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2509 Background: TGF-β plays a key role in regulating the tumor microenvironment. Emerging evidence suggests TGF-β is a key activator of cancer-associated fibroblasts, leading to fibrotic network development and immune exclusion. Preclinical data in murine models showed that TGF-β blockade alleviates intratumoral fibrosis, augmenting the efficacy of PD-1 immunotherapy. NIS793 is a human IgG2 mAb that binds to TGF-β. This study investigates NIS793 + spartalizumab in pts with advanced solid tumors. Methods: Pts initially received NIS793 (0.3–1 mg/kg Q3W) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 + spartalizumab (NIS793 0.3–30 mg/kg Q3W + spartalizumab 300 mg Q3W; or NIS793 20–30 mg/kg Q2W + spartalizumab 400 mg Q4W) in pts with/without prior anti-PD-(L)1 therapy. In dose expansion, pts with non-small cell lung cancer (NSCLC) resistant to prior anti-PD-(L)1 or pts with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE). Paired tumor biopsies were required from all pts. The primary objectives were to characterize safety and tolerability of the combination and determine the RDE. Results: By December 1, 2020, 60 pts were treated in the dose-escalation phase, mainly with NIS793 + spartalizumab (n = 49), and 60 pts were treated in dose expansion (MSS-CRC: n = 40; NSCLC: n = 20). Two pts were still receiving treatment. No dose-limiting toxicities were observed, and the RDE was established as 30 mg/kg (2100 mg) NIS793 + 300 mg spartalizumab Q3W. Overall 50% pts experienced ≥1 treatment-related AE (TRAE). The most common were rash (n = 15/120), pruritus (n = 10/120), fatigue (n = 9/120), and nausea (n = 8/120). Grade 3/4 TRAEs occurred in 11% pts, with rash (3%) being the most common. Treatment-related serious AEs were reported in 8 pts; 6 were grade 3/4 in severity. No deaths occurred due to AEs; 3 (2.5%) pts discontinued due to AEs. PK for NIS793 was linearly dose proportional with no obvious correlation between exposure and response. Two pts achieved a partial response (PR; one confirmed in clear cell renal cell carcinoma and one unconfirmed in NSCLC) during dose escalation of the combination. Two confirmed PRs were achieved in the MSS-CRC dose-expansion group. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression and protein analyses in tumor biopsies displayed decreased TGF-β target genes, decreased TGF-β signatures and increased immune signatures suggesting modulation of the TGF-β pathway and preliminary evidence of biological activity. Conclusions: Data showing target engagement and TGF-β pathway inhibition supported the proof of mechanism of NIS793. The RDE of the combination was established and well tolerated in pts with advanced solid tumors. Clinical trial information: NCT02947165.

Purpose TrasGEX is a second-generation monoclonal antibody of trastuzumab, glyco-optimised to enhance antibody-dependent cellular cytotoxicity while fully retaining trastuzumab’s antigen-binding properties to human epidermal growth factor receptor 2 (HER2). A phase I dose-escalation study was conducted to establish the optimal TrasGEX dose and regimen for phase II studies and to define the safety, pharmacokinetics (PK) and preliminary antitumour activity of TrasGEX. Patients and methods A total of 37 patients with advanced HER2-positive carcinomas and progressive disease received TrasGEX intravenously every 3 weeks until disease progression in doses of 12–720 mg in a three-plus-three dose escalation design, including an expansion cohort at the highest dose. Results No dose limiting toxicity was observed, and no maximum tolerated dose was reached. Drug-related adverse events were mainly infusion-related reactions occurring during the first infusion in 51% of patients; all but two were mild-to-moderate. Compared with trastuzumab, the PK parameters were dose dependent, with a mean terminal half-life (t 1/2 ) of 263±99 hours for the 720 mg dose. Clinical benefit in 15 out of 30 (50%) evaluable patients included one ongoing complete response, two partial remissions lasting 16 and 77 weeks and disease stabilisation (SD) in 12 patients lasting a median (range) of 17 (7–26) weeks; three of them had SD of 24, 25 and 26 weeks, respectively. Conclusion TrasGEX was safe, well-tolerated and showed antitumour activity in 50% of evaluable patients, all with progressive disease at study entry. Infusions at an interval of 2–3 weeks should achieve clinically relevant trough levels for future studies (NCT01409343).

