A phase II trial of pyrazine diazohydroxide in patients with disseminated malignant melanoma and no prior chemotherapy--Southwest Oncology Group study

Malignant melanoma is rapidly increasing inthe United States. Metastatic diseaseresponds poorly to currently availablechemotherapy. Pyrazine diazohydroxide(PZDH) is a new agent inhibiting DNAsynthesis that is active in mouse tumormodels and human xenografts and lackscross resistance withmultiple standard agents. In this phase IItrial, patients with no prior chemotherapyor immunotherapyfor metastatic disease and performancestatus (SWOG) of 0–1, were treated withpyrazine diazohydroxide at a dose of 100 mg/m²/day by IV bolus injectionover 5–15 minutes for 5 consecutive daysevery 6 weeks. There were 23 eligiblepatients entered on this trial with 74%having PS of 0 and 91% having visceralmetastases. There were no confirmed anti-tumor responses. Theoverall response rate is 0% (95% CI 0%–15%). Median overall survival is sixmonths (95% CI 5-8months). The most common toxicities were hematologic and consisted of lymphopenia,thrombocytopenia, anemia, and leukopenia. Fatigue, and nausea and vomiting were thenext mostcommon toxicities. Pyrazine diazohydroxideby this dose and schedule has insufficientactivity in thetreatment of disseminated malignantmelanoma to warrant further investigation.     

Phase II study of CI-980 (NSC 635370) in patients with previously treated advanced soft-tissue sarcomas

Doxorubicin and ifosfamide are the two most active agents in the treatment of soft-tissue sarcomas. Patients whose tumors have failed these two drugs have very limited systemic therapy options. It is, therefore, important to identify newer drugs with activity against this disease. CI-980 is a synthetic mitotic inhibitor that binds to tubulin at the colchicine binding site and inhibits the polymerization of tubulin and blocks cell cycle progression in mitosis. Given its broad spectrum activity against several solid tumor models in vivo, we decided to perform a phase 2 study of this drug in previously treated soft-tissue sarcomas. A total of 18 eligible and evaluable patients were entered in the first stage of the trial. The median age was 53 yrs (range, 17–72). No objective responses have been noted. Six patients had stable disease after a median of 3.5 cycles of chemotherapy while 12 others had progressive disease. A total of 48 cycles were administered, 42 of which were administered at dose level 0 (4.5 mg/m²/d × 3). 3). The median AGC nadir was 1.2/µl (0.1–4.7) on day 10 and the median platelet nadir was 150,000/µl (31,000–338,000). Twenty cycles were complicated with grade 3–4 neutropenia and two cycles were complicated with FUO. There were no CNS toxicities. One patient had a grade 1 thrombophlebitis in 2 cycles and one other patient had a grade 4 thrombophlebitis in one cycle. In conclusion, CI-980 was well tolerated at this dose and schedule but inactive in soft-tissue sarcomas.     

Neoadjuvant chemotherapy with gemcitabine and cisplatin in stage IIIA/B non-small cell lung cancer

Purpose. We studied cisplatin plusgemcitabine as induction (neoadjuvant)therapy in patients with stage IIInon-small cell lung cancer (NSCLC) toassess its objective remission rate,resectability, survival, and toxicity. Patients and methods. Patients with stageIII NSCLC received 2 cycles of gemcitabine1250 mg/m² on days 1, 8, and 15,plus cisplatin 100 mg/m² on day 2.Subsequently, patients were assigned tolocal therapy – surgery or radiotherapy. Results. Twenty-nine eligiblepatients (male/female: 21/8) with a medianage of 59 years (range, 43–71 years) wereenrolled between October 1996 and February1999. A total of 80 cycles were given,with a median of 3 per patient (range, 1–4cycles). Overall, toxicities were mild;only one patient had febrile neutropenia,and there were no grade 4 non-hematologicaltoxicities. There was one toxic deathfollowing afebrile grade 4 neutropenia.Overall clinical response rate (2 completeresponses [CRs] + 16 partial responses[PRs]) was 62% (95% CI, 45%–79%);10 patients had stable disease and noneprogressed; one patient was not evaluable.Eight of the 18 operated patients hadpathological response: 1 CR and 7downstagings to N(–); 14 patients wereresected. Median survival was 17 months(95% CI, 13–21 months), with 1-year and2-year actuarial survival rates of 61%and 29%, respectively. Conclusions. Gemcitabine pluscisplatin is a very active andwell-tolerated induction regimen in stageIII NSCLC. Comparative studies with otherstandard regimens are warranted.     

