Phase II study of amonafide in the treatment of patients with advanced squamous cell carcinoma of the head and the neck

Summary Amonafide (nafidimide), a synthetic organic compound with an inhibitory effect on cellular replication, was used in a phase II study conducted by the Illinois Cancer Center in order to assess its efficacy and toxicity in advanced or recurrent squamous cell cancer of the head and neck. Eligible patients had received no more than one prior adjuvant or neoadjuvant chemotherapy, had normal bone marrow, renal and hepatic function, ECOG performance status of 0–2, and bidimensionally measurable disease. Eligible patients were administered amonafide at a starting dose of 300 mg/m² for five consecutive days every 3 weeks with dose escalation or de-escalation according to established hematologic criteria in the absence of disease progression. Nineteen of 22 entered patients were evaluable for response and all patients were evaluable for toxicity. Eleven of 19 patients achieved stable disease. Median time to progression after start of treatment was 57 days, for the 18 patients for whom the date of progression is known. There were no partial or complete responses. Hematologic toxicity was dose limiting with grade 3–4 neutropenia in 50 percent of patients and 4 deaths associated with neutropenic sepsis. Non-hematologic toxicity was mild to moderate with nausea and vomiting predominating. In this study, amonafide was a myelotoxic, inactive treatment in advanced/ recurrent head and neck cancer. Further use in head and neck cancer appears unwarranted.     

Phase II study of amonafide in gastric adenocarcinoma

Summary Twelve patients with recurrent, metastatic, or inoperable gastric adenocarcinoma were enrolled in an Illinois Cancer Center phase II trial of amonafide (nafidimide), a novel compound that acts as a DNA intercalator. Treatment consisted of a 60-minute infusion of amonafide which was administered daily for 5 consecutive days every 3 weeks at a starting dose of 300 mg/m²/d. Doses were modified according to the grade of toxicity experienced and eight patients underwent dose escalations. All 12 patients were evaluable for response and toxicities were predominantly hematologic. Stabilization of disease for at least 28 days was observed in seven patients and disease progression was noted in five. The median survival was 7.4 months. Doses were sufficient to produce severe bone marrow toxicity in one-third of the patients treated. None of the patients responded to therapy, implying a true response rate less than.221. Based on the results of this study, amonafide showed no activity against gastric adenocarcinoma; however toxicity appeared acceptable at the 300 mg/m₂/d x 5 consecutive days every 3 weeks dose and schedule.     

Phase II evaluation of teniposide (VM-26) in metastatic breast carcinoma

The Southeastern Cancer Study Group performed a Phase II study of teniposide in previously treated patients with metastatic breast cancer. No responses were observed in 11 evaluable patients who received teniposide 60 mg/m² by IV infusion for five consecutive days every three weeks. Toxicity was primarily gastrointestinal and hematologic and was frequently severe. This study demonstrated no therapeutic activity for teniposide when given in this dose and schedule to patients with heavily pretreated metastatic breast cancer.     

Phase II evaluation of gallium nitrate by continuous infusion in breast cancer

Summary We evaluated the role of gallium nitrate infusion in the treatment of metastatic breast cancer. Gallium nitrate was administered at 300 mg/m²/day for 7 days every 3 weeks by continuous infusion concomitantly with oral calcium supplement of 500 mg twice daily and oral hydration. Fifteen patients with refractory metastatic breast cancer received such treatment for a total of 30 courses. Median age was 51, and median performance status (Zubrod scale) was 1. These patients had minimal prior chemotherapy (median 1 regimen). All patients were evaluable for toxicity and 14 for response. Nine patients had one to two metastatic sites, five patients had three to four sites. No major objective response was seen, but one patient had a minor response (10 weeks), and another showed no change in disease (16 weeks). Diverse low-grade toxicities were observed, including nausea and vomiting in 11 patients, anorexia in 11, diarrhea in eight, stomatitis in five, dysgeusia in six, musculoskeletal pain in five, skin rash in seven, partially reversible tinnitis and/or mild hearing loss in four and sensory neuropathy in two. A consistent drop in hemoglobin (median of 3.2 g/dL per patient) necessitated blood transfusion in seven patients. There was no granulocytopenia or thrombocytopenia; however, significant lymphopenia was noted. Reversible, moderate nephrotoxicity occurred in two patients. The hypocalcemic effect was consistent, with a median drop in serum calcium of 1.25 mg/dL per course. There was no hepatic toxicity. While no single toxicity was severe, overall toxicity adversely influenced treatment tolerance. Gallium nitrate by continuous infusion, as given in this study, has no activity in metastatic breast cancer.     