The aim of this phase I study was to identify a feasible dose and schedule for the combination of cisplatin and trabectedin. The regimen evaluated consisted of cisplatin at a fixed dose of 75 mg/m(2) 1-hour intravenous (i.v.) infusion followed by escalating doses of trabectedin 3-hour i.v. infusion, both administered on day 1 every 3 weeks (q3wks). Two dose-limiting toxicities (DLTs), grade 4 neutropenia longer than 7 days duration and grade 3 vomiting despite standard antiemetic therapy, occurred at the starting dose of trabectedin (0.75 mg/m(2)). The immediately lower dose (trabectedin 0.60 mg/m(2)) was evaluated in a total of 8 patients; no DLTs occurred and this was declared the recommended dose (RD). The safety profile of the combination at this dose and schedule was consistent with the known side effects of each agent alone: nausea, fatigue, transient transaminase elevations and neutropenia. No new or unexpected adverse reactions were observed. Two partial responses were reported at the RD in patients with pretreated ovarian cancer. Comparison with population pharmacokinetic data suggests a PK interaction between trabectedin and cisplatin leading to increased plasma exposure of trabectedin in the first 48 h, lower platinum clearance and longer half-life. In conclusion, although the trabectedin dose achieved with this combination was low (50 % of single-agent when given q3wks), this day 1 q3wks trabectedin plus cisplatin combination showed a feasible administration, a tolerable safety profile and some antitumor activity.

Background Upregulation of N-cadherin promotes dysregulated cell growth, motility, invasiveness, plus maintenance of vascular stability and is associated with cancer progression in several human tumour types. N-cadherin is expressed also on tumour cells and the anti-N-cadherin cyclic pentapeptide ADH-1, tested in the present study, can exert a direct antitumour effect. Patients and methods Adult patients with advanced solid malignancies expressing N-cadherin on tumour biopsies carried out in the previous 12 months received escalating i.v. doses of ADH-1 given weekly (initially for 3 of 4 weeks, then every week). Plasma pharmacokinetics (PK) was studied at cycle 1. Blood flow changes were assessed after first dosing in all patients treated in the initial regimen. Results In all, 129 patients were screened, 65 (50%) were N-cadherin positive, and 30 were enrolled. The doses ranged from 150 to 2400 mg/m2; no maximum tolerated dose was reached. Treatment was well tolerated with asthenia as the most frequent adverse event. Two patients with ovarian cancer showed prolonged disease stabilisation while one patient with fallopian tube carcinoma achieved a mixed response. PK was linear in the range of doses tested. Conclusion ADH-1 is the first anti-N-cadherin compound tested in humans. In N-cadherin-positive patients, ADH-1 showed an acceptable toxicity profile, linear PK and hints of antitumour activity in gynaecological cancers.

Background: BMS-310705, a water-soluble semi-synthetic analogue of epothilone B, was selected for clinical development because of its in vivo anti-tumour activity and toxicity profile similar to that of ixabepilone, currently the most extensively evaluated and promising epothilone B analogue. The improved solubility of BMS-310705 allowed a cremophore-free formulation that avoided the need for pre-medication. Patients and methods: Two schedules were tested, one with drug administrations on days (D) 1, 8 and 15 followed by 1-week's rest, the other with administrations on D1 and 8 (D1&8 schedule) followed by 1-week's rest. Treatment was given as a 15-min infusion without pre-medication against hypersensitivity. The plasma pharmacokinetics of BMS-310705 was studied in 30 patients. An accelerated titration design 2B was applied for dose escalations. Twenty-seven patients were accrued in the D1, 8, 15 and 32 in the D1&8 schedule. Results: The dose was escalated from 5–30 mg/m2/week with diarrhoea as dose-limiting toxicity; 15 and 20 mg/m2 were the recommended doses in the D1, 8, 15 and D1&8 schedule, respectively. Other frequent non-haematological toxicities were neurotoxicity, mainly paraesthesia, asthenia and myalgia. Preliminary results showed linear pharmacokinetics along the range of doses tested with a short half-life. Five objective responses were reported. Conclusions: Further clinical development of BMS-310705 might be worthwhile in solid tumours where ixabepilone or other epothilones are not indicated.

