Multicenter phase II trial of brequinar sodium in patients with advanced squamous-cell carcinoma of the head and neck

A total of 19 patients with advanced squamous-cell carcinoma of the head and neck who had not previously been exposed to chemotherapy were treated with brequinar sodium as first-line chemotherapy. Brequinar was given intravenously at a median weekly dose of 1,200 mg/m². The toxicity was moderate, with 7 patients (37%) experiencing grade 3 or 4 toxicity. In all, 16 patients who were evaluable for efficacy showed no objective response. We conclude that brequinar given at this dose and on this schedule has no significant activity in advanced squamous-cell carcinoma of the head and neck.This study was supported by DuPont Pharmaceutical Company (Wilmington, Del., USA)     

Multicenter phase II study of brequinar sodium in patients with advanced lung cancer

Summary A total of 53 patients with advanced lung cancer [non-small-cell (NSC), 21; small-cell (SC), 32] were treated with brequinar sodium. All of the NSC patients were chemotherapy-naive, but 31/32 (97%) SC patients had failed a multiagent chemotherapy program prior to study entry. Brequinar was given intravenously at a median weekly dose of 1200 mg/m². The toxicity was moderate, with 19 patients (36%) experiencing grade 3 or 4 toxicity. Objective responses were observed in one NSC and two SC patients. We conclude that at this dose and on this schedule, brequinar does not have sufficient activity in patients with NSC or in patients with previously treated SC to warrant further evaluation. However, since responses were observed in previously treated SC lung-cancer patients, further evaluation in chemotherapy-naive patients may be warranted.This study was supported by The DuPont Pharmaceutical Co., Wilmington, Delaware     

Biochemical modulation of 5-fluorouracil with brequinar: results of a phase I study

Biochemical modulation can increase the efficacy of 5-fluorouracil (5-FU). Pizzorno et al. have previously shown that brequinar, a de novo pyrimidine synthesis inhibitor, enhances the antitumor effect of 5-FU in vivo [Cancer Res 52: 1660–1665, 1992]. On the basis of their data, we conducted a phase I study of brequinar in combination with 5-FU in patients with refractory solid tumors. The initial dose (100 mg/m²) of brequinar was raised in 100-mg/m² increments in cohorts of three assessable patients. The initial dose of 5-FU was 500 mg/m², but escalation was allowed in patients who showed no significant toxic reaction. Brequinar was administered over 1 h and 5-FU over 2 h starting 18–20 h after the initiation of infusion of brequinar. Treatments were repeated weekly. Responses were evaluated after 4 weeks (one course) and then every 8 weeks thereafter. Pharmacokinetics of brequinar and determination of plasma uridine levels were performed in at least three patients at each dose level. Of the 25 patients registered in the study, 21 were assessable for toxicity studies. The dose of brequinar was escalated up to 600 mg/m². In addition, the dose of 5-FU was increased to 600 mg/m² as a result of a lack of a significant toxic reaction in the first nine patients. No objective responses were observed. One patient developed grade 3 stomatitis, and one developed grade 3 esophagitis at the 400 and 600 mg/m² dose of brequinar, respectively. Brequinar produced a dosedependent decrease in plasma uridine levels at doses up to 500 mg/m². No additional decrease in plasma uridine occurred with higher doses of brequinar, thus suggesting a plateau effect. This observation prompted us to terminate the study before reaching the maximum tolerated dose of brequinar. Our data indicate that brequinar in doses400 mg/m² results in significant biochemical modulation. The lack of toxicity seen at these doses of brequinar suggests that the initial dose of the effector agent 5-FU should be increased in future studies.Abbreviations 5-FU 5-Fluorouracil - PALA N-(phosphonacetyl)-l-aspartic acid - UXP total uridine nucleotide - AGC absolute granulocyte count - MTD maximum tolerated dose - ECOG Eastern Cooperative Oncology Group     

Interferon in combination with vinblastine in advanced malignant melanoma. A phase I-II study

Nineteen patients with advanced malignant melanoma were treated with a combination of recombinant alfa-interferon (alpha-IFN) and vinblastine (VBL). The alpha-IFN was administered subcutaneously daily at an initial dose of 3 X 10(6) IU escalating to a maximal dose of 9 X 10(6) U daily for the first 10 weeks followed by 3 X/week for 6 months. The VBL was given once every week at a dose of 0.025 mg/kg. Of the 19 patients 17 were evaluable for tumor response. Thirteen patients had received chemotherapy previously. Median performance status (World Health Organization) was 0, ranging from 0 to 2. One complete response and one partial response was observed. All patients experienced flu-like symptoms attributed to alpha-IFN. Leukopenia was observed in 12 patients and a planned dose escalation of VBL was undertaken for the patients only. It is concluded that combined alpha-IFN and VBL is only marginally effective in patients with advanced malignant melanoma who have had prior chemotherapy.     

