Showing papers in "Investigational New Drugs in 2003"

Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma.

Abstract: Fifty-five patients with metastatic renal cell carcinoma (RCC) were treated on a multicenter, single-arm Phase II trial. Patients received single-agent Cetuximab (C225) administered by intravenous infusion at a loading dose of 400 or 500 mg/m2 followed by weekly maintenance doses at 250 mg/m2. None of the patients treated with C225 achieved either a complete or partial response. The median time to progression was 57 days. The most frequently reported grade 3 or 4 toxicity treatment-related adverse events were acne (17%) and rash or dry skin (4%). The lack of clinical response or suggestion of prolonging time to progression compared to historical data with interferon-alfa supports no further study of single-agent C225 in patients with metastatic RCC.

Reversal of tumor-induced immunosuppression by TGF-beta inhibitors.

Abstract: The immune system is responsible for the early detection and destruction of newly transformed malignant cells. Some transformed cells become immunologically invisible by passive avoidance of immune surveillance (i.e., when tumor cells are immunologically indistinguishable from normal cells). Other transformed cells actively secrete cytokines that effectively blind the immune system to the presence of abnormal antigens on the tumor cell surface. Transforming growth factor-beta ("TGF-beta"), which is expressed by a majority of malignant tumors, is the most potent immunosuppressor and therefore, the most likely cytokine to be responsible for the latter phenomenon. In addition to playing a key role in tumor-induced immunosuppression, TGF-beta stimulates angiogenesis. Interestingly, tumor cells eventually become refractory to TGF-beta-mediated growth arrest, either due to loss of TGF-beta receptors or due to dysregulation in TGF-beta signaling pathways. Neutralization of TGF-beta or inhibition of its production is an effective method of cancer treatment in variety of animal models. Several agents targeting TGF-beta are in the early stages of development and include anti-TGF-beta antibodies, small molecule inhibitors of TGF-beta, Smad inhibitors and antisense gene therapy. Since tumors may express more than one isoform of TGF-beta, these new drugs should target all three TGF-beta isoforms produced by human tumors. The effects of therapies targeting TGF-beta are likely to be synergistic with cytotoxic chemotherapy and immunotherapy. Reversal of TGF-beta-induced immunosuppression is a new and promising approach to cancer therapy, with potential applications in other diseases such as AIDS.

Positron emission tomography (PET): expanding the horizons of oncology drug development.

Abstract: Positron emission tomography (PET) allows three-dimensional quantitative determination of the distribution of radioactivity permitting measurement of physiological, biochemical, and pharmacological functions at the molecular level. Until recently, no method existed to directly and noninvasively assess transport and metabolism of neoplastic agents as a function of time in various organs as well as in the tumor. Standard preclinical evaluation of potential anticancer agents entails radiolabeling the agent, usually with tritium or 14C, sacrifice experiments, and high-performance liquid chromatography (HPLC) analysis to determine the biodistribution and metabolism in animals. Radiolabeling agents with positron-emitting radionuclides allows the same information to be obtained as well as in vivo pharmacokinetic (PK) data by animal tissue and plasma sampling in combination with PET scanning. In phase I/II human studies, classic PK measurements can be coupled with imaging measurements to define an optimal dosing schedule and help formulate the design of phase III studies that are essential for drug licensure [1]. Many of the novel agents currently in development are cytostatic rather than cytotoxic and therefore, the traditional standard endpoints in phase I and II studies may no longer be relevant. The use of a specialized imaging modality that allows PK and pharmacodynamic (PD) evaluation of a drug of interest has been proposed to permit rapid and sensitive assessment of the biological effects of novel anticancer agents. The progress to date and the challenges of incorporating PET technology into oncology drug development from the preclinical to clinical setting are reviewed in this article.

Mechanistic models for myelosuppression.

Abstract: As myelosuppression is the dose-limiting toxicity for most chemotherapeutic drugs, modelers attempt to find relationships between drug and toxicity to optimize treatment. Mechanistic models, i.e. models based on physiology and pharmacology, are preferable over empirical models, as prior information can be utilized and as they generally are more reliable for extrapolations. To account for different dosing-regimens and possible schedule-dependent effects, the whole concentration-time profile should be used as input into the pharmacokinetic-pharmacodynamic model. It is also of importance to model the whole time course of myelosuppression to be able to predict both the degree and duration of toxicity as well as consecutive courses of therapy. A handful of (semi)-mechanistic pharmacokinetic-pharmacodynamic models with the above properties have been developed and are reviewed. Ideally, a model of myelosuppression should separate drug-specific parameters from system related parameters to be applicable across drugs and useful under different clinical settings. Introduction of mechanistic models of myelosuppression in the design and evaluation of clinical trials can guide in the decision of optimal sampling times, contribute to knowledge of optimal doses and treatment regimens at an earlier time point and identify sub-groups of patients at a high risk of myelosuppression.

