Treatment of advanced recurrent NSCLC with daily oral vinorelbine: A phase I trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19108-e19108
Author(s):  
Amanda Tufman ◽  
Astrid Borgmeier ◽  
Sylvia Guetz ◽  
Joachim Von Pawel ◽  
Achim Rittmeyer ◽  
...  
Keyword(s):  
Phase I ◽  
Advanced Nsclc ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Daily Administration ◽  
Recommended Dose ◽  
Oral Vinorelbine ◽  
Pretreated Patients ◽  
Grade 3

e19108 Background: Metronomic regimens, in which small, frequent doses of chemotherapy are administered, have been suggested to lower toxicities while maintaining, or even improving, efficacy. The high frequency of administration aims to expose the tumor continuously to the drug, thereby preventing the recovery of malignant cells between cycles. Previous studies have shown that the administration of oral vinorelbine thrice weekly is feasible and well tolerated. We present a phase I dose finding study in which a regimen of daily oral vinorelbine was evaluated in pretreated patients with advanced NSCLC. Methods: Pretreated patients with advanced NSCLC were treated with vinorelbine (Navelbine oral) at fixed daily doses of 20 mg, 30 mg, 40 mg or 50 mg for 21 days of each four-week cycle. The primary end point was the identification of the maximum tolerated dose, which was reached when two out of six patients experienced dose limiting toxicity (DLT) in cycle 1 or 2. Results: 27 patients with advanced NSCLC (78% stage IV, median age 65 y) were enrolled. Most (93%) had received previous systemic therapy (mean: 2.6 lines). Daily administration of oral vinorelbine was well tolerated up to 30 mg/d without any DLT. At 40 mg one of three patients experienced DLT in cycle 1 and another patient in cycle 2. Three out of six patients had DLT at the dose level of 50 mg. Therefore, the recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2 if no DLT had occurred. Eleven patients (2 out of 7 treated with the recommended dose) experienced treatment-related toxicities of grade 3 or higher. The adverse events were primarily hematological (febrile neutropenia: 14.8%, leukopenia: 29.6%, lymphopenia: 18.5%, neutropenia: 18.5%). One patient died as a result of colitis. The frequency of non-hematological toxicities of grade 3 or higher was low with only single cases reported for nausea, fatigue, neutropenic sepsis, pneumonia, increased gamma-glutamyltransferase and anorexia. Conclusions: Daily administration of oral vinorelbine in pretreated patients is feasible and safe. An initial dose of 30mg/d is well tolerated and can be increased to 40mg/d in cycle 2. Further studies are warranted to evaluate the efficacy and safety of this novel approach. Clinical trial information: EudraCT number 2006-001573-25.

Phase I/II trial of combination nab-paclitaxel and pemetrexed in advanced solid tumor patients (pts) with emphasis on non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19147-e19147
Author(s):  
Jonathan Riess ◽  
Cheryl Ho ◽  
Angela M. Davies ◽  
Derick Lau ◽  
Primo Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Advanced Nsclc ◽  
Patient Characteristics ◽  
Maximum Tolerated Dose ◽  
Prior Therapy ◽  
Early Closure ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

e19147 Background: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in NSCLC. Preclinical evaluation has demonstrated additive cytotoxicity of pemetrexed and taxanes. We evaluated the safety and efficacy of combining nab-paclitaxel (nP) and pemetrexed (P) in solid tumors with a focus on NSCLC for the phase II expansion. Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: P 500 mg/m2 day 1 plus nP on day 1 at doses of 180, 220, and 260 mg/m2 every 21 days. Dose limiting toxicity (DLT) in cycle 1 was defined as: grade 4 platelets or grade 3 platelets with bleeding, neutropenia with fever or documented infection, or other grade ≥ 3 non-heme toxicity. Phase II eligibility included advanced NSCLC, ≤ 2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. Results: Planned dose escalation during the Phase I portion was completed without reaching the MTD. The RP2D was P 500 mg/m2 and nP 260 mg/m2. The phase II portion accrued 37 pts before early closure due to increasing use of first-line pemetrexed/platinum doublet therapy in non-squamous NSCLC. Phase II patient characteristics: median 63 (45-77); M:F 23:14; median cycles 3. In 31 assessable patients: 5 PR, 12 SD and 14 PD. Efficacy: RR =14%; disease control rate (DCR) = 46%; median survival time (MST) = 8.7 months. Pts in the DCR group had a MST of 15.4 vs 4 months in the PD group (p=0.02). Conclusions: P 500 mg/m2 day 1 with nP 260 mg/m2 was feasible and well tolerated. The phase II component demonstrated activity in second-line therapy of advanced NSCLC. Practice patterns have evolved; so further trials of this regimen are not planned. Clinical trial information: NCT00470548.