Phase II evaluation of L-alanosine (NSC-153353) for patients with disseminated malignant melanoma

The authors conducted a phase II study of L-alanosine in 39 patients (19 without prior chemotherapy) in advanced malignant melanoma. The intravenous dose was 250 mg/m2/days 1-3 repeated at 3-week intervals. There were two objective regressions (5%) in conjunction with generally transient and tolerable hematologic and gastrointestinal toxicity. L-alanosine as used in our study has limited activity against malignant melanoma.     

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 evaluation of bryostatin-1 in metastatic melanoma

In this phase II study we assessed the efficacy of bryostatin-1 (NSC 339555) in metastatic melanoma patients when given intravenously either once a week at a dose of 25 microg/m2 per day over 24 h for 3 weeks or at 40 microg/m2 per day over 72 h every 2 weeks. Treatment courses were repeated every 4 weeks. Patients who had received one prior chemotherapy regimen for advanced melanoma, with or without biotherapy, were randomized to one or the other bryostatin-1 dose schedules until 12 patients were registered to each arm. Because there was one confirmed response among the 12 patients who received the 72 h dose schedule, 25 more patients were added to that arm. No prophylactic medications were given. Objective tumour measurements were used to assess the efficacy of the regimen. The National Cancer Institutes common toxicity criteria were used to grade reactions. In total, 49 patients with metastatic melanoma, none having symptomatic brain metastasis, were studied. Of these, 12 patients received the 24 h bryostatin-1 regimen, while the remaining 37 received the 72 h regimen. One patient receiving the 72 h regimen had a partial response lasting over 7 months. Muscle pain occurred in over 90% of the patients and was the dose-limiting side effect of the 72 h regimen. Grade 3/4 nausea and vomiting were more common on the 24 h regimen than on the 72 h one (35% versus 5% of patients). There was no therapy-related thrombocytopenia. Neutropenia was mild and mainly limited to patients receiving the 72 h regimen. Bryostatin-1 has limited activity against melanoma when given by 72 h intravenous infusion.     

Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients

Gemcitabine and treosulfan are DNA-damaging agents. Preclinical studies suggest that synergism exists when melanoma cells are exposed to both drugs concurrently. We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan. Cohorts of three patients received increasing doses of gemcitabine, commencing at 0.5 g m(-2), followed by a fixed dose of 5.0 g m(-2) treosulfan on day one of a 21-day cycle. Patients alternately received a first cycle of single-agent gemcitabine or treosulfan before subsequent cycles of both drugs. Peripheral blood lymphocytes were collected in cycles 1 and 2 at various time points until 48 h post-treatment. The single-cell gel electrophoresis (Comet) assay was used to measure chemotherapy-induced DNA damage. A total of 27 patients were enrolled, no objective responses were observed, but two uveal melanoma patients had minor responses. Dose-limiting myelosuppression was reached at 3.0 g m(-2) gemcitabine. DNA single-strand breaks were detected 4 h post-gemcitabine, repaired by 24 h. DNA interstrand crosslinks were detected 4 h post-treosulfan, fully removed by 48 h. Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity. The recommended regimen for further study is 2.5 g m(-2) gemcitabine combined with 5.0 g m(-2) treosulfan.     

A phase II study of oxaliplatin, docetaxel, and GM-CSF in patients with previously treated advanced melanoma

Purpose

Although much focus has been placed on immunotherapy for melanoma, further development of chemotherapy approaches is needed. Melanoma is responsive to platinum compounds and taxanes, but there is limited experience with combinations of these agents. Oxaliplatin has been reported to have detectable activity in melanoma, and a phase I study has identified a tolerable dose and schedule of oxaliplatin in combination with docetaxel and hematopoietic growth factor support. GM-CSF has a theoretical advantage of immune potentiation. These considerations supported the study of oxaliplatin, docetaxel, and GM-CSF in patients with advanced melanoma.