Phase II study of amonafide in advanced and recurrent sarcoma patients

Summary The activity of amonafide, a benzisoquinoline-1,3-dione, was assessed in 15 patients with advanced or recurrent sarcoma (11 previously treated). Eligible patients had ECOG performance status 0–2, and acceptable renal, hepatic and bone marrow function. Amonafide 300 mg/m² was given intravenously over one hour daily on five consecutive days, every 3 weeks. Leukopenia and granulocytopenia were the most common and severe toxicities (grade 3 or 4 toxicity in 20% and 27% of patients, respectively). Local irritation and nausea/vomiting, the most common nonhematologic toxicities, were generally mild. No objective responses were seen, though 2 patients had brief stabilization of disease. Amonafide at this dose and schedule has no activity against advanced, recurrent sarcoma.     

Phase II evaluation of teniposide (VM-26) in metastatic breast carcinoma. A Southeastern Cancer Study Group trial

The Southeastern Cancer Study Group performed a Phase II study of teniposide in previously treated patients with metastatic breast cancer. No responses were observed in 11 evaluable patients who received teniposide 60 mg/m2 by IV infusion for five consecutive days every three weeks. Toxicity was primarily gastrointestinal and hematologic and was frequently severe. This study demonstrated no therapeutic activity for teniposide when given in this dose and schedule to patients with heavily pretreated metastatic breast cancer.     

Monthly gemcitabine (days 1, 8 and 15) plus cisplatin (days 1-3) in advanced non-small cell lung cancer: a phase II study

On the basis of the reported efficacy of gemcitabine plus cisplatin in patients with non-small cell lung cancer (NSCLC), this combination has been selected to be given as our firstline service regimen for advanced or metastatic disease. Patients recruitment was almost unlimited: no exclusion criteria were made, except for disease-related Karnofsky's performance status below 50%, the presence of central nervous system or spinal involvement by uncontrolled metastases, or creatinine clearance below 50 ml/min. Cisplatin 30 mg/m2/day on days 1-3 and gemcitabine 1250 mg/m2/day on days 1, 8 and 15 every 4 weeks were given on an outpatient schedule to consecutive patients with locally advanced or metastatic NSCLC. Forty-three successive NSCLC patients with histologically or cytologically proven disease were treated. Adenocarcinoma was diagnosed in 35% of cases, squamous cell carcinoma in 60% and broncho-alveolar type in 5%. Smoking was mentioned by 63% of the patients. Numerous medical problems were recorded in 75% of the patients. Stage IIIB was observed in 10 of 43 patients, while metastatic disease was found in the rest. All the patients, except for two, were symptomatic. Two patients achieved complete response (5%) and 16 achieved partial response (37%), yielding an overall objective response rate of 42%. Minimal response was observed in seven patients (16%) and disease stabilization in 7%. Adding the objective response rate to the minimal response and stabilization rates, the disease-control (progression-free) rate reaches 65%. The time to progression ranged from 0 to 69 weeks in all the patients. The overall survival of the group ranged from 4 to 98 weeks, with a median of 45 weeks. Clinical benefit response was observed mainly in patients who also achieved an objective response. We conclude that outpatient cisplatin plus gemcitabine combination is feasible, efficacious and justified in patients with advanced or metastatic NSCLC.     

