Phase I Assessment of the Pharmacokinetics, Metabolism, and Safety of Emitefur in Patients With Refractory Solid Tumors

2000 ◽  
Vol 18 (19) ◽  
pp. 3423-3434 ◽  
Author(s):  
J. Nemunaitis ◽  
R. Eager ◽  
T. Twaddell ◽  
A. Corey ◽  
K. Sekar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Prolonged Exposure ◽  
Circadian Variation ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Minimum Effective Concentration ◽  
Grade 3

PURPOSE: To determine the toxicities, dose-limiting toxicities (DLT), maximum-tolerated dose, and pharmacokinetic profile of emitefur (BOF-A2) in patients with advanced solid tumors. METHODS: This was a phase I dose-escalating trial in which cohorts of patients received BOF-A2 (cohort 1, 300 mg/m2 orally [PO] tid; cohort 2, 200 mg/m2 PO tid; cohort 3, 200 mg/m2 bid; and cohort 4, 250 mg/m2 bid) for 14 consecutive days followed by 1 week of rest (cycle 1). Pharmacokinetics, toxicity, and tumor response were monitored. RESULTS: Nineteen patients received 110 cycles (three patients in cohort 1, three patients in cohort 2, 10 patients in cohort 3, and three patients in cohort 4). DLT (grade 3 stomatitis, diarrhea, leukopenia) was observed in cohorts 1, 2, and 4. Pharmacokinetics indicated that prolonged systemic expression of fluorouracil (5-FU) is maintained after administration of BOF-A2 at a dose of 200 mg bid for 14 days. The mean steady-state concentration of plasma 5-FU was ≥ 24 ng/mL, which was 184-fold greater than the minimum effective cytotoxic concentration in vitro. Lack of variation of 5-FU trough levels within a day at steady-state indicates suppression of circadian variation. One patient in cohort 3 achieved a partial response and five patients maintained stable disease in excess of 6 months. CONCLUSION: BOF-A2 at a dose of 200 mg PO bid for 14 days followed by 7 days of rest is well tolerated. Prolonged exposure to 5-FU above the predicted preclinical minimum effective concentration is maintained, without evidence of circadian variation. Furthermore, evidence of antitumor activity is suggested.

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study.

1998 ◽  
Vol 16 (7) ◽  
pp. 2494-2499 ◽  
Author(s):  
A M Langevin ◽  
D T Casto ◽  
P J Thomas ◽  
S D Weitman ◽  
C Kretschmar ◽  
...  
Keyword(s):  
Steady State ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Malignant Tumors ◽  
Hepatic Metabolism ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Recommended Phase Ii Dose

PURPOSE A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.

Phase I dose-finding and pharmacokinetic study of a combination of elisidepsin (E) and erlotinib (T) in patients (pts) with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3093-3093
Author(s):  
Sanjay Goel ◽  
Teresa Moran ◽  
Cinthya Coronado ◽  
Santiago Viteri Ramirez ◽  
Imran Chaudhary ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Standard Dose ◽  
Therapeutic Option ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Grade 3

3093 Background: E is a new marine compound that has shown synergism with T in vitro even in T-resistant non-small-cell lung cancer (NSCLC) cell lines. Based on these findings, a phase I clinical trial was undertaken to identify the maximum tolerated dose (MTD) and recommended dose (RD) of E (3-h iv, days 1, 8 and 15) followed by T (once daily) in 3-week cycles. Secondary objectives were evaluation of safety and feasibility, PK and preliminary efficacy results. Methods: Patients (pts) with advanced solid tumors with no standard therapeutic option were recruited. Cohorts of 3-6 pts were included at each dose level (DL), with escalating doses of E in increments of 25-50% according to toxicities, and 2 different T doses (100 and 150 mg/day). Results: Thirty pts (median age, 57 years; 19 females) were evaluable. Main tumor types included NSCLC, colorectal, melanoma, and ovarian cancer. Six DLs were assessed. Starting DL was E 0.33 mg + T 100mg. One dose-limiting toxicity (DLT) out of 6 pts (grade 3 bilirubin increase) was observed at DL3 (E 0.75 mg + T 150 mg). Another DLT (dose omissions due to ALT increase) was found at DL6 (E 2.25 mg + T 100 mg). Frequent toxicities were diarrhea (53%), nausea (23%), vomiting (33%), rash (47%), pruritus (43%), dry skin (27%) and acneiform dermatitis (17%). Grade 3/4 toxicities included diarrhea (2 pts), rash (2 pts) and pruritus (1 pts). Main biochemical abnormalities were ALT (grade 3/4 in 4 pts) and total bilirubin increase (grade 3 in 2 pts). No severe hematological abnormalities were observed. Most toxicities were related to T; therefore, T dose was reduced to 100 mg/day. No PK interaction between E and T was observed. No objective responses were reported. Six pts attained stable disease >3 months (3 NSCLC; 1 ovarian cancer, 1 colorectal cancer, 1 invasive thymoma). Conclusions: E + T was a manageable combination; however, the difficulty of combining E with the standard dose of T (150mg) and the lack of activity made this combination unattractive for further development in the current schedule. Possibly, other schedules may demonstrate more efficacy.

