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INTRODUCTION: Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In pre-clinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising pre-clinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. METHODS: Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. RESULTS: Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. CONCLUSIONS: Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.

To evaluate the toxicity and efficacy of interferon and thalidomide combination in a phase II clinical trial.Eligibility included metastatic renal cancer with a maximum of two prior regimens, performance status of 0-2 and adequate renal, hepatic and bone marrow function.Twenty patients were enrolled on this phase II trial. Median age was 60.5 years (Range: 39-75 years). 17 patients had visceral metastases (lung/liver/both) and 3 patients had lymph node only metastases. A total of 26 cycles of 4 weeks each were administered; median of 1 cycle and range from 0-9 cycles. The therapy was poorly tolerated with grade 3 adverse events noted in 12 (60%) of the 20 patients. No objective responses were noted. Of the 14 response evaluable patients, one had an unconfirmed response (38% decrease in size) and one had prolonged disease stabilization for 10 months. The median time to progression was 1.0 month and median survival was 2.8 months. Pre and post therapy PET scans were performed nine weeks apart on one patient. The mean standardized uptake values (SUV) declined from 1.45 (SUV min-max 0.89-1.76) to 1.12 (SUV min-max 0.55-1.47), denoting anti vascular effect. The patient did not have an objective response but had a disease stabilization sustained for 10 months.The combination of interferon and thalidomide has minimal efficacy and considerable toxicity which makes this combination unworthy of future investigation in metastatic renal cancer.

Summary Background .P ancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer. Methods. The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m 2 over 100 minutes, cisplatin 35 mg/m 2 I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days. Results .T wenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9 ). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6‐7.6 months). The probability of survival at 6 months was 46% (90% CI, 27‐62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients. Conclusions. The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.

Purpose: Fenretinide, a synthetic form of retinoid, induced apoptosis even in chemotherapy resistant cell lines. A phase II study was hence conducted to evaluate toxicity and efficacy of fenretinide in metastatic renal cancer. Methods: Eligibility included unresectable or metastatic renal cell carcinoma (RCC), adequate organ function and Zubrod performance status ≦2. Prior immunotherapy and a maximum of one prior chemotherapy regimen were allowed. Fenretinide was administered at a dose of 900 mg/m2 twice daily orally for 7 days in a 21-day cycle. Toxicity was assessed at the start of each cycle, and response every 2 cycles. Results: Nineteen eligible patients enrolled of which fifteen had visceral/bone metastases. Seventeen patients had prior nephrectomy and 11 had prior immunotherapy. 76 cycles of therapy were delivered. Therapy was very well tolerated with few severe toxicities consisting of thrombosis in 1 individual and grade 3 fatigue, nausea and diarrhea in 1 patient. 5 patients had grade 2 nyctalopia and 3 patients had transient grade 2 visual toxicity. No objective responses were noted. Stable disease was seen in seven of nineteen cases (37%, 90% C.I. 0.21–0.59). Median time to progression was 1.5 months and median duration of stable disease was 5.8 months (90% C.I. 3.0–8.4). Median survival was 10 months. Tumor fenretinide levels were obtained in three patients and were in the lower end of the therapeutic range. Conclusion: Fenretinide was well tolerated but demonstrated minimal activity that was consistent with results of intratumoral drug measurements. Strategies are needed that will increase systemic and tumor levels of fenretinide.

Objectives: CI-994 (N-acetyl dinaline, PD123654) is a novel oral agent active in a broad variety ofmurine and human tumor xenografts. While cytotoxic in theBrown Norway (BN) rat leukemia model, growth inhibition inother murine and human tumor xenografts is predominantlycytostatic. Its specific mechanism of action remains unknown.Following CI-994 administration, inhibition of both histonedeacetylation and cellular proliferation at the G1 to Stransition phase of the cell cycle are observed. This Phase 1study in patients with solid tumors was carried out todetermine a maximum tolerated daily oral dose (MTD) for CI-994administered on a chronic basis. Methods: Fifty-threepatients received CI-994 daily for treatment durations rangingfrom 2 to 10 weeks. Dosage escalation proceeded in 2 phases;an Acute Dosing Phase (n = 11) to define the MTD for CI-994administered over 2 weeks and a Chronic Dosing Phase (n = 29)to define the MTD for daily administration for 8 weeks. Uponcompletion of the Chronic Dosing Phase, a third cohort ofpatients (n = 13) received CI-994 at the recommended Phase 2dose and schedule with 2 additional single doses of drugadministered separated by a 1-week washout to assess theeffect of food on CI-994 pharmacokinetics. Results:Thrombocytopenia was dose limiting at the MTD of 8mg/m2/day for 8 weeks. Other toxicities includedfatigue and gastrointestinal effects such as nausea, vomiting,diarrhea, constipation and mucositis. Pharmacokinetic studiesrevealed that peak plasma levels and AUC's generally increasedwith dose and that food intake did not affect the rate orextent of drug absorption. One patient with heavilypre-treated adenocarcinoma of the lung achieved a PartialResponse (PR) lasting over 2 years and 3 additional patientsachieved Stable Disease (SD), 1 each with non-small cell lung,colorectal, and renal cancer. Conclusions: Therecommended Phase 2 starting dose is 8 mg/m2/dayfor 8 weeks repeated after a 2-week drug-freeinterval.

