A phase I trial combining motexafin gadolinium (MGd) with docetaxel in the treatment of advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13115-13115
Author(s):  
K. J. Pandya ◽  
S. Phan
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Foot Drop ◽  
Advanced Solid Tumors ◽  
Motexafin Gadolinium ◽  
Grade 3

13115 Background: MGd is a novel therapeutic agent that concentrates in tumors and generates reactive oxygen species. Pre-clinical models show that MGd enhances in tumors the cytotoxic activity of selected chemotherapies, including taxanes. This phase I trial studied the combination of MGd and docetaxel. Methods: Patients (pts) with advanced solid tumors, adequate bone marrow, hepatic and renal function were eligible. Cohorts of 3 pts were treated with MGd starting at 2.5 mg/kg followed 30 minutes later by docetaxel 75 mg/m2. Treatments were repeated q3wks. The primary objective was to determine the maximum tolerated dose (MTD) of MGd in combination with docetaxel on this schedule and to determine the dose limiting toxicities (DLT). The secondary objective was to evaluate the response rate. MGd dose was escalated in successive cohorts while docetaxel dose remained fixed. Results: Sixteen pts were entered (9 males, 7 females) at MGd dose of 2.5 to 10 mg/kg. The median age was 60.5 yrs (range 35 -75). ECOG PS0 (4), 1 (14). Diagnoses included prostate (1); ovarian (2); breast (2) and non-small cell lung (NSCLC) (11). Median number of prior chemotherapy regimens: 2 (range 1–14), 7 pts had previously received a taxane: paclitaxel 5, docetaxel 2. Reported toxicities (all grades) include urine discoloration from excretion of MGd (68%), fatigue (87%), diarrhea (81%) and nausea (56%), Grade 3 neutropenia (37.5%) febrile neutropenia (6%), neuropathy (foot drop) was seen in 1 patient, therefore additional pts were entered (4 registered, but 1 never treated) at 10 mg/kg dose. Recurrence of prior radiation esophagitis was seen in 1 pt therefore it was felt that DLT was reached and study was closed. Responses are as follows: PR by CT in 1 breast and 4 NSCLC, and by PSA in 1 prostate; SD by CT in 1 breast and 2 NSCLC. Conclusion: MGd 10 mg/kg in combination with docetaxel 75 mg/m2 is feasible and did not increase docetaxel toxicity while showing promising responses. Phase II study of this combination is underway in NSCLC. [Table: see text]

scholarly journals Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e000870
Author(s):  
Aung Naing ◽  
Joseph P Eder ◽  
Sarina A Piha-Paul ◽  
Claude Gimmi ◽  
Elizabeth Hussey ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Ex Vivo ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Dual Inhibitor ◽  
Indoleamine 2,3 Dioxygenase

BackgroundM4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy, of M4112 monotherapy in patients with advanced solid tumors.MethodsIn preclinical studies, M4112 was administered to mice with IDO1-expressing tumors to determine tumor IDO1 and liver TDO2 inhibition. In the phase I trial, patients received doses of M4112 two times per day in 28-day cycles until progression, toxicity, or withdrawal of consent. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), and treatment-emergent changes in safety parameters. Other endpoints included pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsIn mice, M4112 significantly decreased the kynurenine:tryptophan ratio in the liver and tumor. Fifteen patients received M4112 at five distinct dose levels (three patients per cohort: 100, 200, 400, 600, and 800 mg two times per day orally). Initially, all doses inhibited IDO1 ex vivo, but plasma kynurenine levels returned to or exceeded baseline levels after day 15. Despite initial changes in kynurenine, there was no significant reduction of plasma kynurenine at steady state. There was one DLT (grade 3 allergic dermatitis; 800 mg two times per day) and one grade 2 QT prolongation (800 mg two times per day), resulting in dose reduction (not a DLT). M4112 was well tolerated, and neither the MTD nor the RP2D was established. TEAEs included fatigue, nausea, and vomiting. The best overall response was stable disease (n=9, 60%).ConclusionsThere were no serious safety concerns at any dose. Although M4112 inhibited IDO1 activity ex vivo, plasma kynurenine levels were not reduced despite achieving target exposure.Trial registration numberNCT03306420.

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]

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]

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.

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 trial of sunitinib (S) and temsirolimus (T) in metastatic renal cell carcinoma (mRCC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 433-433
Author(s):  
Matthew T. Campbell ◽  
Randall E. Millikan ◽  
Emre Altinmakas ◽  
Lianchun Xiao ◽  
Nizar M. Tannir
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mtor Inhibitors ◽  
Median Number ◽  
Primary Objective ◽  
Best Response ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Mean Time

433 Background: Anti-VEGF agents and mTOR inhibitors are mainstay therapies in mRCC. Pre-clinical data suggests synergistic anti-tumor effect when combining these 2 classes. A previous phase I trial using sunitinib (S) 25 mg/d 4 wks on, 2 wks off, and temsirolimus (T) 15 mg/wk was stopped after 2 of the first 3 pts developed dose limiting toxicity (DLT). Methods: Pts with any subtype mRCC (PS 0-1) were eligible. Each cycle consisted of daily S for 14 days on, 7 days off, and weekly T. The continuous reassessment method (CRM) was used. The primary objective was to find the maximum tolerated doses (MTD) of S and T. The total planned accrual was 60 pts. Results: Accrual was stopped after 20 pts received study drugs. Median age was 63.5 years; 13 pts received prior targeted therapy, 7 pts were treatment naïve; median number of prior treatments 1 (range 0-6). Treatment cohorts (#pts, S, T, dose in mg): 2 (S12.5,T6), 1 (S25,T12.5), 1 (S12.5,T8), 8 (S12.5alt25,T9), 2 (S25,T6), 2 (S25alt37.5,T6), 2 (S37.5,T6), 2 (S37.5,T8). Dose reduction was required in 6 of 20 pts; the most common DLT was mucositis in 3 of 20 pts, followed by thrombocytopenia in 2 of 20 pts. The mean number of cycles for all pts was 6.6±5.36, with mean time on study 159±120 days. One pt experienced DLT in cycle 1 and received no study related imaging, 1 had a partial response, 16 pts had stable disease, and 2 pts had progressive disease (PD) as best response. A total of 21 grade 3/4 adverse events (AEs) attributed to drug occurred in 11 of 20 pts. Reasons for study discontinuation were PD in 12 pts, toxicity in 6 pts, and pt preference in 2 pts. There were no treatment related deaths. Conclusions: The MTD of S and T using the CRM were not reached due to premature trial closure. However, we believe S 37.5 mg/d, 2 wks on, 1 wk off, and T 8-10 mg weekly may well be close to MTD. Clinical trial information: NCT01122615.

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.

A phase I trial combining motexafin gadolinium with docetaxel in the treatment of advanced solid tumors

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 3203-3203
Author(s):  
S. Phan ◽  
P. Messina ◽  
M. Buffan ◽  
M. L. Salemi ◽  
K. Pandya
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Advanced Solid Tumors ◽  
Motexafin Gadolinium
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