Phase I study of indenoisoquinolines LMP776 in adults with relapsed solid tumors and lymphomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2558-2558 ◽  
Author(s):  
Geraldine Helen O'Sullivan Coyne ◽  
Shivaani Kummar ◽  
Robert S. Meehan ◽  
Howard Streicher ◽  
Naoko Takebe ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Central Line ◽  
Maximum Tolerated Dose ◽  
Resistant Cell ◽  
Dna Breaks ◽  
Common Grade ◽  
Grade 3

2558 Background: Indenoisoquinolines (ID) are non-camptothecin inhibitors of topoisomerase (TOP1) identified following a COMPARE analysis of the National Cancer Institute’s (NCI) in vitro anticancer drug discovery screen. IDs have improved characteristics over camptothecin top1 inhibitors, with better chemical stability (lacking the labile hydroxylactone E-ring) producing stable DNA breaks that are resistant to reversal of the trapped DNA-TOP1 cleavage complex and at different DNA sequence sites to camptothecins (Kohlhagen et al. Mol Pharmacol. 2005). IDs have shown more activity against camptothecin-resistant cell lines and mouse models, as well as in cells overexpressing the ATP-binding cassette (ABC) transporters, and multidrug resistance (MDR-1/ABCB1) genes. A parallel first-in-human Phase I study conducted at the NCI of LMP400 in patients with refractory solid tumors and lymphomas showed this molecule to be well tolerated (Kummar et al, Cancer Chemother Pharmacol. 2016). A trial of LMP776 (NSC725776), has completed accrual. Primary Objectives: define the maximum tolerated dose (MTD) of LMP776 and the dose-limiting toxicities (DLTs). Methods: Phase I trial using Design 4 of the Simon accelerated titration designs (Simon et al. JNCI, 1997), with doses escalated based on toxicity during cycle 1. LMP776 was administered via central line QD over 1 hour on days 1–5 q 28-days. Response is defined by RECIST 1.1 on CT. Results: 32 of 34 patients (pts) were evaluable for toxicity and response. Enrollment was expanded at dose level (DL) 2 to 6 pts due to a hypocalcemia DLT, with subsequent enrollment on a 3+3 design. MTD was established at DL7 (12mg/m2, DLT myelosuppression). Common Grade 3/4 adverse events by CTCAE v.4 included anemia (5 pts, 15%), thrombocytopenia (5), lymphopenia (5) and neutropenia (3 pts, 9%). 12 (37%) pts experienced stable disease (SD), with a median of 4 cycles of treatment (range 2-9). 10 (30%) pts with SD remained on study for ≥4 months, with 4 pts on study ≥6 months. Conclusions: LMP776 is overall well tolerated. Explorative correlatives and additional trials are being considered. Clinical trial information: NCT01051635.

Phase I and Pharmacokinetic Study of Docetaxel and Irinotecan in Patients With Advanced Solid Tumors

2000 ◽  
Vol 18 (20) ◽  
pp. 3545-3552 ◽  
Author(s):  
Corinne Couteau ◽  
Marie-Laure Risse ◽  
Michel Ducreux ◽  
Florence Lefresne-Soulas ◽  
Alessandro Riva ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m2, 50/175 mg/m2, 60/210 mg/m2, 60/250 mg/m2, 60/275 mg/m2, 60/300 mg/m2, and 70/250 mg/m2. Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m2 and 60/300 mg/m2; the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m2, respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.

1992 ◽  
Vol 10 (11) ◽  
pp. 1712-1722 ◽  
Author(s):  
W H Wilson ◽  
V Jain ◽  
G Bryant ◽  
K H Cowan ◽  
C Carter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Solid Tumors ◽  
Autologous Bone Marrow ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Autologous Bone ◽  
Hodgkin's Lymphomas ◽  
Phase I And Ii

PURPOSE High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS Forty-one patients with drug-resistant Hodgkin's and non-Hodgkin's lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkin's and non-Hodgkin's lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.

Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors.

1998 ◽  
Vol 16 (12) ◽  
pp. 3858-3865 ◽  
Author(s):  
L B Saltz ◽  
D Spriggs ◽  
L J Schaaf ◽  
G K Schwartz ◽  
D Ilson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Irinotecan Dose ◽  
Pharmacologic Study

PURPOSE In vitro synergy between cisplatin and irinotecan (CPT-11) has been reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. PATIENTS AND METHODS To maximize the opportunity for synergy, we divided the cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotecan. The dose of cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50 mg/m2/wk and this was escalated by 30% increments in successive cohorts of three to six patients to establish the maximum-tolerated dose (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were analyzed. RESULTS Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50 mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (DLT) encountered in this trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30 assessable patients achieved a partial response. No alteration in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the administration of cisplatin with irinotecan. CONCLUSION The administration of cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the potential to maximize any clinical synergy between the two agents. Evidence of substantial clinical activity was seen in this phase I study.