Bortezomib plus modified R-CHOP as initial therapy for indolent B-cell lymphomas: Phase I results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8577-8577
Author(s):  
C. Flowers ◽  
R. Sinha ◽  
J. Kaufman ◽  
P. Shenoy ◽  
C. Lewis ◽  
...  
Keyword(s):  
Phase I ◽  
Stage Iv ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Initial Therapy ◽  
Hematological Toxicity ◽  
Fiber Density ◽  
Epidermal Nerve Fiber Density ◽  
Stage Iv Disease ◽  
Grade 3

8577 Background: Adding rituximab (R) to chemotherapy improves survival for patients (pts) with follicular lymphoma (FL) and other indolent non-Hodgkin lymphomas (NHL), but not all pts respond. Bortezomib (B) + RCHOP has a high complete response (CR) rate, but higher doses of B with standard vincristine produced severe neuropathy. We developed a phase I/II trial to test if adding B to RCHOP with modified vincristine dosing can be well-tolerated and yield a high CR rate. Methods: Untreated pts with indolent NHL and indications for treatment based on GELF criteria or FLIPI ≥3 received R 375mg/m2, cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, vincristine 1.4mg/m2 (capped at 1.5mg) on day 1, B 1.0- 1.6mg/m2 days 1 and 8, and prednisone 100mg days 1–5 for 6–8 cycles. The maximum tolerated dose (MTD) was defined as the regimen at which <30% grade ≥3 non-hematological or grade ≥4 hematological toxicity (>14 days) occurs. Dose escalation used the Escalation with Overdose Control Bayesian method with upper bound (θ=0.3). This facilitated MTD finding with fewer pts given prior data on B+RCHOP. Functional Assessment of Cancer Therapy (FACT) Neurotoxicity (11-item; 4 point scale), EMG, nerve conduction velocity and epidermal nerve fiber density measures were taken at baseline and after cycle 4. Results: 11 pts with FL (n=6) or other indolent NHL enrolled in phase I. Median age was 59 years (range 29–69). 6 pts (55%) had stage IV disease; 8 (64%) had FLIPI ≥2. Pts received RCHOP + B at 1.0 mg/m2 (n=1), 1.3 mg/m2 (n= 6) or 1.6 mg/m2 (n= 4) and together completed 67 cycles. Treatment was well tolerated. Neuropathy occurred in 4 pts (36%), with 2 grade 1, 1 grade 2 and 1 grade 3 toxicity ( Table ). Grade 4 neutropenia occurred in 4 pts (36%), but none >14 days. Overall response rate was 100% with 5/8 finished pts (63%) achieving CR. 3 continue on treatment. Mean FACT Neurotoxicity after cycle 4 remained < 1 for all items. Conclusions: Adding bortezomib to RCHOP produces limited toxicity when vincristine is capped at 1.5 mg. Phase II will explore the efficacy of this regimen. [Table: see text] [Table: see text]

Phase I trial of vorinostat in combination with erlotinib in advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations after erlotinib progression

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19057-e19057 ◽  
Author(s):  
N. Reguart ◽  
A. F. Cardona ◽  
D. Isla ◽  
F. Cardenal ◽  
R. Palmero ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Advanced Nsclc ◽  
Global Analysis ◽  
Maximum Tolerated Dose ◽  
Egfr Mutations ◽  
Combination Regimen ◽  
Duration Of Treatment ◽  
Grade 3

