Determine Dose-limiting Toxicities Research Articles

A phase I/II study of belinostat (PXD101) in patients with unresectable hepatocellular carcinoma

15081 Background: Hepatocellular carcinoma (HCC) is a common cause of cancer morbidity and mortality. It is a highly aggressive tumor with 90% presenting with unresectable disease, resulting in a median survival of 3–6 months. Inhibitors of histone deacetylase (HDAC) have been demonstrated in HCC cell lines and xenografts to induce apoptosis and tumor regression, and have anti-proliferative, anti-metastatic and anti-invasive effects. Belinostat (N-hydroxy-3-[phenylsulphamoylphenyl] acryl amide) is a novel, low molecular weight, HDAC inhibitor. The Cancer Therapeutic Research Group (CTRG) is conducting a phase I/II study of belinostat as the first line therapy for pts with unresectable HCC. The phase I study aims to determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Methods: Patient eligibilities include histologically or cytologically confirmed unresectable HCC, ECOG = 2, adequate hematologic, renal and hepatic functions. The dose of belinostat was started at 600 mg/m2/day i.v. on day 1–5 every 3 weeks; with increment of 300 mg/m2/day up to 1200 mg/m2/day. Dose limiting toxicities (DLT) are defined as grade 4 hematological toxicity or grade 3 or 4 nonhematological toxicity during cycle 1 (according to NCI CTC v3), or treatment delay >2 weeks. The MTD is defined as the dose below which ≥ 2 of 3 or ≥ 2 of 6 patients experiencing DLT. After determination of the MTD, 3 additional patients will be treated at this dose to further define toxicity. Results: From June-December 2006, 12 pts were entered; 3 were treated at level I (600 mg/m2/day), 3 at level 2 (900 mg/m2/day), and 6 at level 3 (1200 mg/m2/day). There were no DLTs on level 1, 2 or 3. Therefore, the MTD of belinostat was not reached. Overall toxicities were WBC gr. 0/1/2/3/4: 12/0/0/0/0, ANC gr. 0/1/2/3/4: 12/0/0/0/0; Hb gr. 0/1/2/3/4: 4/7/0/1/0; platelet gr. 0/1/2/3/4: 8/4/0/0/0; lethargy gr. 0/1/2/3: 12/0/0/0/0, phlebitis gr. 0/1/2/3: 10/0/2/0; Cough gr. 0/1/2/3: 9/0/3/0; Nausea gr. 0/1/2/3: 7/3/2/0 and vomiting gr. 0/1/2/3: 9/3/0/0. Conclusions: At the maximum dose of 1200 mg/m2/day (level 3), MTD has not been reached. Belinostat is very well tolerated. Phase II study will be started at dose level 1200 mg/m2/day. Sponsor: The Division of Cancer Treatment and Diagnosis, National Cancer Institute, USA. No significant financial relationships to disclose.

GCS-100, a galectin-3 antagonist, in refractory solid tumors: A phase I study

13023 Background: Galectin-3 is a galactoside-binding protein implicated in inhibition of apoptosis, and promotion of angiogenesis, metastasis, cellular proliferation by a direct association with oncogenic K-ras. Modified citrus pectin (MCP) is a complex carbohydrate derived from citrus fruit and is rich in galactoside residues. GCS-100 is an MCP capable of binding to and antagonizing galectin-3, resulting in anti-tumor activity in vitro and in vivo. Methods: GCS-100 was administered to patients with refractory solid tumors in a Phase I dose-escalating study using standard eligibility criteria. Objectives were to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK) and efficacy. Study drug was delivered by IV infusion over 1–2 hours for 5 consecutive days of a 21 day cycle. Results: 24 patients (17 F, 7 M, age 45–80 yo) were enrolled at 6 dose levels between 30–200 mg/m2. DLT and MTD for this dosing regimen were established at 200 mg/m2 and 160 mg/m2, respectively. DLT was a Grade 3 erythematous, maculopapular rash, resolving with systemic steroid treatment. There were no associated systemic findings, and the rash did not preclude further GCS-100 therapy. Skin biopsy revealed a vasculitis similar to findings seen in dog models. 9 other patients experienced Grade 1–2 rashes that did not require systemic treatment. The majority of adverse events (AEs) were Grade 1 or 2; the most common being nausea, vomiting, diarrhea, fatigue, fever and hyperglycemia. AEs thought to be related to treatment were rash, nausea and fatigue. Linear PKs were observed with a terminal half-life (t1/2) between 30–40 h and an effective t1/2 of 36 h. Peak GCS-100 concentrations reached 424 μg/mL at MTD. The median number of cycles was 4 (range 1–17). Best overall response per RECIST was stable disease observed in 16 patients with 6 of these patients on study for ≥ 6 months. Conclusion: Overall tolerability of GCS-100 was excellent with serum concentrations at MTD reaching levels associated with preclinical activity. Sustained periods of stable disease were achieved in patients with previously treated advanced solid tumors warranting Phase II studies. [Table: see text]