Purpose: XK469, a member of the quinoxaline family of antitumor agents, is believed to be unique in its ability to selectively target topoisomerase IIβ. Based on encouraging pre-clinical data, a phase I trial was conducted to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Methods: A 2B accelerated titration schema was employed. XK469 was administered as a 5 or 20 min IV infusion on days 1–5 every 21 days. The starting dose was 9 mg/m2. Pharmacokinetics (PK) were conducted in cycles 1–3. Results: 22 patients (21 evaluable, mean age: 56 years, median performance status: 1) were enrolled. At dose level 11 (260 mg/m2/daily X 5), 1/6 patients experienced a DLT of grade 4 neutropenia. At 346 mg/m2/daily X 5, 2/2 patients experienced DLT's with one episode of febrile neutropenia and one grade 3 infection. The MTD was identified as 260 mg/m2/day. XK469 peak plasma levels and systemic exposure were proportional to dose indicating linear pharmacokinetics. However, secondary peaks in the PK profiles and a rapid decline in drug level from 23 to 24 h occurred in some patients. Drug infusion in the afternoon followed by dense sampling of levels during the elimination phase supported the hypothesis that the drug was being sequestered. No anti-tumor activity was identified. Conclusions: Traditional PK sampling designs were inadequate to describe XK469 disposition. XK469 and related structures work through a unique mechanism of action. A further understanding of the specific mechanism of these compounds might uncover a unique avenue for future drug development.

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 165 mg/m2 daily i.v. over 30–60 min 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.

The spicamycin derivative KRN5500 was considered as a potential anti-cancer agent based on in vitro and preclinical studies. A Phase I study involving 24 cancer patients in whom tumors were refractory to all other conventional therapies was conducted to determine the dose limiting toxicity, maximum tolerated dose, effectiveness, and pharmacokinetic parameters of this drug administered by 1-h IV infusion daily for five consecutive days every 3 weeks. Using an accelerated dose titration strategy, 8.4 mg/m2/d × 5 days was the maximum administered dose. Severe gastrointestinal and hepatic toxicities were observed at doses at or above 4.3 mg/m2/d × 5. The recommended Phase II dose is 4.3 mg/m2/d × 5. The distribution of KRN5500 followed a two-compartment model, and clearance did not decrease significantly over the dose range 0.8–8.4 mg/m2/d × 5. No significant correlation was observed between plasma levels and toxicity. No tumor responses were observed among the 14 patients evaluable for response.

A highly active and broadly active thioxanthone has been identified: N-[[1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthen++ +-4-yl] methylformamide (SR271425, BCN326862, WIN71425). In preclinical testing against a variety of subcutaneously growing solid tumors, the following %T/C and Log10 tumor cell kill (LK) values were obtained: Panc-03 T/C = 0, 5/5 cures; Colon-38 (adv. stage) T/C = 0, 3/5 cures, 4.9 LK; Mam-16/C T/C = 0, 3.5 LK; Mam-17/0 T/C = 0, 2.8 LK; Colon-26 T/C = 0, 1/5 cures, 3.2 LK; Colon-51 T/C = 0, 2.7 LK; Panc-02 T/C = 0, 3.1 LK; B16 Melanoma T/C = 13%, 4.0 LK; Squamous Lung-LC12 (adv. stage) T/C = 14%, 4.9 LK; BG-1 human ovarian T/C = 16%, 1.3 LK; WSU-Brl human breast T/C = 25%, 0.8 LK. The agent was modestly active against doxorubicin (Adr)-resistant solid tumors: Mam-17/AdrT/C =23%, 0.8 LK; and Mam-16/C/Adr T/C = 25%, 1.0 LK, but retained substantial activity against a taxol-resistant tumor: Mam-16/C/taxol T/C = 3%, 2.4 LK. SR271425 was highly active against IV implanted leukemias, L1210 6.3 LK and AML1498 5.3 LK. The agent was equally active both by the IV and oral routes of administration, although requiring approximately 30% higher dose by the oral route. Based on its preclinical antitumor profile, it may be appropriate to evaluate SR271425 in clinical trials.

A series of quinoxaline analogs of the herbicide Assure® was found to have selective cytotoxicity for solid tumors of mice in a disk-diffusion-soft-agar-colony-formation-assay compared to L1210 leukemia. Four agents without selective cytotoxicity and 14 agents with selective cytotoxicity were evaluated in vivo for activity against a solid tumor. The four agents without selective cytotoxicity in the disk-assay were inactive in vivo (T/C > 42%). Thirteen of the fourteen agents with selectivity in the disk-assay were active in vivo (T/C < 42%). Five of the agents had curative activity. These five agents had a halogen (F, Cl, Br) in the 7-position (whereas Assure® had a Cl in the 6 position). All agents with curative activity were either a carboxylic acid, or a derivative thereof, whereas Assure® is the ethyl ester of the carboxylic acid. All other structural features were identical between Assure® and the curative agents. Assure® had no selective cytotoxicity for solid tumors in the disk-assay, and was devoid of antitumor activity. The analog XK469 is in clinical development.

Purpose: Pyrazoloacridine (PZA) is an acridine derivative selected for clinical development because of broad preclinical antitumor activity and solid tumor selectivity. Phase I evaluations with PZA have demonstrated predictable toxicity and suggested clinical efficacy. A phase II trial in patients with previously untreated advanced pancreatic cancer was conducted. Methods: PZA was administered at a dose of 750 mg/m2 intravenously over 3 hours every 21 days. Seventeen patients were treated receiving a total of 46 courses of PZA. Results: Of the 15 patients evaluable for response, no responses were observed (0% response rate, 95% confidence interval 0–22%). Major toxicities directly attributable to PZA included moderate neutropenia and mild neurotoxicity. Conclusion: PZA at this dose and schedule of administration was inactive in patients with pancreatic carcinoma.