e19057 Background: Vorinostat (SAHA) is a histone deacetylase inhibitor that induces differentiation, growth arrest and apoptosis of malignant cells. In vitro, there is a synergistic interaction of vorinostat in combination with gefitinib in NSCLC cell lines. Moreover, vorinostat increases levels of E-cadherin, p21, and downregulates expression of phospho-AKT and phospho-ERK1/2. These molecular findings could reverse resistance to erlotinib in mutant patients. Methods: We conducted a standard 3+3 Phase I trial of oral erlotinib 150 mg QD in combination with oral vorinostat (dose level 1 [DL1], 300 mg QD on days 1–7 every 21 days; DL2, 400 mg QD on days 1–7 every every 21 days, and; DL3, 400 mg QD on days 1–7 and 15–21 in a 28-day cycle). Cycles were repeated for a maximum of 6 cycles until progressive disease (PD) or intolerable toxicity. Pts with advanced NSCLC with EGFR mutations (Exon 19 and 21) after erlotinib progression and ECOG ≤2 were eligible. The main objectives were to determine the maximum tolerated dose (MTD), drug activity and safety of the combination regimen. Results: Thirteen patients have been enrolled up to date, with 9 patients available for this interim analysis (median age, 59 years; range 41–77). One patient (DL3 cohort) experienced a dose limiting toxicity (Grade 3 diarrhoea). The MTD has not been reached. The most common drug-related toxicities of any grade in the first cycle of treatment were anemia (77.8%), skin alterations (66.7%), diarrhoea (66.7%), xerostomy (55.6%), asymptomatic changes in liver function tests (55.6%), and asthenia (55.6%). There were no Grade ≥3 drug-related adverse events during first cycle of treatment and the global analysis of cycles showed asthenia (11.1%), somnolence (11.1%) and hyporexia (11.1%). Four pts discontinued treatment, all due to PD. Of 9 evaluable pts for efficacy, 6 had stable disease as best response (median duration of treatment 6.0 months, range 4–12). Final data will be presented at ASCO meeting. Conclusions: Although accrual continues to determine the MTD, the combination of vorinostat and erlotinib appears to be well tolerated and effective in this group of advanced NSCLC pts with EGFR mutations after erlotinib progression. No significant financial relationships to disclose.

A phase I trial to determine the maximum tolerated dose and evaluate the safety and pharmacokinetics (PK) of docetaxel-PNP, polymeric nanoparticle formulation of docetaxel, in subjects with advanced solid malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13104-e13104 ◽  
Author(s):  
Kyung Hae Jung ◽  
Kyu-Pyo Kim ◽  
Dok Hyun Yoon ◽  
Yong Sang Hong ◽  
Chang-Min Choi ◽  
...  
Keyword(s):  
Phase I ◽  
Maximum Tolerated Dose ◽  
Recommended Dose ◽  
Phase Ii Trials ◽  
Polymeric Nanoparticle ◽  
Dose Linearity ◽  
Solid Malignancies ◽  
Heavily Pretreated ◽  
Infusion Reactions ◽  
Grade 3

e13104 Background: The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose of docetaxel-PNP when administered every 3 weeks in patients with advanced solid malignancies. Methods: Three to six patients received docetaxel at dose levels of 20-75 mg/m2 as 60-min infusions every 3 weeks according to the single dose-escalating 3+3 method. Blood samples at the first dose of docetaxel-PNP were collected for PK analysis. Results: Nineteen pts were treated for a median of two cycles (1-14) in the phase I study. Dose escalation was performed up to 75 mg/m2. The most frequently reported adverse events were grade 4 neutropenia (52.6%, 10/19), grade 1 myalgia (42.1%, 8/19) and grade 1 alopecia (42.1%, 8/19). No acute infusion reactions were noted. Two dose-limiting toxicity was observed at 20 and 60 mg/m2, which were grade 3 hypophosphatemia and death of unknown cause, respectively. Although the MTD was not determined, the recommended dose was determined as 60 mg/m2. This was based on neutropenia and PK parameters which are summarized in the table. PK parameters revealed dose linearity. Partial response was seen in one patient and stable disease in seven patients. Conclusions: Administration of docetaxel-PNP was well tolerated up to 60 mg/m2 every 3 weeks by heavily pretreated patients. Further phase II trials are recommended at this dose level. [Table: see text]

Phase I/II dose-finding study of crizotinib (CRIZ) in combination with erlotinib (E) in patients (pts) with advanced non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2610-2610 ◽  
Author(s):  
Sai-Hong Ignatius Ou ◽  
Ramaswamy Govindan ◽  
Keith D. Eaton ◽  
Gregory Alan Otterson ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
Phase I ◽  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Dry Eyes ◽  
Egfr Inhibition ◽  
Development Of Resistance ◽  
Finding Study ◽  
Dose Finding Study