Cough due to ace inhibitors: a case-control study using automated general practice data

Objectives: To determine the risk of coughing as an adverse reaction to ACE inhibitors under everyday circumstances in a large population, and to study whether this adverse effect was duration or dose dependent. Design: A population-based case-control study. Setting: Ten general practices of 14 Dutch general practitioners (GP), in which all consultations, morbidity and medical interventions, including drugs prescribed, were registered over the 18 month period from 1st September, 1992 to 1st March, 1994. Subjects: 1458 patients with incident coughing and up to four controls per case were obtained (total 4182 controls), matched for GP. All cases and controls were 20 years or older and had no record of respiratory infection, influenza, tuberculosis, asthma, chronic bronchitis, emphysema, congestive heart failure, sinusitis, laryngitis, haemoptysis or respiratory neoplasms during the study period. Results: Cases were 2.1-times more likely than controls to have been exposed to ACE inhibitors (95% CI 1.5–3.1), but after adjustment the odds ratio was 1.4 (95% CI 0.9–2.1). The crude odds ratio for captopril was 1.3 (95% CI 0.7–2.5), for enalapril 2.6 (95% CI 1.6–4.2) and for lisinopril 2.0 (95% CI 0.5–9.3). The adjusted odds ratio for captopril was 0.9 (95% CI 0.4–1.7), for enalapril 1.7 (95% CI 1.03–2.8) and for lisinopril 1.7 (95% CI 0.4–7.9). For patients who had been on ACE inhibitor treatment for no longer than 2 months the odds ratio was 4.8 (95% CI 1.7–13.3). The odds ratio declined to 2.0 (95% CI 1.1–3.8) for those who had taken an ACE inhibitor for 2–6 months, and to 1.6 (95% CI 0.9–2.7) for those on ACE-inhibitors for more than 6 months. Conclusion: The risk of coughing was increased twofold among ACE inhibitor users, but the odds ratios were no longer significant after controlling for several confounding factors. The risk of developing cough due to ACE-inhibitors declines with the duration of treatment, possibly due to depletion of susceptible persons.     

Phase II trial of trimetrexate in untreated advanced gastric carcinoma

Summary Twenty-three evaluable patients with advanced gastric adenocarcinoma were treated with trimetrexate at doses of 8–12 mg/m² intravenously daily for five days, with cycles repeated every 21 days. One complete response was seen for an overall response rate of 4% (95% confidence interval 0–22%). Hematologie toxicities of grade 3 were seen in 10/23 patients, and overall any grade 3 or greater toxicity was seen in 14/ 23 patients. Trimetrexate has minimal activity against gastric adenocarcinoma in this study, and no further investigation of this agent at this dose and schedule is recommended in this disease.     

Captopril does not interact with the pharmacodynamics and pharmacokinetics of digitoxin in healthy man

Summary The chronic oral administration of 0.07 mg digitoxin o. d. for up to 58 days to 12 healthy volunteers caused a small drop in mean heart rate HR (95 % CI: –7.9 to –1.6 beats · min^–1), in mean diastolic blood pressure (95 % CI: –8.3 to –0.4 mm Hg), shortening of the QTc-interval (95 % CI: –42 to –19 ms), shortening of the HR-corrected pre-ejection period PEPc (95 % CI: –16 to –1 ms) and electromechanical systole QS2c (95 % CI: –25 to –1 ms), and an increase in the impedance cardiographic Heather index (dZ/dt_max/RZ, 95 % CI: 0.3 to 4.3) relative to the baseline measurements before digitalisation.The concomitant administration of 25 mg oral captopril b. d. did not significantly alter these responses relative to the concomitant double-blind administration of placebo, nor did it alter the pharmacokinetic characteristics of plasma digitoxin at steady state.Thus, no relevant change in the pharmacokinetic and pharmacodynamic characteristics of chronically administered digitoxin were induced by concomitant treatment with captopril.     

