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.

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]

Phi-53: (NCI#7251): Phase I trial of belinostat (PXD101) in combination with 13-cis-retinoic acid (13c-RA) in advanced solid tumor malignancies—A California Cancer Consortium NCI/CTEP sponsored trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2526-2526 ◽  
Author(s):  
Thehang H. Luu ◽  
Paul Henry Frankel ◽  
Dean Lim ◽  
Mihaela C. Cristea ◽  
Jan Hendrik Beumer ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Phase I ◽  
Solid Tumors ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Qtc Interval ◽  
Advanced Solid Tumors ◽  
Eligibility Criteria ◽  
Grade 3

2526 Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ≥grade 3 that not resolved to <grade 1 within 1 week or non-hematologic toxicity: ≥grade 3. We sought the MTD of belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose levels (DL) were tested starting from belinostat 600 mg/m2/day and 13c-RA 50 mg/m2/day to belinostat 2000 mg/m2/day and 13c-RA 100 mg/m2/day. Only two DLTs were observed: a grade 3 hypersensitivity reaction with dizziness and hypoxia at DL 8 (belinostat 1700 mg/m2/day, 13c-RA 100 mg/m2/day); and a grade 3 allergic reaction in a patient with an ECOG PS 2 at DL 11 (belinostat 2000 mg/m2/day, 13c-RA 100 mg/m2/day). The MTD was not reached. Pharmacokinetics of belinostat suggests dose proportionality. Median number of cycles: 2 (range 1–56). 10 patients had SD including: 1 neuroendocrine pancreatic stable for 56 cycles; 1 breast pt for 12 cycles; 1 lung pt 8 cycles. 2 pt had PRs: a keratinizing squamous cell carcinoma (tonsil) and a lung cancer pt. Conclusions: Belinostat 2000 mg/m2 days 1-5and 13-cis-Retinoic acid 100 mg/m2days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single agent MTD. Future studies building on this combination to belinostat are warranted. Support: U01CA062505 and P30CA033572 (City of Hope); U01CA099168 and P30CA047904 (University of Pittsburgh).

Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2536-2536 ◽  
Author(s):  
Bojana Milojkovic Kerklaan ◽  
Martijn P. J. K. Lolkema ◽  
Lot A. Devriese ◽  
Emile E. Voest ◽  
A. Nol-Boekel ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Treated Patient ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Oral Topotecan

2536 Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-foot-syndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC0-∞ increased 1.58-fold (90%CI: 1.09–1.29) and Cmax increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n=7). Pazopanib AUC0-24 and Cmax ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC0-∞) and 1.78-fold (Cmax). Clinical trial information: NCT00732420.

A phase I dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3592-3592 ◽  
Author(s):  
C. Sweeney ◽  
C. Verschraegen ◽  
G. Chiorean ◽  
F. Lee ◽  
S. Jones ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Curative Therapy ◽  
Grade 3

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.

A first-in-human phase I study of CZ48, a lactone ring protected oral camptothecin, in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2578-2578
Author(s):  
Devalingam Mahalingam ◽  
Montaser F. Shaheen ◽  
John Sarantopoulos ◽  
Steven Weitman ◽  
Beppino C. Giovanella ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Maximum Tolerated Dose ◽  
Poor Correlation ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Open Label

2578 Background: CZ48, the 20-O-propionate ester of camptothecin (CPT), is a prodrug of CPT first described by Cao et al. in 1998. The side-chain is enzymatically cleaved in tissues. This gives rise to CPT, a potent inhibitor of topoisomerase I. Methods: An open-label, single-arm, dose-escalation Phase I study was performed to determine the maximum tolerated dose (MTD) of CZ48 in patients with advanced solid tumors. Initial dosing started qd po 80mg/m2, advancing to 2560mg/m2 for 21 consecutive days, followed by 7 days rest. Dosing was restarted in cohorts of 3 patients tid po at 18mg/m2 and escalated to 1g/m2on a 5 days on, 2 days off schedule for 28 days. Patients were prescreened by measuring CPT levels in plasma following a single pilot dose of CZ48. Dose was doubled until occurrence of at least Grade 2 adverse event, at which time 3+3 patient cohorts with a dose escalation of 33%-100% were implemented. DLT in 2/6 patients defined the MTD as the preceding DLT dose. PK parameters were measured prior to dosing, days 1-5, and day 28 of Cycle 1. Results: Poor absorption led to initial qd dosing reaching 2560mg/m2 with no signs of DLT. Subsequent tid dosing showed improved plasma levels and arrival at DLT. 34 patients were treated across 8 dose levels from 18 to 1000 mg/m2. The most frequent study-related adverse effects were cystitis, vomiting, diarrhea and fatigue. Grade IV toxicities observed were febrile neutropenia, anemia, and thrombocytopenia. Preliminary PK data in the qd dosing showed poor correlation between dose and Cmax or AUC, while PK in tid patients showed slightly improved correlation between dose and both CZ48 AUC (Pearson's correlation coefficient ϱ=0.476, p<0.01) and CZ48 Cmax(ϱ =0.51, p<0.01). Evidence of clinical activity with stable disease ≥ 6 months was observed in 2 heavily pre-treated colon and one breast cancer patient. Conclusions: The MTD of tid po CZ48 administered 5 days on, 2 days off of 28-day cycle is between 750 mg/m2 and 576 mg/m2. Overall toxicity is relatively mild, with DLT being cystitis and myelosuppression. Even with tid dosing, PK values correlate poorly to dose. A new formulation with 3-5 fold higher preclinical absorption values is being considered for introduction into the trial. Clinical trial information: NCT00947739.