Biological role of adduct formation of the ruthenium(III) complex NAMI-A with serum albumin and serum transferrin.

Abstract: NAMI-A is an innovative ruthenium(III) complex with a very encouraging preclinical profile of metastasis inhibition, which is undergoing initial phases of clinical trials. To assess the pharmacological relevance of the drug fraction associated to plasma proteins, adducts of NAMI-A with either serum albumin or serum transferrin were prepared and their biological effects tested in vitro and in vivo. Specifically, adducts of NAMI-A with either serum albumin or serum transferrin, prepared and characterized at a ruthenium-to-protein molar ratio of 4:1, were evaluated in vitro on the KB human tumor cell line and in vivo on the MCa mammary carcinoma tumor. The effects of NAMI-A/protein adducts on cell viability and on cell cycle progression were found to be far smaller than those produced by free NAMI-A. GFAAS measurements point out that the amount of ruthenium that gets into cells is drastically reduced when NAMI-A is presented in its protein-bound form. In vivo use of NAMI-A adducts with albumin and transferrin resulted markedly less effective on lung metastasis reduction, than free NAMI-A. Overall, the present results suggest that binding to plasma proteins causes a drastic decrease of NAMI-A bioavailability and a subsequent reduction of its biological activity, implying that association to plasma proteins essentially represents a mechanism of drug inactivation.

Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks.

Abstract: Purpose: MG98 is a second generation phosphorothioate antisense oligodeoxynucleotide which is a highly specific inhibitor of translation of the mRNA for human DNA MeTase I (DNMT 1). This phase I study examined the toxicity and pharmacologic profile of MG98 administered as a continuous 21-day intravenous infusion every 4 weeks. Patients and methods: Fourteen patients with solid cancers received a total of 25 cycles of MG98 at doses ranging from 40 to 240 mg/m2/day. Steady-state concentrations of MG98 were measured as were several pharmacodynamic assessments including mRNA of the target gene, DNMT1, in PBMC. In addition, other potential surrogate markers of drug effects were explored, including hemoglobin F, Vimentin and GADD45. Results: Dose limiting effects were drug-related reversible transaminase elevation and fatigue seen at doses of 240, 200 and 160 mg/m2/day. The dose level of 80 mg/m2/day was felt to be safe and tolerable when delivered on this schedule. No evidence of antitumor activity was observed. Although pharmacokinetic analysis revealed that at the higher dose levels, mean Css values of MG98 were approximately 10-fold times the IC50 values associated with target inhibition in vitro, the extent of MG98 penetration into target tumors in this trial was not determined. No consistent, dose-related changes in correlative markers including DNMT1 mRNA, hemoglobin F, Vimentin and GADD45, were observed. Conclusions: This schedule of MG98 given as a 21-day continuous intravenous infusion every 4 weeks was poorly tolerated in the highest doses; therefore, further disease-site specific evaluation of the efficacy of this agent will utilize a more favorable, intermittent dosing schedule. Pharmacodynamic evaluations undertaken in an attempt to explore and validate the biological mechanisms of MG98 did not show dose-related effects.

Phase II trial of ZD1839 (IRESSA) in patients with advanced renal cell carcinoma.

Abstract: Eighteen patients with advanced renal cell carcinoma (RCC) were treated on a phase II trial with ZD1839 (IRESSA). Treatment efficacy was determined using the endpoint of improvement in time to progression (TTP) compared to TTP in patients who received interferon-α therapy. The Memorial Sloan Kettering Cancer Center database of renal cell patients shows that patients receiving therapy with interferon-α had a median TTP of 4.7 months, with 40% of patients having disease progression at 4 months. To show efficacy in this trial, 60% of evaluable patients would have to remain progression free at 4 months. Treatment with ZD1839 did not result in any complete or partial responses, and 13 patients (81%) had progression of disease within 4 months of start of therapy. At the dose and schedule used in this trial, the lack of antitumor activity associated with ZD1839 does not support further study in patients with metastatic RCC.

Weekly regimen of irinotecan/docetaxel in previously treated non-small cell lung cancer patients and correlation with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism.