Methods

Eligibility included adequate organ function, PS ≤ 2, at most one prior chemotherapy and one prior immunotherapy, no prior treatment with oxaliplatin or taxanes and no chremophor allergy. After premedication, docetaxel was administered day 1 at 75 mg/m², then oxaliplatin on day 2 at 85 mg/m². GM-CSF (250 mcg/m²) was administered s.c. days 3–12. Cycles were 21 days in length, and disease reevaluation was performed every two cycles by RECIST criteria.

Results

Nineteen patients received at least one cycle, eight with one prior systemic therapy, five with two prior systemic therapies. Five patients did not complete two cycles and were not formally evaluable for response. Five patients had stable disease (SD), including one who failed two prior therapies and went on to receive ten cycles. The remaining nine patients displayed progressive disease (PD) after two cycles. Notable toxicities included seven cases (37%) of grade III/IV neutropenia and two (11%) hypersensitivity reactions.

Conclusions

This combination of oxaliplatin, docetaxel, and GM-CSF has limited clinical activity in previously treated patients with advanced melanoma. Exploration in treatment-naïve patients may still be warranted.     

Detorubicin--an active anthracycline in untreated metastatic melanoma

A phase II study of detorubicin, the semisynthetic 14-diethoxyacetoxy ester of daunorubicin, was conducted in 42 patients with metastatic melanoma. The drug was administered in a dose range of 120 to 180 mg/m2 and repeated at 3-week intervals. One clinical complete remission (soft tissue) and seven partial responses (three visceral and four soft tissue) were observed among the 22 patients who had undergone no prior chemotherapy, a complete and partial response rate of 36%. The duration of response varied from 2 to 27 months with a median of 10 months. There were also four (19%) minor responses (one visceral and three soft tissue). In contrast, among the 20 patients who had undergone prior chemotherapy treatment, only three patients showed a minor response. General toxicities were acceptable and were similar to those of Adriamycin (Adria Laboratories, Columbus, Ohio). Cardiac toxicity was evaluated by cardiac biopsy and radionuclide scan. Cardiac biopsy changes were identical to those observed with Adriamycin and were progressive with cumulative dose. One patient had a high-grade biopsy at a cumulative detorubicin dose of 1,420 mg/m2. Similarly, a trend of decreasing ejection fraction with cumulative dose was noted. Only one patient developed congestive heart failure at a cumulative dose of 1,290 mg/m2, that was well compensated with digoxin and diuretics. In contrast to Adriamycin, detorubicin has shown activity in previously untreated patients with metastatic melanoma.     

Phase II trial of arsenic trioxide and ascorbic acid with temozolomide in patients with metastatic melanoma with or without central nervous system metastases

We conducted a single institution phase II trial to evaluate the tolerability and effectiveness of therapy with arsenic trioxide (ATO) and ascorbic acid (AA) with temozolomide (TMZ) in patients with advanced melanoma. Planned enrollment was for 40 patients. Eligible patients were required to have metastatic melanoma with or without brain metastases, an ECOG performance status of 0-2, and adequate organ function. The primary endpoints were overall response rate and degree of grade 4 toxicity. ATO was administered as a loading dose at 0.25 mg/kg/day for 5 days during week 0, and then twice weekly at 0.35 mg/kg during an 8-week cycle. Each infusion of ATO was followed by an infusion of 1000 mg of AA. TMZ was given at the standard dose of 200 mg/m for 5 days during weeks 1 and 5 of each cycle. Eleven patients were enrolled with 10 evaluable for response, five with central nervous system disease. No responses were seen among the first 10 patients and on the basis of a predetermined stopping rule, the trial was terminated. Common grade 1 and 2 side effects included nausea and vomiting (10), fatigue (six), edema (six), rash (six), and elevated AST or ALT (six). Grade 3 and 4 side effects included nausea and vomiting (three), elevated AST or ALT (two), seizure (one), and renal failure (one). This is the first trial combining ATO with chemotherapy in a solid tumor. ATO and AA were administered in the outpatient setting with TMZ in 11 patients with an acceptable side effect profile. No responses were seen in the first 10 evaluable patients leading to early closure of the study. Further studies using ATO and AA with TMZ with this dosing schedule in advanced melanoma are not warranted.     