Phase II evaluation of topotecan in patients with advanced colorectal cancer. A Southwest Oncology Group trial (SWOG 9241)

The topoisomerase-1 inhibitor, topotecan, was tested in 48 eligible patients with advanced colorectal cancer. The patients had no prior chemotherapy and a Southwest Oncology Group performance status of 0–2. Topotecan was administered intravenously at 1.5 mg/m²/day for five days and repeated every 21 days. The major toxicity was hematologic with 19 out of 48 (40%) patients having grade IV granulocytopenia and 4 out of 48 (8%) patients demonstrating grade IV thrombocytopenia. Two patients (4%) demonstrated partial response. Thirty patients have died and the Kaplan-Meier estimate of median survival is 9 months (95% confidence interval; 7–16 months). Topotecan in this dose and schedule does not appear active in patients with advanced colorectal cancer.     

Weekly irinotecan plus UFT and leucovorin as first-line chemotherapy of patients with advanced colorectal cancer

Summary We evaluated the antitumoral efficacy and safety of CPT-11 125 mg/m² (weekly 90 min i.v. infusion; days 1, 8 and 15) combined with UFT (oral combination of tegafur and uracil) 200 mg/m²/day plus leucovorin (LV) 45 mg/m²/day (both divided into three separate oral doses every 8 h, days 1–21) every 4 weeks as first-line chemotherapy of metastatic colorectal cancer (CRC). Fifty-three patients 18 years old with histologically confirmed diagnosis of advanced CRC and bidimensionally measurable disease were enrolled. Three patients (6%) showed CR and 8 patients (15%) showed PR (ORR = 21% (95% CI, 10–32). Stable disease was reported in 19 patients (36%) [tumor control rate = 57% (95% CI, 43–70)]. The median time to progression and overall survival were 7.9 and 18.2 months, respectively (1-year rate = 74%; 2-years rate = 26%). CPT-11/UFT/LV treatment was well tolerated: the most reported grade 3/4 toxicities were neutropenia (11% of patients) and delayed diarrhea (28% of patients). No significant differences in response rate, survival or toxicity were found between younger (65 years) and older patients (> 65 years). Weekly CPT-11 plus UFT/LV was found effective and safe as first-line chemotherapy for metastatic CRC. The addition of CPT-11 to UFT/LV doubled the response rate compared to the results previously reported with UFT/LV, while myelosuppression remained low.     

Evaluation of merbarone (NSC 336628) in disseminated malignant melanoma

Merbarone, NSC 336628, is an investigational anticancer drug with activity against experimental animal tumors including melanoma. This paper presents results of a Phase II clinical study of merbarone in patients with biopsy proven stage IV malignant melanoma without prior chemotherapy and with no evidence of CNS involvement. Thirty-five patients with median age 58 (range 27–81), with performance status 0–2 were treated with merbarone 1000 mg/m²/day for five days by intravenous continuous infusion repeated every 3 weeks. All patients (21 males and 14 females) were evaluable for toxicity. Two patients were not evaluable for response having been removed from protocol treatment due to toxicity and received other treatment during the first course of chemotherapy. Among the evaluable patients there was one complete response in a supraclavicular lymph node lasting four months and one partial liver response lasting three months. The remaining thirty-one patients were non-reponders. Of these one had a stable disease lasting 21 months. The overall objective response rate was 6% (2/35) with a 95% confidence interval of 1%–19%. Twenty-six of the 35 patients have died. The estimated median survival of the entire group was 9 months with a 95% confidence interval of six to eleven months. Renal toxicity was dose-limiting and manifested as increasing serum creatinine (54% of patients), proteinuria (51%) and hematuria (9%). One patient experienced grade 4 creatinine increase, proteinuria and acute renal failure. Other toxicities included nausea (71%), vomiting (51%), malaise (23%), weakness (20%), alopecia (17%), diarrhea (17%), anorexia (14%), transaminase (SGOT, SGPT) increase (14%), constipation (14%), alkaline phosphatase or 5nucleotidase increase (9%), and fever (9%). Hematologictoxicity (granulocytopenia, leukopenia, and anemia) was generally mild and infrequent (29%, only one patient had grade 4 granulocytopenia). Overall 9 patients (26%) had at least one grade 3 toxicity. We conclude that merbarone at this dose and schedule has detectable but minimal activity in the treatment of metastatic malignant melanoma and given the significant renal toxicity this schedule does not merit further evaluation in this disease.     

Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study

A phase II trial of gemcitabine(Gemzar®), a nucleoside analogue with broadactivity in solid tumors, was performed inpatients with recurrent or metastaticsquamous cell carcinoma of the head andneck. A total of 26 eligible patients wereregistered to receive a dose of1250 mg/m² weekly for 3 weeks,followed by a 1 week rest. Toxicity wasevaluable in 26 patients. Nausea andvomiting occured in 11 and 6 patients,repectively. Grade 3 or 4 hematologictoxicities were infrequent. Two patientsdeveloped neutropenic infections. Onepatient developed fatal liver failure whichwas thought due to progressive livermetastases or infection 14 days after asingle dose of gemcitabine. There were noobjective treatment responses (95% CI0–13%), with a median survival of 6 monthsin this highly resistant diseasepopulation. Gemcitabine is not consideredactive enough as monotherapy for furtherevaluation in this disease population.     

Extrapulmonary β2-responses to intravenous salbutamol during the menstrual cycle

Extrapulmonary ₂-adrenoceptor mediated responses to salbutamol were evaluated in 9 healthy female subjects during the follicular (day 2–4, Visit 1) and luteal (day 21–23, Visit 2) phases of the menstrual cycle, and were compared with those of 9 age-matched male controls. At each visit, salbutamol was given by intravenous infusion for 30 minutes at a dose of 0.2 mg · kg^–1 · min^–1. Plasma salbutamol concentration and responses in heart rate (HR), finger tremor (Tr), Q-T interval (Q-Tc), serum potassium (K), serum insulin (Ins) and serum glucose (Glu) were measured at baseline and at 10, 20 and 30 minutes after commencing the infusion. Comparisons were made between sexes and between visits for peak responses calculated as percentage change from baseline.Mean plasma salbutamol concentration (ng · ml^–1) were not significantly different between males and females on Visit 1: 6.9 (95% CI 6.01, 7.82) vs 7.3 (95% CI 6.4, 8.3), or on Visit 2: 6.9 (95% CI 6.0, 7.8) vs 7.2 (95% CI 6.3, 8.1). On Visit 1, significantly greater responses were demonstrated in females, compared with males for K (as mean difference): 6 (95% CI 1, 11)%, Tr: 17 (95% CI 1, 33)%, Q-Tc: 8 (95% CI 2, 14)% and Ins: 276 (95% CI 71, 481)%. In addition, a significantly greater response was demonstrated in females on Visit 1 compared with males on Visit 2 for HR (as mean difference): 32 (95% CI 1, 63)%, and for Ins: 262 (95% CI 57, 467)%.Thus, despite no difference in plasma salbutamol concentrations, female subjects exhibited greater responsiveness to salbutamol compared with males during the follicular phase of the menstrual cycle. This suggests that in vivo, females have enhanced sensitivity of extrapulmonary ₂-adrenoceptors.     

A phase II study of rebeccamycin analog (NSC-655649) in metastatic renal cell cancer

