Oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG): Experience with retreatment of survivors from the phase I trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2060-2060
Author(s):  
Annick Desjardins ◽  
Matthias Gromeier ◽  
James Emmett Herndon ◽  
Dina Randazzo ◽  
Stevie Threatt ◽  
...  
Keyword(s):  
Study Drug ◽  
Disease Recurrence ◽  
Dose Finding ◽  
Additional Patient ◽  
Soap Bubble ◽  
Eligibility Criteria ◽  
Who Grade ◽  
Finding Study ◽  
Grade 3 ◽  
The Impact

2060 Background: We completed a study evaluating a single intratumoral delivery of PVSRIPO in recurrent WHO grade IV MG patients (N Engl J Med. 2018 Jul 12;379(2):150-161). Some patients who originally benefitted from the infusion of PVSRIPO demonstrated tumor recurrence, and we hypothesized that retreatment could trigger an immune recall effect, further extending their survival. We now report the impact of second and third intratumoral reinfusion of PVSRIPO in patients treated in the original dose finding study. Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG who were experiencing disease recurrence after having benefitted from the first infusion of PVSRIPO. Additional eligibility criteria included: solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. One patient each was retreated at 1 x 107 TCID50 and 1 x 1010 TCID50, and three patients were retreated on the identified phase 2 dose of 5 x 107 TCID50. Results: As of 2/09/2019, five patients have received a second intratumoral dose of PVSRIPO on study, one of which received a total of 3 doses. The patients who received two infusions of PVSRIPO were retreated 72 months, 43 months, 34 months, and 6 months after the first infusion. One additional patient received a second infusion of PVSRIPO 60 months after the first infusion and a third infusion of PVSRIPO 78 months after the first infusion. All patients demonstrated soap bubble degeneration on imaging, and two patients demonstrated tumor contraction. No grade 3 or higher adverse events related to PVSRIPO were observed after retreatment. Three of these patients remain alive more than 81, 80 and 52 months following the first PVSRIPO infusion and more than 9, 20 and 18 months after the second infusion, respectively. Two patients died 63 months and 20 months after the first infusion of PVSRIPO and 19.6 and 14 months after the second, respectively. The patient treated 3 times received the third infusion more than 2 months ago. Conclusions: Intratumoral reinfusion of PVSRIPO via CED is safe, and encouraging efficacy results have been observed. Clinical trial information: NCT01491893.

Dose finding study of the intratumoral administration of the oncolytic polio/rhinovirus recombinant (PVSRIPO) against WHO grade IV malignant glioma (MG).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13533-e13533
Author(s):  
Annick Desjardins ◽  
John H. Sampson ◽  
Gordana Vlahovic ◽  
Katherine B. Peters ◽  
Dina Randazzo ◽  
...  
Keyword(s):  
Internal Ribosomal Entry Site ◽  
Study Drug ◽  
Oral Poliovirus Vaccine ◽  
Dose Finding ◽  
Entry Site ◽  
Convection Enhanced Delivery ◽  
Who Grade ◽  
Finding Study ◽  
Dose Finding Study ◽  
Grade 3