Phase I study of c-Met inhibitor ARQ197 in combination with FOLFOX for the treatment of patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2544-2544
Author(s):  
Suzanne Fields Jones ◽  
Carla Kurkjian ◽  
Manish R. Patel ◽  
Jeffrey R. Infante ◽  
Howard A. Burris ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Advanced Solid Tumors ◽  
Grade 3

2544 Background: C-Met protein is a receptor tyrosine kinase which is overexpressed or mutated in a variety of tumor types, causing cell proliferation, metastasis, and angiogenesis. Tivantinib is an orally bioavailable small molecule which binds to the c-Met protein. This phase I study was designed to determine the maximum tolerated dose (MTD) of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors. Methods: Patients with advanced solid tumors for which FOLFOX (5-FU IV 400 mg/m2 day 1; 5-FU CIV 2400 mg/m2 day 1; Leucovorin IV 400 mg/m2 day 1; Oxaliplatin IV 85 mg/m2 day 1) would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), non-dose-limiting toxicities (NDLTs), safety, and preliminary efficacy were evaluated. Results: Fourteen patients (50% colorectal) were treated across 3 dose levels: 120 mg (n=3); 240 mg (n=5); 360 mg (n=6). No DLTs were observed until the 3rd dose level (treatment delay ≥3 days, secondary to grade 3 neutropenia). Common related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (36%; 0%), neutropenia (0%; 29%), nausea (14%; 14%), vomiting (14%; 14%), dehydration (14%; 7%), and thrombocytopenia (14%; 0%). To date, 7 patients have been evaluated for response including 4 (57%) with stable disease evident at the 8-week evaluation (CRC, 2 patients; unknown primary favoring CRC, 1 patient; esophageal, 1 patient) and 3 (21%) with disease progression. The 4 patients with stable disease are continuing on treatment; three (CRC and unknown primary) had received prior FOLFOX. Conclusions: The addition of tivantinib to standard therapy FOLFOX appears tolerated up to its recommended phase II monotherapy dose of 360 mg. Preliminary efficacy is encouraging, and a phase II study is proceeding with this regimen for the first line treatment of advanced gastroesophageal patients. Clinical trial information: NCT01611857.

Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 475-475
Author(s):  
Johanna C. Bendell ◽  
Lowell L. Hart ◽  
Shubham Pant ◽  
Jeffrey R. Infante ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Standard Dose ◽  
Heat Shock Protein 90 ◽  
Competitive Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Grade 3

475 Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90, with demonstrated activity in a variety of preclinical models. Further preclinical evidence suggests potential synergy between inhibition of HSP90 and fluorouracil treatment (Burkitt et al. 2007). This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Patients with refractory solid tumors for which capecitabine was an appropriate therapy received AUY922 with capecitabine in a standard 3+3 dose escalation. Capecitabine 1000mg/m2 was administered twice daily for days 1-14 of 21-day cycles, with escalating doses of AUY922 administered by intravenous (IV) infusion on days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 patients were treated at 6 dose levels: 22mg/m2 (n = 3); 28mg/m2 (n = 3); 40mg/m2 (n = 3); 55mg/m2 (n = 5); 70mg/m2 (n = 3); 70mg/m2 with capecitabine 1250mg/m2 (n = 6). There were no DLTs observed until the 6th dose level (grade 3 diarrhea). Common adverse events (all grades) included: diarrhea (61%), nausea (57%), fatigue (43%), hand-foot skin reaction (39%), anorexia (39%), vomiting (35%), rash (30%), and darkening vision (22%). Myelosuppression was uncommon, with no instances of grade ≥3 thrombocytopenia, and only 2 patients (9%) with grade 3/4 neutropenia (1 patient each). Of the 19 patients evaluable for response per RECIST 1.1, unconfirmed partial response (PR) was noted in 3 patients (13%; colorectal, 1; breast, 1; stomach, 1), with 1 additional confirmed PR (4%; colorectal); two of these had progressed on prior fluorouracil. Stable disease was noted in 8 patients (35%). Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.

