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Background Current treatment options for PDAC are limited. While PD-1/PD-L1 antagonists have shown promising results in other cancer types, this approach has been ineffective in PDAC. In Cohort 1 of the COMBAT study, the dual combination of BL-8040 (a CXCR4 inhibitor) and Pembrolizumab was safe and showed a promising 7.5 mo OS in 2L patients. BL-8040 modified the TME by promoting infiltration of effector T cells and decreasing immune suppressor cells. Based on these encouraging results, as well as preclinical data supporting the combination of BL-8040, Pembrolizumab and chemotherapy, the study was expanded to include a combination arm (Cohort 2) composed of BL-8040, Pembrolizumab and chemotherapy (Onivyde/5-FU/LV). Here we report the preliminary safety and efficacy of BL-8040 in this expansion cohort. Methods Phase IIa study, Cohort 2, treatment regimen consists of 5 days BL-8040 priming monotherapy followed by combination treatment of Onivyde/5-FU/LV every 2 weeks, Pembrolizumab every 3 weeks and BL-8040 twice a week. Eligibility criteria includes metastatic PDAC subjects with measurable disease by RECIST1.1 that have progressed following first-line treatment with gemcitabine-based chemotherapy. Results This is a snapshot of Cohort 2 of the COMBAT study. As of September 2019, 22 patients have been enrolled, of which 15 are evaluable (i.e. received at least 1 dose of combination and have post-baseline CT). Median age 68, ECOG≤1 and 60% males. 15 SAEs were reported by 10 patients. 2 subjects were discontinued due to SAEs. Best Response by RECISTv1.1 for the evaluable population showed 4 partial response (PR) and 8 stable disease (SD) patients, a total of 12 subjects with disease control (DC) out of 15. Median PFS and OS were not reached. Notably all patients with PR and SD had an initial increase in CA 19-9 followed by a decrease. Tumor shrinkage began during the transient increase of CA 19-9. Conclusion Preliminary data from the ongoing COMBAT study Cohort 2 with the triple combination of BL-8040, Pembrolizumab and chemo, show promising ORR (4/15) and DC (12/15) results. Median PFS and OS have not yet been reached. Clinical trial identification NCT02826486. Legal entity responsible for the study The authors. Funding Biolinerx. Disclosure M. Hidalgo: Full / Part-time employment: Beth Israel Deaconess Medical Center; Full / Part-time employment: Harvard Medical School; Full / Part-time employment: Weill Cornell Medical College. V. Semenisty: Full / Part-time employment: Rambam Health Care Campus. B. Bockorny: Full / Part-time employment: Beth Israel Deaconess Medical Center; Research grant / Funding (institution): NanoView Biosciences. E. Borazanci: Full / Part-time employment: Honor-Health/TGen. D.D. von Hoff: Full / Part-time employment: Honor-Health/TGen. J. Feliu: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Seriver. M. Ponz Sarvise: Full / Part-time employment: Clinica Universidad de Navarra. D. Gutierrez Abad: Full / Part-time employment: Grupo Oncologia Fuenlabrada. A. Peled: Full / Part-time employment: Goldyne Savad Institute of Gene Therapy; Leadership role: Biokine Therapeutics Ltd. O. Bohana-Kashtan: Full / Part-time employment: Biolinerx. Y. Gozlan: Full / Part-time employment: Biolinerx. E. Sorani: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Biolinerx. M. Chaney: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. S. Kadosh: Full / Part-time employment: StatExcellence. A.V. Vainstein: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Biolinerx. T. Macarulla: Full / Part-time employment: Vall d´Hebron University Hospital.

17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin that binds to and inhibits the Hsp90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG.Patients with advanced solid tumors and adequate organ functions received CNF1010 by 1-h intravenous (IV) infusion, twice a week, 3 out of 4 weeks. Doses were escalated sequentially in single-patient (6 and 12 mg/m(2)/day) and three-to-six-patient (≥25 mg/m(2)/day) cohorts according to a modified Fibonacci's schema. Plasma pharmacokinetic (PK) profiles and biomarkers, including Hsp70 in PBMCs, HER-2 extracellular domain, and IGFBP2 in plasma, were performed.Thirty-five patients were treated at doses ranging from 6 to 225 mg/m(2). A total of 10 DLTs in nine patients (2 events of fatigue, 83 and 175 mg/m(2); shock, abdominal pain, ALT increased, increased transaminases, and pain in extremity at 175 mg/m(2); extremity pain, atrial fibrillation, and metabolic encephalopathy at 225 mg/m(2)) were noted. The PK profile of 17-AAG after the first dose appeared to be linear up to 175 mg/m(2), with a dose-proportional increase in C max and AUC0-inf. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects of CNF1010 at doses83 mg/m(2).The maximum tolerated dose was not formally established. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects. The CNF1010 clinical program is no longer being pursued due to the toxicity profile of the drug and the development of second-generation Hsp90 molecules.

SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies.SF1126 was administered IV days 1 and 4, weekly in 28day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained.Forty four patients were treated at 9 dose levels (90-1110 mg/m(2)/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m(2) (diarrhoea). Exposure measured by peak concentration (C(max)) and area under the time-concentration curve (AUC(0-)(t)) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m(2). The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m(2). A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling.SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.

Background AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). Patients and methods AT7519 was administered in a ‘3 + 3’ dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained. Results Twenty-eight patients were treated at seven dose levels (1.8–40 mg/m2/day). At 40 mg/m2/day, one patient developed hypotension and ST segment elevation. At 34 mg/m2/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m2. Conclusion AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.

