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]

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.

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3015-3015
Author(s):  
Andrew Eugene Hendifar ◽  
Sant P. Chawla ◽  
Doris Quon ◽  
Victoria S Chua ◽  
Lita Fernandez ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Minor Response ◽  
Grade 3

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.

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

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
Shubham Pant ◽  
Lowell L. Hart ◽  
Johanna C. Bendell ◽  
Jeffrey R. Infante ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Hsp90 Inhibition ◽  
Grade 3 ◽  
Dose Levels

3564 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. Preclinical evidence suggests potential synergy between HSP90 inhibition and fluorouracil. 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: Pts with refractory solid tumors received AUY922 with capecitabine in a standard 3+3 dose escalation. Dose levels were capecitabine 1000mg/m2 PO BID d 1-14 of 21-day cycles, with escalating doses of AUY922 IV 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 pts 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). No DLTs were observed until the 6th dose level (grade 3 diarrhea). Related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (43%; 17%), fatigue (30%; 13%), nausea (39%; 0), hand-foot skin reaction (30%; 5%), anorexia (30%; 4%), vomiting (30%; 0), and darkening vision (26%; 0). Vision darkening, a class effect of HSP90 inhibitors, was reversible with drug hold and retreatment was possible. Two pts (9%) had hematologic G 3/4 events of neutropenia. Of the 19 pts evaluable for response, partial response was noted in 4 patients (colorectal, 2; breast, 1; stomach, 1); 2 had progressed on prior fluorouracil, and remained on treatment for 13-35 wks. Stable disease was noted in 8 pts (35% [colorectal, 5; pancreas, 2; breast, 1]) with a median duration of 25.5 wks (range: 11-44+). All 5 colorectal pts were refractory to 5-FU. Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, particularly as seen in pts previously resistant to fluorouracil, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.

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.

scholarly journals Phase I study of TAS-115, a novel oral multi-kinase inhibitor, in patients with advanced solid tumors

2019 ◽  
Vol 38 (4) ◽  
pp. 1175-1185 ◽  
Author(s):  
Toshihiko Doi ◽  
Nobuaki Matsubara ◽  
Akira Kawai ◽  
Norifumi Naka ◽  
Shunji Takahashi ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Systemic Exposure ◽  
Treatment Interruption ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Bone Scan Index ◽  
Grade 3

SummaryTAS-115 is a novel MET, VEGFR, FMS and PDGFR inhibitor, developed to improve the continuity of drug administration with a relatively short half-life. We assessed its tolerability, safety, pharmacokinetics, efficacy, and pharmacodynamics in patients with solid tumors. This open-label, dose-escalation phase I study of TAS-115 consisted of three parts: part 1 (TAS-115 was administered orally once daily [SID]); part 2 and an expansion part (SID in a 5 days on/2 days off [5-on/2-off] schedule for 21 days per cycle). In part 1 (200–800 mg SID administered to 21 patients), systemic exposure after single administration increased almost dose-proportionally. Three dose-limiting toxicities (DLTs) were observed in three patients: grade 3 rash (650 mg), thrombocytopenia with bleeding, and rash (800 mg). The maximum tolerated dose (MTD) was determined as 650 mg SID. In part 2, the 5-on/2-off schedule was evaluated at the MTD to improve treatment exposure. No DLTs were observed and no patients required treatment interruption in cycle 1. During part 2 and the expansion part (N = 61), grade ≥3 treatment-related adverse events were reported in 47 patients, with neutropenia (24.6%), hypophosphatemia (21.3%), anemia, and thrombocytopenia (14.8% each), and leukocytopenia (11.5%) occurring in ≥10% of patients. The best overall response was stable disease in 31 of 82 patients (37.8%). An apparent reduction in fluorodesoxyglucose-uptake and bone scan index was observed in some patients. TAS-115 was generally well tolerated, with manageable toxicities and recommended phase II dose was estimated as 650 mg SID, 5-on/2-off. Furthermore, promising antitumor activity was observed.

A phase I study of capecitabine, oxaliplatin (CapOx), and lapatinib (L) in metastatic or advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2579-2579
Author(s):  
T. Dennie ◽  
D. Alberti ◽  
K. Oliver ◽  
N. LoConte ◽  
D. Mulkerin ◽  
...  
Keyword(s):  
Oral Administration ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Phase Iii ◽  
Grade 3 ◽  
Daily Oral Administration

2579 Background: CapOx is a standard treatment for patients (pts) with metastatic colorectal cancer (mCRC) and has been shown to be equivalent to FOLFOX in a phase III study. L is a tyrosine kinase inhibitor with targeting of the EGF and Her-2 receptors. Preclinical data suggest there may be synergy between L and Cap as well as L and Ox. This phase I study was designed to determine the maximum tolerated dose (MTD) of CapOx and L. Methods: Pts eligible for treatment included those with advanced or metastatic cancers, ECOG PS 2 or less, adequate renal and liver function, and ≤ 3 prior chemotherapy regimens. Treatment over a 21-day cycle was as follows: Ox, single IV infusion on Day 1; Cap, twice-daily oral administration on Days 1 through 14; L, continuous once-daily oral administration. Pts were treated with escalating doses of L (starting at 1000 mg daily) and Cap (starting at 1500 mg/m2/day), while Ox was kept at 130 mg/m2. The primary endpoint was determination of MTD. Results: Ten pts (9/10 female, median age 62 yrs.) were enrolled. One pt had breast cancer and the remainder had non- colorectal GI malignancies (esophagus, hepatobiliary, and pancreas). One pt at dose level 0 experienced dose-limiting toxicity (DLT) (dehydration, elevated bilirubin, hypokalemia). Two pts at dose level 1 (L 1000, Ox 130, Cap 2000) had DLTs of hypokalemia and diarrhea. At an intermediate dose level of L 1000, Cap 1700, Ox 130, two pts experienced DLTs (grade 2 fatigue/anorexia, grade 3 fatigue and dizziness). The MTD was determined to be L 1000 mg daily, Cap 1500 mg/m2/day, Ox 130 mg/m2. There were no treatment-related grade 4 toxicities. The most common grade 3 toxicity was diarrhea (4 pts). There were no grade 3 neuropathies, hematologic toxicities, or rash, and only one case of grade 3 fatigue. One pt with pancreatic cancer had a confirmed partial response (PR) to treatment, and 3 others had stable disease for > 90 days. Conclusions: The regimen of CapOx and L has efficacy in the treatment of solid tumors with established responsiveness to fluoropyrimidines or Ox. The MTD was L 1000 mg daily, Ox 130 mg/m2, and Cap 1500 mg/m2/day. This regimen will be investigated further in a Phase II study involving pts with mCRC. [Table: see text]

