Phase I study of axitinib combined with paclitaxel, docetaxel or capecitabine in patients with advanced solid tumours.

BACKGROUND: Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, enhanced the efficacy of chemotherapy in human xenograft tumour models. This phase I study investigated the safety, tolerability, pharmacokinetics and antitumour activity of axitinib combined with chemotherapy. METHODS: A total of 42 patients with advanced solid tumours received a continuous axitinib starting dose of 5 mg twice daily (b.i.d.) plus paclitaxel (90 mg m(-2) weekly), docetaxel (100 mg m(-2) every 3 weeks) or capecitabine (1000 or 1250 mg m(-2) b.i.d., days 1-14). RESULTS: Common treatment-related adverse events across all cohorts were nausea (45.2%), hypertension (45.2%), fatigue (42.9%), diarrhoea (38.1%), decreased appetite (33.3%) and hand-foot syndrome (31.0%). There was one complete response, nine partial responses and seven patients with stable disease. Ten patients (23.8%) remained on therapy for >8 months. Paclitaxel and capecitabine pharmacokinetics were similar in the absence or presence of axitinib, but docetaxel exposure was increased in the presence of axitinib. Axitinib pharmacokinetics were similar in the absence or presence of co-administered agents. CONCLUSIONS: Axitinib combined with paclitaxel or capecitabine was well tolerated; no additive increase in toxicities was observed. Antitumour activity was observed for each treatment regimen and across multiple tumour types.

Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours.

BACKGROUND: This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours. METHODS: In all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin. RESULTS: Two patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade ≥3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination. CONCLUSION: Axitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug-drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.

Neoadjuvant PFL augmented by methotrexate and piritrexim followed by concomitant chemoradiotherapy for advanced head and neck cancer: a feasible and active approach.

To increase the complete remission (CR) rate achieved with two cycles of cisplatin, continuous infusion fluorouracil (5-FU) and oral leucovorin (PFL) we added two antifolate drugs, methotrexate (MTX) and the lipophilic piritrexim (PTX), to the combination (PFL-MP). Twenty-eight patients with previously untreated Stage IV squamous cell carcinoma of the head and neck received 2 cycles of cisplatin 100 mg/m2 on day 1 followed by a 5-day continuous infusion of 5-FU at 800 mg/m2/day and 100 mg of leucovorin administered orally every 4 hours. MTX was administered at 40 mg/m2 IV on day 15 and PTX at 75 mg orally twice daily on days 22 to 26, with cycle 2 starting on day 36. After 2 of the first 5 patients had tumor progression between days 15 and 35, the regimen was intensified to MTX 50 mg/m2, PTX 100 mg twice daily and a cycle duration of 28 days. Local therapy consisted of surgery and/or radiotherapy with concomitant 5-FU and hydroxyurea (FHX) administered every other week. Eleven patients (39%, 95% confidence intervals 21-57%) had a CR, 9 (32%) had a PR, and four patients had no response. Four patients were unevaluable for response to PFL-MP. Patients with poor performance status or N3 disease were less likely to achieve a CR. Mucositis following PFL was the dose-limiting toxicity. Local therapy included surgery in 15 patients and FHX chemoradiotherapy in 19 patients. The administration of FHX in this setting proved feasible and the regimen was given near the intended dose intensity in the majority of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized study comparing two regimens of neoadjuvant and adjuvant chemotherapy in multimodal therapy for locally advanced head and neck cancer.

Two regimens of neoadjuvant chemotherapy for previously untreated patients with locally advanced head and neck cancer were compared with the goal of identifying a regimen with a greater than 50% complete response (CR) rate. Patients with a performance status of 0 to 2 and normal end-organ function were randomized to receive either four cycles of neoadjuvant methotrexate, cisplatin, and continuous infusion 5-fluorouracil (5-FU) (MPF) (arm A), or four cycles of bleomycin, cisplatin, and methotrexate (PBM) alternating with cisplatin and 5-FU (PF) (arm B). Patients with a performance status of greater than 2 or a carbon monoxide diffusion capacity of less than 50% of the predicted value were assigned to the arm A regimen but were analyzed separately (arm C). Local therapy consisted of surgery (for patients with resectable disease) or radiation therapy followed by two cycles of adjuvant chemotherapy with the regimen that was administered initially. Of the 42 patients who were evaluated, 16 were randomized to arm A, 13 to arm B, and 13 to arm C. The clinical CR rate was 19% on arm A (95% confidence interval, 0% to 38%), 39% on arm B (95% confidence interval, 12% to 66%) (P = 0.41), and 54% on arm C (95% confidence interval, 27% to 81%). At a median follow-up time of 35 months, the 2-year actuarial survival rate was 61% on arm A, 69% on arm B (the P value was not significant), and 38% on arm C. The 2-year survival rate for all 42 patients who were treated was 57% and the median survival time was 31 months. Toxicities of neoadjuvant chemotherapy on all arms consisted of mild to moderate myelosuppression and renal toxicity. The incidence of moderate to severe mucositis was significantly higher on arm A than arm B (P = 0.02). Two cycles of adjuvant chemotherapy were administered to only 11 of 42 patients due to patient refusal or cumulative toxicity. In conclusion, both neoadjuvant chemotherapy regimens resulted in similar response and survival rates, but mucositis was more severe with arm A. However, since neither regimen was likely to cause a CR rate of greater than 50%, this study was closed to further patient accrual.

Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: a clinical and pharmacologic analysis.