Background: GDC-0032 is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant cancers. GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that GDC-0032 has enhanced activity against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines. Preclinical data also show enhanced antitumor activity when GDC-0032 is combined with fulvestrant. Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of GDC-0032 doses ranging from 6-9 mg QD in combination with fulvestrant 500mg q4wk (with loading dose of 500mg at day 1, 14 and 28) in a modified 3+3 design. A dose expansion cohort was conducted at the recommended Phase 2 dose of 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment of PI3K pathway inhibition by paired tumor biopsies and by FDG-PET, and anti-tumor activity by RECIST. Results: As of 1 Mar 2013, 17 patients were enrolled onto this study with the completion of dose escalation. No dose limiting toxicities (DLTs) were observed at either the 6 mg or 9 mg dose levels. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in ≥10% of patients, were diarrhea, hyperglycemia, stomatitis, fatigue, asthenia, decreased appetite, nausea, mucosal inflammation and rash. No observed apparent PK interactions were observed between GDC-0032 and fulvestrant. The median number of prior systemic therapies was 6. Metabolic partial responses via FDG-PET (≥ 20% decrease in mSUVmax) were observed in 8 out of 11 patients assessed (73%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg GDC-0032 dose levels. These include patients who have had prior treatment with fulvestrant. As of 29 May 2013, enrollment onto the dose escalation and expansion cohort has been completed (n = 27). Updated data on safety, pharmacodynamics, efficacy, and biomarker correlates will be presented. Conclusions: The combination of GDC-0032 and fulvestrant is a well-tolerated regimen with promising preliminary efficacy. GDC-0032 is being further investigated in combination with fulvestrant for patients with hormone receptor-positive advanced breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-3.

Two recent MPACT subanalyses (Chiorean et al. and Ramanathan et al. Ann Oncol. 2016) demonstrated evidence that decreases from baseline in carbohydrate antigen 19-9 (CA19-9) and tumor uptake of radioactively labeled glucose (18F-FDG) as measured by positron emission tomography (PET) imaging were each significantly associated with longer overall survival (OS) in patients who received first-line treatment with nab-paclitaxel plus gemcitabine or gemcitabine for metastatic pancreatic cancer [1, 2]. These modalities are complementary approaches to monitor treatment efficacy in most patients. However, we raised the question of whether tumor response measured by PET could predict outcome for a subset of patients (15%–20%) with pancreatic cancer who do not secrete elevated levels of CA19-9 [3, 4]. In the MPACT trial, more patients experienced a metabolic response (MR) measured by PET imaging than a tumor response measured by computed tomography. PET imaging may be particularly valuable to predict outcomes in patients without elevated baseline CA19-9 levels. We carried out a post hoc, pooled treatment-arm analysis of OS by PET response in patients without elevated CA19-9 levels at baseline (defined as

Background The aim of this study was to assess the feasibility of administering bizelesin, a cyclopropylpyrroloindole with extraordinarily high potency as a bifunctional DNA-damaging agent and selectivity for specific AT-rich DNA sequences, as a single i.v. bolus injection every 4 weeks in patients with advanced solid malignancies. The study also sought to determine the maximum tolerated dose (MTD) of bizelesin, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. Patients and methods Patients with advanced solid malignancies were treated with escalating doses of bizelesin as an i.v. bolus injection every 4 weeks. The selection of the specific starting dose, 0.1 µg/m2, which was equivalent to one-tenth the toxic dose low in dogs, factored in large interspecies differences in myelotoxicity as gauged using an ex vivo hematopoietic colony-forming assay. Due to concerns about the high potency of bizelesin and the large interspecies differences in toxicity, a conservative dose-escalation scheme was used for dose-level assignment to determine the MTD levels for both minimally pretreated (MP) andheavily pretreated (HP) patients. A variety of analytical assays were assessed to reliably measure bizelesin concentrations in plasma. Results Sixty-two patients were treated with 185 courses of bizelesin at eight dose levels ranging from 0.1 to 1.5 µg/m2. Myelosuppression, principally neutropenia that was always brief, was the most common toxicity observed. Thrombocytopenia and anemia were uncommon and severe non-hematological effects were not observed. Severe neutropenia alone and/or associated with fever was consistently experienced by HP and MP patients at doses exceeding 0.71 and 1.26 µg/m2, respectively. These doses also resulted in functionally non-cumulative myelosuppression as repetitive treatment was well-tolerated. A 40% reduction in measurable disease lasting 24 months was noted in a patient with advanced ovarian carcinoma. Various analytical methods were evaluated but none demonstrated the requisite sensitivity to reliably quantify the minute plasma concentrations of bizelesin and metabolites resulting from administering microgram quantities of drug. Conclusions The highly potent and unique cytotoxic agent, bizelesin can be feasibly administered to patients with advanced solid malignancies. The recommended doses for phase II studies of bizelesin as a bolus i.v. injection every 4 weeks are 0.71 and 1.26 µg/m2 in HP and MP patients, respectively. The characteristics of the myelosuppression, the paucity of severe toxicities with repetitive treatment, the preliminary antitumor activity noted, and, above all, its unique mechanism of action as a selective DNA-damaging agent and high potency, warrant disease-directed evaluations of bizelesin in solid and hematopoietic malignancies and consideration of its use as a cytotoxic in targeted conjugated therapeutics.

The ONYX-015 virus is a mutated adenovirus that in theory selectively replicates and induces cytolysis in tumor cells lacking functional p53. The present study investigated whether ONYX-015 viral infection alone or in combination with conventional chemotherapeutic agents could significantly increase apoptosis in human colon cancer cell lines, regardless of p53 status, compared to untreated cells. A pair of colon cancer cell lines that differ only in their p53 status (RKO with wild-type p53 and RKOp53 with deficient p53) was tested. Two chemotherapeutic agents, 5-fluorouracil (5-FU) and CPT-11, were tested in combination with ONYX-015. Final concentrations of these agents corresponded to peak plasma levels achievable in patients. ONYX-015 concentration was 10 p.f.u./cell. In RKO and RKOp53 cell lines, ONYX-015 viral infection alone or in combination with 5-FU or CPT-11 induced a significant increase in apoptosis compared to chemotherapeutic agents alone, regardless of p53 status. Moreover, the combination of ONYX-015 and chemotherapeutics induced more apoptosis than chemotherapeutics alone in the two colon cancer cell lines independently of their p53 status. We conclude that ONYX-015 virus infection alone or in combination with 5-FU or CPT-11 induced apoptosis in human colon cancer cell lines, independently of p53 status.

Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial. Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days. Patients had AML (n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression. Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed.

