Search

Aims Namitecan is a new camptothecan compound undergoing early clinical development. This study was initiated to build an integrated pharmacokinetic (PK) and pharmacodynamic (PD) population model of namitecan to guide future clinical development. Methods Plasma concentration–time data, neutrophils and thrombocytes were pooled from two phase 1 studies in 90 patients with advanced solid tumours, receiving namitecan as a 2 h infusion on days 1 and 8 every 3 weeks (D1,8) (n = 34), once every 3 weeks (D1) (n = 29) and on 3 consecutive days (D1–3) (n = 27). A linear three compartment PK model was coupled to a semiphysiological PD-model for neutrophils and thrombocytes. Data simulations were used to interrogate various dosing regimens and give dosing recommendations. Results Clearance was estimated to be 0.15 l h–1, with a long terminal half-life of 48 h. Body surface area was not associated with clearance, supporting flat-dosing of namitecan. A significant and clinically relevant association was found between namitecan area under the concentration–time curve (AUC) and the percentage drop of neutrophils (r2 = 0.51, P < 10−4) or thrombocytes (r2 = 0.49, P < 10−4). With a target for haematological dose-limiting toxicity of

Purpose: This is a first-in-human, phase I, dose-escalation study to determine the maximum tolerated dose (MTD) of intravenous, flat-dosed ST-1968 (namitecan), a new hydrophilic camptothecan derivative. Methods: Namitecan was administered intravenously over 2 h on day 1 and day 8 every 21 days (D1-D8-Q21D), starting at a flat dose of 2.5 mg, and increased according to a 3 + 3 cohort design. Due to frequent skipping of day 8 dosing for cytopenias, the study was expanded to test namitecan dosing on day 1 every 21 days (D1-Q21) at a starting dose of 17.5 mg. Major dose-limiting toxicity (DLT) was defined as grade (G) 4 neutropenia persisting >5 days, febrile neutropenia, G3 thrombocytopenia or G2 non-hematological toxicity. Results: Thirty-four patients were included into the D1-D8-Q21D group (2.5, 5, 10, 15, 17.5, 20 mg dosing cohorts), 29 patients into the D1-21D group (17.5, 20, 23, 27, 30 mg dosing cohorts). Neutropenia was the DLT in both groups, with 15 mg being defined as the recommended dose (RD) for the D1-D8-Q21D group, and 23 mg for the D1-Q21D group. Non-hematological toxicity was negligible. One patient with endometrial cancer in the D1-D8-Q21D group and one patient with cholangiocellular carcinoma in the D1-Q21D group experienced a partial remission. Namitecan exhibited fully dose-proportional pharmacokinetics. Conclusions: This study demonstrates clinical safety, favourable pharmacokinetics and preliminary antitumor activity of the novel hydrophilic camptothecin analogue namitecan in patients with heavily pretreated solid malignancies, when given either on a 2 out of 3 weeks or 3-weekly regimen.

Background: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221). Methods: Patients received 28-day cycles of olaparib, continuously (days 1–28) or intermittently (days 1–7), plus PLD (40 mg m−2, day 1); seven olaparib dose cohorts (50–400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)). Results: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ⩾3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation. Conclusions: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m−2) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

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 The safety, pharmacokinetics (PK) and pharmacodynamics of CEP-18770, a new peptide boronic acid proteasome inhibitor, have been investigated after intravenous administration on days 1, 4, 8 and 11 of every 21 d cycle in patients with solid tumours and multiple myeloma (MM). Patients and methods Thirty-eight patients were treated with CEP-18770 at escalating doses from 0.1 to 1.8 mg/m 2 where 2 out of 5 patients showed dose limiting toxicities. The maximum tolerated/recommended dose (MTD/RD) of 1.5 mg/m 2 was tested in 12 additional patients. Skin rash was dose-limiting and occurred in 53% of patients; other frequent toxicities were asthenia (29%), stomatitis (21%) and pyrexia (16%). No significant peripheral neuropathy was observed. PK in plasma was linear with a half-life of the elimination phase of 62.0 ± 43.5 h. Proteasome inhibition in peripheral blood mononuclear cells was dose related in MM patients; it was of 45.4 ± 11.5% at the RD. Conclusions CEP-18770 showed a favourable safety profile with lack of neurotoxicity and linear plasma PK. The definition of the optimal biological dose and schedule of treatment is actively pursued because of the high incidence of skin toxicity of the twice a week schedule.