2610 Background: c Met expression is common in NSCLC tumors and has been implicated in the development of resistance to EGFR inhibitors. CRIZ is an ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies, combining CRIZ with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell lines that were either sensitive or resistant to EGFR inhibition. The phase I portion of a phase I/II study (A8081002; NCT00965731) investigated the combination of E (EGFR TKI) and CRIZ in pts with advanced NSCLC. Methods: Pts had advanced NSCLC, 1 or 2 prior chemotherapy regimens, and no previous MET-directed therapy. Endpoints included maximum tolerated dose (MTD) determination, safety, and pharmacokinetics (PK). Pts received CRIZ 150 or 200 mg BID combined with E 100 mg QD (150/100 and 200/100, respectively). Results: Twenty-five pts have been treated to date. Median duration of combination therapy in 150/100 (n=18) was 6.6 weeks (0.1–25.3); for 200/100 (n=7) was 6.9 weeks (3.0–64.7). Five pts had dose-limiting toxicities (grade [G] 2 and unable to receive at least 80% of the planned dose or ≥G3), all of which resolved: 3 pts at 150/100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and dehydration; and at 200/100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts (92%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were diarrhea (72%), rash (56%) and fatigue (44%). Six pts discontinued therapy due to TRAEs (150/100: G3 diarrhea, G3 dehydration, and G2 rash in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n=1 each; 200/100: G3 dry eyes, G1 esophagitis, n=1 each). One partial response (200/100; duration 61 weeks) and 9 stable diseases (n=7 150/100, n=2 200/100; duration 7–54 weeks) were observed overall. Co-administration of both doses of CRIZ with E increased E AUC by 1.8 fold, while CRIZ PK parameters appeared to be unaffected. Plasma exposure to E 100 mg QD with CRIZ was comparable to that of 150 mg QD from historical data. Conclusions: E plus CRIZ at the MTD was well tolerated, with no unexpected AEs, and showed signs of activity in a pre-treated population. E 100 mg QD plus CRIZ 150 mg BID was defined as MTD.

Phase I study of LY573636-sodium, an acylsulfonamide anti-cancer compound with a novel mechanism of action, administered as 2-hour IV infusion in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2515-2515 ◽  
Author(s):  
R. L. Ilaria ◽  
G. R. Simon ◽  
M. Sovak ◽  
M. K. Burton ◽  
A. L. Cleverly ◽  
...  
Keyword(s):  
Phase I ◽  
Mechanism Of Action ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Lean Body Weight ◽  
Flat Dose ◽  
Elimination Half ◽  
Anti Cancer ◽  
Grade 3

2515 Background: LY573636 -sodium (hereafter referred to as LY573636 ) is a novel anti-cancer compound that induces apoptosis by a mitochondrial-mediated mechanism. Methods: A phase I study was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of LY573636 administered as an intravenous infusion over 2 hours every 21 days. Results: 53 patients (pts) were enrolled on study, 16 males, 37 females, with a median age of 58 (range: 18–83). LY573636 was dose-escalated using a flat dosing paradigm in the first 34 patients (range 100 mg to 2400 mg). PK analysis of this cohort revealed that LY573636 had a low total plasma clearance (CL = 0.02L/hr) and terminal elimination half-life of approximately 340 hours due to high-albumin binding (∼99%). The dose limiting toxicity (DLT) for the flat dose escalation was bone marrow (BM) suppression, which included CTC (ver2) grade 3/4 thrombocytopenia/neutropenia. In some patients, significant BM suppression occurred in cycle 2 and later, attributed to the accumulation of albumin-bound drug with repeated flat dosing. Based on these findings, the dose-finding strategy was modified to an idealized dosing paradigm which calculated LY573636 doses based on pt lean body weight, and used a loading/maintenance dose regimen to achieve a specific Cmax target value. All 3 pts in the first 400 μg/mL Cmax cohort completed at least 2 cycles and no DLTs were reported. Of the 16 pts enrolled to the 420 μg/mL targeted dose group: 1 pt reported a DLT, a transient grade 3 elevation of ALT/AST which did not recur in subsequent cycles; 8/16 pts received 4 or more cycles prior to disease progression and 2 remain on treatment. Overall, 23/53 pts had stable disease (SD) after 2 or more cycles. Seven pts received >8 cycles (SD > 6 mos), including heavily pre-treated pts with ovarian cancer, non-small cell lung cancer, soft tissue sarcoma, and thymoma. Conclusions: LY573636 is a novel anti-cancer compound with a unique mechanism of action. The most common DLT was BM suppression. The individualized, target Cmax dose of 420 μg/mL has been taken forward into phase II clinical trials. No significant financial relationships to disclose.