Abstract: Purpose: Inherited variations in drug metabolizing enzymes may influence drug efficacy. This phase II study assesses the impact of second-line weekly irinotecan (CPT-11)/docetaxel in non-small cell lung cancer (NSCLC) patients, and gauges the uridine diphosphate glucuronosyl transferase (UGT1A1) polymorphism influence in toxicity and antitumor activity. Experimental Design: Fifty-one patients with NSCLC treated with at least one prior chemotherapy regimen were enrolled. Patients received irinotecan 70 mg/m2 followed by docetaxel 25 mg/m2. Both drugs were given on days 1, 8, and 15 every 28 days. UGT1A1 polymorphism were analyzed in blood samples of 47 patients. The UGT1A1 polymorphism are classified according to the number of TA repeats in the promoter region of this gene. Results: Three patients (6%) achieved a partial response and nineteen patients (37%) had stable disease. Median survival was 8 months (95% CI: 4.8–11.2) and 1-year survival 30%. Grade 3–4 hematologic toxicity was low (less than 10% of patients); 15% of patients had grade 3 asthenia and 25% of patients had grade 3/4 diarrhea. The frequency of UGT1A1 genotypes was as follows: 6/6 49%, 6/7 36%, and 7/7 15%. No differences in toxicity were observed according to UGT1A1 polymorphism. A nonsignificant improvement in time to progression (4 vs. 3 months) and median survival (11 vs. 8 months) was detected in patients with the variant alleles (6/7 and 7/7). Conclusions: This weekly irinotecan/docetaxel regimen has shown an acceptable toxicity profile while encouraging median and 1-year survival in heavily pretreated NSCLC patients. The tendency to better prognosis in patients carrying the variant genotypes 6/7 and 7/7 of UGT1A1 gene requires further validation.

Toxicity patterns of cytotoxic drugs.

Abstract: Toxicity is a major concern for anticancer drugs. These compounds present a narrow therapeutic index, with a small difference between the dose required for an antitumor effect and that responsible for unacceptable toxicity. Their recommended doses are determined according to the toxicity endpoint. Moreover, toxicity is observed earlier than the therapeutic effect, so, toxic effects represent a major endpoint for pharmacodynamic studies of cytotoxic drugs. Knowledge of toxicity patterns and main factors of toxicity of anticancer drugs is required before modeling data of these studies. Hematological toxicities represent the main toxicity of the cytotoxic. However, non-hematological toxicities have become more important than hematological toxicities as pharmacodynamic endpoints in some circumstances such as high-dose chemotherapy associated with bone marrow transplantation. This paper will describe the main toxicity of the cytotoxic drugs, and its factors of both inter- and intra-patient variability. The toxicity pattern of topotecan will be examined as an example. Knowledge of the toxicity pattern of a drug constitutes a prerequirement before modeling its pharmacodynamics.

Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

Abstract: Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes

The mechanism of action of docetaxel (Taxotere) in xenograft models is not limited to bcl-2 phosphorylation.

Abstract: Docetaxel is a new taxoid compound with a broad spectrum of antitumor activity. Previous studies have shown that in vitro treatment of specific human tumor lines with docetaxel is associated with the phosphorylation and inactivation of the bcl-2 protein and the occurrence of apoptosis. The goal of this study was to examine whether bcl-2 expression is truly required for in vivo responsiveness to docetaxel. The expression and state of phosphorylation of bcl-2 was examined in human MX-1 breast or DU-145 prostate tumors explanted from nu/nu mice treated with docetaxel. The MX-1 cells accumulated in the G2/M phase of the cell cycle and exhibited phosphorylation of bcl-2 after treatment with docetaxel. By Western blot analysis DU-145 prostate tumor cells did not express bcl-2 protein before or following in vivo treatment with docetaxel. However, docetaxel was highly active against the DU-145 tumor xenograft model. Thus, docetaxel induces apoptosis and cell death through a different, bcl-2-independent mechanism in the DU-145 human prostate tumor, indicating that bcl-2 may not have prognostic value for treatment with docetaxel.

Phase II trial of perillyl alcohol (NSC 641066) administered daily in patients with metastatic androgen independent prostate cancer.