Vatalanib (PTK 787/ZK22584) is an oral poly-tyrosine kinase inhibitor with strong affinity for platelet-derived growth factor and vascular endothelial growth factor (VEGF) receptors. We conducted an open-label, phase II multicenter therapeutic trial investigating the efficacy and tolerability of vatalanib in patients with metastatic or advanced pancreatic cancer who failed first-line gemcitabine-based therapy. Vatalanib treatment consisted of a twice daily oral dosing using a “ramp-up schedule,” beginning with 250 mg bid during week 1,500 mg bid during week 2, and 750 mg bid on week three and thereafter. The primary objective of this study was to evaluate the 6-month survival rate. Sixty-seven patients were enrolled. The median age was 64, and 66 % (N = 43) had only one prior regimen. Common grade 3/4 adverse events included hypertension (20 %; N = 13), fatigue (17 %; N = 11), abdominal pain (17 %; N = 11), and elevated alkaline phosphatase (15 %; N = 10). Among the 65 evaluable patients, the 6-month survival rate was 29 % (95 % CI 18–41 %) and the median progression-free survival was 2 months. Fifteen patients survived 6 months or more. Two patients had objective partial responses, and 28 % of patients had stable disease. Changes in biomarkers including soluble VEGF and vascular endothelial growth factor receptor did not correlate with response to drug. Vatalanib was well tolerated as a second-line therapy and resulted in favorable 6-month survival rate in patients with metastatic pancreatic cancer, compared with historic controls.

Summary Background; Rhizoxin (NSC 332598) is a novel macrolide antitumor antibiotic that inhibits microtubule assembly and also depolymerizes preformed microtubules. In preclinical evaluations, rhizoxin demonstrated broad antitumor activity in vitro and in vivo including both vincristine- and vindesineresistant human lung cancers. Prolonged exposure schedules in xenograft models demonstrated optimal efficacy indicating schedule-dependent antitumor activity. The early phase I and II evaluations a five-minute bolus infusion schedule was studied, however, only modest anti-tumor activity was noted, possibly due to rapid systemic clearance. To overcome these limitations and to exploit the potential for scheduledependent behavior of rhizoxin, the feasibility of administering rhizoxin as a 72-hour continuous intravenous (i.v.) infusion was evaluated. Patients and methods: Patients with advanced solid malignancies were entered into this phase I study, in which both the infusion duration and dose of rhizoxin were increased. The starting dose was 0.2 mg/m 2 over 12 hours administered every 3 weeks. In each successive dose level, the dose and infusion duration were incrementally increased in a stepwise fashion. Once a 72-hour i.v. infusion duration was reached, rhizoxin dose-escalations alone continued until a maximum tolerated dose (MTD) was determined. Results: Nineteen patients were entered into the study. Rhizoxin was administered at doses ranging from 0.2 mg/m 2 i.v. over 12 hours to 2.4 mg/m 2 i.v. over 72 hours every 3 weeks. The principal dose-limiting toxicities (DLT) were severe neutropenia and mucositis, and the incidence of DLT was unacceptably high at rhizoxin doses above 1.2 mg/m 2 , which was determined to be the MTD and dose recommended for phase II studies. At these dose levels, rhizoxin could not be detected in the plasma by a previously validated and sensitive high-performance liquid chromatography assay with a lower limit of detection of 1 ng/ml. No antitumor responses were observed. Conclusions: Rhizoxin can be safely administered using a 72-hour i.v. infusion schedule. The toxicity profile is similar to that observed previously using brief infusion schedules. Using this protracted i.v. infusion schedule the maximum tolerated dose is 1.2 mg/m 2 /72 hours.

This study evaluated the toxicity and efficacy of topical topitriol (calcitriol, 1,25-dihydroxyvitamin D3) to prevent chemotherapy-induced alopecia (CIA). Patients with breast cancer scheduled to receive FAC chemotherapy (5-fluorouracil, adriamycin and cyclophosphamide) were eligible for the study. Initially, the first six patients were randomized in a double-blind fashion to have received topitriol or placebo with all subsequent patients being treated with topitriol. Topitriol cream (0.0025 or 0.005%; 25 and 50 microg/g concentration) was administered topically twice a day. Three different doses and schedules of administration were evaluated including: 500 and 1000 microg daily for 7 days prior to chemotherapy, and 2000 microg daily for 5 days prior and 5 days post-chemotherapy. Fourteen patients were treated (12 with topitriol and two with placebo) at three different dose levels. All patients developed grade 2 alopecia between day 20 and 30 after chemotherapy, demonstrating the lack of efficacy of topical topitriol on this schedule of administration to prevent CIA. Eight patients exposed to topitriol developed a toxic maculopapular dermatitis in areas exposed to the drug. In conclusion, topical topitriol at the doses and schedules evaluated in this trial was ineffective to prevent CIA and induced a local dermatitis in areas exposed to the drug.

Summary Background: The ras gene product regulates transduction of growth-proliferative signals from the membrane to the nucleus. Mutationally-activated Ras is the oncogene most frequently found in human tumors. In order to perform its function in cell signaling, Ras must be farnesylated on the CAAX motif present on the carboxyl terminus of the ras protein. This reaction is catalysed by farnesyl protein transferase. In the present study, SCH 66336, an orally bioavailable nonpeptide tricyclic farnesyltransferase inhibitor, was tested against a large variety of human tumors to define its preclinical activity profile, utilizing the human tumor cloning assay. Materials and methods: A soft agar cloning assay was used to determine the in vitro effects of SCH 66336 against primary human tumor specimens taken directly from patients. A total of 70 evaluable specimens were exposed to SCH 66336 for 14day continuous exposure at concentrations ranging from 0.1 to 2.5 uM. In vitro responses were defined as an inhibition ^ 50% of human tumor colony forming units at a given concentration. Results: There was a positive relationship between concentration and response to SCH 66336. With the highest concentration (2.5 uM), response was demonstrated in 50% (three of six) of breast tumors, 40% (6 of 15) of ovarian tumors, and 38% (5 of 13) of non-small-cell lung tumor colony forming units. Among the 69 specimens tested at the concentration of 2.5 uM, SCH 66336 had activity in 27% of tumor specimens that were resistant to doxorubicin, 38% of tumor specimens resistant to cisplatin, 33% of tumor specimens resistant to paclitaxel, and 27% of tumor specimens resistant to etoposide. Conclusions: The broad spectrum of soft agar growth inhibition by SCH 66336 in the human tumor cloning assay, and its efficacy at physiologically relevant concentrations in animal models, suggest that SCH 66336 may deserve future clinical trials in patients with ovarian, breast and non-small-cell lung cancer.