Purpose To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) in patients with advanced ovarian cancer refractory to or experiencing disease relapse after platinum- and taxane-based chemotherapy. Patients and Methods Fifty-nine patients from four institutions either resistant (n = 30) or sensitive (n = 29) to prior platinum and taxanes were treated with a 3-hour infusion of trabectedin every 3 weeks. Patients were monitored weekly for toxicity and restaged every two cycles for response. Response was assessed according to Response Evaluation Criteria in Solid Tumors Group. Results The peer-reviewed objective response rate in platinum-sensitive patients was 43% (95% CI, 23% to 65%) with an estimated median time to progression of 7.9 months (95% CI, 7.5 to 14.1 months); in platinum-resistant patients two partial responses were observed. Responses were durable for up to 12.9 months (median, 5 months). The predominant toxicities at the recommended dose of 1,300 μg/m2 were neutropenia, asthenia, and self-limited increase of aminotransferases never requiring treatment interruption. Conclusion Trabectedin administered as a 3-hour infusion at 1,300 μg/m2 is a safe new drug with promising activity in relapsed ovarian cancer, showing a 43% objective response rate in patients with platinum-sensitive disease, which favorably compares with other salvage treatments and warrants additional development either alone or in combination.

The association of doxorubicin (DOX) and paclitaxel (PTX) is very active in breast cancer. Unfortunately, PTX may potentiate the cardiotoxic effects of anthracyclines: it causes nonlinear disposition of DOX and its metabolites, leading to persistant of elevated plasma concentrations of the anthracyclines. However, this pharmacokinetic interference is not sufficient to explain the enhanced cardiotoxicity of the combination. Recent data suggest that PTX stimulates the conversion of DOX to cardiotoxic metabolites (namely doxorubicinol) inside cardiomyocytes. Docetaxel (DTX) does not have a major influence on DOX plasma concentration because it does not interfere with its elimination. Clinical data suggest that DTX may not enhance anthracycline cardiotoxicity, but patients seldom received a total anthracycline dose compatible with increased risk. Furthermore, there are experimental data indicating that DTX can also stimulate the metabolism of DOX to toxic species in human heart.

Purpose Synergistic/additive cytotoxicity in tumor models and widespread applicability of fluoropyrimidines in solid tumors prompted the study of the combination of the mammalian target of rapamycin (mTOR) inhibitor, non-prodrug rapamycin analog ridaforolimus, with capecitabine. Patients and Methods Thirty-two adult patients were treated. Intravenous ridaforolimus was given once weekly for 3 weeks and capecitabine was given from days 1 to 14 every 4 weeks. Ridaforolimus was given at 25, 37.5, 50, or 75 mg with capecitabine at 1,650 mg/m2 or 1,800 mg/m2 divided into two daily doses. Pharmacokinetics of both drugs were determined during cycles 1 and 2. Pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) and wound tissue of the skin characterized pathways associated with the metabolism or disposition of fluoropyrimidines and mTOR and ERK signaling. Results Two recommended doses (RDs) were defined: 75 mg ridaforolimus/1,650 mg/m2 capecitabine and 50 mg ridaforolimus/1,800 mg/m2 capecitabine. Dose-limiting toxicities were stomatitis and skin rash. One patient achieved a partial response lasting 10 months and 10 of 29 evaluable patients had stable disease for ≥ 6 months. The only pharmacokinetic interaction was a ridaforolimus-induced increase in plasma exposure to fluorouracil. PBMC data suggested that prolonged exposure to capecitabine reduced the ridaforolimus inhibition of mTOR. Ridaforolimus influenced the metabolism of fluoropyrimidines and inhibited dihydropyrimidine dehydrogenase, behavior similar to that of rapamycin. Inhibition of the target thymidylate synthase by capecitabine was unaffected. mTOR and ERK signaling was inhibited in proliferating endothelial cells and was more pronounced at the RD with the larger amount of ridaforolimus. Conclusion Good tolerability, feasibility of prolonged treatment, antitumor activity, and favorable pharmacologic profile support further investigation of this combination.

