS-102 administered on a three times a day schedule in patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2053-2053 ◽  
Author(s):  
R. A. Wolff ◽  
P. M. Hoff ◽  
A. Mita ◽  
M. Fukushima ◽  
J. C. Blais ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Performance Status ◽  
Tumor Xenograft ◽  
Unknown Primary ◽  
Hematologic Toxicity ◽  
Prior Therapy ◽  
Grade 3 ◽  
And Performance

2053 Background: TAS-102 consists of trifluorothymidine (FTD) and an inhibitor of thymidine phosphorylase (TP). FTD, like 5-fluorouracil, is an inhibitor of thymidylate synthase. However, when orally administered, FTD is rapidly degraded to an inactive form, primarily by TP. Co-administration of FTD with an inhibitor of TP elevates FTD concentrations. Since tumor xenograft models demonstrated greater anti-tumor activity with divided daily dosing of TAS-102, and a phase I trial of once-daily TAS-102 showed a short FTD half-life, this trial was designed to explore a three times a day dosing schedule. Methods: Patients with advanced solid tumors having received prior therapy, with adequate organ function, and performance status Zubrod 0–2, were eligible. TAS-102 was administered orally three times a day for 5 days a week for two weeks, followed by two weeks off. Courses were repeated every 4 weeks. Results: A total of 15 patients (8 female, age 37–72 years) were enrolled into the study; three at 60 mg/m2/day, 6 each at 70 mg/m2/day and 80 mg/m2/day. Nine patients had colorectal cancer, 2 carcinoma of unknown primary, 2 pancreatic cancer, one each medullary thyroid cancer and cholangiocarcinoma. Toxicity was assessed throughout all courses of therapy. Grade 3 and 4 hematological toxicities were the most common, including 3 episodes of grade 3 neutropenia at 60 mg/m2/day, 5 at 70 mg/m2/day, 5 at 80 mg/m2/day with only 1 instance of grade 3 thrombocytopenia at 80 mg/m2/day. Non-hematological grade 3 toxicities included nausea/vomiting (1 at 70 mg/m2/day), colitis, gout, and hematuria (1 each at 70 mg/m2/day), and fatigue (1 at 70 mg/m2/day and 2 at 80 mg/m2/day) Two episodes of dose-limiting toxicity were observed at 80 mg/m2/day: grade 3 fatigue and grade 4 neutropenia. Although there were no objective responses, nine patients (60%) maintained stable disease with a median duration of disease stabilization of 4.3 months (range, 1.9 to 8.6 months). Conclusions: TAS-102 is well tolerated with manageable hematologic toxicity and few non-hematological toxicities. The most common grade 3 or 4 toxicity was neutropenia. The suggested phase II dose of TAS-102 is 70 mg/m2/day when administered orally three times a day for 5 days a week for two weeks followed by two weeks off every 4 weeks. [Table: see text]

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