Objective: Rebeccamycin analog (NSC-655649) is an antibiotic with antitumor properties demonstrated in preclinical and phase I studies. We conducted a phase II trial to evaluate the efficacy and toxicity of this agent in patients with advanced renal cell cancer (RCC). Methods: Eligible patients had histologically or cytologically confirmed diagnosis of RCC that was either locally advanced unresectable, locally recurrent, or metastatic. Patients had to have measurable disease, no prior chemotherapy, life expectancy of greater than 12 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, adequate-organ function, and be 18 years old. Patients were treated with NSC-655649 at a dose of 165mg/m² daily i.v. over 30–60min for 5 days. Treatment was repeated every 21 days. Response was assessed every two courses. Results: Twenty-four patients were enrolled. There were sixteen males and eight females with a median age of 60.5 years (range 42–76). Nineteen were Caucasians, seventeen had prior nephrectomy, and thirteen had prior immunotherapy. The major toxicity was myelosuppression with grade 3 and 4 neutropenia in 38% of patients and anemia in 33% of patients. There were two partial responses (2/24, 8%) and 11 patients (46%) achieved stable disease (SD). The 6-month progression-free rate for patients with SD was 30%. Of the seventeen patients with progressive disease at registration, one had a PR and eight had SD. The overall median survival time for all 24 patients was 10.0 months (90% CI=5.2, 17.4 months). The 12-month survival rate was 39%, with 90% CI=(0.21, 0.58). Nine patients are still alive with survival times ranging from 3.8 to 24.2 months, at a median follow-up time of 11.9 months. Conclusion: Rebeccamycin analog (NSC-655649) is well tolerated and has modest antitumor activity in patients with advanced RCC.     

Phase I/II study of gemcitabine and vinorelbine plus cisplatin in non-small cell lung cancer

Purpose. We determine the maximum tolerated dose (MTD) and efficacy ofgemcitabine plus vinorelbine combined withcisplatin in patients with non-small celllung cancer (NSCLC). Patients and methods. Chemo naive patientswith stage IIIA to IV non-small cell lungcancer received outpatient administrationof gemcitabine 1000 mg/m² andvinorelbine 25 mg/m² intravenously ondays 1 and 8 every 21 days. Doses ofgemcitabine and vinorelbine were escalatedby 250 mg/m² and 5 mg/m²,respectively, at each dose level. Cisplatin was administered at a fixed doseof 50 mg/m² on days 2 and 9. Afterthe MTD was reached, the study wascontinued as a phase II trial. Results. From January 1998 to March 1999, sixty-five patients were enrolled. Thefirst 38 patients participated in the phaseI evaluation. After 130 cycles, thedose-limiting toxicities were neutropenia,stomatitis, asthenia, and hepatotoxicityoccurring at the third and fourth doselevels (doses of gemcitabine/vinorelbine of1500/25 and 1000/30 mg/m²).For the subsequent phase II evaluation, 27additional patients, out of a total of 53,receiving the MTD of gemcitabine andvinorelbine (1000–1250/25 mg/m²)followed (24 hours later) by cisplatin50 mg/m². Thirty one (58%) of 53 assessable patients responded. Objectiveresponse for patients with stages III andIV disease, respectively, were 65% and47%. The median time to progression andthe overall survival time were 9 months(95% CI: 5–12) and 11 months (95 % CI:9–13), respectively. World HealthOrganization toxicity grade 3neutropenia was registered in 28 (54%) of52 assessable patients (2% with febrileneutropenia), and grade 3thrombocytopenia in 15 (29%) patients (4%with bleeding). Nausea/vomiting( grade 2) and asthenia (moderate tosevere) occurred in 24 (46%) and 14 (27%)patients, respectively. Conclusion. Gemcitabine1000–1250 mg/m plus vinorelbine25 mg/m² on days 1 and 8, followed bycisplatin 50 mg/m² 24 hours later, issafe for outpatient administration andactive in patients with NSCLC.     

A phase II study of S-1 plus irinotecan and oxaliplatin in heavily-treated patients with metastatic colorectal cancer