e13533 Background: The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report results of the dose finding trial evaluating PVSRIPO delivered intratumorally by convection-enhanced delivery (CED). Methods: Eligible patients were adults with recurrent supratentorial WHO grade IV MG; solitary tumor 1-5.5cm in diameter; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS≥70%; and positive anti-polio titer. The original two-step continual reassessment method dose escalation was amended to decrease to dose level(DL) -1 and DL -2 after observing prolonged steroid use in patients treated on higher DLs. Results: As of 2/01/2017, 52 pts were treated on study (1 each at DL1 and DL3, 7 at DL2, 2 at DL4, 4 at DL5, 24 at DL -1 and 13 at DL -2). Only one DLT was observed, a grade 4 intracranial hemorrhage at the time of catheter removal on DL5. Grade 3 or higher adverse events possibly, probably or definitely related to PVSRIPO include: lymphopenia (grade 3, n = 1), steroid myopathy (grade 3, n = 1), cerebral edema (grade 4, n = 1), headache (grade 3, n = 1), dystonia (grade 3, n = 1), pyramidal tract syndrome (grade 3, n = 6), seizure (grade 3, n = 1; grade 4, n = 1), delusions (grade 3, n = 1), hypertension (grade 3, n = 1), and thromboembolic events (grade 3, n = 2). At a median follow-up of 20.1 months, 20.8% of pts remain alive at 36-month post PVSRIPO infusion, compared to 4% of an historical control. Four pts remain alive more than 22 months post treatment without having received any additional intervention following PVSRIPO at 57.5+, 56.4+, 27.9+ and 23.2+ months. Conclusions: Infusion of PVSRIPO via CED is safe and encouraging efficacy results are observed. The dose finding study is now completed and we are initiating clinical trials evaluating combination of PVSRIPO with other therapies. Clinical trial information: NCT01491893.

Safety and pharmacokinetics (PK) of AMG 706 in combination with gemcitabine for the treatment of patients (pts) with solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14005-14005 ◽  
Author(s):  
T. J. Price ◽  
L. Lipton ◽  
J. Williams ◽  
J. McGreivy ◽  
S. McCoy ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Multikinase Inhibitor ◽  
Vein Thrombosis ◽  
Finding Study ◽  
Label Dose ◽  
Grade 3 ◽  
Deep Vein

14005 Background: AMG 706 is an oral, investigational multikinase inhibitor (MKI) with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF and Kit receptors. Methods: This is a fully enrolled, phase 1b, open-label, dose- finding study. The objectives are to determine the maximum tolerated dose and to assess safety and PK of AMG 706 in pts with solid tumors receiving AMG 706 plus gemcitabine. Pts =18 years with ECOG 0–2 and no prior treatment with bevacizumab or VEGFr MKIs were assigned to cohorts receiving escalating doses of AMG 706 (50mg QD, 125mg QD or 75mg BID continuously from day 2 of cycle 1) plus gemcitabine (1000mg/m2 weekly for 7/8 wks, then 3/4 wks per cycle) for up to 11 cycles. Assessments include dose-limiting toxicities (DLT) (weeks 1–4) and tumor response (every 3 months). Results: 26 pts were enrolled and received at least 1 dose of AMG 706 (50mg QD n=11; 125mg QD n=6; 75mg BID n=9). All but 2 pts have completed the study. Median (range) age was 57 (25–77) yrs. 65% of pts received prior chemotherapy; 4 pts received prior gemcitabine (50mg QD n=2; 125mg QD n=1; 75mg BID n=1). There were 2 DLTs: grade 4 neutropenia (125mg QD), grade 3 deep vein thrombosis (75mg BID). Treatment-related adverse events (AE) occurring in = 10% of pts are shown in the table . The mean AMG 706 PK profiles were not markedly different when AMG 706 was dosed on the same day or 24 hours after gemcitabine administration. Objective tumor responses per RECIST for 26 evaluable pts were: 2 unconfirmed PR (50mg QD n=1; 125mg QD n=1), 7 SD (50mg QD n=3; 125mg QD n=1; 75mg BID n=3), 11 PD (50mg QD n=7; 125mg QD n=3; 75mg BID n=1), and 6 not available (125mg QD n=1; 75mg BID n=5). Conclusions: These preliminary data suggest that, in pts with solid tumors, AMG 706 combined with gemcitabine had an expected AE profile at the target once-daily dose of 125mg QD, with little effect on AMG 706 PK. The data provide a foundation for conducting further trials, potentially including biliary tumors. Final data will be presented. [Table: see text] No significant financial relationships to disclose.