埃克替尼与吉非替尼治疗既往化疗失败的局部晚期或转移性非小细胞肺癌患者的系统性评价

目的:比较埃克替尼与吉非替尼治疗既往化疗失败的局部晚期或转移性非小细胞肺癌(NSCLC)患者的近期疗效及不良反应情况。方法:通过Medline、Embase、Cochrane图书馆、中国生物医学文献数据库、中国期刊全文数据库、中文生物医学期刊文献数据库和数字化期刊全文数据库等全面检索国内外相关文献,纳入埃克替尼和吉非替尼治疗既往化疗失败的局部晚期或转移性NSCLC的随机对照试验(RCTs),并对文献进行筛选、评价与分析。采用RevMan 4.2软件对入选研究的近期疗效及不良反应进行Meta分析。结果:共纳入符合标准的RCTs 2项,涉及423例病例。系统评价显示,异质性检验结果良好,可用固定效应模型进行分析。埃克替尼组与吉非替尼组比较,4周疾病控制率、半年总生存率、1年总生存率均无明显差异;埃克替尼组的28周疾病控制率优于吉非替尼组(P=0.01);埃克替尼组与吉非替尼组的皮疹、腹泻、咯血发生率均无显著差异,但埃克替尼治疗组的总不良反应发生率显著低于吉非替尼(P<0.000 01)。结论:对于既往化疗失败的局部晚期或转移性NSCLC,埃克替尼的疗效与吉非替尼相当,且总的耐受性优于吉非替尼。     

Multicenter phase II study of amrubicin, 9-amino-anthracycline, in patients with advanced non-small-cell lung cancer (Study 1): West Japan Thoracic Oncology Group (WJTOG) trial

Summary Purpose: Amrubicin is a novel 9-aminoanthracycline. This multicenter phase II study was conducted to evaluate the efficacy and safety of amrubicin in patients with non-small-cell lung cancer (NSCLC). Patients and methods: Sixty-one previously untreated patients with stage III or IV NSCLC were entered this study. The patients were required to have cytologically or histologically proven measurable NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and adequate organ function. Amrubicin was administered by daily intravenous injection at 45 mg/m²/day for 3 consecutive days every 3 weeks. At least 3 cycles of treatment were administered to each patient. Results: All 61 patients registered in this trial were eligible and assessable for efficacy and toxicity. Of them, 17 patients achieved objective responses, consisting of one complete response and 16 partial responses, and the overall response rate was 27.9% (95% confidence interval [CI], 17.1% to 40.8%). The median survival time was 9.8 months (95% CI, 7.7 months to 14.9 months). The major toxicity was myelosuppression. The incidences of grade 3 or 4 toxicity were 72.1% for neutropenia, 52.5% for leukopenia, 23.0% for anemia, and 14.8% for thrombocytopenia. As noticeable toxic events, grade 3 hypotention and alkaline phosphatase elevation were transiently observed in one patient each. In addition, three patients who had had asymptomatic interstitial pneumonitis, identified by diagnostic imaging before treatment, aggravated after amrubicin treatment; two of them died. Other non-hematologic toxicities were relatively mild. Conclusion: Amrubicin was an active, well-tolerated agent in the treatment of NSCLC.     

多西他赛联合顺铂治疗晚期非小细胞肺癌26例

目的:探讨多西他赛联合顺铂4 wk治疗晚期非小细胞肺癌方案的疗效和安全性。方法:经病理组织学或细胞学确诊的ⅢB期或Ⅳ期非小细胞肺癌病人26例,年龄在35-78 a,ECOG PS评分为0-2分;d 1,8 多西他赛37．5 mg·m-2,d 1-3顺铂75-100 mg·m-2,分3 d,均予静脉滴注。每4 wk重复,2个周期后评价疗效与不良反应,并随访生存期。结果:24例可评价疗效病人中,部分缓解(PR)8例,完全缓解(CR)1例,总有效率为38％。ECOG PS评分0-1分病人有效率明显高于ECOG PS评分2分病人。中位生存期为11 mo,1年生存率为50％。Ⅲ-Ⅳ度白细胞减少的发生率为20％。结论:多西他赛联合顺铂4 wk方案治疗晚期非小细胞肺癌安全且有效。     