Summary  Three-drug combination of fluoropyrimidine, irinotecan and oxaliplatin has shown survival benefits in patients with metastatic colorectal cancer (mCRC). Recently we performed a phase II study of a new 3-drug regimen, TIROX (S-1 plus irinotecan and oxaliplatin) to evaluate efficacy and safety in refractory mCRC patients. Patients with refractory to all of 3 drugs, age ≥18 years, PS 0–2, ≥1 measurable lesion(s) and adequate organ functions were eligible. S-1 was given 40 mg/m² twice a day on D1–14, oxaliplatin 85 mg/m² and irinotecan 150 mg/m² on D1 every 3 weeks. The primary endpoint was overall response rate (ORR). Between Mar 2007 and Nov 2007, 19 patients (of 18 planned) were enrolled; median age 50 years; M/F 12/7; PS 0/1/2 5/13/1; colon/rectum 11/8. By intent-to-treat analysis, ORR was 21.1% (95% CI, 8.7–43.7) and disease control rate was 52.6% (95% CI 31.5–72.8) with four PRs and six SDs. Median duration of disease control was 4.3 months (95% CI 1.7–6.9). Median PFS was 2.6 months (95% CI 2.2–2.9) and median OS was 9.8 months (95% CI 5.3–14.4) after median F/U of 15.4 months. G3/4 toxicities per pt included neutropenia (five, 26.3%), febrile neutropenia (two, 10.5%), thrombocytopenia (one, 5.3%), diarrhea (two, 10.5%) and fatigue (two, 10.5%). TIROX seemed to be feasible and efficacious for refractory mCRC patients, and could be an alternative for patients with good PS but no further treatment options.     

Cellular transport of CI-980

Summary CI-980, originally synthesized as a potential folate antagonist, is a tubulin-binding mitotic inhibitor currently in pediatric phase I and adult phase II clinical trials. Because of its extensive tissue distribution in animals and its favorable activity against multidrug resistant (MDR) cells compared with other mitotic inhibitors, such as vincristine, we examined the membrane transport properties of CI-980. CI-980 accumulated rapidly in L1210 and CHO/K1 cells, reaching intracellular levels 40- and 8-fold higher, respectively, than those in the extracellular medium. Efflux was also quite rapid, but a small fraction of drug remained associated with the cells in drug-free medium. The uptake of CI-980 was not temperature or energy dependent, nor was it saturable up to an extracellular concentration of 100 M. Inhibitors of nucleoside transport had no effect on CI-980 uptake. A cell line deficient in the transport of reduced folate was not resistant to CI-980, nor did it exhibit reduced CI-980 uptake. A 100-fold excess of the R-enantiomer inhibited CI-980 uptake by only 50%. These results are consistent with a model of CI-980 uptake involving passive diffusion followed by significant but largely reversible binding to intracellular or membrane components.     

Phase II trial of N-methylformamide in patients with metastatic melanoma

Summary Sixteen patients with metastatic melanoma were treated with N-methylformamide (NMF), a polar-planar compound with in vitro cytotoxic and differentiating properties. Sixteen patients were evaluable for toxicity and 14 for response. The initial four patients received an intravenous bolus of NMF 800 mg/m² daily for 5 consecutive days every 28 days. Because of excessive gastrointestinal toxicity, the dose was reduced to 700 mg/m²/day for the subsequent 12 patients. Two patients had immediate adverse effects from NMF; one had a grand mal seizure and the other developed severe abdominal pain. Nausea, vomiting and abdominal pain were dose-limiting. Transient elevation of liver function tests occurred in all patients. Myelosuppression was not observed. There were no objective responses among 14 evaluable patients (95% confidence limits 0–20%). One patient with pulmonary metastases had a minor response lasting 13 months. Median time to progression of disease was one month. NMF in these doses and schedule lacks clinical efficacy in the treatment of metastatic melanoma.     

A phase II trial of pemetrexed in patients with metastatic renal cancer

Background. Metastatic renal cell carcinoma (RCC) is rising in incidence but remains difficult to treat. This clinical trial evaluated the effects of pemetrexed (multitargeted antifolate, ALIMTA®) for the treatment of metastatic RCC. Patients and methods. Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy. In addition, patients were required to have a World Health Organization (WHO) performance status of 0–2 and adequate bone marrow reserve. Patients received pemetrexed at a dose of 600mg/m² as a 10min infusion every 3 weeks. Patients did not receive folic acid or vitamin B₁₂ supplementation. Results. Thirty-nine patients were enrolled and thirty two were evaluable for response. Three patients had a partial response for a response rate of 9% (95% CI 2–25%). The median time to progressive disease was 10.5 months. Of the nonresponders, twenty two had stable disease (median duration was 5.8 months; range 1.5–27.7) and seven had progressive disease (median time to progression was 5.4 months). Median time to progression for all qualified patients was 5.7 months. Common toxicities experienced were diarrhea and infection. Fatigue, stomatitis, and rash were also reported. The most common hematologic toxicity was grade 3/4 lymphopenia in 76% of patients. Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported. Conclusion. Single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.     

