Phase II study on lapatinib in advanced EGFR-positive chordoma

BackgroundTo report on a prospective, investigator-driven, phase II study on lapatinib in epidermal growth factor receptor (EGFR)-positive advanced chordoma patients.Patients and methodsFrom December 2009 to January 2012, 18 advanced progressing chordoma patients entered this study (median age: 61 years; disease extent: metastatic 72% and locally advanced 28%). Epidermal growth factor receptor (EGFR) expression and activation were evaluated by immunohistochemistry and/or phospho-arrays, real-time polimerase chain reaction, fluorescence immunostaining. Fluorescence in situ hybridization analysis was also carried out. Patients received lapatinib 1500 mg/day (mean dose intensity = 1282 mg/day), until progression or toxicity. The primary study end point was response rate (RR) as per Choi criteria. Secondary end points were RR by Response Evaluation Criteria in Solid Tumor (RECIST), overall survival, progression-free survival (PFS) and clinical benefit rate (CBR; RECIST complete response + partial response (PR) + stable disease (SD) ≥ 6 months).ResultsAll patients were evaluable for response. Six (33.3%) patients had PR and 7 (38.9%) SD, as their best Choi responses, corresponding to RECIST SD in all cases. Median PFS by Choi was 6 [interquartile (IQ) range 3–8] months. Median PFS by RECIST was 8 (IQ range 4–12) months, with a 22% CBR.ConclusionsThis phase II study showed a modest antitumor activity of lapatinib in chordoma. The clinical exploitation of EGFR targeting in chordoma needs to be further investigated, both clinically and preclinically. Clinical trial Registration No: EU Clinical Trials Register trial no. 2009-014456-29.     

伊马替尼治疗晚期脊索瘤患者的临床研究

目的：研究晚期脊索瘤患者口服伊马替尼治疗的临床疗效分析。方法本研究收集2007年6月至2012年6月,在解放军总医院第一附属医院住院治疗的晚期脊索瘤患者63例,其中失访病例24例,我们长期追踪到的39例为可评价患者。患者在接受伊马替尼治疗前通过病理组化检测 PDGFRβ蛋白表达情况,分为低表达组和高表达组。所有患者均口服伊马替尼的剂量为每天400 mg ,每3个月进行1次 CT或 MRI 检查肿瘤生长情况,按照 RECIST 标准评价临床治疗效果,同时比较两组患者对伊马替尼治疗疗效的差别,并以 SPSS13.0作统计分析,P＜0.05具有统计学意义;采用 Kaplan-Meier 法绘制患者生存曲线。结果免疫组化提示高表达PDGFRβ患者为25例,占64.1%,14例低表达患者,占35.9%;在39例可评价患者中,完全缓解（CR）病例为0例（0%）,部分缓解（PR）病例为3例（8%）,病情稳定（SD）患者为27例（69%）,疾病进展（ PD ）病例为9例（23%）;临床获益率为76.9%（ CR%＋PR%＋SD%）;中位无疾病进展期为9个月,中位生存时间为31.2个月。PDGFRβ高表达组临床获益人数为22例（临床获益率88%）,低表达组临床获益人数8例（临床获益率57.1%）;两组患者相比差异有统计学意义,P值为0.0282。结论本研究提示伊马替尼在治疗晚期脊索瘤方面具有抗肿瘤活性,临床获益率较好,同时在 PDGFRβ高表达的患者获得了更好的疗效。     

Response to imatinib plus sirolimus in advanced chordoma

BackgroundImatinib (IM) is active in advanced chordoma. The evidence of upstream and/or downstream mammalian target of rapamycin (mTOR) pathway activation prompted us to combine an mTOR inhibitor, sirolimus, to IM in IM-resistant advanced chordoma.Patients and methodsSince July 2007, 10 progressive advanced chordoma patients with secondary resistance to IM, and biochemical and/or immunohistochemical evidence of upstream and/or downstream mTOR effector activation, started IM (400 mg/day) plus sirolimus (2 mg/day) on a named basis.ResultsThe mean treatment duration was 9 months. Of nine patients assessable for response, at 3 months, we had one RECIST partial response (PR), seven stable disease (SD) and one progressive disease (PD). According to Choi criteria applied even to magnetic resonance imaging, we had seven PR (≥10% decrease in size in four cases), one SD and one PD. Seven patients had a positron emission tomography response. The clinical benefit [RECIST complete response + PR + SD ≥6 months] was 89%. Pretreatment mTOR effectors analysis carried out in nine cases was positive in all patients (AKT activation in six patients, S6Sp6 expression/activation in seven). Post-treatment biopsy in one responsive patient confirmed S6 switch off.ConclusionIn addition to PDGFRB, mTOR pathway can be activated in chordomas and the combination of IM plus rapalogs may be effective in IM-resistant chordomas.     

