A phase I trial of oral ridaforolimus (AP23573; MK-8669) in combination with bevacizumab for patients with advanced cancers.

AIMS: This phase I dose-escalation study was designed to evaluate the combination of the mammalian target of rapamycin inhibitor ridaforolimus with the vascular endothelial growth factor inhibitor bevacizumab. MATERIALS AND METHODS: Seventeen adult patients with refractory advanced solid tumours received oral ridaforolimus (30 or 40 mg) once daily for 5 days per week (QDx5/wk) combined with intravenous bevacizumab (10 mg/kg every 2 weeks [Q2wk] or 15 mg/kg every 3 weeks [Q3wk]). Patients were evaluated for dose-limiting toxicities, safety and anti-tumour activity. RESULTS: A 40 mg dose of ridaforolimus with either bevacizumab dosing schedule was the recommended phase II dose. No dose-limiting toxicities were reported; the most common drug-related adverse events were mucosal inflammation and anorexia. Seven patients, with clinical features that included primary tumour of the abdominal origin (colorectal, pancreatic or gynaecological cancers) and previous abdominal radiotherapy, reported serious adverse events related to bowel perforations. There were no objective responses, but 65% of patients had a best response of stable disease. CONCLUSION: Oral ridaforolimus (40 mg QDx5/wk) is feasible to combine with standard doses of bevacizumab, although careful patient selection would be needed to mitigate the risk of bowel perforation-related adverse events. Combination therapy produced prolonged stable disease in several heavily pretreated patients.

Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial.

BACKGROUND: This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer. METHODS: Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more. RESULTS: In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhoea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anaemia (27%) and hyperglycaemia (11%). CONCLUSION: Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted.

Phase I clinical and pharmacokinetic study of zeniplatin, a new platinum complex.

Forty-six patients with refractory solid malignancies received the new platinum complex [2,2-bis(aminomethyl)-1,3-propanediol-N-N'] [1,1-cyclobutanedicarboxylato] [(2-)0,0')] platinum (zeniplatin). Zeniplatin was given, without hydration or mannitol, as a 60- to 90-min i.v. infusion every 3 weeks at doses ranging from 8 to 145 mg/m2. The maximum tolerated dose of zeniplatin was 145 mg/m2. The dose-limiting toxicity of zeniplatin was dose-related leukopenia and neutropenia, with the nadir usually observed between 1 and 2 weeks after therapy and recovery usually occurring by 3 weeks after therapy. Thrombocytopenia was rare. The most prominent non-hematological side-effect of zeniplatin was nausea and vomiting. Other non-hematological side-effects were mild or absent. Zeniplatin did not induce significant neurological or auditory toxicity. Zeniplatin was not nephrotoxic at doses less than or equal to 120 mg/m2. At 145 mg/m2, the clearance decreased by a mean of 40% after 2 cycles of therapy. Two patients, one with malignant melanoma and one with renal cell cancer, achieved a partial response. Pharmacokinetics of free (plasma ultrafiltrates) and total platinum in plasma were determined in 5 patients. An in vitro study of the rate and extent of zeniplatin binding to protein in human plasma was also performed. Free and total platinum were measured by flameless atomic absorption spectrometry; free zeniplatin was measured in ultrafiltrate by HPLC. Total and free plasma platinum concentrations were co-modelled using the information from the in vitro study.(ABSTRACT TRUNCATED AT 250 WORDS)

Neoadjuvant chemotherapy with cisplatin, methotrexate, bleomycin and vincristine (CABO) in patients with stage III and IV squamous cell carcinoma of the head and neck.

Forty-six patients with Stage III-IV previously untreated squamous cell carcinoma of the head and neck were treated with neoadjuvant chemotherapy with cisplatin, methotrexate, bleomycin and vincristine. The overall response rate was 70%, with a 9% complete response rate. The most frequent side effects were myelosuppression, nausea and vomiting, alopecia, neurotoxicity and stomatitis. Definitive local therapy consisted of surgery alone in 13 cases, surgery plus radiation in another 13, and radiotherapy alone in 14. Six patients, four of whom died, received no definitive local therapy and two were lost to follow-up. The median disease-free survival time was 10.5 months, and the most frequent cause of failure was local regional relapse (85%). Median survival time was 13 months and there were eight long-term survivals (median 48 months). Response to chemotherapy was independent of all analysed prognostic factors. Disease-free survival and survival were significantly influenced by the presence or absence of lymph nodes. Our results do not support the routine use of neoadjuvant chemotherapy with cisplatin, methotrexate, bleomycin, and vincristine in patients with advanced cell carcinoma of the head and neck.

Intraperitoneal chemotherapy with cisplatin and melphalan.