BACKGROUND: Patients with small-cell lung cancer (SCLC) that progress after first-line chemotherapy have a poor prognosis and the evidence of a benefit from second-line (SL) chemotherapy is limited. Patients relapsing or progressing more than 90 days after completion of first-line treatment are considered platinum sensitive and may be rechallenged with platinum-based chemotherapy. Topotecan is approved as SL treatment independent of time to progression. This retrospective analysis evaluates the clinical outcomes of SCLC patients who received SL chemotherapy after platinum-etoposide chemotherapy. PATIENTS AND METHODS: We retrospectively reviewed 161 patients who received SL chemotherapy for SCLC. Patients were divided into four subgroups by type of SL treatment: (1) platinum-based rechallenge; (2) anthracycline-based regimens; (3) topotecan; (4) other single agents. The endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival. RESULTS: The median age was 63. There were 125 males and 36 females. Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0, 1 and 2 in 12.5%, 62.5% and 25% of patients, respectively. Platinum sensitive/platinum resistant/platinum refractory/unknown=121/29/3/8 patients. Median time to SL chemotherapy was 6.9 months. The median PFS from starting second-line treatment was 4.3 months and median OS was 5.8 months. The overall RR was 22.9%. There was a trend toward higher RR (34.5% vs 17.5%, p for trend: 0.06) and OS (9.2 months vs 5.8 months, p=0.08) for patients with sensitive disease who were rechallenged with platinum-based chemotherapy. A multivariate analysis that adjusted for the time to SL treatment showed that a platinum-containing regimen achieves better RR, PFS and OS independently of the time to SL chemotherapy and that response to first-line treatment and PS at SL are the only independent prognostic factors. CONCLUSIONS: The outcome for second-line therapy for SCLC was poor and benefit appeared to be limited to those patients with good PS and rechallenged with platinum-based chemotherapy. Platinum-based rechallenge should be considered as a standard comparator in future randomized controlled trials of SL chemotherapy.

Background: The broad spectrum of antitumor activity of the oral platinum satraplatin (S) and vinorelbine (V) were the rationale for performing a phase I trial to define the maximum tolerated (MTD) and the recommended (RD) dose in adult patients with advanced solid tumors. Patients and Methods: 4 dose levels (DLs) of S (mg/m2/day, days 1–5) and V (mg/m2/day, days 1, 8, 15, and 22) every 28 days were explored: S60/V60 on days 1, 8 and 15 only; S60/V60; S70/V60; and S80/V60. Subsequently, 3 further DLs were evaluated with V omitted on day 22: S70/V60, S80/V60, and S80/V80. Results: Treating 27 patients, the MTD was S80/V80 on days 1, 8, and 15, with 2 dose-limiting toxicities in 2 patients (nausea and vomiting grade (G) 3 with skipping of V on day 15, and neutropenia G4 with infection). The RD was S80/V60 on days 1, 8, and 15. The most frequent toxicities (any G) were nausea (70%), diarrhea (59%), anorexia (37%), vomiting (33%), asthenia (26%), constipation (26%), and paresthesia (18%). Partial responses were observed in 2 platinum-sensitive ovarian cancer patients and in 1 prostate cancer patient. Conclusion: The combination of S and V is tolerable at a DL of S80/V60 on days 1, 8, and 15; further evaluations in platinum- and V-sensitive tumor types would be of interest.

Background EMD 521873 (Selectikine or NHS-IL2LT) is a fusion protein consisting of modified human IL-2 which binds specifically to the high-affinity IL-2 receptor, and an antibody specific for both single- and double-stranded DNA, designed to facilitate the enrichment of IL-2 in tumor tissue. Methods An extensive analysis of pharmacodynamic (PD) markers associated with target modulation was assessed during a first-in-human phase I dose-escalation trial of Selectikine. Results Thirty-nine patients with metastatic or locally advanced tumors refractory to standard treatments were treated with increasing doses of Selectikine, and nine further patients received additional cyclophosphamide. PD analysis, assessed during the first two treatment cycles, revealed strong activation of both CD4+ and CD8+ T-cells and only weak NK cell activation. No dose response was observed. As expected, Treg cells responded actively to Selectikine but remained at lower frequency than effector CD4+ T-cells. Interestingly, patient survival correlated positively with both high lymphocyte counts and low levels of activated CD8+ T-cells at baseline, the latter of which was associated with enhanced T-cell responses to the treatment. Conclusions The results confirm the selectivity of Selectikine with predominant T-cell and low NK cell activation, supporting follow-up studies assessing the clinical efficacy of Selectikine for cancer patients.