Phase II study of 9-nitro-camptothecin in patients with advanced chordoma or soft tissue sarcoma.

PURPOSE: The purpose of this trial was to assess the objective clinical response, toxicity, and time to progression of treatment with 9-Nitro-Camptothecin (9-NC) in patients with advanced chordoma, soft tissue sarcoma (STS), and gastrointestinal stromal tumor (GIST). PATIENTS AND METHODS: Patients with locally advanced and/or metastatic chordoma, STS, or GIST received 9-NC 1.25 mg/m2 orally for 5 consecutive days followed by 2 days of rest. Patients continued on therapy until disease progression, uncontrollable toxicity, or withdrawal of consent. RESULTS: From January 2000 to May 2003, 51 patients (15 chordoma, 23 STS, 13 GIST patients) enrolled. One patient (7%) with chordoma and one patient (4%) with STS had an objective response. Median time to progression was 9.9, 8.0, and 8.3 weeks for chordoma, STS, and GIST patients, respectively. Three- and 6-month progression-free survival rates were 47% and 33% for chordoma patients, 26% and 22% for STS patients, and 31% and 23% for GIST patients, respectively. Ten patients (10%) stopped study drug before disease progression secondary to toxicity. Common adverse events included anemia (42 patients, seven with grade 3/4 toxicity), leukopenia (33 patients, nine with grade 3/4 toxicity), fatigue (30 patients, three with grade 3/4 toxicity), nausea (34 patients, six with grade 3/4 toxicity), and diarrhea (28 patients, five with grade 3/4 toxicity). CONCLUSION: 9-NC has modest activity in delaying progression in patients with unresectable or metastatic chordoma. 9-NC is associated with moderate toxicity and shows little benefit in patients with advanced STS and GIST.     

Phase II study of motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate

Purpose

Motesanib (AMG 706) is a multitargeted anticancer agent with an inhibitory action on the human vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and the cellular stem-cell factor receptor (KIT). The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent motesanib in Japanese patients with advanced gastrointestinal stromal tumors with prior exposure to imatinib mesylate.

Methods

All patients had experienced progression or relapse while undergoing with imatinib as 400 mg/day or higher. The patients were administered 125 mg of motesanib once daily. The primary endpoint was overall response. Efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumor, and safety was assessed according to the Common Terminology Criteria for Adverse Events (version 3).

Results

Of 35 enrolled and treated patients, no patient showed a complete response, and one patient showed a partial response (PR). Seven had stable disease (SD) for at least 24 months, two of whom continued to have SD for more than 2 years. The median progression-free survival time was 16.1 weeks. Motesanib was well tolerated; commonly reported treatment-related adverse events were hypertension, diarrhea, and fatigue. Anemia was the only hematological toxicity that was reported.

Conclusions

One patient showed PR, and seven patients showed SD more than 24 weeks. Motesanib was found to be safe and well tolerated. The observed toxicities were consistent with Phase I study findings.     

Phase II study of teniposide in advanced breast cancer

Summary In a phase II study, 19 patients with previously treated, advanced breast cancer received 50 mg/m² teniposide (VM-26) i. v. on days 1–5 every 3 weeks. One partial response (PR) (5%) was observed. Toxicity consisting of leukopenia and thrombocytopenia was frequent and severe. VM-26 has minimal therapeutic activity when given at this dose and on this schedule to patients with heavily pretreated metastatic breast cancer.     

Phase II study of mitoxantrone in advanced breast cancer

A phase II study of mitoxantrone in cases of advanced breast cancer was conducted by a cooperative study group involving 7 institutions. Mitoxantrone was administered at doses of 10-12 mg/m2 at 3-4-week intervals. A total of 36 patients were entered and 31 were evaluable. There were 4 CRs (13%) and 3 PRs (10%) with an overall response rate of 23% and the durations of responses were between 6 and 25 weeks. Leukopenia was a dose-limiting effect of toxicity and occurred in all patients, while gastrointestinal toxicity and alopecia were mild.     