Phase II study of sunitinib malate in head and neck squamous cell carcinoma

Background Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor of RET, VEGFR, PDGFR, and c-KIT. We conducted a phase II trial to evaluate the tolerability and efficacy of sunitinib in metastatic and/or recurrent SCCHN patients. Methods Patients who had received no more than two prior chemotherapy regimens were eligible and, depending on ECOG performance status (PS), were entered into either Cohort A (PS 0-1) or Cohort B (PS 2). Sunitinib was administered in 6-week cycles at 50 mg daily for 4 weeks followed by 2 weeks off. Primary endpoint for Cohort A was objective tumor response. A Simon two-stage design required twelve patients to be enrolled in the first stage and if 1 or fewer responses were observed, further study of this cohort would be terminated due to lack of treatment efficacy. Primary endpoint of Cohort B was to determine the feasibility of sunitinib in patients with ECOG performance status 2. Results Twenty-two patients were accrued (Cohort A — 15 patients, Cohort B — 7 patients). Median age in cohort A and B was 56 and 61 years, respectively. Grade 3 hematologic toxicities encountered were lymphopenia (18%), neutropenia (14%) and thrombocytopenia (5%). There was only one incidence of grade 4 hematologic toxicity which was thrombocytopenia. Fatigue and anorexia were the most common non-hematologic toxicities. Grade 3 fatigue occurred in 23% of patients. The only grade 4 non-hematologic toxicity was one incidence of gastrointestinal hemorrhage. Non-fatal hemorrhagic complications occurred in 8 patients: epistaxis (3 patients), pulmonary hemorrhage (2 patients), gastrointestinal hemorrhage (2 patients) and tumor hemorrhage (1 patient). Four patients were not evaluable for tumor response (Cohort A — 3patients, Cohort B — 1 pt). One partial response was observed in the entire study. Dose reduction was required in 5 patients (Cohort A — 3 patients for grd 3 fatigue, grd 3 mucositis and recurrent grd 3 neutropenia; Cohort B — 2 patients for grd 3 fatigue and grd 3 nausea). Median time to progression for cohort A and B were 8.4 and 10.5 weeks, respectively. Median overall survival for cohort A and B was 21 and 19 weeks, respectively. Conclusions Sunitinib had low single agent activity in SCCHN necessitating early closure of cohort A at interim analysis. Sunitinib was well tolerated in PS 2 patients. Further evaluation of single agent sunitinib in head and neck is not supported by the results of this trial.     

13-Cis-retinoic acid and interferon alpha-2a in patients with advanced esophageal cancer: A phase II trial

Summary The aim of this study was to investigate the possible therapeutic effect of 13-cis-retinoic acid plus interferon alpha-2a in patients with inoperable squamous cancer of the esophagus. Patients with advanced, measurable, histologically confirmed squamous carcinoma of the esophagus with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 who had adequate bone marrow, liver, and renal function were eligible for study. Patients were given cis-retinoic acid 1 mg/kg/day per mouth continuously and interferon alpha-2a 3 Mu/day for 3 days followed by 6 Mu subcutaneously daily thereafter. Seventeen patients were entered on study. Fifteen patients were evaluable for toxicity. The most common toxicities were grade 1 and 2 cheilitis, dry skin and flu-like symptoms which occurred in all patients. Two patients had grade 3 toxicity (1 anorexia and 1 fatigue). No grade 4 toxicity occurred. Fifteen patients were evaluable for response. No objective response was documented. The median survival time was 15 weeks. With no response seen it is unlikely that the combination of treatment as used in this study will be of benefit in patients with advanced squamous cancer of the esophagus.     

Activity of gefitinib in advanced non-small-cell lung cancer with very poor performance status

Advanced non-small-cell lung cancer (NSCLC) patients with poor performance status (PS) are less likely to respond to chemotherapy, or to have an improvement in survival, but more likely to experience toxicity. We retrospectively evaluated the efficacy and tolerability of gefitinib in patients with advanced NSCLC and very poor PS in Taiwan. Patients with stage IIIB, IV NSCLC with an Eastern Cooperative Oncology Group (ECOG) PS of 3-4 received oral gefitinib 250 mg once daily. Totally, 52 patients were included (25 men, 27 women). Forty-three patients (82.7%) were in a PS of 3. Tumor response rate was 25.0% (13/52). Tumor response rate to gefitinib was highest in chemonaive patients 38.1% (8/21) vs. failed 1 chemotherapy regimen 13.3% (2/15) vs. failed 2 or more chemotherapy regimens 18.8% (3/16), p = 0.015. The median overall survival was 2.5 months (response group 9.1 months, stable disease 3.1 months, and progressive group 0.8 month, p < 0.001). Adverse events, mainly skin reactions and diarrhea, were generally mild (grade 1 or 2) except paronychia and acne. Thus, gefitinib has clinically antitumor activity and good tolerability in Taiwan patients with advanced NSCLC and very poor performance status, with a higher response rate than that seen Europe or in European heritage Americans. Chemonaive patients responded better than patients with prior chemotherapy. Formal clinical trials are warranted to evaluate the role of gefitinib in this situation.     