Phase I/II study of sorefenib and erlotinib for patients with recurrent glioblastoma (GBM) (NABTC 05–02)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2005-2005
Author(s):  
M. Prados ◽  
M. Gilbert ◽  
J. Kuhn ◽  
K. Lamborn ◽  
T. Cloughesy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Outcome Data ◽  
Recurrent Glioblastoma ◽  
Dose Finding ◽  
Pharmacokinetic Studies ◽  
Eligibility Criteria ◽  
Prior Chemotherapy ◽  
Grade 3

2005 Background: Single agent targeted therapy has been disappointing in GBM. Combination therapy simultaneously targeting both EGFR and the MAP kinase pathway may be more effective. Methods: The NABTC conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with erlotinib (EGFR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 yrs old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior therapies for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design and the MTD was defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 17 patients were enrolled. Median age 50 years (35–69); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and erlotinib 100mg qd. MTD was 400 mg bid of sorafenib daily combined with 100 mg of erlotinib daily. At this dose 1/6 evaluable patients had a DLT (grade 4 lipase). Other grade 3 or 4 toxicities included transaminitis, hypertension, hypophosphatemia, and increased lipase. Pharmacokinetic studies showed no alterations in sorafenib PK, but no accumulation of erlotinib, suggesting a drug-drug interaction with sorafenib altering erlotinib metabolism or clearance. In phase II, 19 patients were accrued to stage I. Median age 51 years (30–75); median prior chemotherapy 2 (range 1–3). Phase II toxicity and outcome data are not yet mature but will be available at the time of presentation. Conclusions: This combination was moderately well-tolerated. MTD was below other combination phase I studies. Sorafenib affected the PK of erlotinib preventing drug accumulation. Phase II toxicity and outcome data will be reported. [Table: see text]

A phase I study of pazopanib (P) combined with bevacizumab (B) in patients with metastatic renal cell carcinoma (mRCC) or other advanced refractory tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4614-4614
Author(s):  
Sylvie Negrier ◽  
David Pérol ◽  
Rastilav Bahleda ◽  
Antoine Hollebecque ◽  
Etienne Chatelut ◽  
...  
Keyword(s):  
Steady State ◽  
Kinase Inhibitors ◽  
Dose Finding ◽  
Uncontrolled Hypertension ◽  
Apparent Clearance ◽  
Finding Study ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Vegfr Inhibitor ◽  
Ecog Ps

4614 Background: Since previous experiments of B with VEGFR tyrosine kinase inhibitors showed overlapping and limiting toxicities, a dose-finding study was designed to explore the safety and feasibility of the combination of a new VEGFR inhibitor P with B, in mRCC treatment-naive patients (pts) or in pts with other advanced refractory solid tumors. Methods: This bicentric trial is conducted with 3+3+3 escalation doses of P + B. The MTD is the highest dosage not expected to cause a dose limiting toxicity (DLT) in more than 2/3, 3/6 or finally 3/9 pts, during the first 8 weeks of treatment. The effect of B on steady-state pharmacokinetic (PK) of P is also investigated. Major inclusion criteria are: ECOG PS ≤1, ALT and AST <=2.5 x ULN, serum creatinine <=1.5 mg/dL or creatinine clearance <=50 mL/mn and absence of uncontrolled hypertension. Results: 15 pts were enrolled with mRCC (n=7), melanoma (n=2), adrenocortical carcinoma (n=1), mesothelioma (n=1), pancreatic cancer (n=1), oesophageal cancer (n=1), bladder cancer (n=1) and seminoma (n=1). Median age is 61 (43-78), 12 pts are male. No DLT were reported at DL1 (P 400 mg/d + B 7.5 mg/kg q2w) (n = 9), or at the first step of DL2 (P 600 mg/d + B 7.5 mg/kg q2) (n=3), but the 3 following nephrectomized pts experienced DLT: a grade 3 transaminitis, a grade 3 pulmonary embolism and a reversible microangiopathic hemolytic anemia. Inclusion of nephrectomized pts was completed, but enrolment of 3 additional non-nephrectomized pts at DL2 was approved by IDSMB in November 2011 and these treatments are ongoing. Preliminary results of PK analysis showed a significantly higher P AUC at steady-state in pts with DLT. Moreover, lower P apparent clearance was observed in nephrectomized pts. Conclusions: The MTD of the combination of P and B is 400 mg/d and 7.5mg/kg respectively, in nephrectomized patients, but is not yet reached in other patients. Unexpected effect of nephrectomy status was observed on P pharmacokinetics.