The combination of trabectedin (T) and doxorubicin (D) was brought into clinical development in soft tissue sarcoma (STS) and advanced breast cancer (ABC) because of its in vitro and in vivo additive anti-tumour effect, the fact that there are no overlapping toxicities and the anti-tumour activity of T in those tumours. Feasibility and anti-tumour activity of T+D administered every 3 weeks were evaluated in 38 patients (STS=29, ABC=9) untreated for advanced disease. D was given at 60mg/m 2 and T at escalating doses from 600 to 800μg/m 2 , which was the maximum tolerated dose due to dose-limiting febrile neutropenia and asthenia. The recommended dose - given to 18 patients in total - was 700μg/m 2 T with 60mg/m 2 D. The pharmacokinetic profile of T and D at cycle 1 was analysed in 20 patients. The most common toxicities included a severe but reversible ASAT/ALAT increase (94%), nausea/vomiting, neutropenia, asthenia/fatigue, stomatitis. Partial response and stable disease were assessed in 18% and 56% of STS patients and in 55% and 33% of ABC patients. No pharmacokinetic interaction between T and D was observed. The lack of cumulative toxicity and related complications and the promising activity in STS support further development of T+D.

During tumor progression, cancer cells undergo dramatic changes in the expression profile of adhesion molecules resulting in detachment from original tissue and acquisition of a highly motile and invasive phenotype. A hallmark of this change, also referred to as the epithelial-mesenchymal transition, is the loss of E- (epithelial) cadherin and the de novo expression of N- (neural) cadherin adhesion molecules. N-cadherin promotes tumor cell survival, migration and invasion, and a high level of its expression is often associated with poor prognosis. N-cadherin is also expressed in endothelial cells and plays an essential role in the maturation and stabilization of normal vessels and tumor-associated angiogenic vessels. Increasing experimental evidence suggests that N-cadherin is a potential therapeutic target in cancer. A peptidic N-cadherin antagonist (ADH-1) has been developed and has entered clinical testing. In this review, the authors discuss the biochemical and functional features of N-cadherin, its potential role in cancer and angiogenesis, and summarize the preclinical and clinical results achieved with ADH-1.

2515 Background: TrasGEX is a glyco-optimized anti-HER2 antibody. It is designed to fully retain the antigen-binding properties of trastuzumab. It is manifold improved by fully human glycosylation and optimized for its antibody dependent cellular cytotoxicity (ADCC)-mediated anti-tumor efficacy for all FcɣRIIIa genotypes as well as for lower HER2 expressing tumors. In vitro studies showed an approximate 10 to 140 fold improvement of ADCC-mediated anti-tumor activity for TrasGEX depending on the level of HER2 expression and of the FcɣRIIIa receptor status. Methods: This is a phase I, dose-escalation trial of TrasGEX 12 to 720 mg IV flat-dose q3w in patients progressive with advanced or metastatic cancer for whom no effective standard treatment is available and ErbB2 (HER2) positivity (at least 1+). The primary objective of this first-in-human study was to determine the optimal dose and regimen of TrasGEX in the study population. Results: A total of 37 patients were treated with up to 720 mg TrasGEX IV flat...