SarCNU in recurrent or metastatic colorectal cancer: A phase II study of the National Cancer Institute of Canada Clinical Trials Group

Summary Purpose: To evaluate the activity and toxicity of SarCNU, an oral chloroethylnitrosourea in patients with recurrent or metastatic colorectal cancer who have progressed after first-line chemotherapy. Patients and Methods: Eighteen patients with recurrent or metastatic colorectal cancer following first-line chemotherapy were treated with SarCNU 860 mg/m² orally day 1, 5 and 9 every 6 weeks. The patient’s median age was 64 and the ECOG performance status was 0 in six, 1 in eleven and 2 in one patients. All patients were evaluable for toxicity and 16 were evaluable for response. Results: There were no objective responses (0%). One patient had stable disease and 15 had progressive disease at their first follow-up assessment. Median survival was 7.36 months (3.75–7.49 95% C.I). Neutropenia and thrombocytopenia were the most severe toxicities (grade 3-4 in six and nine patients respectively). Pulmonary toxicity was also seen in five patients who had a drop of DLCO grade from baseline and two patients who had a fall in FVC from baseline. Conclusions: SarCNU is inactive in recurrent or metastatic colorectal patients who have progressed after first-line chemotherapy. Supported by a grant from the Canadian Cancer Society via the National Cancer Institute of Canada.     

Evaluation of amonafide in refractory and relapsing multiple myeloma: a Southwest Oncology Group study.

This study involved the administration of amonafide intravenously 300 mg/m2 daily times five days every three weeks to 16 refractory and relapsed myeloma patients. Doses were escalated to toxicity. These doses caused severe thrombocytopenia and granulocytopenia in seven patients. No responses were seen in this heavily pretreated group of patients.     

Phase II Study of Interferon Gamma in Malignant Carcinoid Tumors (E9292): A Trial of the Eastern Cooperative Oncology Group

PURPOSE: To determine the safety and efficacy of treatment with gamma interferon (IFNgamma) in patients with metastatic carcinoid tumor. PATIENTS AND METHODS: 51 patients were enrolled on this Phase II Eastern Cooperative Oncology Group (ECOG) study. Seventy five percent of them had hormonally active tumors. Treatment consisted of IFNgamma subcutaneously at a daily dose of 0.1 mg/m(2). Patents were evaluated for toxicity weekly for the first month and monthly thereafter; response was determined radiologically every 8 weeks. RESULTS: Patients received treatment with IFNgamma for a median of 17.9 weeks (range 2-175). Toxicity was generally mild and expected: 61% experienced noninfected fever and 21% developed granulocytopenia. Three patients (6%) had a partial response; there were no complete responses. Median time to progression was 5.5 months (95% confidence interval 3.9-11.1). The 1-year progression free rate was 28% (13.4-43.4%). Median survival was 42 months, with a 1-year survival rate of 67% (53.3-80%). DISCUSSION: This Phase II study demonstrated that therapy with IFNgamma in patients with metastatic carcinoid tumor was well-tolerated, but did not produce significant antitumor effects. The overall results were somewhat comparable to those previously seen with alpha interferons as well as cytotoxic drugs.     

Gefitinib in the adjuvant setting: safety results from a phase III study in patients with completely resected non-small cell lung cancer

