Hepatic arterial infusion therapy in advanced cancer and liver-predominant disease: the MD Anderson Experience.

BACKGROUND/AIMS: Liver metastases in patients with cancer are associated with a poor prognosis. We assessed the clinical outcomes in patients with advanced cancer and predominant liver involvement treated on hepatic arterial infusion (HAI chemotherapy protocols. METHODOLOGY: We retrospectively analyzed the outcomes of patients referred to the Phase I Clinical Trials Program between April 2004 and September 2009. RESULTS: Overall, 202 consecutive patients were identified. Of 189 evaluable patients, the rates of partial response (PR) and stable disease (SD) >4 months were 6.3% and 23%, respectively. In patients with hepatocellular carcinoma or cholangiocarcinoma (n = 15), 5 (33%) had SD ≥ 4 months. In patients with colorectal cancer (n = 67) treated with HAl oxaliplatin or irinotecan combination therapy, the rates of PR and SD ≥ 4 months were 7.5% and 34.3%, respectively. In patients with breast cancer (n = 17) treated with HAI cisplatin-based therapy, the rates of PR and SD -4 months were 17.6% and 35.3%, respectively. The median survival of patients with PR and SD ≥ 4 months was 11.6 months. Independent factors predicting shorter survival were male gender; decreased albumin and hemogloblin; and elevated bilirubin, lactate dehydrogenase and alanine aminotransferase. CONCLUSIONS: HAI combination therapies have antitumor activity in selected heavily pretreated patients with certain tumor types and liver involvement.

Pharmacokinetics and antitumor activity of patupilone combined with midazolam or omeprazole in patients with advanced cancer.

PURPOSE: Patupilone is a novel microtubule-targeting cytotoxic agent with potential interaction with CYP3A4/CYP2C19 enzymes. Midazolam and omeprazole are primarily metabolized by CYP3A4 and CYP2C19, respectively. We evaluated the inhibitory effects of patupilone on the CYP3A4/CYP2C19 pathways. METHODS: This study had 2 parts: in an initial core phase, patients were randomly assigned to receive midazolam 4 mg or omeprazole 40 mg PO (days 1 and 29) and patupilone 10 mg/m(2) IV (days 8 and 29). Patients without progression continued patupilone every 3 weeks until disease progression or unacceptable toxicity (extension phase). RESULTS: Forty-six patients were treated. The areas under the concentration-time curves (AUC)s of midazolam with or without patupilone co-administration were similar. The C (max) of midazolam when co-administered with patupilone was highly variable and was lower compared with midazolam alone; however, the oral clearance and terminal half-lives were similar. Both the C (max) and AUC of omeprazole when co-administered with patupilone were highly variable and lower than with omeprazole alone. However, the oral clearance and terminal half-lives were similar. The latter data suggest that patupilone decreased the absorption of omeprazole (by ~20%). The overall safety profile was consistent with that of previous single-agent patupilone studies; 2 partial responses (ovarian and pancreatic cancer) and 1 complete response (serous ovarian adenocarcinoma) were observed. CONCLUSIONS: Patupilone was not a potent CYP3A4 or CYP2C19 inhibitor. No dose adjustment is required when omeprazole or midazolam is used in patients treated with patupilone. Patupilone exhibited promising antitumor activity in heavily pretreated patients with ovarian and pancreatic cancer.

Phase I clinical trial outcomes in 93 patients with brain metastases: the MD anderson cancer center experience.

PURPOSE: Patients with brain metastases are often excluded from clinical trials, but it is unclear whether they pose an enhanced risk. EXPERIMENTAL DESIGN: We reviewed the records of 1,181 consecutive patients, with and without brain metastases, treated in our Phase I Clinical Trials Program. RESULTS: Ninety-three patients had brain metastases at the time of referral. Their median age was 54 years; median follow-up, 8 months. The rates of stable disease ≥ 4 months, partial response, and complete response combined in patients with and without brain metastases were 17% and 27%, respectively (P = 0.03). Although the median survival of patients with brain metastases was shorter than that of patients without brain metastases (7.5 vs. 10.3 months; P = 0.002), in multivariate analysis, the presence of brain metastases was not an independent factor predicting survival. There was no difference in time-to-treatment failure (1.74 vs. 1.84 months, respectively; P = 0.61) or in grade 3 and 4 toxicity rates (including neurologic; 12% vs. 10%, respectively; P = 0.77) between patients with and without brain metastases. CONCLUSIONS: The rates of survival and response of patients with brain metastases were lower than those for other patients in the phase I setting, but the presence of brain metastases was not an independent prognostic factor predicting survival, indicating that other covariates that coexist with brain metastases were more significant. Time-to-treatment failure for patients with brain metastases was not decreased, nor was the incidence of serious adverse effects (including neurologic toxicity) increased, suggesting that these patients should be eligible for early clinical trials.