Phase I study of safety and pharmacokinetics of fruquintinib, a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3038-3038
Author(s):  
Jin Li ◽  
Junning Cao ◽  
Jian Zhang ◽  
Songhua Fan ◽  
Yang Sai ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Dose Range ◽  
Human Study ◽  
Human Tumor ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Vegf Receptor ◽  
Grade 3

3038 Background: Fruquintinib is a novel oral small molecule compound discovered and developed by Hutchison MediPharma that selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 and has demonstrated potent inhibitory effects on multiple human tumor xenografts. This first-in-human study is conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of fruquintinib. Methods: This phase I study used the 3+3 design for dose-escalation of fruquintinib given once daily (QD) in 28-day cycles in patients with solid tumors who had failed standard therapies. Endpoints included safety, PK, and preliminary efficacy measurements. Results: To date 16 patients were enrolled in 5 dose cohorts of 1-6 mg QD, with age 42-69 yr, 44% male, ECOG 0-1 and all heavily pretreated. Tumor types included 9 colorectal, 3 lung, 3 breast, and 2 gastric (one patient with bi-primary carcinoma of breast and colon). The most common adverse events included hypertension (50%), proteinuria (43.8%), hand-foot syndrome (HFS 43.8%), diarrhea (31.2%), and hoarseness (25%). Grade 3/4 AEs were diarrhea (25%), HFS (12.5%), thrombocytopenia (6.2%), and hyperbilirubinemia (6.2%). Three DLTs were observed: 2 grade 3 HFS both at 6mg and 1 grade 3 hyperbilirubinemia at 4mg. PK analysis showed good and rapid absorption followed by slow terminal elimination with a half-life of approximately 37 hours which was consistent across all dose groups. Both Cmax and AUC exhibited good dose proportionality over the studied dose range with low inter-patient variability following single and multiple doses. Among 8 evaluable patients, 2 (1 colorectal and 1 gastric) had confirmed partial response for more than 4 months; 5 had stable disease, including 3 SDs of 3-8 months. Conclusions: Fruquintinib was well tolerated at doses up to 4 mg QD to date and demonstrated excellent pharmacokinetic properties. Encouraging clinical activity was observed. Further clinical studies are warranted and under planning.

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.

A Phase I Study of Irinotecan As a 3-Week Schedule in Children With Refractory or Recurrent Solid Tumors

2003 ◽  
Vol 21 (20) ◽  
pp. 3844-3852 ◽  
Author(s):  
Gilles Vassal ◽  
Francois Doz ◽  
Didier Frappaz ◽  
Karima Imadalou ◽  
Evelyne Sicard ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
High Dose ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
The Mean ◽  
Grade 3

Purpose: A phase I study was performed to determine the maximum-tolerated dose (MTD) and safety profile of irinotecan (CPT-11) administered as a single intravenous infusion every 3 weeks in children with recurrent or refractory solid tumors. Patients and Methods: Eighty-one patients were enrolled, including 48 less heavily, and 33 heavily pretreated patients (cranial irradiation and/or high-dose chemotherapy). Children received CPT-11 as a 120-minute infusion at doses ranging from 200 to 720 mg/m2. The dose-limiting toxicities (DLT) on first cycle were determined in both cohorts. Results: One hundred twenty-two cycles and 81 cycles were administered in less heavily, and heavily pretreated patients, respectively. The primary DLT was delayed diarrhea in less heavily pretreated patients, and neutropenia in heavily pretreated patients. MTD was 600 mg/m2 in both cohorts. Grade 3 to 4 neutropenia occurred in 33% and 38% of cycles in less heavily, and heavily pretreated patients, respectively. Grade 3 to 4 nonhematologic toxicities included nausea/vomiting (7% and 4% of cycles in less heavily, and heavily pretreated patients, respectively), asthenia (7% and 4% of cycles, respectively), and delayed diarrhea (6% and 2.5% of cycles, respectively). Four partial responses at 600 mg/m2 (high-grade glioma, neuroblastoma, medulloblastoma, and rhabdomyosarcoma) and 21 minor responses and stable diseases were observed. Pharmacokinetic analysis of CPT-11 and SN-38 was performed in 77 patients. The mean ± standard deviation (SD) CPT-11 plasma clearance was 20.7 ± 9.5 L/h/m2 (range, 5 to 54). The mean ± SD SN-38 metabolic ratio was 1.5% ± 1.1% (range, 0.15% to 5.55%). Conclusion: The recommended phase II dose of CPT-11 in a 3-week schedule is 600 mg/m2 in less heavily, and heavily pretreated children with solid tumors.

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