Standard therapy for stage I-IIIA non-small cell lung cancer (NSCLC) is surgery, although adjuvant therapies are required to prevent disease recurrence and improve patient survival. This is the first study that planned to administer adjuvant gefitinib (Iressa) 250 mg/day or placebo to randomized patients with completely resected NSCLC (stage IB-IIIA) 4-6 weeks following surgery, for 2 years, until recurrence/withdrawal. However, recruitment was stopped after the randomization of 38 patients, because interstitial lung disease (ILD)-type events were being increasingly reported in Japan in the advanced disease setting. Finally, the trial was halted. Safety data for 38 recruited patients (18 gefitinib and 20 placebo) showed no unexpected adverse drug reactions (ADRs), with the most common being grade 1/2 gastrointestinal and skin disorders in 12 and 16 patients receiving gefitinib and in five and six patients receiving placebo, respectively. Grade 3/4 ADRs occurred in four patients receiving gefitinib and one patient receiving placebo. ILD-type events were reported in one patient receiving gefitinib (concomitantly with other ILD-inducing drugs) who died and two patients receiving placebo. Eight patients receiving gefitinib withdrew due to ADRs compared with three patients receiving placebo. Adverse events associated with surgical complications were reported for six patients receiving gefitinib and four patients receiving placebo. In the adjuvant setting there were no unexpected adverse events observed. Gefitinib had no impact on surgery-related complications when given within 4-6 weeks post-operatively.     

Phase II trial of vinorelbine tartrate in patients with treatment-naive metastatic melanoma

Metastatic melanoma carries a dismal prognosis and there is a need to develop new treatment strategies. Vinca alkaloids have shown consistent activity in melanoma patients, as monotherapy and as part of combination regimens. The current study evaluates the clinical activity and tolerability of vinorelbine as first-line monotherapy in patients with metastatic melanoma. Patients were eligible if they presented metastatic melanoma not amenable to curative resection, had received no prior systemic therapy for advanced disease and had an adequate performance status (ECOG 0-1). Patients received vinorelbine at a dose of 30 mg/m2 on days 1 and 8 of a 21-day cycle, on an outpatient basis. Thirteen patients were accrued into the study and received 64 cycles. All patients were assessable for response, toxicity and survival. No objective responses were documented, for an overall response rate of 0% [95% confidence interval (CI) 0-19%] and the trial was terminated in accordance to the predetermined early discontinuation rule. The median progression-free survival was 3.3 months (95% CI 2.3-4.3 months) and the estimated median overall survival was 8.1 months (95% CI 6.0-10.2 months). No life-threatening toxicities occurred. Neutropenia was the main hematologic toxicity, but none of the three episodes of grade 3-4 neutropenia were complicated by infection. The most common non-hematologic toxicities were asthenia, nausea, neuropathy and myalgia. We conclude that vinorelbine as a single agent on days 1 and 8 of a 21-day cycle has a favorable toxicity profile, but appears to have no relevant clinical activity in patients with metastatic melanoma.     

Neoadjuvant chemotherapy in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is a systemic illness. More than half of those patients who present with stage I-IIIA disease and are resected will experience distant relapse. Postoperative adjuvant chemotherapy has been evaluated in several randomized trials but the results of these trials have been inconclusive with increased survival reported in few trials. In resectable stage IIIA NSCLC the findings of three randomized trials have indicated that the survival of these patients is better with neoadjuvant chemotherapy plus surgical resection than with resection alone. Phase II trials using preoperative concurrent chemoradiotherapy have been carried out with encouraging results. The majority of patients with stage IIIA NSCLC require multimodality therapy if they are to achieve a 5-year survival. Combined modality treatment in locally advanced NSCLC continues to evolve and is a subject of ongoing research. One focus for present research is to integrate new active agents into the neoadjuvant setting. Another challenge is to find better treatment approaches in earlier stages of disease. Some data suggest that induction chemotherapy in stage I-II is feasible, does not appear to compromise surgery and yields high response rates. A further aim is to use molecular biological markers of malignancy to identify patients at highest risk of metastatic relapse.     

Synthesis of 18F‐radiolabeled diphenyl gallium dithiosemicarbazone using a novel halogen exchange method and in vivo biodistribution

¹⁸F‐radiolabeled diphenyl gallium thiosemicarbazone was prepared by [¹⁸F] fluoride exchange of a nitrato anion under mild conditions. The diphenyl gallium thiosemicarbazone chloride is easily prepared in gram quantities and can be used at room temperature in the presence of oxygen. The corresponding nitrate complex is prepared using silver nitrate in methanol solvent and can be stored under nitrogen for weeks before radiolabeling. The biodistribution of this new tracer was studied in mice using positron emission tomography (PET).