2535 Background: O, a vascular-disrupting agent derived from combretastatin A4-phosphate, induces rapid tumor vascular shutdown via endothelial cell damage. Resistance to O may occur by surges in circulating endothelial progenitors (CEP) that repopulate the tumor vasculature. Experimental models suggest prolonged and synergistic antitumor activity when O is combined with VEGF-blockade, with reduction in CEP surge. This phase I study was performed to determine the maximum tolerated dose, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O combined with B. Methods: Patients (pts) with advanced treatment-refractory solid tumors, ECOG PS ≤1, and adequate organ function were eligible. O (mg/m²) was administered intravenously (IV) on day (d)1 with B (mg/kg) IV on d2 in 21d cycles (C). A Bayesian model informed dose escalation steps. PK sampling, dynamic contrast-enhanced ultrasound (DCE-US) for tumor perfusion, and CEP samples were collected. Results: 39 pts (M:F 10:29; median age 51 years [range 25-75]) were treated at 12 dose levels combining O [8 to 50mg/m2] with B [5, 10, or 15mg/kg]. Ovary (16/39, 41%) and colon (4/39, 10%) were the most common primary sites. No C1 dose-limiting toxicities occurred in 37 evaluable pts. Drug-related grade 3-4 treatment emergent adverse events (AE) were hypertension (6/39, 15%), intestinal perforation (2/39, 5%), headache (1/39, 3%), myocardial infarction (1/39, 3%), and pulmonary embolism (1/39, 3%). 36 pts (14 ovarian) were evaluable for response by RECIST 1.1. Antitumor activity was observed at O 20mg/m2+ B 10mg/kg and above, with confirmed partial responses in 2/14 pts with ovarian primary (14%), CA125 responses in 2 further ovary/endometrial cancers lasting ≥ 6 months, and stable disease in 15/36 pts (42%) lasting ≥ 6 months in 3 pts. PK indicated no interactions of O+B. Analyses of CEP levels post O and paired DCE-US data are ongoing. Conclusions: The maximum administered dose (MAD) was O 50mg/m2 with B 15mg/kg, with no dose-limiting toxicities and vascular toxicity that was manageable. Promising antitumor activity was observed at doses below the MAD and warrants further evaluation. Clinical trial information: NCT01193595.

3080 Background: O is a vascular-disrupting agent derived from combretastatin A4-phosphate that induces rapid but transient tumor vascular shutdown. In experimental models, the combination of O with VEGF-blockade induced more regressions than O alone. This phase I study was performed to determine the maximum tolerated dose (MTD), and assess the overall safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O plus B. Trial is funded by sanofi. Methods: Patients (pt) with advanced solid tumors, ECOG PS ≤1, and adequate organ function were eligible. Increasing doses of O (mg/m²) was administered intravenously (IV) on day (d) 1; B (5 or 10mg/kg) was administered IV on d2, in 21d cycles (C). A Bayesian design was applied to determine dose escalation steps and MTD. PK sampling was performed in C1 and C2. PD sampling for circulating endothelial cells (CEC) and progenitors (CEP) were performed throughout. Dynamic contrast-enhanced ultrasound (DCE-US) to assess tumor perfusion was performed before and after C1 and C2 dosing. Results: 25 pts (M:F 6:19; median age 49 years [range 27-75]) have been treated at 8 dose levels of O/B: 8/5 (3), 11.5/5 (4), 11.5/10 (3), 15.5/10 (3), 20/10 (3), 25/10 (3); 35/10 (3) and 42/10 (3). Ovarian cancer was the most frequent tumor type (n=11). Median Cs received was 3 (1 to 14). No DLTs were observed during C1. Drug-related grade (g) 3-4 adverse events (AE) included hypertension in 2 pts (8/5; 11.5/5) and ileal perforation in 1 pt with peritoneal carcinomatosis at laparotomy (11.5/10). A case of duodenal perforation was unlikely related (25/10). Two pts with ovarian cancer (11.5/5; 20/10) had confirmed partial responses (4.4 months (mo) and 7+ mo). 13/23 (57%) pts with ≥ 1 tumor assessment had stable disease (n=8; median 4.3 mo [1.8-9.5]; 5 ongoing). Data from cohorts 1 and 2 demonstrated no evidence of a PK interaction.17/25 patients demonstrated a peak in CEC, and 7/9 patients a peak in CEP. 4/7 DCE-US evaluable pts had >50% drop in tumor perfusion (AUC) at Day 8 of C1. Conclusions: O combined with B is well tolerated with early evidence of clinical activity. The MTD has not been reached (current dose level 50/10); cohorts of O combined with B at 15 mg/kg will be tested.