Abstract: Objective. We conducted a phase II multicenter trial of perillyl alcohol in patients with advanced hormone refractory prostate cancer (HRPC). The primary endpoint was to evaluate the 6-month progression-free survival given the potential cytostatic nature of the drug. Secondary objectives included assessing acute and chronic toxicities, as well as measuring objective response rates. Methods. Patients with metastatic androgen-independent prostate cancer that failed at least one prior chemotherapeutic or experimental regimen were eligible. Perillyl alcohol was administered orally at 1200 mg/m2/dose four times daily and continued until disease progression or development of unacceptable toxicity. Results. Fifteen patients were eligible. Six patients received less than one cycle (4 weeks) of drug, four of which stopped because of drug intolerance. Only six patients received more than two cycles of therapy and were considered evaluable for response. Main toxicity included grade 1–2 gastrointestinal intolerance (nausea/vomiting in 60% of the patients) and fatigue (47%). One patient developed a grade 4 hypokalemia that was felt likely attributable to the drug. No objective responses were seen. All patients either progressed or withdrew from the study secondary to drug intolerance before the 6-month time period. Conclusion. Perillyl alcohol administered at this dose and formulation did not have any objective clinical activity in this patient population.

In vivo antitumor activity of a novel sulfonamide, HMN-214, against human tumor xenografts in mice and the spectrum of cytotoxicity of its active metabolite, HMN-176.

Abstract: The cytotoxic effects of HMN-176 ((E)-4-[[2-N-[4-methoxybenzenesulfonyl] amino] stilbazole] 1-oxide; a newly synthesized compound, were evaluated and compared with those of the clinically used antitumor agents cis-platinum, adriamycin, etoposide, taxol, and vincristine in 22 human tumor cell lines isolated from various organs. HMN-176 exhibited potent cytotoxicity with IC(50) values in the nM range, and the variance of its cytotoxic efficacy was remarkably small. Drug-resistant cell lines also showed low cross-resistance to HMN-176 corresponding to overall resistance indices of less than 14.3. HMN-214 was synthesized as an oral prodrug because of the poor oral absorption of HMN-176 itself. Pharmacokinetic studies showed that HMN-214 was an acceptable oral prodrug of HMN-176. In the in vivo analysis of the schedule-dependency of HMN-214, the repeated administration for over 5 days elicited potent antitumor activity, as expected from the exposure-dependency of the cytotoxicity of HMN-176 and from the cytometric studies. The antitumor activity of HMN-214 against human tumor xenografts was equal or superior to that of clinically available agents, including cis-platinum, adriamycin, vincristine, and UFT without severe toxicity such as neurotoxicity. Because of its good activity in preclinical trials, HMN-214 has entered Phase I clinical trials in the USA.

Different Effects of Vinblastine on the Polymerization of Isotypically Purified Tubulins from Bovine Brain

Abstract: Vinblastine, a highly successful antitumor drug, targets the tubulin molecule. Tubulin, the subunit protein of microtubules, consists of an α- and a β-subunit, both of which consist of isotypes encoded by different genes. We have purified three isotypes of bovine brain tubulin, namely, αβII, αβIII and αβIV. Microtubule associated protein-2 (MAP2) and Tau-induced assembly of these isotypes were compared in the presence and absence of vinblastine. MAP2-induced assembly of unfractionated tubulin and all the isotypes except αβII tubulin was resistant to 1 μM vinblastine. Vinblastine at low concentrations (<10 μM) progressively inhibited the assembly of all of the isotypes but the vinblastine concentration required for inhibition of MAP2-induced microtubule assembly was minimal for αβII. The tau-induced assembly of unfractionated tubulin and αβIII were equally sensitive to 1 μM vinblastine whereas αβII and αβIV were much more sensitive to vinblastine. The microtubules obtained in the presence of tau from unfractionated tubulin, αβII and αβIV could be easily aggregated by 20 μM vinblastine whereas such as aggregation of microtubules obtained from αβIII and tau required approximatedly 40 μM vinblastine. Our results suggest that among the tubulin isotypes, αβII is the most sensitive to vinblastine in the presence of MAPs while αβIII is the most resistant and this intrinsic resistance of αβIII dimers persists in the polymeric form of αβIII tubulin as well. These results may be relevant to the therapeutic and toxic actions of vinblastine.

Use of positron emission tomography in anticancer drug development

Abstract: Positron emission tomography (PET) is increasingly being used in anticancer drug development The technique is applicable to studies of drug delivery, and where specific probes are available, to provide pharmacodynamic readouts noninvasively in patients Mathematical modeling of the imaging data enhances the quality of information that is obtained from such studies This section provides a review of the PET methodologies that have been used for the development of new cancer therapies Other than imaging of radiolabeled drugs, PET modeling has found extensive application in studies with 2-[11C]thymidine, [18F]fluorodeoxyglucose, H2(15)O, C15O, and receptor ligands

Primary tumor, lung and kidney retention and antimetastasis effect of NAMI-A following different routes of administration