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

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]

Phase I dose escalation study of SR271425 administered as 24-hour intravenous continuous infusion in patients with refractory solid tumors

3116 Background: SR271425 is a DNA-binding agent from a new class of cytotoxics. This clinical trial aims to determine dose-limiting toxicities (DLTs), maximal tolerable dose (MTD) and PK profile of SR271425 given as 24-hour (h) IV infusion every 3 weeks. Methods: An accelerated dose escalation schema has been used similar to the 2b method (Eisenhauer EA, et al, JCO 2000). SR271425 was administered intravenously over 24 hr every 3 wks. Bloud samples were obtained during the infusion and up to 24 h post-infusion for the determination of SR271425 in plasma using a validated LC-MS/MS Method: Since a predecessor thioxanthone agent has been shown to prolong QTc and caused Torsade de pointes, careful monitoring of QTc was done including central reading of ECGs. Results: 31 patients have been enrolled; 20 men, 11 women, median (med) age 54 range 31–72, med ECOG performance status: 0 range 0–1. Tumor types: 7 colorectal, 5 pancreas, 4 sarcoma, 4 melanoma, 3 renal, 3 prostate, 1 lung, 4 others, eleven dose-levels from 128 mg/m2to 2920 mg/m2, med number of cycles was 2 (1–8). Grade (Gr) 1–2 toxicities included QTc prolongation, nausea/vomiting, venous inflammation at injection site and yellow skin discoloration. Two pts experienced DLT’s (Gr 3 QTc prolongation as defined using CTCv3) with no clinical symptom at 1524 and 2432 mg/m2. Gr 3 neutropenia occurred in 2 pts at the highest dose-levels tested: 2432 and 2920 mg/m2; in 1 pt concomitant Gr 3 anemia and Gr 1 thrombocytopenia were observed. PK data is available in 24 patients; steady state plasma drug concentrations appeared to be reached by the end of infusion, consistent with the drugs elimination half-life of around 8 h. Both Cend and AUC increased in a dose related manner. Mean (± SD) Cl and Vss were 28.0 ± 10.7 L/h and 303 ± 149 L, respectively, and independent of dose. One biological response (PSA decrease in prostatic cancer) and 3 stable disease were observed. Conclusions: Preliminary data show that the 24 h schedule allows increase in the total dose administered by reducing the peak plasma which appears to be correlated with QTc prolongation DLT. At these higher doses tested so far hematological toxicity is observed. The study is ongoing to define the MTD. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis

Fractionated administration of topotecan and cisplatin in elderly patients with small-cell lung cancer: A phase I study

7245 Background: This phase I study was designed to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a fractionated regimen of topotecan and cisplatin in elderly patients ...

Phase I Study of Clofarabine Plus Idarubicin and Clofarabine Plus Idarubicin Plus Cytarabine (ARA-C) in Patients (PTS) with Relapsed and Primary Refractory Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Myeloid Blast Phase of Chronic Myeloid Leukemia (CML).

Phase I and II clinical studies demonstrated activity of Clofarabine in acute leukemias. In previous studies we have investigated clofarabine, plus ara-C combinations and reported a CR rate of 24% in relapsed AML and 52% in previously untreated AML ≥ 50 years (yrs) with acceptable toxicity profile. Anthracyclines are active in AML. To explore clofarabine further in AML combinations we conducted a phase I study of clofarabine with idarubicin with or without ara-C in pts with relapsed AML, MDS, and CML. Considered as dose-limiting toxicities (DLT) are ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) will be determined by “3+3” dose escalation scheme. On the clofarabine (C)/idarubicin (I) combination (CI), 9 AML pts are enrolled (2 primary refractory, 7 first relapse). Median age: 58 yrs (range 24–71). Median first remission duration (CRD1): 3.1 mos. (0–7.6). For the first dose level, C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d. Among the first 6 pts, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation of C to 15mg/m2 i.v. daily x 5 and I 8mg/m2 i.v. daily x 3. Among 3 pts, 1 ≥ gr.3 toxicity (↑ bili) was observed. No responses occurred. On the CI + ara-C arm (CIA), 7 AML pts are enrolled (1 primary refractory, 6 first relapse). Median age: 58 yrs. (24–78). Median CRD1: 11.2 mos. (0–13.1). First dose level: C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d. Of 3 pts, 2 developed ≥ gr.3 toxicities (↑ bili, diarrhea) leading to the following de-escalation: C 15mg/m2 i.v. daily x 5d, I 6mg/m2 i.v. daily x 3d, A 0.75g/m2 i.v. daily x 5d. Of 4 pts (1 ≥ gr. 3 rash, ↑ bili), 3 pts achieved CR. The phase I study is ongoing until determination of DLT and MTD for each arm. Our preliminary results indicate clinical activity of CIA even at the low dose level.