Effects of patupilone on the pharmacokinetics and pharmacodynamics of warfarin in patients with advanced malignancies: a phase I clinical trial.

Patupilone is a novel microtubule-targeting cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of warfarin when administered concomitantly with patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center, drug-drug interaction study. In the core phase of the study, treatment consisted of warfarin 20 mg orally (days 1 and 29) and patupilone 10 mg/m(2) i.v. (days 8 and 29). Patients benefiting from patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for C(max) and area under the curve(0-168) of warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of warfarin were not affected by patupilone coadministration. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, anorexia, dehydration, asthenia, and peripheral neuropathy. Five (29.4%) patients experienced grade 3 study drug-related adverse events (diarrhea, 17.6%; increased INR, 11.8%; dehydration, 5.9%; and neutropenia, 5.9%). One patient with triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of warfarin were not affected by patupilone coadministration, suggesting that patupilone has no clinically relevant effect on CYP2C9 metabolism. Patupilone showed antitumor activity in triple-negative breast cancer.

Phase I clinical trial of hepatic arterial infusion of paclitaxel in patients with advanced cancer and dominant liver involvement.

PURPOSE: The survival of patients with liver metastases from solid tumors is poor. We conducted a phase I study of hepatic arterial infusion (HAI) paclitaxel in patients with advanced cancer and predominant liver involvement. METHODS: Patients were treated with HAI paclitaxel 150-275 mg/m(2) (and 15,000 IU heparin intraarterially) every 28 days. A "3 + 3" study design was used. RESULTS: Twenty-six patients were treated (median age, 59 years). Diagnoses were colorectal cancer (n = 10), breast cancer (n = 7), and other (n = 9). The median number of prior therapies was four (range, 0-10). The maximum tolerated dose (MTD) was HAI paclitaxel 225 mg/m(2). Dose-limiting toxicities (DLTs) included Grade 3 neuropathy (1 of 5 patients) at HAI paclitaxel 275 mg/m(2) and Grade 4 thrombocytopenia and neutropenia, and Grade 3 mucositis (1 of 4 patients) at 250 mg/m(2). None of the eight patients treated with HAI paclitaxel 225 mg/m(2) experienced a DLT. The most common toxicities were nausea and peripheral neuropathy. Of 22 patients evaluable for response, 3 (13.6%) patients had SD for ≥4 months (colorectal cancer, n = 1; thyroid cancer, n = 1; and hepatocellular carcinoma, n = 1; duration of response was 4 months, 7.1 months, and 22.2+ months, respectively). CONCLUSION: The MTD of HAI paclitaxel was 225 mg/m(2). This regimen was well tolerated and had antitumor activity in selected patients.

Phase 1 clinical trials in 83 patients with pancreatic cancer: The M. D. Anderson Cancer Center experience.

BACKGROUND: The outcomes of patients with pancreatic cancer treated on early phase clinical trials have not been systematically analyzed. The purpose of this study was to report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer treated on phase 1 clinical trials at a single institution. METHODS: The authors reviewed the records of consecutive patients with metastatic pancreatic cancer who were treated in the Phase I Clinical Trials Program at The University of Texas M. D. Anderson Cancer Center from November 2004 to March 2009. Data recorded and analyzed included survival, response, and disease characteristics. RESULTS: Eighty-three patients were identified. The median age was 62 years (range, 39-81 years). Of 78 patients evaluable for response, 2 (3%) had a partial response (PR), and 10 (13%) had stable disease (SD) for ≥ 4 months. With a median follow-up for survivors of 3.7 months, the median survival from presentation in the phase 1 clinic was 5.0 months (95% confidence interval [CI], 3.3-6.2). The median overall survival from diagnosis was 22.1 months (95% CI, 17.9-26.5). The median time to treatment failure was 1.5 months (95% CI, 1.3-1.8). Independent factors associated with lower rates of PR/SD were liver metastases (P = .001) and performance status >0 (P = .01). Independent factors associated with shorter survival were liver metastases (P = .007), low calcium level (P = .015), and elevated CEA level (>6 ng/mL) (P = .005). CONCLUSIONS: Our results suggest that phase 1 clinical trials offer a reasonable therapeutic approach for patients with advanced pancreatic cancer.

Phase I clinical trial of MPC-6827 (Azixa), a microtubule destabilizing agent, in patients with advanced cancer.