Impact of care at NCI comprehensive cancer centers (NCICCC) on outcomes in children, adolescents, and young adults (AYA) with central nervous system tumors (CNSt).

2013 ◽  
Vol 31 (31_suppl) ◽  
pp. 123-123
Author(s):  
Julie Anna Wolfson ◽  
Can-Lan Sun ◽  
Tongjun Kang ◽  
Smita Bhatia
Keyword(s):  
Population Based ◽  
Low Ses ◽  
Who Grade ◽  
Barriers To Access ◽  
Race Ethnicity ◽  
Grade 3 ◽  
And Gender ◽  
Evidence Based Care ◽  
The Impact ◽  
To Receive

123 Background: AYA (15-39yo) have not seen the same survival improvement as younger cancer patients with similar diagnoses (dx), leaving an AYA Gap. Treatment on pediatric trials is associated with superior survival in 15-21yo. However, impact of care at NCICCC for complex diseases with poor prognosis that require evidence-based care available at NCICCC (e.g. CNSt), remain unstudied. Methods: We constructed a cohort of 560 children (0-14yo) and 785 AYA with newly-dx CNSt, reported to the LA County (LAC) cancer registry between 1998 and 2008. While 82% of children (0-14y) and 65% of young AYA (15-18y) were treated at one of 3 NCICCC or 3 COG sites in LAC, only 17% of older AYA (19-39y) were treated at one of 3 NCICCC. We sought to determine the impact of NCICCC/COG on overall survival (OS) and barriers to access to care at NCICCC/COG in AYA with CNSt. Since distance to NCICCC/COG could serve as a barrier to accessing care, Geographic Information Systems were used to derive distance between patient’s residence to the nearest NCICCC/COG. Results: OS rates were uniformly good for children and AYA with grade 1 CNSt (96 vs. 89% at 5y, p=0.2) and uniformly poor for children and AYA with grade 3/4 CNSt (43 vs. 43% at 5y, p=0.6). Among patients with WHO grade 2 CNSt, AYA had worse outcome (HR=1.9, p<0.01) after adjustment for race/ ethnicity, SES, and gender. This difference in outcome between AYA and children was abrogated by care at NCICCC (HR 1.4, p=0.2). Furthermore, patients cared at non-NCICCC saw worse outcome (HR=1.6, p=0.04). Compared with children, young AYA (15-18yo) were less likely to receive care at NCICCC (OR=0.3, p=0.02); race/ ethnicity, SES and distance to NCICCC did not influence care at NCICCC. Among older AYA (19-39yo), low SES (OR 0.4, p=0.01), public/ no insurance (OR 0.3, p<0.01) and longer distance to NCICCC (5-12mi: OR=0.3 , p<0.01; >12mi OR 0.5 , p=0.05) reduced likelihood to receive care at NCICCC. Conclusions: Population-based data reveal that receipt of care at NCICCC abrogates the inferior outcome in AYA with WHO grade 2 CNSt. Young AYA are less likely to use NCICCC than children, as are older AYA with low SES, public/ no insurance, or living > 5 miles from an NCICCC.

scholarly journals Phase I Dose-Finding Study of Eltrombopag Following High Dose Cytarabine and Mitoxantrone Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4426-4426
Author(s):  
Mahesh Swaminathan ◽  
Amanda Przespolewski ◽  
Elizabeth A. Griffiths ◽  
James E. Thompson ◽  
Amro Elshoury ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Dose Finding ◽  
High Dose ◽  
Advisory Committees ◽  
High Dose Cytarabine ◽  
Finding Study ◽  
Dose Finding Study ◽  
Grade 3