Abstract: Imidazolium-trans-dimethylsulfoxideimidazoletetrachlororuthenate (NAMI-A) is a ruthenium compound effective on solid tumor metastases. In this study, we evaluated the effects of different routes of administration of NAMI-A on the distribution to primary tumor, lungs and kidneys in BD2F1 hybrids with Lewis lung carcinoma or in CBA inbred mice with MCa mammary carcinoma. NAMI-A concentration and the percentage of cumulative dose (%Dtot) retained in these tissues is independent of the animal strain and of the tumor model used. Also the presence of the tumor does not change the distribution of NAMI-A in the lungs and in the kidneys. A dose-dependent antimetastatic effect is evident with intraperitoneal (i.p.) treatments at three different doses. Treatment of tumor bearing mice with NAMI-A administered i.p., per os or by aerosol showed a similar effect on lung metastases, although the concentration of ruthenium reached in the lungs was markedly different. On the basis of the data obtained, we can conclude that the antimetastatic effects are related to the amount of NAMI-A administered, rather than to the lung's concentration of the compound.

Clinical trial design for target specific anticancer agents.

Abstract: Recently a large number of new anticancer agents targeting specifically one or more of the extracellular, transmembrane, or intracellular (but extranuclear) processes involved in malignant transformation of cells or carcinogenesis have been developed. These agents show target specificity, predominantly resulting in growth inhibition in tumor models and less frequently in tumor regression, acting in a cytostatic rather than a cytotoxic way. In addition, based on their specific mechanism of action, these target specific agents are expected to have a more favorable toxicity profile. In exploring new anticancer agents, phase I studies generally focus on toxicity and are primarily designed to describe dose limiting toxicity and to determine the maximum tolerated dose and the dose recommended for phase II studies. These phase II studies are subsequently performed in small groups of patients using the percentage tumor regression to screen for anticancer efficacy. Due to the anticipated low toxicity profile and the mainly growth inhibiting activity of target specific agents, the design of phase I and II studies involving these agents will have to be adapted in several ways. It is emphasized that, although it is helpful to distinguish cytotoxic from cytostatic anticancer agents, this dichotomy can be a simplification. In this paper, we will discuss important issues that will have to be faced when developing clinical trials with these agents and we will specifically translate this into the already known concepts of trial design exploring cytotoxic and cytostatic agents.

Discovery and preclinical antitumor efficacy evaluations of LY32262 and LY33169.

Abstract: The discoveries of a new antitumor agent (LY32262) (N-[2,4-dichlorobenzoyl]phenylsulfonamide) and a close analog (LY33169) are described. For this discovery, a disk-diffusion-soft-agar-colony-formation-assay was used to screen a portion of the Eli Lilly inventory, with the evaluation of each agent against normal cells, leukemic cells and several solid tumors, including a multidrug-resistant solid tumor (with marked selective cytotoxicity for Colon-38 and Human-Colon-15/MDR compared to normal fibroblasts and L1210 leukemic cells characterizing the discovery). In mice, LY32262 and/or LY33169 had curative activity against Colon Adenocarcinoma-38, Human Colon-116, Human Prostate LNCaP, and Human Breast WSU-Br-1. In addition, many other tumors were highly sensitive: Panc-03 = 2.4 log kill (LK); Panc-02 = 2.9-4.1 LK; Squamous Lung LC-12 = 2.1 LK; Colon-26 = 2.2 LK; AML1498 = 2.7 LK; Human Sm Cell Lung DMS-273 = 6.3 LK; Human Squamous Lung 165 = 3.7 LK; Human Ovarian BG-1 = 3.7 LK; Human Colon CX-1 (H29) = 1.6 LK; Human Colon-15/MDR (a p-glycoprotein positive multidrug resistant tumor) = 2.3 LK; Human CNS-gliosarcoma-SF295 = 3.8 LK. Several tumors were only marginally responsive or totally unresponsive: Mammary Adenocarcinoma-16/C = 0.6 LK; Mammary Adenocarcinoma-17 = no kill; Colon Adenocarcinoma-11 = no kill; L1210 leukemia = 1.3 LK; Human Prostate PC-3 = 0.5 LK; Human Adenosquamous Lung H125 = no kill; and Human Breast Adenocarcinoma MX-1 = 0.9 LK. There was no absolute tissue of origin correlation with antitumor efficacy, although colon tumors were most responsive and mammary tumors least responsive. The cause of the "hit and miss" efficacy has not been determined.