Purpose Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data. Patients and Methods After 21 days of standard-dose cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m2 per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). Results The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m2 were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions ≥ grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors. Conclusion Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.

Background EMD 521873 (Selectikine), an immunocytokine comprising a DNA-targeting antibody, aimed at tumour necrosis, fused with a genetically modified interleukin-2 (IL-2) moiety, was investigated in this first-in-human phase I study. Methods Patients had metastatic or locally advanced solid tumours failing previous standard therapy. Selectikine was administered as a 1-hour intravenous infusion on 3 consecutive days, every 3weeks. A subgroup of patients also received 300mg/m 2 cyclophosphamide on day 1 of each cycle. Escalating doses of Selectikine were investigated with the primary objective of determining the maximum tolerated dose (MTD). Results Thirty-nine patients were treated with Selectikine alone at dose levels from 0.075 to 0.9mg/kg, and nine were treated at doses of 0.45 and 0.6mg/kg in combination with cyclophosphamide. A dose-dependent linear increase of peak serum concentrations and area under curve was found. The dose-limiting toxicity was grade 3 skin rash at the 0.9mg/kg dose-level; the MTD was 0.6mg/kg. Rash and flu-like symptoms were the most frequent side-effects. No severe cardiovascular side-effects (hypotension or vascular leak) were observed. At all dose-levels, transient increases in total lymphocyte, eosinophil and monocyte counts were recorded. No objective tumour responses, but long periods of disease stabilisation were observed. Transient and non-neutralising Selectikine antibodies were detected in 69% of patients. Conclusions The MTD of Selectikine with or without cyclophosphamide administered under this schedule was 0.6mg/kg. The recommended phase II dose was 0.45–0.6mg/kg. Selectikine had a favourable safety profile and induced biological effects typical for IL-2.

The broad spectrum of antitumor activity of both the oral platinum analogue satraplatin (S) and capecitabine (C), along with the advantage of their oral administration, prompted a clinical study aimed to define the maximum tolerated dose (MTD) of the combination.Four dose levels of S (mg/m(2)/day) and C (mg/m(2)/day) were evaluated in adult patients with advanced solid tumors: 60/1650, 80/1650, 60/2000, 70/2000; a course consisted of 28 days with sequential administration of S (days 1-5) and C (days 8-21) followed by one week rest.Thirty-seven patients were treated, 24 in the dose escalation and 13 in the expansion phase; at the MTD, defined at S 70/C 2000, two patients presented dose limiting toxicities: lack of recovery of neutropenia by day 42 and nausea with dose skip of C. Most frequent toxicities were nausea (57%), diarrhea (51%), neutropenia (46%), anorexia, fatigue, vomiting (38% each). Two partial responses were observed in platinum sensitive ovarian cancer and one in prostate cancer.At S 70/C 2000 the combination of sequential S and C is tolerated with manageable toxicities; its evaluation in platinum and fluorouracil sensitive tumor types is worthwhile because of the easier administration and lack of nephro- and neurotoxicity as compared to parent compounds.

Aim of the study To define the maximum tolerated dose (MTD) and toxicity of trabectedin (T) and cisplatin (C) given on days 1 and 8 every 3weeks to adult patients with advanced solid tumours. Plasma pharmacokinetics at cycle 1 and a preliminary anti-tumour activity assessment in ovarian and non-small cell lung cancer (OC, NSCLC) were secondary objectives. Methods In the dose finding part (DFP) of the study the dose of T given at each administration was escalated by 100μg/m 2 increments from 300μg/m 2 up to the MTD, with a fixed dose of C of 40mg/m 2 . The recommended dose (RD) was assessed in the previously treated and untreated OC and NSCLC patients in the expansion of the RD (ERD) part of the study. T was administered with corticosteroids pre-medication as 3-h infusion and C as 30-min infusion. Results Thirty-nine patients were treated in the DFP and 10 in the ERD. The MTD of T was 700μg/m 2 due to dose-limiting neutropaenia and the RDs in the previously treated/untreated patients were 500 and 600μg/m 2 , respectively. Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%). Time to recovery from myelosuppression was dose-dependent and treatment could be repeated after ⩾4weeks in the majority of patients at 600μg/m 2 . Confirmed partial responses were observed in 4 of 13 evaluable OC patients and in 1 with uterine leiomyosarcoma. No pharmacokinetic interaction was observed. Conclusion The administration of T and C on days 1 and 8 resulted in prolonged neutropaenia requiring treatment delay. The evaluation of a single every 3week schedule is worthwhile because of the hints of anti-tumour activity observed in OC.