Intraarterial infusion chemotherapy in regionally advanced malignant melanoma

The therapeutic effectiveness of intraarterial cisplatin (CDDP) and dacarbazine (DTIC) infusion was examined in 30 evaluable patients with regionally advanced melanoma that was refractory to standard treatments. Objective responses were achieved in 11 patients (37%), including three complete (10%) and eight partial (27%) tumor regressions. Successful debulking surgery was performed in seven of the eleven patients with response. Six remained free of regional disease after a median time of 25 months, and four are also free of distant metastases at 24+, 25+, 41+, and 54+ months. Nineteen of thirty patients with no significant tumor response underwent alternative treatments. Debulking surgery was performed in nine, but with little palliative gain, since seven relapsed at a median time of 5 months. Our results suggest that a combined therapeutic approach--preoperative chemotherapy followed by surgery in responding tumors--represents an effective treatment for patients with regionally advanced melanoma.     

奈达铂联合替加氟治疗晚期食管癌

目的 评价奈达铂(NDP)联合替加氟(Fr-207)治疗晚期食管癌的疗效和毒副反应.方法 65例晚期食管癌患者中,初次化疗患者27例,术后接受辅助化疗38例.NDP 20 ms/m2,静脉滴注2 h,第1～5天;Fr-207 500 m/m2,静脉滴注8 h,第1～5天;21 d为1个周期.结果 65例患者共完成193个化疗周期,其中可评价疗效的患者63例.27例初次化疗的患者中,CR 6例,PR 16例,有效率为81.5%;36例复治的患者中,CR6例,PR 10例,有效率为44.4%.所有患者的中位疾病进展时间(TTP)为5.6个月,中位生存时间为9.3个月,1年生存率为24.9%.临床毒副反应为恶心、呕吐,患者均能耐受.63例可评价毒副反应的患者中,有2例(3.2%)出现Ⅲ～Ⅳ度中性粒细胞降低.结论 NDP联合FT-207对晚期食管癌疗效肯定,毒副反应轻,可作为治疗晚期食管癌的主要治疗方案.     

HLF方案治疗晚期胃癌的临床疗效观察

目的观察拓僖(HCPT)、甲酰四氢叶酸钙(LV)和5-Fu联合组成的HLF方案治疗晚期胃癌的近期疗效及毒副作用.方法 36例晚期胃癌患者均接受HLF方案化疗,其中HCPT 10 mg/m2,静滴,d1～3;LV 100 mg,静滴d1～5;5-Fu 500 mg/m2,静滴10 h,d1～5,28 d为一周期,2～3个周期后判定疗效及毒副作用.结果部分缓解(PR)19例,稳定(NC)14例,进展(PD)3例,总有效率为52.8%.主要毒副作用为白细胞减少和口腔、胃肠黏膜炎,无明显肝肾功能损害.结论 HLF方案为治疗晚期胃癌安全、有效的方案.     

Recovery of blood and bone marrow stem cells following intense chemotherapy and autologous bone marrow transplantation

Sixteen patients with advanced (stage III) malignant melanoma were treated with escalating doses of intravenous BCNU and melphalan starting at 400 and 35 mg/m2, respectively, and escalating to 1,000 and 110 mg/m2, respectively, combined with autologous marrow transplantation. The duration of granulocytopenia and time to granulocyte recovery was similar in all groups regardless of chemotherapy dose. Platelet recovery was delayed in patients receiving the highest doses of chemotherapy. This study showed that bone marrow colony-forming units in culture took as long as 6 months to recover. This was adequate to bring peripheral blood counts to normal but not to pretreatment levels. These studies indicate that autologous bone marrow transplantation is beneficial in enhancing short-term recovery, but may not be beneficial in the long-term hematopoietic recovery.     

PALA (NSC-224131) in advanced carcinoma of the cervix. A phase II study of the Gynecologic Oncology Group

Thirty-six patients with advanced carcinoma of the cervix received PALA at a dosage of 5 gm/m2 every three weeks. Thirty-three patients had received prior irradiation therapy and chemotherapy. No complete or partial responses were seen. The major toxicity was dermatologic and occurred in 16/36 (44%) of patients. Three patients experienced dose limiting disorientation or confusion. PALA was not associated with any antitumor activity in patients with advanced carcinoma of the cervix who had received prior chemotherapy. The results of this study indicate that PALA has no substantial activity in patients with advanced squamous carcinoma of the cervix who have previously received chemotherapy.     