A Phase II Study of Rebeccamycin Analog NSC 655649 in Patients with Metastatic Colorectal Cancer

Abstract: The analog, rebeccamycin tartrate salt (NSC 655649, Cancer Therapy Evaluation Program, National Cancer Institute) has broad preclinical anti-neoplastic activity. Preliminary data from phase I study demonstrated anti-tumor activity in colorectal carcinoma. This phase II trial evaluates its efficacy in patients with minimally treated metastatic colorectal cancer. Eligibility included Karnofsky performance status ≥70%, age ≥18 years and bidimensionally measurable disease. Thirteen patients were treated with NSC 655649 at 500 mg/m2 by central venous catheter once every 3 weeks by bolus injection. Thirty-four cycles (median [range] 2 [1–6]) of therapy were administered. Twelve patients are eligible for response assessment. No major objective responses were seen using the RECIST criteria; however stable disease was observed in three patients with mean duration of 15 weeks. The median time to progression was 8 weeks. There was no toxic death. Four patients received only one cycle of treatment, and three had disease progression. Toxicities were tolerable and hematologic toxicity was the most common. The median (range) granulocyte and platelet nadir counts were 2043/μl (116–16,374/μl) and 276×103/μl (5–769), respectively. Non-hematologic toxicities were moderate, including generalized weakness/fatigue, nausea/vomiting, diarrhea and anorexia. One patient required dose reduction; three patients required dose delays. NSC 655649 at this dose and schedule is inactive against advanced previously minimally treated metastatic colorectal cancer and further study of this drug as a single agent in this disease using an every three-week schedule is not warranted.

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

Abstract: 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.

Phase II study of XR5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with advanced ovarian cancer.

Abstract: Background. XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of the present study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with ovarian cancer who had relapsed within 1 year after first-line chemotherapy with taxanes and platinum for advanced disease. Patients and methods. Patients received XR5000 at the dose of 3010 mg/m2 through a 120-h central venous infusion every 3 weeks. Toxicity was graded according to the Common Toxicity Criteria (CTC), version 2.0. An independent panel assessed response every two cycles according to the World Health Organization (WHO) criteria. Gehan's rule was used for sample size determination. Results. Sixteen patients were enrolled; one patient was ineligible because of prior melphalan single agent treatment. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (eight patients), 1 (five patients), or 2 (two patients). The 15 eligible patients received 43 cycles of XR5000 (median 2, range 1–8). Hematological toxicity was mild with only one grade 3 anemia in one patient. Other drug-related toxicities never exceeded grade 3 and included fatigue (four patients), thrombosis (one patient), nausea (one patient), stomatitis (one patient) as well as dyspnea/cough (one patient). One patient who had refused further therapy and controls after the first cycle was not assessable for response evaluation. No objective responses were observed. Four patients experienced stable disease and 10 patients progressive disease. The median time to progression was 42 days (CI 95% 40; 54). Conclusions. The complete lack of any objective response does not justify further evaluation of XR5000 in patients with advanced ovarian cancer using this dose and schedule, although the therapy was generally well tolerated.

Pharmacokinetics and safety of ILX23-7553, a non-calcemic-vitamin D3 analogue, in a phase I study of patients with advanced malignancies.

Abstract: Purpose: Differentiation therapy is an alternative to chemotherapy with potentially less toxicity, improved quality of life, and survival. We conducted a phase I trial of ILX23-7553, a formulation of 1,25-dihydroxy-16-ene-23-yne-vitamin D3, a 1,25-dihydroxyvitamin D3 analog with preclinically demonstrated antitumor and differentiating effects and diminished hypercalcemic effects. Patients and methods: The protocol consisted of five daily oral treatments during 14-day cycles at 15 dose levels from 1.3 to 45.0 μg/m2/day. We treated 42 heavily pretreated patients who had a variety of malignancies with 162 treatment cycles, and obtained pharmacokinetics from three patients at the two highest dose levels. Results: There were no grade 3 or 4 toxicities. Grade 1–2 toxicities included diarrhea, nausea, fatigue, constipation, and one grade 1 hypercalcemia. Average day 6 calcium was 9.26 ± 0.55 mg/dl in cycle 1 and 9.30 ± 0.67 mg/dl in cycle 2. Pharmacokinetics at dose levels 14 (40 μg/m2/day) (1 patient) and 15 (45 μg/m2/day) (2 patients) demonstrated an average C max of 30.4 ± 7.8 pg/ml (0.07 nM) and 104 ± 38.2 pg/ml (0.25 nM), and AUCs of 222.5 ± 225.2 pg·h/ml and 855 ± 536 pg h/ml, respectively. Eight patients (19%) had stable disease. While in vitro effects have been reported at these concentrations, they were at least 10-fold lower than ED50s, and the study was terminated before an MTD was reached. Conclusion: The drug is safe and has potential benefits at serum concentrations where effects begin to be noted in vitro. Further study is needed with a reformulated higher unit dose compound to determine the safety and efficacy of higher serum concentrations.