2517 Background: T is a synthetic compound originally derived from the marine organism Ecteinascidia turbinata with a mechanism of action based on DNA binding and involving the transcription-depend...

5050 Background: Based on synergism between mTOR inhibitor R and doxorubicin, a dose finding study of R with PLD was designed. Methods: Eligibility required: progressive advanced solid tumor, ≤ 2 p...

16527 Background: Preclinical studies demonstrate that the chimeric α5β1 integrin antibody volociximab inhibits tumor angiogenesis by blocking binding of activated vascular endothelial cells to fib...

13123 Background: Both gefitinib and paclitaxel are metabolized by CYP3A4, thus co-administration may result in a pharmacokinetic interaction (Miller V.A. et al. JCO 2003, 21:2094–2100). Paclitaxel is formulated in Cremophor EL (crEL), which also has the potential for pharmacokinetic interactions by either altering protein binding or inhibition of P-glycoprotein transporter systems (Gelderblom H. et al. EJC 2001, 37:1590–1598). Gefitinib is a high extraction ratio drug so changes in protein binding are not a concern, but inhibition of P-glycoprotein transporter systems could change gefitinib’s absorption profile. Methods: In a Phase II study, 17 patients (pts) with metastatic breast cancer received paclitaxel (100 mg/m2 on days 8, 15 q21) with gefitinib (250 mg daily, from day 1 to day 15). Blood samples were collected to measure plasma concentrations of gefitinib on days 7, 8, and 15 from six pts at pre-dose and at 3, 7 and 25 hours after gefitinib administration. The AUC at steady-state (AUCss) was calculated by the linear trapezoidal rule using WinNonlin and the minimum concentration at steady-state (Css, min) was taken directly from the data. Results: The effect of paclitaxel or crEL on the exposure to gefitinib was assessed by comparing the AUCss and Css,min on days 8 and 15 in the presence of paclitaxel to those on day 7 when gefitinib was alone. The geometric mean AUCss increased by 30 to 42% and Css,min by 28 to 58% in the presence of paclitaxel. Individual ratios of days 8 and 15 to day 7 also showed a trend to be greater than 1.0, further indicating an increase in exposure to gefitinib in the presence of paclitaxel. Conclusions: Steady state exposure to gefitinib increased by about 30 to 40% in the presence of paclitaxel. As the increase on day 15 was similar to that on day 8, the effect of paclitaxel appears to be transient, and would be unlikely to affect the safety profile of 250 mg gefitinib when in combination with paclitaxel compared to gefitinib monotherapy. [Table: see text]