A call for global harmonization of phase I oncology trials: Results from two parallel, first-in-human phase I studies of DS-7423, an oral PI3K/mTOR dual inhibitor in advanced solid tumors conducted in the United States and Japan.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2536-2536
Author(s):  
Tomoya Yokota ◽  
Johanna C. Bendell ◽  
Patricia LoRusso ◽  
Takahiro Tsushima ◽  
Ved Desai ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
The United States ◽  
Maximum Tolerated Dose ◽  
Serum Glucose ◽  
Advanced Solid Tumors ◽  
Dual Inhibitor ◽  
Phase I Studies ◽  
Akt Phosphorylation ◽  
Grade 3

2536 Background: The aim of this study was to determine the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of DS-7423, a novel inhibitor of PI3K/mTOR, in US and Japanese population. We further compared toxicities and recommended phase 2 dose (RP2D) of DS-7423 and approved oncology drugs in the two populations. Methods: We conductedparallel, first-in-human studies in US and Japan in patients with advanced solid tumors. We conducted a Pubmed search of pivotal and corresponding phase I studies to compare the RP2D and final approval doses of molecularly targeted agents (MTA) between US and Japan. Results: 69 patients were enrolled (n = 42 from US and n = 27 from Japan). Between populations, the only difference at baseline was body weight (BW) and body mass index (BMI). Dose-limiting toxicities included grade 3 rash (48 mg), grade 3 stomatitis (240 mg), grade 3 lung infection (240 mg), grade 4 hyperglycemia (240mg), grade 3 fatigue (320 mg), and grade 3 dehydration (320mg). The MTD and RP2D was 240 mg/d in both populations. Frequent treatment-related adverse events included diarrhea, fatigue, decreased appetite, rash, and stomatitis. No remarkable difference in AUC and Cmax were observed between populations. Prolonged stable disease was seen in cholangiocarcinoma, thymic cancer, non-small cell lung cancer, squamous cell carcinomas, carcinoid, and sarcoma. DS-7423 demonstrated PD effects on serum glucose, C-peptide and Akt phosphorylation and 18F-FDG uptake in tumors. The final RP2D of 17 MTA approved in US and Japan from 2001 to 2015 was near identical. The approved doses in both regions were identical. Conclusions: Despite differences in BW, BMI, and ethnicity, DS-7423 showed no difference in PK, PD, toxicity or efficacy between populations. We found near identical RP2D in phase I oncology studies and approved doses in pivotal studies. This supports increased international collaboration in the conduct of phase I oncology trials. Clinical trial information: NCT01364844, Japic CTI, 12766.

Phase I Trial and Pharmacokinetic Study of Pemetrexed in Children With Refractory Solid Tumors: The Children's Oncology Group

2007 ◽  
Vol 25 (12) ◽  
pp. 1505-1511 ◽  
Author(s):  
Suman Malempati ◽  
H. Stacy Nicholson ◽  
Joel M. Reid ◽  
Susan M. Blaney ◽  
Ashish M. Ingle ◽  
...  
Keyword(s):  
Folic Acid ◽  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Vitamin B ◽  
Pharmacokinetic Studies ◽  
Purine Nucleotides ◽  
Phase Ii Studies

Purpose We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. Patients and Methods Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. Results Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. Conclusion Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

Phase I and Pharmacologic Study of Oral (PEG-1000) 9-Aminocamptothecin in Adult Patients With Solid Tumors

1999 ◽  
Vol 17 (7) ◽  
pp. 2219-2219 ◽  
Author(s):  
Maja J.A. de Jonge ◽  
Cornelis J.A. Punt ◽  
A. Hans Gelderblom ◽  
Walter J. Loos ◽  
Vera van Beurden ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase Ii ◽  
Topoisomerase I ◽  
High Performance ◽  
Specific Inhibitor ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Time Curve ◽  
Phase Ii Studies

PURPOSE: 9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors. PATIENTS AND METHODS: Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m2/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay. RESULTS: Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m2/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r2 = 0.86). One partial response was noted in a patient with metastatic colorectal cancer. CONCLUSION: DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m2/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.

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