A phase I dose escalation study of sunitinib in combination with gemcitabine + cisplatin for advanced non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18057-18057 ◽  
Author(s):  
M. Reck ◽  
N. Frickhofen ◽  
U. Gatzemeier ◽  
H. Fuhr ◽  
S. Lanzalone ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Dose Escalation Study ◽  
Finding Study ◽  
Grade 3 ◽  
Multitargeted Tyrosine Kinase Inhibitor

18057 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. SU has also shown single- agent activity in NSCLC. In this study we assess the safety, tolerability, and pharmacokinetics (PK) of SU in combination with gemcitabine (G) and cisplatin (C). Methods: This is a phase I, dose-finding study in pts with untreated, stage IIIB/IV NSCLC not amenable to curative treatment. Planned dose levels include: oral SU (37.5 or 50 mg/day for 2 wks followed by 1 wk off treatment [2/1 schedule]) plus G (1000 or 1250 mg/m2 iv on days 1 and 8 of a 21-day cycle) and C (80 mg/m2 iv on day 1 of each cycle). SU doses are escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) for both schedules. SU continuous dosing (CD) schedule will also be tested. PK and antitumor efficacy are also assessed. Results: As of Oct 2006, 13 pts were treated on the 2/1 schedule: 6 pts with SU 37.5 mg + G 1000 mg/m2 + C 80 mg/m2, and 7 pts with SU 50 mg + G 1000 mg/m2 + C 80 mg/m2. No dose-limiting toxicities (DLTs) were observed with SU 37.5 mg, while 2 pts experienced neutropenia and infection as DLTs with SU 50 mg. Grade 3/4 hematological AEs included neutropenia (n=3 at dose level 1 and n=5 at dose level 2), thrombocytopenia (n=1 and 5) and anemia (n=2 and 0). 3 pts achieved a partial tumor response at the SU 50 mg/day dose level. There were no apparent drug-drug interactions between SU in combination with G and C based on their systemic exposures in this study. Conclusions: The combination of SU (37.5 mg) on schedule 2/1 with G (1000 mg/m2) and C (80 mg/m2) in advanced NSCLC appears safe and tolerable in this pt population. Testing with G escalated to 1250 mg/m2 or with SU administered on a CD schedule is ongoing. No significant financial relationships to disclose.

Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (LV) (SCOUT) in patients with advanced colorectal cancer (ACRC): A phase I/II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4084-4084
Author(s):  
H. Sheikh ◽  
J. W. Valle ◽  
K. Palmer ◽  
G. Wilson ◽  
A. Sjursen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Hand Foot Syndrome ◽  
Label Dose ◽  
Grade 3

4084 Background: The feasibility of UFT (tegafur-uracil) plus LV with alternating irinotecan and oxaliplatin was investigated in a two-stage, phase I/II, open-label, dose-finding trial in patients with ACRC. The study is now closed. Here we present results from the phase II cohort and overall results from the phase I/II study. Methods: Eligible patients aged =18 years had histologically confirmed, advanced, inoperable, measurable metastatic disease, no prior chemotherapy other than adjuvant bolus 5-FU administered =6 months previously, and adequate hematologic, hepatobiliary, and renal function. Patients in the phase I study received irinotecan 180 mg/m2 on d1, oxaliplatin 85–100 mg/m2 on d15 plus UFT 200–300 mg/m2/d with LV 90 mg/d on d1–21 of a 28-d cycle. Diarrhea, lethargy, and vomiting were dose limiting. The maximum tolerated dose (MTD) established was irinotecan 180 mg/m2, oxaliplatin 100 mg/m2, UFT 250 mg/m2/d, and LV 90 mg/day. Patients were treated at the MTD in the phase II study. Primary endpoints in the phase II study were objective response rate (ORR) and time to progression (TTP). Results: Forty-five patients (median age 62 [range 24–79] years, median 4 marker lesions) were entered, 16 and 29 patients in the phase I and II studies, respectively. The ORR in all 38 evaluable patients was 66% (95% CI 49–80%), with clinical benefit (CB) in 89% (95% CI 75–97%). At a median follow-up of 10.3 months, median TTP was 8.5 months (95% CI -7.6 to 10.4 months) in 40 evaluable patients and median OS (ITT population; n=45) was 16.8 months (95% CI -11.3 to 28.3 months). In the phase II study (n=29) median TTP was 8.1 months (95% CI -6.7 to 11.3 months) and median OS was 19.6 months (95% CI -7.7 to >25.6 months); ORR in 25 evaluable patients was 68% (95% CI -46.5 to 85.1%) with CB in 100% (95% CI -86.3 to 100%). Of 30 patients with confirmed radiologic progression, 21 (70%) had second-line therapy. At the MTD, 3 patients (10%) had grade 3 diarrhea, 1 patient (3%) had grade 3 neurotoxicity, and 2 patients (7%) had grade 2 alopecia. No hand-foot syndrome (HFS) was seen. Conclusions: UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for patients with ACRC, with minimal alopecia and neurotoxicity and no HFS. No significant financial relationships to disclose.

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.

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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