Purpose: This study was undertaken to evaluate the feasibility of administering docetaxel (Taxotere; Rhone-Poufenc-Rorer) as a one-hour intravenous (i.v.) infusion on day I combined with 5-fluorouracil (5-FU) as a bolus i.v. injection for five (days I 5) or three (days 1-3) consecutive days every four weeks. Patients and methods: Thirty-seven patients with advanced solid malignancies were treated with 115 total courses involving seven dose levels of the two regimens of docetaxel and 5-FU (docetaxel/5-FU [mg/m 2 ] mg/m 2 /d]). In an effort to reduce fluid retention and hypersensitivity phenomena related to docetaxel, patients received premedication with dexamethasone 8 mg orally twice daily for three consecutive days beginning 24 hours before treatment, Results Severe (grade 4) neutropenia lasting longer than seven days with or without fever and/or severe mucositis, precluded further dose escalation above docetaxel 60 mg/m 2 on day I and 5-FU 300 mg/m 2 /day administered on days 1-5 every four weeks. The rates of these toxic effects were also unacceptably high above docetaxel 60 mg/m 2 on day 1 and 5-FU 300 mg/m 2 /day administered on days 1-3 every flour weeks. Nine patients experienced various manifestations of fluid-retention that were potentially related to study drugs. However, neither treatment delay nor discontinuation of treatment was required. Nausea, vomiting, diarrhea, and fatigue. were mild to modest in severity and occurred infrequently ( < 10% of courses ). Two patients with metastatic breast cancer experienced complete responses and a partial response occurred in a patient with metastatic non-small-cell lung cancer. Conclusion: Based on the results of this study, the regimen of docetaxel 60 mg/m 2 on day I followed by 5-FU 300 mg/m 2 /d i.v. for three or five days every four weeks is well tolerated and these doses are recommended for further evaluations. The feasibility of administering docetaxel 60 mg/m 2 followed by 5-FU 300 mg/m 2 for three or five days every four weeks and the preliminary antitumor activity noted indicate that further disease-directed studies of docetaxel and 5-FU are warranted in patients with relevant solid malignancies.

Telomerase is an RNA-dependent polymerase that synthesizes telomeric DNA (TTAGGG)n repeats. The overall goal of our work was to establish human cancer models that can be used to design clinical trials with telomerase inhibitors. The objectives of this study were (1) to set up a human breast cancer system that allows evaluation of the effects of telomerase inhibitors in cultured cells using a non-amplified telomerase assay and (2) to test this system using two drugs (cisplatin and TMPyP4) that affect the telomerase expression in breast cancer cells in culture. We first compared the telomerase activity in a variety of human breast cancer cell lines to that of other tumour types using a new biotinylated-primer extension assay. Our method, based on a non-amplified primer extension assay shows the direct incorporation of 32P-labelled nucleotides induced by telomerase on human telomeric primers. The 32P-dGTP labelled telomerase-extended 5′-biotinylated (TTAGGG)3 primer can subsequently be separated using streptavidin-coated magnetic beads. As compared to other non-amplified method, we showed that this procedure improved the characterization and the quantification of the banding pattern resulting from telomerase extension by reducing the radioactive background. Using this method, we observed that telomerase activity varies markedly in a panel of 39 human cancer cell lines. For example, MCF7 breast cancer cells in culture showed intermediate telomerase activity corresponding to 33.8 ± 3.4% of that of the HeLa cells (reference cell line). Similarly, the telomere length varied with each cell line (average: 6.24 ± 6.16). No correlation between the level of telomerase and telomere length was observed, suggesting that a high processivity is not required to maintain telomeres and that, in some cell lines, another mechanism of telomere elongation can maintain telomere length. From this study, we selected MCF7 and MX1 models that showed reproducible telomerase activity and a relatively limited telomere length for the testing of potential telomere–telomerase interacting agents. Using cisplatin and a new porphyrin-derived compound TMPyP4, we showed that our model was able to detect a down-regulation of the telomerase activity in MCF7 cells in culture and in a human MX1 tumour xenografts. Based on these results, a breast cancer model for evaluating telomerase and telomere interactive agents is proposed. © 1999 Cancer Research Campaign

Hydroxyurea (HU) increases extrachromosomal DNA elimination in tumor cell lines. The c-myc oncogene is one of the many relevant amplified genes contained within the extrachromosomal DNA compartment. Spontaneous loss of amplified copies of c-myc induces terminal differentiation and apoptosis in the human HL-60 leukemia cell lines. In the present study, we evaluate HU's ability to induce apoptosis by eliminating extrachromosomally located c-myc oncogene in human tumor cell lines. The consequences of eliminating extrachromosomal DNA by HU were explored in two different cell lines using the TdT assay and acridine orange/ethidium bromide labeling. COLO 320 clone 3 and COLO 320 clone 21 cell lines contain the same number of amplified copies of c-myc oncogene, but located respectively on extrachromosomal DNA, and intrachromosomally in homogeneously staining regions. HU induced apoptosis in the COLO 320 clone 3 cell line by a time and concentration dependent mechanism but could not induce apoptosis in the COLO 320 clone 21 cell line. These results suggested that HU-induced apoptosis in COLO 320 cell lines depends on elimination of extrachromosomal amplified copies of the c-myc oncogene. The ability of HU to eliminate extrachromosomally amplified copies of the c-myc oncogene and to induce apoptosis should be considered when targeting malignancies with amplification of the c-myc oncogene in an extrachromosomal site.