Abstract Background: Thrombocytopenia is prevalent at presentation and following induction chemotherapy (chemo) regimens in patients (pts) with newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML). Eltrombopag (EPAG), oral, nonpeptide thrombopoietin (TPO)-receptor agonist, is currently approved for treatment of chronic immune thrombocytopenia, hepatitis-associated thrombocytopenia, and aplastic anemia. It has also been evaluated as a strategy to mitigate chemo-induced thrombocytopenia in pts with solid tumors, myelodysplastic syndrome, and following allotransplant. Prior studies have demonstrated that EPAG can directly inhibit the proliferation of human AML cells in vitro. Although EPAG has been studied following induction and consolidation chemo in the frontline AML setting, to date, the tolerability and efficacy of EPAG in pts receiving salvage chemo for R/R AML is not known. Objectives: This study's objectives were to (a) estimate the maximum tolerated dose (MTD) and tolerability of EPAG, (b) examine platelet (plt) response (defined as plt count ≥ 100 x 10 9/L), and (c) anti-leukemic activity of EPAG in pts receiving high dose cytarabine (HiDAC) and mitoxantrone (Mito) for R/R AML. Methods: In this phase I open-label study, adult pts (³ 18 yrs) with R/R AML with adequate organ functions and grade 4 thrombocytopenia following HiDAC (given every 12 hrs (3 g/m 2 for age &lt; 50; 1.5 g/m 2 for age ≥50) for 12 doses) and Mito (dosed at 12 mg/m 2 x 3 doses every other day) were eligible. All pts must have had marrow hypoplasia demonstrated on Day 14 ± 3 days from the initiation of HiDAC. EPAG was started daily on Day 14 ± 3 days with dose determined using a standard '3+3' dose-escalation design. EPAG was discontinued if an adequate plt response was achieved or following 9 weeks of therapy. The dose-limiting toxicity (DLT) window was defined as the first 15 days of EPAG dosing. Results: Nine pts with R/R AML were enrolled (Table 1). Median age was 64 yrs (range, 33-80), and 5 pts were men. All pts had intermediate (6/9, 67%), adverse (2/9, 22%), or unknown (1/9, 11%) cytogenetic risk disease. One (1/9) pt had NPM1+FLT3-ITD+ disease. Five pts (56%) had relapsed disease (2pts had prior allotransplant). All pts received HiDAC+Mito chemo and started on EPAG on Day 14 ± 3 days. Three received EPAG 150 mg, and 6 pts received 200 mg daily. The median duration on EPAG was 26 days (range, 11-82). One pt experienced a DLT of grade 3 myocardial ischemia while receiving EPAG 200 mg/day and was taken off study. No other DLTs were reported, and no MTD was determined. The most frequent grade ³3 adverse events (AEs, Table 2): were bacteremia (56%), neutropenic fever (44%), and hyperbilirubinemia (33%). Similarly, common grade 1-2 AEs consisted of hyperbilirubinemia, tachycardia, and confusion (33% each, respectively). At a median follow-up of 30.3 months (mo), all 9 pts had discontinued EPAG. Six pts (67%) achieved plt response (3 each in 150 mg and 200 mg/day dose level). The median time to achieve plt response and the duration of plt response was 27 days (range, 14-41) and 40.5 mo (range, 2-49.6), respectively. Three other pts discontinued EPAG therapy: 1 each due to cardiac ischemia, donor lymphocyte infusion, and patient choice, respectively (Table 3). Of note, 7/9 pts (78%) had clinical response: CR in 5 (56%), CRc (CR+CRp) in 6 (67%), MLFS in 1 (11%, Table 4). Two (2/7 responders) went on to subsequent allotransplant, and 6 died; 2-progressive disease, one each from pneumonia, failure to thrive, encephalopathy, and unknown cause, respectively. Among the 6 pts who achieved plt recovery on EPAG, 5 achieved CR and 1-MLFS following HiDAC+Mito. Conclusion: This phase 1 dose-finding study demonstrated that EPAG 150-200 mg daily following HiDAC+Mito chemo for R/R AML was well tolerated with one DLT of cardiac ischemia (200 mg dose). Two-thirds (67%) of pts achieved plt recovery on EPAG after a median of 27 days (range, 14-41). In these small number of pts (n=9), addition of EPAG therapy did not seem to adversely affect clinical outcomes (CRc 67%) and may have contributed to long-term platelet recovery. Further studies are required to determine the optimal schedule and potential benefit of EPAG added to chemo regimens for R/R AML. Figure 1 Figure 1. Disclosures Przespolewski: Jazz: Research Funding. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Taiho Oncology: Consultancy, Honoraria; Boston Biomedical: Consultancy; Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Elshoury: Bristol Meyers Squibb: Other: advisory board. Wang: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Phase II study of irofulven in recurrent or metastatic gastric cancer: A Cancer Therapeutic Research Group (CTRG) study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14105-14105
Author(s):  
H. C. Chung ◽  
W. Yeo ◽  
S. Y. Rha ◽  
M. Boyer ◽  
S. Y. Ong ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Study Drug ◽  
Metastatic Gastric Cancer ◽  
Eligibility Criteria ◽  
First Line Therapy ◽  
Kaplan Meier ◽  
Impact On Survival ◽  
Grade 3 ◽  
Therapeutic Research