Phase II study of doxifluridine in advanced colorectal adenocarcinoma

Doxifluridine, a new fluoropyrimidine derivative, was tested in a cooperative phase II trial by the Swiss Group for Clinical Cancer Research in advanced measurable colorectal cancer. The drug was given in a five consecutive day schedule by a bolus intravenous injection at a dose of 4 g/m2 per day and repeated every three to four weeks. Of 42 eligible patients, 40 had no previous chemotherapy. Response was defined in 27 patients having received two or more courses of doxifluridine. Seven responses (26%) were observed. Responses were seen only in sigmoid and rectum primary tumors. Toxicity consisted mainly of leukopenia (53% of the evaluable patients), nausea and vomiting (38%). Other toxicities such as dermatitis, myocardial injury, and hair loss were also observed. Doxifluridine has therapeutic activity, albeit limited, in advanced rectosigmoid adenocarcinoma.     

Phase II study of idarubicin in advanced cervical carcinoma

Idarubicin, an anthracycline analogue, was studied in a Phase II trial of 18 patients with advanced cervical carcinoma. Fourteen patients had received no prior chemotherapy (11 had received radiotherapy and three were untreated). All patients received at least two courses of idarubicin at a dose of 12.5 mg/m2 i.v. every 3 weeks. No responses were noted. Fifteen patients had uninterrupted progression of disease and three were stable for 4, 5, and 6 months respectively. Myelosuppression was the most common side effect. Idarubicin displayed no antitumor effect in 18 minimally pretreated cervical carcinoma patients.     

Phase II study of iproplatin in advanced ovarian carcinoma

Iproplatin (cis-dichloro-trans dihydroxy-bis-isopropyl-amine platinum [IV]; CHIP) was administered intravenously (IV) at monthly intervals at doses of 300 mg/m2 and 240 mg/m2 to ten previously untreated and 97 previously treated patients with advanced ovarian carcinoma. The overall response rate was 78% among patients with no prior chemotherapy, 42% among patients with prior chemotherapy not including cisplatin, and 22% among patients with prior chemotherapy including cisplatin. Overall response rates to iproplatin were 6.4% and 54% in patients with/without clinical evidence of tumor resistance to cisplatin. Thrombocytopenia was the dose-limiting toxicity, median time to nadir and to recovery being 2 and 4 weeks, respectively. Patients who had received prior chemotherapy regimens for greater than 1 year showed a 10% greater reduction in platelet count (mean platelet nadir +/- SD, 57.5 +/- 49.96 X 10(3)/microL) and a higher incidence of grade 3 to 4 thrombocytopenia after the first cycle than patients who had received prior chemotherapy regimens for less than 1 year (94.7 +/- 65.99 X 10(3)/microL) Moderate to severe vomiting and diarrhea occurred in 84% and 16% of patients pretreated with chemotherapy. Neuropathy (6%) was reported only in patients with prior cisplatin treatment. Mild and reversible renal toxicity was observed in 6% of cases. Iproplatin is an active drug in ovarian cancer; the results achieved in patients previously treated with cisplatin strongly suggest that the two drugs are cross-resistant.     

Phase II study with ifosfamide in advanced malignant melanoma

Ifosfamide was tested in a phase II study in 12 evaluable patients with advanced malignant melanoma. The drug was administered at the dose of 3 g/m2 on days one and two every 3-weeks. Seven patients were not previously treated and 5 received only minimal prior chemotherapy. Visceral involvement was present in 9 patients, and the remaining 3 had only soft tissue lesions. No patient showed objective tumor response. Mild vomiting was observed in 75% of patients; alopecia occurred in all of them. No other major side effects were observed, in particular, myelotoxicity and urotoxicity. Lack of response advised us to discontinue patient accrual. Our data do not support a therapeutic role of ifosfamide at the given dose schedule in the treatment of metastatic malignant melanoma.     