Background Ecteinascidin-743 (ET-743), a member of the ecteinascidin family selected for clinical development, is a tetrahydroisoquinolone alkaloid isolated from the marine ascidian, Ecteinascidia turbinata. This novel compound is a minor groove binding, guanine-specific alkylating agent which also interacts with the microtubule network and blocks cell cycle progression at late S/G2. Materials and methods A soft agar cloning assay was used to determine the in vitro effects of ET-743 against primary human tumor specimens taken directly from patients. A total of 93 evaluable specimens were exposed to ET-743 for one-hour (n = 25) and/or 14-day continuous exposure (n = 92) at concentrations ranging from 0.1 nM to 1 microM. In vitro responses were defined as an inhibition > or = 50% of human tumor colony forming units at a given concentration. Results One-hour exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM induced in vitro responses in 0% (0/17), 6% (1/17), 16% (4/25), 13% (1/8), and 25% (2/8) of specimens, respectively. Continuous exposure to ET-743 at concentrations of 0.1 nM, 1 nM, 10 nM, 100 nM and 1 microM, inhibited 0% (0/16), 13% (2/16), 49% (44/90), 62% (47/76), and 77% (58/75) of tumor specimens, respectively. Tumor-specific responses and concentration-dependent relationships were observed with a continuous exposure to ET-743. At 100 nM, the compound inhibited 79% (11/14) breast, 69% (9/13) non-small-cell lung, 58% (7/12) ovary, and 88% (7/8) melanoma specimens. At 1 microM, ET-743 inhibited 100% (14/14) breast specimens, 85% (11/13) non-small-cell lung, 67% (8/12) ovary and 86% (6/7) melanoma specimens. Activity of ET-743 at and above 10 nM was also observed against sarcoma and kidney tumors. At 10 nM concentration and continuous exposure ET-743 demonstrated incomplete cross-resistance with paclitaxel, alkylating agents, doxorubicin and cisplatin. Conclusions Our data from the cloning assay indicate that the duration of exposure to ET-743 is an important factor in human tumors. Therefore, long-term exposure to ET-743 may be preferred in future clinical trials. The activity of ET-743 in breast, non-small-cell lung, and ovarian cancers as well as in melanoma may deserve further clinical evaluations. The potential of ET-743 in sarcoma and renal tumors might also be considered. In addition, our data indicate that a plasma concentration of 100 nM of ET-743 must be considered as a target during the clinical development of the compound; also the concept of continuous/protracted exposure in clinical trials with ET-743 has to be taken into account.

Mitoguazone (methylglyoxal bisguanylhydrazone, methyl-GAG or MGBG) is a synthetic polycarbonyl derivative with activity in patients with Hodgkin's and non-Hodgkin's lymphoma, head and neck cancer, prostate cancer, and esophageal cancer. Mitoguazone has also recently been documented to have activity in patients with AIDS-related lymphoma. Among anticancer drugs, mitoguazone has a unique mechanism of action via interference with the polyamine biosynthetic pathway. Polyamines stabilize DNA structure by non-covalent cross-bridging between phosphate groups on opposite strands. In addition, mitoguazone causes uncoupling of oxidative phosphorylation. In this study, the ability of mitoguazone to induce apoptosis by inhibiting the polyamine pathway was assessed in three Burkitt's lymphoma cell lines (Raji, Ramos and Daudi) and one prostate carcinoma cell line (MPC 3). Additional evaluations were performed in two human breast cancer cell lines (MCF7 with wild-type p53 and VM4K with mutated p53) to determine whether the p53 tumor suppressor gene was required for efficient apoptosis induction. The present study demonstrated that mitoguazone induces apoptosis in all the different human cancer cell lines tested in a concentration- and time-dependent way, and triggers a p53-independent programmed cell death in the human breast cancer MCF7 cell line.

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks. PATIENTS AND METHODS Fifty-six courses of LU103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities. RESULTS Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax values than patients who did not, whereas nonhematologic DLTs were more related to dose. CONCLUSION The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU103793 on the schedule evaluated in this study.

Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivative that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical models. In this study investigating the pharmacokinetic and toxicity of brequinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three-week administration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; median performance status 1) received 69 courses of therapy. Six dose levels were explored, with cisplatin/ brequinar doses, respectively, of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2. The serum concentration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of brequinar indicate that the presence of 50, 60, and 75 mg/m2cisplatin did not change the protein binding and the pharmacokinetics of brequinar in any of the three brequinar-dose groups. Total cisplatin plasma pharmacokinetic followed a triphasic-shape curve and unbound cisplatin decayed at a very rapid rate. Since pharmacokinetic parameters for total cisplatin in this study were similar to those reported in the literature, the presence of brequinar is unlikely to alter the pharmacokinetics of cisplatin. Main dose-limiting toxicities included myelosuppression (including neutropenia and thrombocytopenia) and mucositis. Cisplatin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows that co-administration of brequinar and cisplatin does not affect the pharmacokinetic properties of either drug and that the MTDs of cisplatin/brequinar combinations are 60/860 mg/m2 or 75/650 mg/m2. From this study, we conclude that full dose of 75 mg/m2 cisplatin (day 1) can be administered with 650 mg/m2 brequinar (days 1, 8 and 15) without significant modifications of individual drug pharmacokinetic parameters.

Pancreatic cancer is a major cause of death from cancer in both men and women in the USA and Europe. The disease causes pain and has a significant impact on the performance status of the patient. In a randomized trial vs 5-fluorouracil, the novel nucleoside analogue gemcitabine (GEMZAR) has been shown to provide clinical benefit for patients (decreased pain and improved performance status) as well as to improve the time to tumour progression and survival for patients with the disease. There are also other new agents that are presented in this discussion, such as the multi-targeted antifolate MTA, capecitabine and the ONYX-015 adenovirus, which replicates in, and kills, only p53-abnormal cells, which have the potential to have an impact on this terrible disease.