3065 Background: AP23573 is a novel mTOR inhibitor with anti-tumor activity in Phase1 and 2 trials. In vitro, AP23573 is at least additive with chemotherapy agents including 5FU. CAPE is activated to 5FU by thymidine phosphorylase which may be highly expressed in tumors and correlates with progression through angiogenic mechanisms controlled by mTOR. Given the potential for a positive interaction, this trial studied the combination of AP23573 and CAPE in adult patients with solid tumors. Methods: Starting doses were: AP23573 25 mg i.v. on Days 1, 8, and 15 of a 28-day cycle, and CAPE 1650 mg/m2 p.o. daily on Days 1–14. Planned PK and PD studies include analysis of plasma VEGF, PBMC, skin, and tumor samples for effects on pathways associated with mTOR and on the metabolism of CAPE and fluoropyrimidines. Dose limiting toxicity (DLT) was defined as: febrile neutropenia; neutrophils 6/L for ≥ 5 days; ≥ Grade 3 (CTC) thrombocytopenia; non-haematological toxicities ≥ Grade 2 (diarrhea, cardiac or renal); or missing two consecutive weekly doses due to any toxicity. Results: 15 patients have been treated. Three dose levels of weekly AP23573 (25, 37.5 and 50 mg) were completed without DLT. Treatment-related toxicity was mostly mild or moderate (≤ grade 2), with mucositis/stomatitis the most frequent. Anti-tumor activity included a partial response in a case of endometrial cancer, and stable disease > 4 months in 3 cases (1 renal, 1 uterine and 1 head & neck cancer). AP23573 did not affect the PK of CAPE or 5FU but a trend toward a decreased exposure to the catabolite 5-FuH2 was apparent in the presence of AP23573. In keeping with this observation, the activity of dihydro-pyridine-dehydrogenase gradually decreased to 60% of that before AP23573. This decrease was not associated with reduced tolerability. Conclusions: The combination of AP23573 with CAPE is safe with initial indications of anti-tumor activity. This is the first description of a feasible combination of an mTOR inhibitor with an anti-metabolite. Additional dose levels of AP23573 (75 mg) and CAPE (1850 mg/m2/day) are ongoing and PK and PD studies are continuing. [Table: see text]

3042 Background: N-cad is a cell adhesion molecule expressed by vascular endothelium and tumor cells of invasive tumors. ADH-1, a cyclic pentapeptide, antagonizes N-cad, causing rapid tumor vascular disruption and apoptosis in preclinical models. We report results from a Phase I study of weekly doses of intravenous ADH-1 given to patients with N-cad+ solid tumors, to evaluate safety, PK, antitumor activity, and effect of ADH-1 on tumor vasculature assessed by DCE-MRI. Methods: ADH-1 starting dose was 150 mg/m2 administered weekly for 3 W in 28 D cycles. DCE-MRI was performed to assess changes in tumor perfusion 90 mins after the first dose of ADH-1, and repeated on D 15 if no changes were noted. Following the 3rd dose level (DL 3, 600 mg/m2 ), the schedule was amended to weekly ADH-1 without interruption, in 21 D cycles. Results: 55 pts with refractory solid tumors were screened, 56% were N-cad+ [screened/N-cad+: GYN 16/21 (Ovarian 13/17), GI 5/14, breast 2/6, renal 5/5, head & neck 2/3, others 2/6]. 13 pts (5 males, median age 53 yrs.) received 20 cycles of ADH-1 by bolus injection at 150, 300 and 600 mg/m2/weekly ×3 W Q21–28 D. No DLTs have occurred to date. No pts have experienced > grade 2 study drug related AEs. One pt, with fallopian tube ca. had a mixed response. There was a 30% reduction in retroperitoneal nodal disease at the end of cycle 3, and a 37% reduction at the end of Cy 4. However, new bone lesions were also noted at the end of cycle 4 assessment. Tumor blood flow reduction of ≥40% was noted in this patient, and she also reported pain in the region of the tumor following multiple doses of ADH-1. PK parameters are available for the first 3 DLs (150, 300, and 600 mg/m2): mean Cmax 22.1, 37.0, and 50.8μg/mL, respectively; AUCinf 24.3, 60.6, and 110.3 h·μg/mL; Vss 12.6, 15.1, and 16.3 L/m2; and T1/2 1.8, 2.7, and 2.4hr. Conclusions: ADH-1 has been well tolerated in 4 dose levels tested to date, dose escalation is proceeding. No DLTs have occurred and the MTD has not been reached. Anti-tumor activity has been noted. Updated clinical, PK and PD results will be presented. [Table: see text]