A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: A Southwest oncology group (SWOG 9924) study

Ninety per cent of pancreatic adenocarcinomas (PC) contain mutations of the K-Ras proto-oncogene resulting in constitutively activated Ras protein. A critical step in Ras activation is farnesylation of Ras protein. Farnesyl transferase inhibitors are compounds that inhibit farnesylation. We report the results of a phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with surgically incurable locally advanced or metastatic PC. Between 6/1/2000 and 11/20/2001, 58 cases were accrued, 53 of whom were eligible and analyzable. Patients were required to have a performance status (PS) 0 to 1, be able to take oral medications, and to have adequate renal, hepatic, and hematologic functions. Fifty-five percent were male. Median age was 64.7 years (38.9 to 80.6), and patients had no previous systemic therapy for advanced PC. Treatment consisted of R115777 300 mg po bid given for 3 out of every 4 weeks. Toxicities were as follows: Grade 3 in 19/53 (36%), grade 4 in 53 (173%), and grade 5 in 53 (8%). Most frequent toxicities were: anemia 35/53 (66%), fatigue and malaise 33/53 (62%), nausea 31/53 (58%). Grade 5 toxicities included: thromboembolism 1, infection 2, other 1. Median survival was 2.6 months (mo) (95% CI 2.1–3.6), 6-mo survival is 19% (95% CI, 8–29%), median time to treatment failure was 1.4 mo (95% GI 1.1–1.6). R115777 is ineffective as monotherapy in advanced pancreatic cancer.     

A phase II trial of CI-921 in advanced malignancies

CI-921, (9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino]-N,5-dimethyl-4-acridinecarboxamide 2-hydroxyethanesulfonate (11)), an anilinoacridine derivative with activity in experimental solid tumors was studied in a multicenter phase II trial in patients with solid tumors. Eligible tumor types included cancers of the breast, stomach, pancreas, nonsmall cell lung, small cell lung, colon, head and neck area, and melanoma. Prestudy requirements included an ECOG performance status of 2, no CNS metastases, and measurable disease. CI-921 was administered intravenously over 1–2 hours on days 1,8, and 15 of a 35-day course at an initial dose of 270 mg/M², with modification in subsequent courses based upon tolerance. Principal toxicities included leukopenia, marked phlebitis, and mild nausea and vomiting. One hundred fifty patients were entered of whom 132 were evaluable for response. There was one complete and one partial response among 19 patients with breast cancer, and two partial responses, one each among 14 head and neck and 36 nonsmall cell lung cancer patients.     

Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck

Summary Ispinesib (SB-715992) inhibits the mitotic kinesin spindle protein (KSP), a novel target for anticancer therapy. A phase II study was conducted to examine the efficacy of ispinesib in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSC). Patients with up to one prior line of chemotherapy for RMHNSC were treated with ispinesib 18 mg/m² IV over 1 hour every 21 days. Twenty-one patients were enrolled onto this study with a target stage I sample size of 19. Of 20 evaluable patients, no objective responses were seen and stable disease > 2 cycles was observed in five patients (25%). The median time to progression was 1.4 (95% CI 1.3–2.3) months, median survival was 3.5 (95% CI 2.8–7.8) months, and 1 year overall survival was 20% (95% CI 8.3–48.1%). The most frequent attributable grades III–V adverse events were neutropenia (60% of patients) and leukopenia (55%). The pharmacokinetic profile was consistent with results from phase I studies. Archival tissues (n = 14) demonstrated low to moderate KSP expression by immunohistochemistry. In addition, no pharmacodynamic changes were observed in peripheral blood mononuclear cells. We detected no antitumor activity of ispinesib in RMHNSC on this dosing schedule. Presented in part at the European Society for Medical Oncology, Istanbul, Turkey, September 29–October 3, 2006.