Background Human corticotropin-releasing factor (hCRF) is an endogenous peptide responsible for the secretion and synthesis of corticosteroids. In animal models of peritumoral brain edema, hCRF has significant anti-edematous action. This effect, which appears to be independent of the release of adrenal steroids, appears mediated by a direct effect on endothelial cells. We conducted a feasibility and phase I study with hCRF given by continuous infusion to patients with brain metastasis. Patients and methods Peritumoral brain edema documented by MRI and the use of either no steroids or stable steroid doses for more than a week were required. MRIs were repeated at completion of infusion and estimations by dual echo-image sequence (Proton density and T2-weighted images) of the amount of peritumoral edema were performed. The study was performed in two stages. In the feasibility part, patients were randomized to receive either 0.66 or 1 microgram/kg/h of hCRF or placebo over 24 hours. The second part was a dose finding study of hCRF over 72 hours at escalating doses. Results Seventeen patients were enrolled; only one was receiving steroids (stable doses) at study entrance; dose-limiting toxicity (hypotension) was observed at 4 micrograms/kg/h x 72 hours in two out of four patients, while zero of five patients treated at 2 micrograms/kg/h developed dose-limiting toxicities. Flushing and hot flashes were also observed. Improvement of neurological symptoms and/or exam were seen in 10 patients. Only small changes were detected by MRI. Improvement in symptoms did not correlate with changes in cortisol levels, and changes in cortisol levels were not correlated with changes in peritumoral edema. Conclusions hCRF is well tolerated in doses up to 2 micrograms/kg/h by continuous infusion x 72 hours. Hypotension limits administration of higher doses. The observation of clinical benefit in the absence of corticosteroids suggests hCRF may be an alternative to steroids for the treatment of patients with peritumoral brain edema. Further exploration of this agent in efficacy studies is warranted.

Summary Background Telomerase is an important enzyme whose activity has been convincingly demonstrated in humans recently. It is required for maintenance of ends of chromosomes (telomeres) during cell division. Since its presence has been selectively demonstrated in dividing cells including tumor cells, it has generated considerable excitement as a potential anticancer strategy. Design In this article, we review the current relevant biology of the enzyme, the challenges encountered in the preclinical phase of target development and the current efforts that focus on telomeres and telomerase as therapeutic targets. We also speculate on the potential toxicities and mechanisms of resistance that may be encountered during use of such therapies.

Telomerase is an enzyme required by actively dividing cells to maintain the ends of chromosomes (telomeres). It is present in germline tissue, stem cells and cancer cells, but is repressed in somatic cells. Efforts are underway to exploit this selective expression of telomerase in cancer therapeutics. This review describes the status of telomerase research, which although at present predominantly preclinical, has the potential to enter clinical research.

The purpose of this study was to evaluate the diblock copolymer poly(DL-lactide)-block-methoxy polyethylene glycol as an i.v. delivery vehicle for paclitaxel. Nude mice were implanted s.c. with fragments of MV-522 lung carcinomas and treated with paclitaxel on a daily x 5 schedule when tumors were approximately 5 x 5 mm in size. Cremophor paclitaxel or polymeric micellar paclitaxel were given i.p. or i.v. at the maximum tolerated dose (Cremophor paclitaxel MTD: 20 mg/kg/day i.v. or i.p.; micellar paclitaxel MTD: 25 mg/kg/day i.v. or 100 mg/kg/day i.p.). The tumors were measured using callipers during the experiment and accurately weighted at the end. Two biodistribution studies were carried out. In one study, the nude mice were given micellar paclitaxel at a dose of 25 mg/kg i.v. or 100 mg/kg i.p. in another study, BDF-1 mice were given either micellar paclitaxel or Cremophor paclitaxel at a dose of 20 mg/kg i.v. The mice were sacrificed after a given time and the organs were harvested. Paclitaxel in the organs was extracted with acetonitrile and analyzed using HPLC. Tumor growth inhibitions of 98.5 and 98.7% were obtained from i.v. administered micellar paclitaxel and Cremophor paclitaxel at their MTDs, respectively. Micellar paclitaxel was more efficacious i.p. (98.7% tumor growth inhibition) than Cremophor paclitaxel i.p. (83.0% tumor growth inhibition) at their MTDs. The highest concentrations of paclitaxel were found in the liver after administration of paclitaxel formulations. Paclitaxel was also found in spleen, kidney, lung and blood, in order of decreasing concentration. The preliminary results indicate that polymeric micellar paclitaxel could be a clinically useful chemotherapeutic formulation.

The 55-kilodalton (kDa) protein from the E1B-region of adenovirus binds to and inactivates the p53 gene, which is mutated in half of human cancers. We have previously shown that the replication and cytopathogenicity of an E1B, 55-kDa gene-attenuated adenovirus, ONYX-015, is blocked by functional p53 in RKO and U20S carcinoma lines. We now report that normal human cells were highly resistant to ONYX-015-mediated, replication-dependent cytolysis. In contrast, a wide range of human tumor cells, including numerous carcinoma lines with either mutant or normal p53 gene sequences (exons 5-9), were efficiently destroyed. Antitumoral efficacy was documented following intratumoral or intravenous administration of ONYX-015 to nude mouse-human tumor xenografts; efficacy with ONYX-015 plus chemotherapy (cisplatin, 5-fluorouracil) was significantly greater than with either agent alone.

PURPOSE Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

Using vanadyl sulphate, sodium orthovanadate or bis(maltolato)oxovanadium (BMOV), Cruz TF, Morgan A, Min W (1995, Mol Cell Biochem 153: 161-166) have recently demonstrated the antineoplastic effects of vanadium in mice. In this study, the antineoplastic effects of BMOV against human tumour cell lines was confirmed, and this effect was shown to depend on the prolonged exposure of the cells to the drug. We have investigated a polymeric drug delivery system for the sustained delivery of BMOV as an antineoplastic agent in mice. The objective was to design and evaluate an injectable polymer-BMOV paste that would act as a drug implant for the slow but sustained release of BMOV in the mice. In vitro studies showed that the biodegradable polymer poly (Ghlr epsilon epsilon-caprolactone) (PCL) released BMOV in a sustained manner with rates of drug release increasing with increased loading of the drug in the polymer. In vivo studies showed that PCL-BMOV paste implants produced a concentration-dependent inhibition of MDAY-D2 tumour growth via systemic drug delivery. Further in vivo studies showed that 5% BMOV-loaded PCL (containing 20% methoxypolyethylene glycol) was effective in preventing tumour regrowth of resected RIF tumour masses in mice when the PCL-BMOV paste was applied to the resected site for localized drug delivery. The results confirm the potential of vanadium as an antineoplastic agent and show that the injectable PCL-BMOV formulation releases a chemotherapeutic dose of vanadium for the systemic treatment of whole tumours as well as the localized treatment of resected RIF tumours. Images Figure 3