Both cisplatin and leucovorin (LV) interact with fluorouracil (5-FU) by increasing intracellular reduced folate levels and thereby the inhibition of thymidylate synthase. Therefore, the addition of LV to cisplatin and 5-FU (PFL) may increase the activity of that combination in head and neck cancer. We treated 31 patients with locally advanced head and neck cancer with two cycles of neoadjuvant PFL consisting of 100 mg/m2 of cisplatin on day 1 followed by a 5-day continuous infusion of 5-FU at 1,000 mg/m2/day and oral LV at 100 mg administered every 4 hours during the entire duration of chemotherapy infusion. Two patients died during neoadjuvant chemotherapy of sudden death and sepsis, respectively, and were not evaluated for response. Of 29 evaluable patients, nine had a complete response (CR), 17 had a partial response (PR), and three had stable disease. Toxicities consisted of mild to moderate myelosuppression and moderate to severe mucositis, necessitating reduction of 5-FU on cycle 2 to less than or equal to 80% of the intended dose in 22 of 29 patients. Administration of LV by repeated oral dosing resulted in total reduced folate plasma concentrations of 5.3 (+/- 2.9) and 6.7 (+/- 3.4) mumol on days 2 and 4 of the 5-FU infusion. The sum of 1-LV and its metabolite 5-CH3-tetrahydrofolate exceeded the concentration of d-LV, consistent with selective absorption of the biologically active 1-stereoisomer from the gastrointestinal tract.

Platinol (CDDP) and continuous intravenous infusion 5-fluorouracil in refractory stage IV breast cancer: a phase II study.

Twenty-four patients with refractory Stage IV breast cancer were treated with platinol (100 mg/m2 i.v. Day 1) and 5-fluorouracil (1000 mg/m2 as a continuous infusion over 24 h daily for 5 days). Objective responses occurred in 12 of 24 patients (50%). The median duration of response was 4.9 months. Platinol and 5-fluorouracil in combination are active agents in patients with refractory breast cancer, and clinical trials are warranted in previously untreated patients.

Response to secondary therapy in patients with adenocarcinoma of the breast previously treated with adjuvant chemotherapy.

The response to secondary therapy, chemotherapy or hormonal, is examined in 26 patients with adenocarcinoma of breast who failed adjuvant chemotherapy. Response rates to tamoxifen or combination chemotherapy, cyclophosphamide, methotrexate, and 5-FU (CMF) or Adriamycin and vincristine (AV) were similar to response rates reported for Stage IV patients, never exposed to cytotoxic agents. Survivals in these 26 patients were similar to those reported for Stage IV patients never exposed to cytotoxics. It is concluded that adjuvant chemotherapy does not lessen future response to secondary therapies or decrease survival.

Multimodality therapy of stage III adenocarcinoma of the breast.

The results of a pilot multimodality program (surgery + radiotherapy + chemotherapy) are reported in 34 women with advanced stage III and IV adenocarcinoma of the breast. The median relapse-free survival for all patients was 24 months, with 74% of the premenopausal patients and 37% of the postmenopausal alive at five years (P = 0.18). The relapse rate was significantly lower in premenopausal patients when compared to the postmenopausal subgroup. Estrogen receptor status was not predictive for relapse or survival.

Acute nephrotoxicity following cis-dichlorodiammine-platinum.

The effects of a single dose of cis-diamminedichloroplatinum (DDP) on the kidney function were investigated in 14 patients with disseminated malignancy and normal renal function. A single dose of DDP (30-50 mg/m2) caused severe proximal tubular dysfunction with increased urinary losses of calcium, magnesium, and amino acids. Phosphate excretion was not affected. DDP can cause proximal tubular dysfunction and close attention must be paid to serum calcium and magnesium levels.

Prognostic value of the estrogen receptor level in pathologic stage I and II adenocarcinoma of the breast.

The relationship between estrogen receptor levels and recurrence of breast cancer was examined in 302 patients with adenocarcinoma of the breast, pathologic stage (PS) I and II. All 117 patients with PS II adenocarcinoma of the breast received adjunctive chemotherapy. In this series, there was no association between the estrogen receptor level and recurrence in either the 185 patients with PS I adenocarcinoma of the breast or the 117 patients with PS II adenocarcinoma of the breast. The most important prognostic variable was the presence or absence of axillary metastases.

Melphalan, vincristine, and 5-FU in advanced colonic carcinoma: results of a pilot study.

The results of treatment with melphalan, vincristine, and 5-FU (MVF) in 32 patients with advanced colonic carcinoma are reported. The objective response rate among 31 patients with measurable disease was 16% (five patients responded). The projected survival for all 32 patients was 277 days. Patients with objective response to MVF had a projected survival of 314 days, significantly longer than the survival of patients with no response to therapy, 84 days (P = 0.01). While toxic effects were mild with MVF, this regimen appears to have greater activity in advanced colonic carcinoma than therapy with 5-FU alone or in combination with nitrosoureas.

Intracavitary bleomycin for the control of malignant effusions.

The results of treatment with intracavitary bleomycin are reported in twenty patients with a malignant pleural effusion and five patients with malignant ascites. The control rate was 17/20 (85%) patients with malignant pleural effusions and 3/5 (60%) patients with malignant ascites. Toxicities were minimal with fever being the most common side effect in four patients (16%. Bleomycin is an effective and nontoxic sclerosing agent.

Treatment of metastatic pancreatic and gastric adenocarcinomas with 5-fluorouracil, adriamycin, and mitomycin C (FAM).

Twenty-six patients with metastatic pancreatic or gastric adenocarcinoma were treated with 5-fluorouracil, Adriamycin, and mitomycin C. One complete and five partial responses were observed among 15 patients with pancreatic adenocarcinoma (40% response rate) and six partial responses were observed among 11 patients with gastric adenocarcinoma (55% response rate). Responders had a significantly longer survival than nonresponders in both groups.