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.

Background The combination of a proteasome inhibitor with a taxane has potential clinical synergism that prompted a clinical test. Patients and methods The maximum tolerated dose (MTD) and recommended dose (RD) of intravenous (i.v.) Bortezomib (B) (days 1, 4, 8, 11) and i.v. Paclitaxel (PTX) (days 1, 8) every 3 weeks was evaluated in patients with advanced solid tumours. The RD was tested in patients with breast, ovarian and prostate cancer. At the RD, microarray analysis of transcriptional profiles was carried out before and after the first dosing in peripheral blood mononuclear cells (PBMC). Results Thirty-one patients were enrolled and 22 were treated at the RD that corresponded to B 1.3mg/m 2 and PTX 100mg/m 2 . The main toxicity was cumulative peripheral neuropathy (76% of patients; grade 3–4 in 9%) that required treatment discontinuation in six patients, followed by diarrhoea (55%) and fatigue (41%). Nine partial responses (30%) were observed (three breast cancer, four ovary, two prostate patients). Significant ( p 70% of patients) in transcriptome were observed. Conclusions The incidence of peripheral neuropathy and the anti-tumour activity comparable to that of single-agent PTX do not support further development of this regimen.

2560 Background: S is a novel, oral platinum (P) analogue with a preclinical safety and activity profile comparable to carboplatin. C is an oral pro-drug of 5’-DFUR approved as single agent or in combination with other cytotoxic agents for the treatment of breast and colon cancer. A sequential administration schedule of S and C was assessed in an open-label phase Ib study in adult patients (pts) with advanced solid tumours. Methods: S was given QD to fasting pts from d1 to 5, C BID from d8 to 21 of a 4-week cycle. The starting daily doses were S 60 mg/m2 and C 1,650 mg/m2 (825 BID). Prophylactic oral 5HT 3 antagonists and steroids were given 30–60 min before S. Three to six pts were entered per dose level (DL). The maximum tolerated dose (MTD) was one dose level below the dose at which ≥2 of 3 or ≥2 of 6 pts experienced dose-limiting toxicities (DLTs). Eligibility criteria included ECOG PS ≤2, adequate renal/liver function, ≤2 lines of prior chemotherapies (CTs) for advanced disease, lack of resistance to...

13029 Background: Proteasome inhibition blocks the chemotherapy-induced activation of NF-кB increasing chemosensitivity to anticancer agents due to increased apoptosis. NF-кB is frequently aberrantly activated in primary human carcinomas and over-expressed in aggressive breast cancer lines1 supporting the rationale for combining B with P. We designed a phase I-II and PD trial to determine the recommended dose (RD) of the B&P combination, to screen for antitumor activity in patients with potentially taxane-sensitive tumors, to search for drug-induced changes and to identify potential surrogate markers of drug activity and toxicity in peripheral blood mononuclear cells (PBMC). Methods: Eligibility included ECOG performance status < 2, neurotoxicity < 2 and adequate organ functions. Treatment was given Q21 days: B on days 1,4, 8 and 11 and P on days 1 and 8. PBMC for gene expression profiling have been collected on day 1 and 4 before and after therapy. RECIST for response was applied. Results: Twenty-nine patients (20 female, median age 60 yrs) were accrued and 25 are evaluable (breast cancer: 13, ovarian cancer: 7, prostate cancer 1, other 4) ; 16 pts were treated in 4 escalation levels and the RD defined respectively at 1.3 mg/m2/dose & 100 mg/m2/dose for B&P. Neurotoxicity was the main toxicity (G1 36%, G2 20% and 1 case G3) requiring treatment discontinuation in 2 pts at cy 6 & 7. Other toxicities (all grades) were nausea and vomiting (68%), diarrhea (56%, G3 12%), alopecia (52%), asthenia (36%, G2 4%), and myalgia (32%, G2 8%). Antitumor activity consisted of 3 PR in pts with ovarian cancer lasting respectively 14, 8+ and 16 wks; 2 PRs in pts with breast cancer (12+ wks,14+ wks) and 1 PR in a pt with prostate cancer. Conclusions: Thus far the regimen has acceptable toxicity with evidence of antitumor activity. The trial will continue until accrual of four additional patients as planned. Footnotes 1 Adams J Current Opin Oncol 2002, 14:628–634. [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]