14105 Background: Cytotoxic chemotherapy has been widely used in patients (pts) with advanced or metastatic gastric cancer, but the reported high response rates in phase II settings have not been confirmed by randomized trials. Moreover, the therapeutic impact on survival has been modest. The purpose of this study was to evaluate Irofulven, a DNA interacting acylfulvene analog, as first line therapy for pts with recurrent or metastatic gastric cancer. Methods: The main eligibility criteria were: Histologically or cytologically confirmed disease; age > 18 yrs; ECOG ≤ 2; measurable disease; no prior chemotherapy for recurrent or metastatic disease; life expectancy > 3 months. Irofulven was given at 0.45 mg/kg i.v. over 30-min infusion (max. 50 mg), on Day 1 and 8, every 3 weeks. The primary endpoint was treatment response and toxicity; the secondary end-point was survival. A 2-stage phase II design was used. In the first stage, the target enrollment was 20, if ≤ 2 responses were observed, the study would be stopped and the treatment concluded to be ineffective; if ≥ 6 responses were observed, the study drug would be concluded to be active. Otherwise, another 15 pts would be entered into the second stage. Survival was constructed using the Kaplan-Meier method. All patients entering the trial were included in the survival analysis. Results: 23 pts were entered into the first stage. The median no. of cycles per pt was 2 (range: 1–6). 2 pts (9%) had ≥ 1 week delay in administration of subsequent cycle of chemotherapy. For the day 8 chemotherapy, 7 pts (30%) required dose reductions; 5 (22%) had dose omitted. 22% and 17% pts developed grade 3/4 anemia and neutropenia respectively. There was no grade 4 thrombocytopenia or neutropenic fever. Of the 20 evaluable pts, no responses was observed, 3 pts had stable disease after 2 cycles of treatment which was not confirmed by a further assessment. Median overall survival was 6.05 months (95% CI 4.55–9.39). Conclusions: Irofulven was tolerated at the described dose but showed no evidence of antitumor activity in patients with advanced gastric cancer. Acknowledgement: The study was sponsored by the Division of Cancer Treatment and Diagnosis, National Cancer Institute, U.S.A, and its collaborator MGI Pharma, Inc. No significant financial relationships to disclose.