抗PD-1单抗联合化疗及抗血管生成药物治疗晚期黑色素瘤的疗效和安全性

目的： 探讨抗PD-1单抗联合化疗及抗血管生成药物治疗晚期黑色素瘤的疗效和安全性。 方法： 收集2020年4月至2021年6月在北京大学肿瘤医院接受抗PD-1单抗联合化疗药物替莫唑胺±顺铂、白蛋白结合型紫杉醇及抗血管生成药物贝伐珠单抗治疗的14例（男6、女8例）不可切除的晚期黑色素瘤患者的临床资料。主要研究终点为无进展生存期（PFS）,次要终点为客观有效率（ORR）、疾病控制率（DCR）、总生存期（OS）及安全性数据（CTCAE 5.0标准）。 结果： 14例晚期黑色素瘤患者均纳入生存分析,中位随访时间为5.50个月（95% CI: 0~13.12个月）,中位PFS为7.43个月（95% CI: 3.07~11.79个月）,中位OS为13.50个月（95% CI: 5.19~21.81个月）,中位起效时间为1.5个月;ORR为28.6%（4例均为部分缓解）,DCR为85.7%;不良反应多为1~2级。结论： 抗PD-1单抗联合化疗及抗血管生成药物治疗在晚期黑色素患者中显示出初步的有效性及良好的安全性,此可能为晚期黑色素瘤的联合治疗策略提供了新思路。     

Chemotherapy for metastatic melanoma

Melanoma is a neoplasm with a rising incidence. Early-stage melanoma is curable, but advanced, metastatic melanoma almost uniformly is fatal, and patients with such advanced disease have a short median survival. Systemic therapy remains unsatisfactory, inducing complete durable responses in a small minority of patients. For the current review, the authors focused on the current role of cytotoxic chemotherapy in the treatment of metastatic melanoma and the future prospects for improvements for multiagent chemotherapy and chemotherapy combined with immunomodulatory and/or molecularly targeted agents. They discuss roles of single-agent chemotherapy, combination chemotherapy, combinations of chemotherapy with immunomodulatory or hormone agents, biochemotherapy, and combination chemotherapy with targeted therapies.     

Phase II trial of Paclitaxel and Dacarbazine with filgrastim administration in advanced malignant melanoma

A Phase II trial was conducted in patients with advanced malignant melanoma with intravenous Paclitaxel and Dacarbazine (DTIC). The initial starting dose for Paclitaxel was 135 mg/m² followed by DTIC 800 mg/m². Due to the lack of myelosuppression and other toxicities, the starting dose for Paclitaxel was escalated to 250 mg/m² and the dose for DTIC escalated to l000 mg/m². Twenty-five patients were enrolled in this study. Among the 25 patients assessable for response, three patients had a partial response with a response rate of 12% (CI 3-31%) and one patient had stable disease. Three additional patients showed evidence of anti-tumor activity with minor responses. For patients who had no prior chemotherapy or biochemotherapy, the response rate was 20%. Toxicity was generally tolerable and included mainly neurotoxicity from Paclitaxel. At the doses and schedule used, the combination of Paclitaxel and DTIC did not appear to increase the response rate compared to each agent used singly.     

A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma

The purpose of this study was to compare the response rate, overall and 1-year survival in patients with advanced melanoma treated with a standard therapy, dacarbazine and interferon-alpha (DTIC/IFN), or combination chemotherapy, consisting of dacarbazine, BCNU, cisplatin and tamoxifen (DBCT). Treatment toxicity and time spent in hospital were secondary end points. One hundred and five patients (of whom 100 were eligible) were randomized to receive either DTIC/IFN or DBCT. The trial was designed to detect a 25% absolute difference in response rate or in 1-year survival with 80% power. There was no significant difference in response rate: this was 17.3% with DTIC/IFN and 26.4% with DBCT. Median overall survival was similar at 199 and 202 days respectively. One-year survival rate favoured standard treatment (30.6 vs 22.6%), but did not differ significantly between arms. DBCT was associated with significantly greater haematological toxicity, and a greater need for time spent in hospital (5.75 days/treatment cycle vs 2.29 with dacarbazine and interferon). DBCT combination therapy cannot be recommended as standard treatment for advanced melanoma. Dacarbazine remains the standard chemotherapy for this condition.