Phase I study of the anti-neovascular agent MBT-0206 to evaluate safety and efficacy in patients with metastatic or advanced unresectable gastrointestinal cancer (GI cancer)

3163 Background: MBT-0206 is a highly innovative anti-neovascular cytostatic compound designed to target and destroy newly formed tumor blood vessels. Its superior anti-tumor activity based on this new concept has been shown in several animal models. A phase I clinical study was conducted to determine dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and to explore anti-tumor activity. Methods: MBT-0206 was administered as intravenous short infusion at 4 dose levels (lipid-complexed paclitaxel mg/kg body weight (b.w.): 0.28 (n=8), 0.55 (n=8), 1.1 (n=10) and 1.65 (n=5)) on day 1, 3, 5 of a 4 week cycle. Up to 3 cycles were administered to patients with metastatic, unresectable GI cancer and tumor progression after standard chemotherapy. Safety was assessed on the basis of reported adverse events and efficacy was measured as objective tumor response according to WHO criteria. The studies were accompanied by quantitative analysis (LC-MS/MS) of paclitaxel and the main cationic lipid compound. Results:Non-haematological DLTs were observed in a dose dependent manner with the strongest incidence in the highest dose group. The main DLTs were fatigue and hypersensitivity. Other side effects commonly occurring with conventional chemotherapy were not observed. Haematological DLTs were detected only in the highest treatment group. The MTD was defined as 1.1 mg/kg b.w. lipid-complexed paclitaxel on a 3 times a week schedule. The overall assessment of tumor response performed at the first follow-up examination resulted in 13% stable disease. Conclusions: MBT-0206 showed a very good tolerability and low levels of mild side-effects. Therefore MBT-0206 will be suitable for prolonged treatment regimens and also for treatment in combination with conventional chemotherapeutics. There is no indication for paclitaxel accumulation and prolonged circulation of paclitaxel due to lipid complexation. The lipid compound showed a lower clearance, however only 2–5% remained in circulation after 24h. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Munich Biotech AG Munich Biotech Munich Biotech

Phase I-II study of the combination of NED, ADM, and 5-FU for the treatment of previously untreated advanced esophageal cancer

4149 Background: Esophageal cancer has a poor prognosis. Several strategies including chemotherapy (CDDP+5-FU), either alone or with radiotherapy, depends on document reviewhave been used to improve prognosis. However, since CDDP itself has substantial toxicities, including renal and gastrointestinal toxicities, newer platinum analogues, such as nedaplatin (NED), have been developed, and it is of interest to test this new platinum analogue in a combination chemotherapy. Methods: We conducted a phase I-II study of the combination of NED (3 levels, 60–80 mg/m2 on day 1), ADM (30 mg/m2 on day 1), and 5-FU (700 mg/m2 on day 1–5) for treatment of previously untreated advanced esophageal squamous cell carcinoma. Cycles were repeated every 28 days. Objectives were to determine dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), recommended dose (RD) for a phase II study, and to explore antitumor effect. Results: Phase I: 12 patients (pts) (male/female=11/1) were evaluable. Median age 65 (range 46–74), PS 0/1=7/5. At level 1, 1 pt developed DLT (grade 4, neutropenia). At level 2, 2 pts developed DLT (grade 4 neutropenia and grade 3 diarrhea). Level 2 (70 mg/m2) was determined as the MTD and the dose at level 1 (60 mg/m2) was recommended. Phase II: 13 pts (male/female= 10/3) were at RD of level 1 at the present time. Median age 65 (range 46–75), PS 0/1= 10/3. Median number of cycles on phase II study at RD was 2 (range 1–3). 10 PRs were obtained. Response rate was 69%. Median survival time (MST) is not reached at the present time. Conclusions: This combination therapy appears to be highly active and generally well tolerated for advanced esophageal cancer. No significant financial relationships to disclose.