Phase I/II trial of bortezimib and pemetrexed in patients with advanced non-small cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18145-18145 ◽  
Author(s):  
R. B. Natale ◽  
M. McKinley ◽  
J. Hilger ◽  
T. Myers
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Mantle Cell ◽  
Finding Study ◽  
Heavily Pretreated ◽  
Level 3 ◽  
Previously Treated Patients ◽  
Grade 3 ◽  
Dose Levels

18145 Background: Bortezomib (Vc) is a novel proteosome inhibitor with activity in several malignancies including multiple myeloma, mantle cell lymphoma, and NSCLC. In NSCLC, Vc has additive activity combined with carboplatin and gemcitabine in first line and with docetaxel in second line treatment. Pemetrexed (P) is active in NSCLC and preclinical data suggests a pro-apoptotic synergy between Vc and P. Therefore, we initiated a phase I/II dose finding study of Vc + P in previously-treated patients (pts) with advanced or metastatic NSCLC. Methods: Fifteen pts have been accrued to 3 of 4 planned dose levels of Vc + P. Starting doses (and # pts treated) were Vc 1.4 mg/m2 day 1 & 8 + P 400 mg/m2 day 1 every 3 weeks (3 pts). The 2nd and 3rd dose levels were Vc 1.6 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (8 pts, 5 new + 3 from dose level 1) and Vc 1.8 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (7 pts). Results: 15 pts are evaluable for response and toxicity and include 8 males, 7 females, median age 67 (range, 55–82), PS 0/1 (3/12 pts), median of 2 prior therapies (range 1–3). Confirmed PRs occurred in 2 pts (13%) and stable disease in 5 (33%). Dose limiting toxicities consisted of grade 4 fatigue (1 pt) and neutropenia/fever (1 pt) at dose level 2, and grade 3 abdominal pain and fatigue (1 pt) and grade 3 diarrhea and vomiting (1 pt) at dose level 3. Conclusions: The above combination is safe at the doses tested thus far and active in pts with heavily pretreated, advanced NSCLC. We are currently exploring Vc 2.0 mg.m2 Day 1 & 8 + P 500 mg/m2 day 1 every 3 weeks to determine the MTD and plan a multi-site Phase II study to determine response rate and survival in a larger pt population. No significant financial relationships to disclose.

Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4559-4559
Author(s):  
C. Kim ◽  
J. Lee ◽  
Y. Choi ◽  
B. Kang ◽  
M. Ryu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Finding Study ◽  
Level 3 ◽  
Dose Finding Study ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

4559 Background: We conducted a phase I dose-finding study of sorafenib (S) in combination with capecitabine (X) and cisplatin (P) in patients with previously untreated metastatic or inoperable advanced gastric cancer. Methods: Four dose levels of S, X, and P combination were tested. The doses of S (p.o. daily), X (p.o. on days 1–14), and P (i.v. on day 1) were escalated at the following schedule; level 1: S 400 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 2: S 800 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 3: S 800 mg/d, X 2,000 mg/m2/d, P 80 mg/m2; level 1A: S 800 mg/d, X 1,600 mg/m2/d, P 60 mg/m2. The cycle was repeated every 3 weeks. Dose limiting toxicities (DLTs) were evaluated only in the first cycles and a standard 3+3 dose escalation design was implemented. Results: A total 21 pts were enrolled in the study. No DLTs were observed at dose level 1 (n=3). One DLT (grade 3 diarrhea) was noted at dose level 2 (n=6), and 2 DLTs (two grade 4 neutropenias longer than 5 days in duration) were observed at dose level 3 (n=6), which made the level 3 dose the maximum tolerated dose (MTD). However, at cycle 2 and thereafter at dose level 2, the relative dose intensity (RDI) of S and X could not be maintained (mostly below 80%) due to the frequent dose reductions and cycle delays. So, we explored a new dose level (1A) between dose level 1 and 2. Since no DLTs were found in 6 patients at level 1A with RDI mostly above 80% throughout the treatment period, level 1A was determined as recommended dose (RD). Most frequent grade 3 and 4 hematologic toxicities were neutropenia (25.0% of cycles), and most frequent grade 2 and 3 non-hematologic toxicities were hand-foot syndrome (9.4%), asthenia (7.0%), and anorexia (5.5%). The objective responses were confirmed in 10 out of 16 patients with measurable lesions (62.5%; 95% CI, 38.8–86.2%). With a median follow-up of 8.1 months, estimated median progression-free survival was 10.0 months (95% CI, 1.6–18.4 months) and median overall survival has not been reached. Conclusions: Diarrhea and neutropenia were DLTs in this S, X, and P combination. The dose schedule of sorafenib 400 mg po bid daily with capecitabine 800 mg/m2 po bid on days 1–14, and cisplatin 60 mg/m2 iv on day 1 in every 3 weeks is recommended for further development in AGC. [Table: see text]