Phase I study of intravenous CCI-779 in combination with bryostatin-1 in solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3067-3067 ◽  
Author(s):  
N. B. Haas ◽  
N. Lewis ◽  
R. B. Cohen ◽  
L. Malizzia ◽  
M. B. Einarson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Messenger Rna ◽  
Bryostatin 1 ◽  
Naive Patient ◽  
Peripheral Blood Mononuclear ◽  
Mtor Inhibition ◽  
Resistant Disease ◽  
Grade 3

3067 Background: mTOR regulates translation of messenger RNA critical for angiogenesis and cell growth. CCI-779 inhibits mTOR signaling through p70S6 kinase (S6K), which phosphorylates the ribosomal S6 protein (S6). CCI-779 is active in renal carcinoma (RCC) and other solid tumors. Based on our finding that bryostatin-1 (bryo) inhibits S6K, and that CCI-779 + Bryo additively inhibit S6K and RCC growth in vitro, we initiated a phase I trial to determine the maximum tolerable (MTD) doses and dose-limiting toxicities of this novel combination in patients with solid tumors. Methods: Bryo (20 μg/m2) was administered over 60 minutes IV followed by CCI-779 (10 and 15 mg, planned escalation to 75 mg) IV over 30 minutes, both weekly for 3 of 4 weeks. Serum and peripheral blood mononuclear cell (PBMC) samples were collected for analysis of pharmacokinetics and markers of mTOR inhibition (phospho-S6 and p21waf1). Results: Nine patients (median age 57, 6 RCC, 2 sarcoma and 1 neuroendocrine) are evaluable for toxicity (total cycles=27 cycles, median 4, range 1–7) at the initial 2 dose levels (Bryo 20 μg/m2, CCI-779 10 mg and 15 mg). Cycle 1 toxicity includes grade 3 hypophosphatemia and myelosuppression in one patient each and grade 2 fatigue, stomatitis, and anemia. One patient developed reversible grade 3 pneumonitis after 7 cycles. Of 7 patients with therapy-resistant disease, 5 (4 RCC and 1 sarcoma) had stable disease lasting up to 7 months. A therapy-naive patient with RCC has 23% tumor reduction after 2 cycles at dose level 2 (CCI-779=15 mg). PBMC proteins from 5 patients show consistent decreases in phospho-S6 at 2–6 hours-post treatment compared with pre-treatment baseline measurement, with recovery by 24–72 hours after dosing. In parallel with inhibition of phosphorylation of S6, PBMC levels of p21waf1 were completely inhibited in all 5 patients. Conclusions: The combination of bryo and CCI-779 is feasible, with antitumor activity in RCC and mTOR pathway inhibition observed at submaximal doses. Dose escalation is continuing. No significant financial relationships to disclose.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3034-3034 ◽  
Author(s):  
P. M. Lorusso ◽  
E. Heath ◽  
M. Valdivieso ◽  
M. Pilat ◽  
A. Wozniak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Selective Inhibitor ◽  
Minor Response ◽  
Heavily Pretreated ◽  
Grade 3

3034 Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2 q2 weeks; Arm 1); irinotecan 300 mg/m2 q3 week (Arm 2); docetaxel 75 mg/m2 (Arm 3) and pemetrexed 500 mg/m2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 & 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome & grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses. [Table: see text]

Phase I clinical trial of CX-3543, a pro-apoptotic antitumor agent

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3082-3082 ◽  
Author(s):  
R. F. Marschke ◽  
A. D. Ricart ◽  
D. D. Von Hoff ◽  
J. K. Lim ◽  
K. Papadopoulos
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Three Dimensional ◽  
Antitumor Agent ◽  
Maximum Tolerated Dose ◽  
Therapeutic Window ◽  
Disease Response ◽  
Grade 3 ◽  
Xenograft Tumor Growth

3082 Background: CX-3543 is a novel small molecule specifically designed to target three dimensional nucleic acid motifs, and thus induce apoptosis in cancer cells. Preclinically, CX-3543 demonstrated potency in suppressing xenograft tumor growth with a broad therapeutic window. The objectives of this phase I study are: to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), to establish the pharmacokinetics (PKs), and to determine the recommended dose for further clinical development of CX-3543. Methods: Eligible patients with advanced solid tumors or lymphomas whose tumors progressed on standard therapy or for whom there are no standard therapies receive CX-3543 in successive dose cohorts at: 10, 20, 40, 80 and 160 mg/m2. Dosing is by one hour intravenous infusion daily for five consecutive days repeated on a three week cycle. Therapy is continued until the patient shows signs of intolerance to CX-3543 or evidence of advancing disease. Response by RECIST criteria is determined after every 2 cycles. Results: Ten patients with solid tumors (3–4 per cohort) have received intravenous CX-3543. Doses have been well tolerated. Seven grade 3 adverse events have been reported during the study, but none of these are related to CX-3543. To date no objective responses have been observed. One patient with advanced refractory prostate cancer has stable disease of longer than 4 months duration. CX-3543 has demonstrated good linearity in PK parameters between the dose cohorts with a terminal half life of approximately 12 hours following the first dose. Conclusions: To date, CX-3543 has shown no drug related toxicity and has predictable PKs. No DLTs have yet been observed, and the MTD remains to be defined in this Phase I study. Further enrollment to the planned dose escalation cohorts is ongoing. [Table: see text]

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