Paclitaxel shows a broad clinical activity in ovarian, breast and non-small cell lung cancers. However, controversy remains about the respective effects of doses and schedules in paclitaxel cytotoxicity. This study was conducted to compare the cytotoxic activity of short-term (1 h) versus prolonged exposure (14 days) to paclitaxel in human cancer cells. A soft-agar cloning system assay was used to determine the in vitro effects of 0.025-25.0 microg/ml paclitaxel against cancer cells taken directly from patients. A decrease in tumor colony formation resulting from drug exposure was considered an in vitro response if survival of colonies was up to 50% of that in positive controls. Among 11 evaluable patients' biopsies, both short- and long-term exposure to paclitaxel had significant concentration-dependent effects on the growth inhibition of human cancer cells. With the 1 h exposure schedule, in vitro responses were observed in 9,18 and 64% of evaluable tumor specimens at final concentrations of 0.25, 2.5 and 25.0 microg/ml, respectively. With the prolonged exposure schedule, concentrations of 0.25, 2.5 and 25.0 microg/ml induced 27, 45 and 91 in vitro response rates, respectively. In those patients' biopsies prolonged exposure to paclitaxel induced significantly more in vitro tumor responses than 1 h administration (p < 0.01). Similar trends were observed in ovarian, breast and non-small cell lung cancers. Our data indicate that the duration of exposure to paclitaxel is an important factor in paclitaxel cytotoxicity in human tumors and suggest that long-term exposure may improve the antitumor activity of paclitaxel.

PURPOSE Topotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS Patients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. RESULTS Thirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point "t" [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function. CONCLUSION The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.

Summary Background Tecogalan sodium is an angiogenesis inhibitor isolated from a sulfated polysaccharide produced by the bacterium Arthrobacter. The antiangiogenic effect of tecogalan sodium is thought to be mediated by the inhibition of binding of basic fibroblast growth factor to cellular receptors. Patients and methods A phase I study was conducted in thirty-three patients with refractory malignancies, including AIDS-associated Kaposi's sarcoma Patients received a single i.v. infusion every three weeks with the infusion duration ranging from one to twenty-four hours. Seven different dosage levels were studied (125, 185, 240, 300, 390, 445, and 500 mg/m2). Results The primary dose-limiting toxicity was prolongation of the activated partial thromboplastin time with peak retimes being between 1.0–4.0 times the upper limit of normal. This toxicity was ameliorated at a given dose level by prolonging the infusion time. Other common toxicities included fever (40%) and rigors (31%) which were well controlled with acetaminophen and meperidine. The serum half-life of tecogalan sodium was between 1–1.5 hours and < 25% of unchanged drug was excreted in the urine. Conclusions The recommended phase II dose of tecogalan sodium on this schedule is 390 mg/m2 over 24 hours. Other schedules including continuous administration should be investigated to maximize the efficacy of this novel angiogenesis inhibitor.

The purpose of this study was to evaluate the feasibility of chronic oral administration of etoposide with granulocyte-macrophage colony-stimulating factor (GM-CSF) [sargramostim (Immunex)] coadministration or premedication; to estimate and compare the frequency of toxicities accompanying etoposide administration alone, etoposide/GM-CSF coadministration and etoposide with GM-CSF premedication. Thirty-nine patients with advanced treatment-refractory malignancies were enrolled to this study. Eligible patients were randomized to one of three treatment arms: daily oral etoposide alone for 21 days (arm A); daily oral etoposide for 21 days with GM-CSF, 250 micrograms/m2, s.c. twice daily for the first 10 days of etoposide administration (arm B); or daily oral etoposide for 21 days with GM-CSF twice daily for the sixth through second days preceding etoposide administration (arm C). Courses of treatment were repeated every 28 days. Etoposide dosages for each arm were 25, 50, 75 and 100 mg/m2/day. At least three patients were treated at each dosage level until dose-limiting toxicity was observed. Patients had twice weekly blood counts and weekly clinical examinations to assess toxicity. Patients with measurable or evaluable evidence of cancer were assessed for antitumor response after every other course of therapy. Nadir neutrophil counts at each dosage level were compared between treatment arms by non-parametric Wilcoxen rank sum tests. GM-CSF coadministration (arm B) or premedication (arm C) with daily chronic oral etoposide was feasible and did not lead to excessive hematological toxicity. Pairwise comparisons of neutrophil nadirs for the first course of therapy for each treatment arm did not demonstrate any significant differences and, at most, a slight trend favoring improved neutrophil nadirs was shown for arm C compared to arm A (p = 0.07). Dose intensity as measured by mean days of etoposide administered per patient for each arm suggested only slight improvement in etoposide tolerance for treatment arms B and C. The conclusion, GM-CSF can be safely administered to patients receiving chronic daily oral etoposide. It appears that GM-CSF provides no clinically useful improvement in granulocyte tolerance of therapy.

Interleukin-12 (IL-12) has important immunomodulatory effects on T and natural killer (NK) cells that might be exploited in anticancer treatment. Murine IL-12 models have shown antimetastatic and antitumor effects against murine tumors in vivo. Data on the effects of human IL-12 on human tumors are confined to 51Cr-release assay studies showing that IL-12 increases NK activity against cancer cells. We used a human tumor cloning assay (HTCA) to investigate the effects of human IL-12 on solid tumors taken directly from patients. The HTCA is suitable to test direct, as well as immune-mediated, antitumor effects of cytokines on heterogeneous cell preparations derived from fresh tumors. Single cell suspensions prepared from 193 tumors were continuously exposed (14 days) to 10, 100 and 1000 ng/ml of human IL-12 in a capillary HTCA. Seventy-four (38%) specimens were evaluable. Inhibition of tumor growth was observed in 35 specimens (47%; concentration-related in 33 cases), including cancers of the ovary, lung, prostate, breast, colon and kidney, as well as melanoma. Antitumor effect was observed in 10 (14%), 18 (24%) and 32 (43%) tumors, at 10, 100 and 1000 ng/ml of IL-12, respectively. One specimen (1%), a melanoma, showed stimulation of tumor proliferation only at 100 mg/ml of IL-12. Our results show that IL-12 has substantial in vitro activity against a variety of solid tumors taken directly from patients. Clinical trials of IL-12 in patients with solid tumors are warranted.