A prospective PGx and PK/PD dose-finding study of irinotecan based on UGT1A1*6 and *28 genotyping (UGT0601)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14560-e14560
Author(s):  
T. Esaki ◽  
T. Satoh ◽  
T. Ura ◽  
T. Tsujinaka ◽  
Y. Sasaki ◽  
...  
Keyword(s):  
Initial Dosage ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Hematological Toxicity ◽  
Continual Reassessment Method ◽  
Continual Reassessment ◽  
Finding Study ◽  
Dose Finding Study ◽  
Grade 3 ◽  
Dose Limiting Toxicity

e14560 Background: UGT1A1*6 as well as UGT1A1*28 polymorphisms is associated with decreased glucuronidation of SN-38, the active metabolite of irinotecan (CPT-11). Although the maximum tolerated dose (MTD) and the recommended dose (RD) in Hetero was determined 150 mg/m2 (approval dose in Japan), those of Homo were unknown. Methods: Pts received prior chemotherapies except for CPT-11 for metastatic gastrointestinal cancer were enrolled. UGT1A1 polymorphisms were categorized into Wild(*1/*1), Hetero(*1/*28, *1/*6), and Homo(*28/*28, *6/*6, *28/*6). CPT-11 was administered biweekly. Starting doses were 150 mg/m2 in Wild, 100 mg/m2 in Hetero, and 75 mg/m2 in Homo. DLT was defined as grade 4 hematological, or grade 3 non-hematological toxicity. MTD closest to dose-limiting toxicity (DLT) appearance of 30% was guided by the continual reassessment method in the cohort of Hetero and Homo. DLT and pharmacokinetic (PK) sampling was evaluated during the 1st cycle. Results: Eighty-two pts were enrolled from November 2006 to November 2008 (Wild, Hetero, Homo: 41, 20, and 21, respectively). The dose level reached at 150 mg/m2 in Homo. At 150 mg/m2, DLT was observed in six pts of Homo (grade 4 neutropenia, grade 3 diarrhea: 6 and 1, respectively). The probability of DLTs were 22.2% at 125 mg/m2, and 37.4% at 150 mg/m2. The MTD was determined 150 mg/m2 in pts with Homo group. However, the incidences of grade 3/4 neutropenia at 150 mg/m2 during the 1st cycle were 9.8% (4/41), 18.8% (3/16), and 62.5% (10/16) in Wild, Hetero, and Homo, respectively. And the second administration was delayed 7 days or more in most pts in Homo (63% at 150 mg/m2). In one pt of Homo for *28/*28 died of septic shock during the 2nd cycle. SN-38 AUC (0–24h, ng*hr/mL, median) was 239 in Wild, 237 in Hetero, and 410 in Homo. Pts with Homo showed the different trend of PK/PD compared to those with Wild and Hetero. Conclusions: The MTD was 150 mg/m2 in pts with Homo group and the most frequent DLT was grade 4 neutropenia. However, our findings suggest that 150 mg/m2 q2w is difficult to recommend and the initial dosage and administration should be considered carefully for pts with Homo. [Table: see text]

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