Phase I-II study of the combination of NED, ADM, and 5-FU for the treatment of previously untreated advanced esophageal cancer

4149 Background: Esophageal cancer has a poor prognosis. Several strategies including chemotherapy (CDDP+5-FU), either alone or with radiotherapy, depends on document reviewhave been used to improve prognosis. However, since CDDP itself has substantial toxicities, including renal and gastrointestinal toxicities, newer platinum analogues, such as nedaplatin (NED), have been developed, and it is of interest to test this new platinum analogue in a combination chemotherapy. Methods: We conducted a phase I-II study of the combination of NED (3 levels, 60–80 mg/m2 on day 1), ADM (30 mg/m2 on day 1), and 5-FU (700 mg/m2 on day 1–5) for treatment of previously untreated advanced esophageal squamous cell carcinoma. Cycles were repeated every 28 days. Objectives were to determine dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), recommended dose (RD) for a phase II study, and to explore antitumor effect. Results: Phase I: 12 patients (pts) (male/female=11/1) were evaluable. Median age 65 (range 46–74), PS 0/1=7/5. At level 1, 1 pt developed DLT (grade 4, neutropenia). At level 2, 2 pts developed DLT (grade 4 neutropenia and grade 3 diarrhea). Level 2 (70 mg/m2) was determined as the MTD and the dose at level 1 (60 mg/m2) was recommended. Phase II: 13 pts (male/female= 10/3) were at RD of level 1 at the present time. Median age 65 (range 46–75), PS 0/1= 10/3. Median number of cycles on phase II study at RD was 2 (range 1–3). 10 PRs were obtained. Response rate was 69%. Median survival time (MST) is not reached at the present time. Conclusions: This combination therapy appears to be highly active and generally well tolerated for advanced esophageal cancer. No significant financial relationships to disclose.

Protracted Intermittent Schedule of Topotecan in Children With Refractory Acute Leukemia: A Pediatric Oncology Group Study

PURPOSE: To determine dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of a protracted, intermittent schedule of daily 30-minute infusions of topotecan (TPT) for up to 12 consecutive days, every 3 weeks, in children with refractory leukemia. PATIENTS AND METHODS: Forty-nine children were enrolled onto this phase I trial (24 with acute nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m2/d for 5 days and 2.4 mg/m2/d from 7 days to the same dose for 9 and 12 days in cohorts of three to six patients when no DLT was identified. TPT pharmacokinetics were studied in 33 children once or twice (first and last doses in patients who received TPT for > 7 days). RESULTS: Seventy assessable courses of TPT were administered to 49 children who had refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and the MTD was 2.4 mg/m2/d for 9 days in this group of heavily pretreated children. In 33 patients, the median TPT lacto...

Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin in combination with folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer

To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of oxaliplatin administered as hepatic arterial infusion. Patients with isolated hepatic metastases from colorectal cancer were treated every three weeks with increasing doses of oxaliplatin (4 hours; starting dose 25 mg/m2, escalation in steps of 25 mg/m2) in combination with folinic acid (1 hour, 200 mg/m2) and 5-fluorouracil (2 hour, 600 mg/m2). Twenty-one patients (median age, 61 years) have been entered all of whom are fully evaluable. The DLT has been observed at dose level 6, i.e., at 150 mg/m2/cycle and consisted of leucopenia, obliteration of the hepatic artery, and acute pancreatitis. Overall, toxicity mainly consisted of nausea/vomiting (16 of 21 patients), anemia (16 of 21), upper abdominal pain (15 of 21), sensory neuropathy (10 of 21), diarrhea (9 of 21), and thrombocytopenia (9 of 21). The mean PK parameters were: terminal half-life of ultrafiltrable platin, 17.75 +/- 9.29 hours; renal elimination, 48.7% +/- 14.1% of the applied dose; renal clearance 135.55 +/- 45.32 ml/min. The mean area under the plasma-concentration curve (AUC) increased linearly from 3.22 +/- 0.61 microg x h/ml to 18.45 +/- 8.90 microg x h/ml through the first five dose levels (P = 0.0004). Ten of eighteen evaluable patients achieved a complete or partial response (59%). The recommended dose for phase II studies is 125 mg/m2 oxaliplatin.