PURPOSE To assess the effect of gemcitabine in patients with metastatic pancreas cancer that had progressed despite prior treatment with 5-FU. PATIENTS AND METHODS Seventy-four patients were enrolled in this multicenter trial. Alleviation of cancer-related symptoms was the primary endpoint. Sixty-three patients completed a pain stabilization period and were treated with gemcitabine. Clinical Benefit Response was defined as a > or = 50% reduction in pain intensity, > or = 50% reduction in daily analgesic consumption, or > or = 20 point improvement in KPS that was sustained for > or = 4 consecutive weeks. RESULTS Seventeen of 63 pts (27.0%) attained a Clinical Benefit Response (95% CI: 16.0%-38.0%). The median duration of Clinical Benefit Response was 14 weeks (range: 4-69 weeks). Median survival for patients treated with gemcitabine was 3.85 months (range: 0.3-18.0+ months). Therapy was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. CONCLUSION Systematic assessment of subjective outcomes can be used to evaluate the clinical impact of new therapies for pancreas cancer, a highly symptomatic disease. Our findings suggest that gemcitabine is a useful palliative agent in patients with 5-FU-refractory pancreas cancer.

CPT-11 is a new agent with a unique mechanism of action, namely the inhibition of topoisomerase I. An examination of data from the laboratory reveals several leads which should be pursued in the clinic. A dose-response effect for CPT-11 activity has been noted in the human tumour cloning assay. CPT-11 has activity against breast and mesothelioma colony-forming units in a human tumour cloning assay, and has in vivo activity against a number of paediatric malignancies. Promising combinations in preclinical in vivo models include CPT-11/mitomycin C and CPT-11/cytosine arabinoside. There is incomplete cross-resistance among topoisomerase I inhibitors, suggesting that combinations of topoisomerase I inhibitors should be investigated. Several natural products have been identified which have potential to decrease CPT-11-induced diarrhoea. The level of carboxylesterase in a patient's tumour appears to be related to the in vitro activity of CPT-11, suggesting that measurement of carboxylesterase in a patient's tumour could be used to identify patients who are most likely to respond to treatment with CPT-11. These preclinical findings suggest substantial further clinical potential for CPT-11 in terms of decreased CPT-11-induced diarrhoea as well as increased antitumour activity, which should be explored in phase I and II studies.

PURPOSE A phase II study was undertaken to determine the efficacy of docetaxel in patients with metastatic malignant melanoma. PATIENTS AND METHODS Between June 1992 and March 1994, 40 patients with metastatic malignant melanoma and no prior chemotherapy were treated with docetaxel 100 mg/m2 administered intravenously over 1 hour every 21 days. None of the patients had brain metastasis. Toxicity and follow-up data are provided. RESULTS One patient had a histologically confirmed complete response that lasted for 14+ months. Four patients had partial responses, bringing the overall response rate to 12.5% (95% confidence interval [CI], 6% to 30%). A patient with a partial response had a single chest-wall metastasis and was rendered free of disease surgically after a maximal response to docetaxel and remained free of tumor recurrence after 18+ months. Tumor was stabilized in 22 patients. The overall median survival time was 13 months. The main hematologic toxicity was neutropenia, which was severe but transient. Peripheral neuropathy was the limiting nonhematologic toxicity in three patients. Other important toxicities included cutaneous toxicity, fluid retention, oral mucositis, and hypersensitivity reactions. Preadministration of dexamethasone and diphenhydramine reduced the incidence of hypersensitivity reactions, cutaneous toxicities, and fluid retention. CONCLUSION Docetaxel has definite but low-level activity against malignant melanoma. Further investigation of this drug should be conducted in multidrug combination programs.

PURPOSE To determine if a rapid 3H-uridine uptake assay using breast tumor cells from biopsy specimens could predict clinical response to fluorouracil (5FU) in patients with metastatic breast cancer. PATIENTS AND METHODS A double-blind prospective study was conducted of 60 patients with measurable, metastatic breast cancer who had failed to respond to at least one prior chemotherapy regimen. Patients received 5FU 300 mg/m2/d by continuous infusion and were monitored for response. Tumor cells from biopsy specimens were grown in microwells and exposed for 3 days to 0.1, 1.0, 10.0, and 100.00 micrograms/mL of 5FU on strips coated with drug and extracellular matrix. Cells were pulsed with 3H-uridine overnight. Incorporated radioactivity was compared for wells with and without drug. Results were available 4 days from specimen submission. RESULTS Of 45 eligible patients, 11 (24%) were not assessable in vitro. Nine patients were assessable in vitro, but not clinically. Of the remaining 25 patients, who were assessable both clinically and in vitro, there was one complete response (CR), five partial responses (PRs), five cases of stable disease, and 14 cases of progressive disease, for an objective response rate of 24%. Response in vitro was significantly correlated with clinical response (P = .002). Of six clinical responders, five also responded in vitro, for an assay sensitivity of 83%. Of 19 nonresponders, 17 were nonresponders in vitro, for a specificity of 89%. The positive predictive value of the test was 71% (five of seven), and the negative predictive value was 94% (17 of 18). CONCLUSION Results of an in vitro assay were significantly correlated with clinical response in patients with metastatic breast cancer treated with continuous infusion 5FU.

Ormaplatin is a platinum analog that was developed because of an altered toxicity profile and non-cross resistance to cisplatin in both in vitro and in vivo models. To determine the toxicities and maximum tolerated dose of ormaplatin on a daily times five schedule, patients with refractory solid tumors received ormaplatin on five consecutive days at nine dose levels ranging from 1.0 to 15.0 mg/m2/day. A total of 35 patients received 70 cycles of therapy. Nausea and vomiting and myelosuppression were moderate and not dose-limiting. Dose-limiting neurotoxicity, consisting of a sensory peripheral neuropathy, was seen in all five patients who received cumulative doses greater than or equal to 165 mg/m2. This neurotoxicity was symptomatic in all patients and caused significant functional impairment in four patients with inability to walk in two patients. A sensitive atomic absorption spectroscopy analysis performed for one patient at the 13.0 mg/m2/day dose level showed a Cpmax of 163 ng/ml and a t1/2 of 10.9 min for free platinum. A phase II dose could not be determined due to the onset of peripheral neuropathy at low cumulative doses and not at absolute dose levels.