Cisplatin and melphalan given ip exert a synergistic therapeutic effect against ascitic P388 leukemia in mice and have different dose-limiting toxic effects as well as favorable pharmacokinetic characteristics in ip phase I studies. We gave a total of 98 courses of cisplatin (escalated from 40 to 120 mg/m2) and melphalan (escalated from 12 to 30 mg/m2) to 30 patients with ip tumors, most of whom had residual ovarian cancer following iv cisplatin-containing regimens. Treatment was delivered in 2 L of 0.9% NaCl through a Tenckhoff catheter with or without a Port-a-Cath system every 28 days for one to nine cycles. Myelosuppression was dose-related and leukopenia was dose-limiting. The maximum tolerated dose was 120 mg of cisplatin/m2 and 20 mg of melphalan/m2. With the exception of treatment-induced nausea and vomiting, nonhematologic toxic effects were mild and no (or very little) local toxicity occurred. Pharmacokinetic analyses showed that the areas under the peritoneal concentration versus time curve averaged 16-fold and 17-fold more than the area under the plasma curve for cisplatin and melphalan, respectively. Objective responses were documented by third-look laparotomy in ovarian cancer patients with minimal (less than 2 cm) residual disease.

In vitro chemosensitivity testing of flavone acetic acid (LM975; NSC 347512) and its diethylaminoethyl ester derivative (LM985; NSC 293015).

The antitumor effect of flavone acetic acid, LM975, and its diethylaminoethyl ester derivative, LM985, was studied in four human malignant cell lines [WiDr, a colon carcinoma; LICR (LON) HN-3, a tongue carcinoma; MCF7, a breast carcinoma; K-562, a leukemia] using a colorimetric assay based on the reduction of dimethylthiazol-2-yl-diphenyltetrazolium. The cell lines were exposed continuously for 4-6 days to drug concentrations ranging between 0.1 and 500 micrograms/ml. For LM975, the concentrations inhibiting the growth of the various cell lines by 50% were 200 +/- 10, 97 +/- 7, 171 +/- 16 and greater than 500 micrograms/ml for LICR (LON) HN-3, WiDr, MCF-7, and K-562, respectively. The corresponding concentrations for LM985 were 151 +/- 3, 36 +/- 4, 86 +/- 3 and 140 +/- 18 micrograms/ml, respectively. The difference between LM985 and LM975 was statistically significant for the WiDr and LICR (LON) HN-3 lines. We also evaluated the cytotoxic activity of the two agents on normal human marrow myeloid progenitor cells in a colony-forming assay. Continuous exposure to the drugs gave a dose-dependent inhibition. The concentrations inhibiting the growth by 50% were 76 +/- 31 micrograms/ml for LM975 and 134 +/- 41 micrograms/ml for LM985. One hour incubation with either compound had no toxic effect on the myeloid progenitor cells. In conclusion, LM975 and LM985 do not appear to have a specific cytotoxicity for tumor cells. Our results indicate that, in vitro, toxicity on bone marrow myeloid progenitor cells is concentration dependent. Considering the low plasma concentration found in man after i.v. administration of LM985, our observations correlate well with the absence of drug-induced myelosuppression in patients.

Clinical and pharmacokinetic phase I trial with the diethylaminoester of flavone acetic acid (LM985, NSC 293015).

The diethylaminoester of flavone acetic acid (LM985) is a new anticancer agent with curative effects against slow growing murine tumors. Thirty-one adult patients with solid tumors received a total of 57 courses of LM985 given on days 1 and 8 every 4 weeks. The drug was given as a short infusion (1-2 hr) at doses ranging from 120 to 1900 mg/sq.m/day. The dose-limiting toxicity consisted of acute expressive aphasia; this neurotoxicity usually appeared at the end of the infusion and resolved spontaneously within a few minutes to 1 hr after the end of the infusion. In some patients, neurotoxicity was avoided by reducing the infusion rate. Neurotoxicity was observed in 5 out of 6 patients receiving 960 mg/sq.m over 1 hr and in 3 out of 3 patients receiving 1900 mg/sq.m over 2 hr. The drug did not induce any significant myelosuppression. Other side-effects were very mild and consisted mainly of occasional nausea and/or vomiting at all dose levels. One patient with breast cancer resistant to several hormonal and chemotherapy regimens had stable disease for 6 months. LM985 was detected in plasma in very small concentrations (0-2.5 micrograms/ml) but there was extensive formation of flavone acetic acid (peak concentration ranging between 8.3 and 64 micrograms/ml). A dose of 1500 mg/sq.m on days 1 and 8 every 4 weeks could be recommended for phase II studies with LM985; however, since LM985 is a prodrug of flavone acetic acid, phase II studies with LM985 should not be activated prior to the completion of the ongoing phase I trials with flavone acetic acid, which may be devoid of the acute toxicity of LM985.