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

Abstract: 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 600 mg/m2 as a 10 min 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.

An open label, non-comparative phase II study of topotecan as salvage treatment for patients with soft tissue sarcoma.

Abstract: Background: The number of effective cytotoxic agents for the treatment of patients with metastatic soft tissue sarcoma (STS) is limited, especially when patients have failed anthracyline-based chemotherapy. Patients and methods: Between 1999 and 2000 a total of 16 patients with histologically proven STS progressing during or after first-line anthracycline-based chemotherapy were entered into this open-label, noncomparative study. Topotecan was administered as a 30-min infusion at a dosage of 1.5 mg/m2 on five consecutive days every 3 weeks. All patients had received an anthracycline- or ifosfamide-based first-line chemotherapy. Results: None of the 16 included patients achieved an objective response to topotecan. Six patients achieved stable disease (38%), lasting for at least 6 weeks in four patients (25%) and for less than 6 weeks in two patients (13%). Ten patients (62%) had progressive disease. The median time to progression was 79 days calculated from the start of topotecan therapy (range, 28–230). The treatment was well tolerated; however, both anemia and thrombopenia grade III/IV occurred in 25% of the patients as well as severe neutropenia in 69% of the patients. Nonhematologic toxicities grade III/IV such as diarrhea and severe bleeding occurred only in one patient each (6%). Discussion: Topotecan is well tolerated in anthracycline-resistant patients with metastatic STS, but no objective response has been observed in this trial.

Noninvasive Methods to Study Drug Distribution

Abstract: Positron emission tomography (PET) and nuclear magnetic resonance spectroscopy (MRS) are two techniques that allow the noninvasive monitoring of drug distribution in living systems (humans, animals), and dynamic contrast-enhanced magnetic resonance imaging (dMRI) provides noninvasive physiological information relevant for drug distribution. PET yields series of cross-sectional images that can be used to monitor the absolute radioactivity concentrations in tissues pixel-by-pixel, but does not allow direct identification of each of the products present. MRS produces spectra showing changes in the concentration of both the parent drug and of the metabolites separately for a sensitive volume, but does not provide a simple means for measuring absolute concentrations. dMRI, which measures the changes in the rates of relaxation of water, proportional to the concentrations of the contrast agent (usually Gd-DTPA), readily allows the determination of functional changes in cross-sectional images down to a pixel-by-pixel level. All of these methods are of special interest to evaluate the amounts of drug that can reach the target tissue, penetrate it, remain present at such targets for a sufficient length of time, and how they are metabolized at the target site. Such information may be of particular interest in the study of solid malignant tumors and may become very relevant for determining better treatment strategies. This article presents examples of successful studies of tissue pharmacokinetics with MRS and dMRI. The following article is devoted to PET.

Phase II trial and pharmacokinetic study of thalidomide in patients with metastatic colorectal cancer.

Abstract: Introduction. This study was designed to estimate the percentage of objective tumor responses, toxicity profile, and obtain additional information about the plasma pharmacokinetics of thalidomide in patients with refractory and progressing metastatic colorectal cancer. Study design. This phase II clinical trial was conducted according to the two-stage Simon method with the inclusion of consecutive patients. The study protocol was approved by the Institutional Review Board (IRB) of the Academic Hospital (HCPA) of the Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Patients and methods. Seventeen patients with previously treated, refractory progressive metastatic colorectal cancer were eligible. Six patients had prior radiotherapy. The patients had a median of one previous chemotherapy regimen. Patients were initially treated with 200 mg/day of thalidomide with an increase in dose by 200 mg/day every 2 weeks until a final daily dose of 800 mg/day was achieved. Patients were evaluated every 8 weeks for response by radiographic criteria. Plasma pharmacokinetics studies were performed in four patients at 200 mg level and in one patient at 600 mg during the first 24 h. Main outcome measures and results. A total of 17 patients were accrued, all of them being evaluable for toxicity and 14 for response. Thalidomide was well tolerated, with constipation, somnolence, dizziness, and dry mouth being the major toxicities. There were no objective response or stable disease. The median survival was 3.6 months. Single-agent thalidomide is a generally well-tolerated drug that showed no antitumor activity in patients with advanced pretreated metastatic colorectal cancer. Although thalidomide did not show antitumor activity in this patient population, future studies of this agent in patients at initial stages of the disease (when its antiangiogenic properties may be more relevant to disease progression) could be considered.