Phase II study of medroxyprogesterone acetate in advanced breast cancer

A phase II study of high-dose medroxyprogesterone acetate (MPA) was performed in 18 patients with advanced breast cancer. MPA was administered at a dosage of 1,200mg orally per day. Of the 15 evaluable patients, partial response was obtained in 3, minor response in 1, no change in 5 and progressive disease in 6 patients. The response rate was 20%, which was as effective as that of tamoxifen. As the responders had been previously treated with tamoxifen, the result suggested that MPA showed no cross-resistance to the latter. Eight patients (53%) experienced weight gain which, in 4 cases (27%), necessitated discontinuation of the treatment. One patient exhibited an allergic reaction and the drug was discontinued. Palpitation in 4 patients (27%), vaginal bleeding in 2 (13%), and edema in 1 (7%) were observed, but these effects were tolerable. We therefore conclude that high-dose MPA is an effective therapy for advanced breast cancer, and that further study is warranted.     

Phase II study of epirubicin in advanced soft tissue sarcoma

Thirty-seven patients (pts) with previously untreated and measurable advanced soft tissue sarcoma entered this phase II study: 22 men and 15 women were included. Median age was 58 (range: 20-71). The starting dose of epirubicin was 100 mg/m2 IV bolus every 3 wks. In the case of minimal myelosuppression, the dose was increased by 10 mg/m2 to 130 mg/m2 (Mean dose per cycle: 105 mg/m2). Median cumulative dose of epirubicin administered was 445 mg/m2 (range: 200-1320 mg/m2). From 32 evaluable pts, one had a complete response (CR), 5 a partial response (PR), (CR + PR = 18.7% +/- 13.8%), 12 showed no change (37.5%) and 14 had progressive disease. The number of complete or partial responses observed was not modified by increasing the doses of epirubicin. Median time to progression was 4 months. From 32 pts evaluable for toxicity, hematologic toxicity at d 21 was mild. Non hematological toxicities consisted of nausea and vomiting in 74% of pts (WHO grade 3 = 5%), stomatitis in 12.2% (WHO grade 3 = 3%) and alopecia in 91% (WHO grade 2-3 = 72%). No cardiac dysfunction was recorded during the treatment, even though 7 patients received more than 800 mg/m2 of epirubicin (median: 850 mg/m2, range: 810-1320 mg/m2). The results of this study show that epirubicin is an active drug in advanced soft tissue sarcoma.     

Phase II study of divided-dose vinblastine in advanced cancer patients

A better therapeutic index has been obtained in breast cancer patients when vinblastine is given by a 5-day continuous infusion program than by i.v. bolus; the continuous infusion pharmacokinetics has been reproduced by an iv divided bolus at 0 and 48 h, which may be more easily applied to outpatients. We performed a broad phase II study in 97 advanced cancer patients in which vinblastine was administered by i.v. divided bolus at 0 and 48 h at the starting dose of 3.5-4 mg/m2, every 3 weeks. Our aim was to confirm the results achieved by continuous infusion and to investigate the toxicity pattern of this novel administration schedule. Neurotoxicity and myelosuppression were the main side effects: constipation and peripheral neurotoxicity respectively developed in 28% and 38% of patients and were severe in 5% and 1%. Leukopenia and thrombocytopenia respectively occurred in 70% and 40% of patients and were severe in 11% and 4%. Four partial responses, 38 no changes and 42 progression were obtained out of 84 evaluable patients. Responses were seen in tumors of breast, lung, and head and neck. Our results do not support the use of vinblastine in divided doses in advanced cancer patients.     

Phase II study of vinblastine in advanced refractory ovarian carcinoma

Fourteen patients with advanced ovarian carcinoma previously treated with chemotherapeutic agents including cisplatin were treated with vinblastine 0.1 mg/kg intravenously every week. There were no responses in 13 evaluable patients. The median survival was 19+ weeks following the initiation of vinblastine (VBL) therapy. Toxicity consisted of minimal myelo-suppression (WBC count less than 2500/microliter in 8/78 courses, WBC count less than 1500/microliter in 0/78 courses, platelets less than 150,000/microliter in 0/78 courses), nausea (4/13 patients), vomiting (2/13 patients), neuropathy (4/13 patients), and weakness and fatigue (6/13 and 5/13 patients, respectively). Although data derived from the human tumor stem cell assay (HTSCA) suggest that VBL may be an active agent against previously treated ovarian carcinoma, this study in patients with refractory advanced disease suggests that VBL is inactive (less than 20% response rate with 90% confidence levels) in that setting. Whether significant durable benefit can be achieved with VBL therapy in patients whose tumor is sensitive in the HTSCA remains to be seen.