10599 Background: The epidermal growth factor receptor (EGFR) may be overexpressed in breast cancer. Inhibition of EGFR signaling by gefitinib (Iressa) enhances the in vitro antitumor activity of many cytotoxic drugs including paclitaxel. Methods: In this phase II study patients (pts) with measurable metastatic breast cancer and maximum prior exposure to two chemotherapies were randomized to paclitaxel (100 mg/m2 on days 1, 8 q21) and continuous gefitinib, 250 mg daily for 21 days (arm A); or paclitaxel (100 mg/m2 on days 8, 15 q21) with gefitinib 250 mg daily from day 1 to 15 (arm B). Therapy continued for at least 4 cycles after best response. After 6 cycles, responding pts continued with gefitinib monotherapy until progression or unacceptable toxicity. Results: 16 pts in arm A and 17 in arm B were enrolled; 25 had visceral disease (12 in arm A and 13 in arm B). Median age was 53 years (range 29–70). All but one pt received prior anthracyclines and 9 also prior taxanes. Overall 17 pts responded to therapy (intent to treat analysis; arm A: 62.5%, 95% CI: 35.4–84.8%; arm B: 41.2%, 95% CI: 18.4–67.1%). Disease control (CR+PR+SD) was achieved in 81.3% of pts in arm A and 76.5% in arm B, with 10 and 6 pts who continued with gefitinib monotherapy after completing the combination schedule. Median time to progression was 250 (arm A) and 204 days (arm B), while median response duration was 212 (arm A) and 285 days (arm B). Tolerability was good with either schedule of gefitinib. Diarrhea was frequent (68.8% and 64.7%) and of grade 3–4 severity in 6% of pts in arm A and in arm B. Grade 3–4 neutropenia affected 6% and 12% of pts respectively, and 6% of pts in both arms had a grade 3–4 increase of AST and ALT. Other grade 1–2 adverse events included acneiform rash (100% in arm A and 58.8% in arm B), sensory neuropathy (68.8% and 58.8%), anemia (50.0% and 52.9%), neutropenia (25.0% and 17.6%) and myalgia (37.5% and 41.2%). Conclusions: The combination of paclitaxel with gefitinib given continuously or for 2 out of every 3 weeks is feasible and well tolerated. The discontinuous schedule caused less skin toxicity. The good antitumor activity deserves further studies to identify sensitive subgroups and mechanisms of sensitivity. IRESSA is a trademark of the AstraZeneca group of companies. [Table: see text]

PURPOSE: A pharmacokinetic interaction may cause increased cardiotoxicity of paclitaxel (PTX) and high cumulative dose of doxorubicin. We tested antitumor activity, tolerability, and pharmacokinetics of the lesser cardiotoxic epirubicin (EPI) and PTX (ET combination). PATIENTS AND METHODS: Twenty-seven women with untreated metastatic breast cancer, median age of 56 years, and prominent visceral involvement (74%) were studied. Three-weekly EPI (90 mg/m2) and PTX (200 mg/m2 over 3 hours) were given for a maximum nine cycles. EPI was administered 24 hours before PTX (E → T) in cycle 1, and 15 minutes before PTX (ET) thereafter. EPI, epirubicinol (EOL), EPI-glucuronide (EPI-glu), EOL-glucuronide (EOL-glu), PTX, and 6α-OH-PTX were measured in plasma and urine in 14 women. RESULTS: Patients received 205 cycles of ET and a median EPI dose of 720 mg/m2. Grade 4 neutropenia (49% of cycles) was the most frequent toxicity. Cardiac contractility was decreased in five patients. Mild congestive heart failure occurred in two (7.4%). Response rate was 76% (28% complete). Median overall survival was 29 months. On the basis of intrapatient comparison in the first 24 hours of E → T and ET cycles, PTX did not affect EPI disposition, but significantly increased plasma exposure to EOL (by 137%), EPI-glu (threefold) and EOL-glu (twofold). Urinary excretion of EPI dose went from 8.2% in E → T to 11.8% in ET cycles. Clearance of PTX was 30% slower in ET than E → T. ET cycles caused lower neutrophil nadir than E → T (644 ± 327 v 195 ± 91, P < .05) CONCLUSION: ET is feasible, devoid of excessive cardiac toxicity, and active. A reciprocal pharmacokinetic interference between the two drugs has pharmacodynamic consequences, and suggests a direct effect of PTX on EPI metabolism requiring ad hoc investigation.