MPC-6827 (Azixa) is a small-molecule microtubule-destabilizing agent that binds to the same (or nearby) sites on ß-tubulin as colchicine. This phase I study was designed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MPC-6827 in patients with solid tumors. Patients with advanced/metastatic cancer were treated with once-weekly, 1- to 2-hour intravenous administration of MPC-6827 for 3 consecutive weeks every 28 days (1 cycle). Dose escalation began with 0.3, 0.6, 1, and 1.5 mg/m(2), with subsequent increments of 0.6 mg/m(2) until the MTD was determined. A 3 + 3 design was used. Pharmacokinetics of MPC-6827 and its metabolite MPI-0440627 were evaluated. Forty-eight patients received therapy; 79 cycles were completed (median, 1; range, 1-10). The most common adverse events were nausea, fatigue, flushing, and hyperglycemia. The DLT was nonfatal grade 3 myocardial infarction at 3.9 mg/m(2) (1/6 patients) and at 4.5 mg/m(2) (1/7 patients). The MTD was determined to be 3.3 mg/m(2) (0/13 patients had a DLT). Five (10.4%) of the 48 patients achieved stable disease (Response Evaluation Criteria in Solid Tumors) for 4 months or greater. MPC-6827 has a high volume of distribution and clearance. Half-life ranged from 3.8 to 7.5 hours. In conclusion, MPC-6827 administered intravenously over 2 hours at a dose of 3.3 mg/m(2) once weekly for 3 weeks every 28 days was safe in patients with heavily pretreated cancer. Clinical trials with MPC-6827 and chemotherapy are ongoing.

Phase I clinical trial of hepatic arterial infusion of cisplatin in combination with intravenous liposomal doxorubicin in patients with advanced cancer and dominant liver involvement.

PURPOSE: We conducted a phase I study of hepatic arterial infusion (HAI) cisplatin and systemic chemotherapy in patients with advanced cancer and dominant liver involvement. METHODS: Patients were treated with HAI cisplatin 100-125 mg/m(2) (and 3,000 IU heparin) intraarterially and liposomal doxorubicin (doxil) 20-35 mg/m(2) IV (day 1) every 28 days. A "3 + 3" study design was used. RESULTS: Thirty patients were treated (median age, 56 years). Diagnoses were breast cancer (n = 11), colorectal cancer (n = 8), ocular melanoma (n = 4), and other (n = 7). The median number of prior therapies was 5. The maximum tolerated dose (MTD) was at the 100/35 mg/m(2) level. Dose-limiting toxicities were Grade 4 neutropenia (2 of 4 patients), and Grade 4 thrombocytopenia (n = 1) at the cisplatin 125 mg/m(2) and systemic doxil 35 mg/m(2) dose level. The most common toxicities were nausea/vomiting and fatigue. Of 24 patients evaluable for response, 4 (17%) had a partial response (PR) and 7 (29%) had stable disease (SD) for ≥4 months. Of the 11 patients with breast cancer, 3 (27%) had a PR and 5 (45%) had SD for ≥4 months. Of 4 patients with ocular melanoma, 1 had a PR and 1 SD for 4 months. One patient with hepatocellular carcinoma had SD for 4 months. Of 12 evaluable patients treated at the MTD, 2 (17%) had a PR and 5 (42%) had SD. CONCLUSION: The MTD was HAI cisplatin 100 mg/m(2) and systemic doxil 35 mg/m(2). This regimen demonstrated antitumor activity, especially in breast cancer.

A phase I clinical trial of darinaparsin in patients with refractory solid tumors.

PURPOSE: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer. EXPERIMENTAL DESIGN: Patients with solid malignancies refractory to conventional therapies were treated with i.v. darinaparsin daily for 5 days every 4 weeks. The starting dose (78 mg/m(2)) escalated to 109, 153, 214, 300, 420, and 588 mg/m(2). A conventional "3 + 3" design was used. RESULTS: Forty patients (median age, 61.5 years; median number of prior therapies, 5) received therapy; 106 cycles were given (median, 2; range, 1-12). Twenty patients reported no drug-related toxicities. No DLTs were reported at a dose of <420 mg/m(2). At 588 mg/m(2), two of four patients developed DLTs, including grade 3 altered mental status and ataxia. Of four patients treated at the de-escalated dose of 500 mg/m(2), one developed similar toxicities. De-escalating the dose to 420 mg/m(2) (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m(2) (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for > or =4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer. CONCLUSIONS: The recommended dose for phase II trials is 300 mg/m(2) i.v. given daily for 5 days every 4 weeks.