An Overview on the Antileukemic Potential of D-homo-aza- and Respective 17β-Acetamido-Steroidal Alkylating Esters

Abstract: In order to reduce toxicity and to increase antineoplastic activity, steroid molecules were utilized as biological vectors for chemotherapeutic agents. Several modified steroid compounds as 17β-acetamido and D-homo-aza steroids that contain the NHCO group outside or inside D steroid ring, respectively, were used in the synthesis of steroidal esters carrying alkylating moieties. As it has been reported previously, several of these compounds produced important both antileukemic and antitumor results. In this work, we comparatively study, evaluate, and conclude on the acute toxicity on mice, the in vivo antileukemic activity against P388 and L1210 murine leukemias, as well the in vitro antileukemic effect on three well established human leukemia cell lines (K562, MOLT-4, ML-1) of eight D-homo-aza-steroidal (HASE) and the corresponding steroidal 17β-amido-esters (SAE) of three alkylating molecules. The compound screening indicated that HASE induced lower acute toxicity and significant higher antileukemic effect than SAE, both in vivo and in vitro. Furthermore, the structure of the homo-aza-steroidal vector seems to be a determinant of the toxicity and antineoplastic activity of the esters. Conclusively, HASE presented low acute toxicity but significant high antileukemic activity. These results point out that HASE may be of important therapeutic efficacy in the treatment of leukemia in humans.

A phase I clinical trial of spicamycin derivative KRN5500 (NSC 650426) using a phase I accelerated titration "2B" design.

Abstract: 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 randomized phase II evaluation of bryostatin-1 (NSC #339555) in recurrent or persistent platinum-sensitive ovarian cancer: a Gynecologic Oncology Group Study.

Abstract: Objectives. The Gynecologic Oncology Group (GOG) performed a randomized phase II study to determine the antitumor activity and toxicity of two different schedules of bryostatin-1 administration in patients with recurrent or persistent platinum-sensitive epithelial ovarian cancer or primary peritoneal carcinoma. Methods. Eligible patients were randomized to receive either bryostatin-1 25μg/m2 as a 1h infusion weekly for 3 weeks followed by a 1-week rest (Regimen I) or bryostatin-1 120μg/m2 as a 72h continuous infusion every 2 weeks (Regimen II). Results. Fifty-five patients were enrolled on this study. There was one durable response among 27 eligible patients (response rate=3.7%) on Regimen II and no responses in the 27 eligible patients on Regimen I. Nineteen patients (eleven on Regimen I and eight on Regimen II) had stable disease. The most common adverse event was myalgia, with 12 of 27 patients (44%) on each regimen experiencing some degree of myalgia. There were no other significant toxicities on either treatment arm. Conclusions. Both of these schedules and doses of bryostatin-1 are inactive as single agents in previously treated epithelial ovarian cancer.

Quinolizidinyl derivatives of iminodibenzyl and phenothiazine as multidrug resistance modulators in ovarian cancer cells

Abstract: The development of multidrug-resistance (MDR) in neoplastic cells is often responsible for the therapy failure and poor outcome of a number of human cancers. MDR may be associated with the expression of the multidrug transporter glycoprotein p170, encoded by the MDR1 gene, which acts as an ATP-dependent efflux pump by reducing the intracellular accumulation of some cytotoxic agents. A variety of iminodibenzyl and phenothiazine derivatives, characterized by the presence of a bicyclic, strongly basic, and highly lipophilic quinolizidine nucleus, were synthesized to investigate their ability to modulate the MDR phenotype. A set of 10 of them (named 1–10), bearing quinolizidine moiety linked through different connecting chains, were tested as chemoresistance-reversing agents on doxorubicin-resistant ovarian cancer cells (A2780-DX3). A 51-fold resistance to doxorubicin was reported in the A2780-DX3 compared to the parental sensitive A2780 WT with mean IC50 values of 0.02 and 1.02 μM, respectively. Moreover, overexpression of the glycoprotein p170 in the resistant cell line was detected by Western blot analysis. By cytotoxicity assays and time-course experiments, different treatment schedules with resistance modulators (including clomipramine as reference drug) and doxorubicin were taken into account. The 16 h exposure of cells to 1 μM of modulator before doxorubicin demonstrated to be superior in sensitizing the resistant cell line. In particular, compounds 8, 7, 10, and 4 increasingly potentiated doxorubicin cytotoxicity, up to 5.6-fold in A2780-DX3 cells. The present results suggest promising indications for further development of these compounds as chemosensitizing drugs.