The safety profile of eltrombopag, a novel oral platelet growth factor, in thrombocytopenic patients and healthy subjects

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 18596-18596 ◽  
Author(s):  
D. Provan ◽  
M. Saleh ◽  
S. Goodison ◽  
R. Rafi ◽  
N. Stone ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Phase Ii ◽  
Platelet Function ◽  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Serious Adverse Events ◽  
Parallel Group ◽  
Apparent Relationship ◽  
Tolerability Data

18596 Background: Eltrombopag (SB-497115) is an oral, non-peptide, small molecule, thrombopoietin receptor agonist being tested as a potential treatment for thrombocytopenia. Eltrombopag has been shown to increase platelet counts in both healthy subjects and thrombocytopenic patients. Methods: Safety and tolerability data for eltrombopag (3–75 mg for up to 6 weeks) is presented from randomized, placebo-controlled, parallel group clinical trials involving 115 healthy subjects and 104 immune thrombocytopenic purpura (ITP) patients. Safety and tolerability endpoints involved assessment of adverse events (AE) and clinical laboratory parameters, including ECGs and platelet function. Results: In 3 Phase I trials, 98 healthy males received active eltrombopag QD for up to 10 days at 3–75 mg. In the Phase II dose ranging study, 78 chronic ITP patients (28 male/50 female) received active eltrombopag QD for 6 weeks at doses of 30–75 mg. There was no apparent relationship between active and control arms, the dose of eltrombopag and the incidence or severity of AEs, changes in laboratory values, platelet function or cardiac parameters in any of the studies. There were no serious adverse events (SAEs) reported by subjects in the 3 Phase I studies. 5 SAEs were reported in 1 patient in the ITP study that were considered by the investigator as possibly associated with administration of 50 mg eltrombopag. No SAEs were related to 30 mg or 75 mg eltrombopag, and 2 SAEs in 2 patients were related to placebo. Conclusions: There was no apparent relationship between eltrombopag dose and safety endpoints in these studies. These encouraging safety and tolerability data support the further testing of eltrombopag in phase II and III studies involving patients with ITP and chronic liver disease, and cancer patients receiving thrombocytopenic chemotherapy. [Table: see text]

Association of serious adverse events with type and sponsorship of clinical trials in patients with lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6576-6576
Author(s):  
T. L. Koeneke ◽  
J. O. Armitage ◽  
P. J. Bierman ◽  
R. Bociek ◽  
J. M. Vose ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Phase I ◽  
Phase Ii ◽  
Medical Center ◽  
Stage Iv ◽  
Large Cell ◽  
Phase Iii ◽  
Serious Adverse Events ◽  
Early Phase Clinical Trials

6576 Background: Arguments have been made against early phase clinical trials (CTs) as possibly being unethical because its risk may outweigh its potential benefits. Whether this is true in the light of newer biological treatment for cancer is unknown. We therefore examined the association between the incidence of serious adverse events according to type and sponsorship of CTs in pts with lymphoma. Methods: All IRB approved CTs at the University of Nebraska Medical Center from Jan 2000-June 2005 classified as therapeutic for lymphoma involving a biological agent were included. CTs were classified in two ways: by type of CTs (phase I vs II vs III) and sponsorship (Investigator-initiated vs Industry-initiated. Multivariate logistic regression was used to evaluate the association between types/sponsorship of CTs with the incidence of IRB serious adverse events (SAE; no vs yes) and fatal adverse events (FAE; no vs yes) while adjusting for age, sex, race, lymphoma type and stage, interval from dx to tx, co-morbid conditions, and previous tx. Results: 357 pts with lymphoma enrolled in 29 CTs were included. The median age of pt was 54y (21–88). 41% of the pts had follicular lymphoma, 36% diffuse large cell, 14% mantle cell and 9% were other types. 59% had Stage IV lymphoma. 71% of the pts participated in investigator-initiated CTs, while 29% participated in industry-initiated CTs. 21% of pts were enrolled in phase I, 65% in phase II and 14% in phase III studies. SAEs were seen in 49 pts (14%), while FAEs occurred in 13 pts (4%). Multivariate analysis showed the risk of having SAE was independent of the type or sponsor of CTs. Additionally, the risk of FAEs was not associated with the type of CTs. However, the risk of having FAEs was less in investigator- iniatiated CTs than in industry-iniatiated trials (Odds Ratio: 0.13 (95% CI, 0.03–0.61, p = 0.01). Conclusions: Our study showed that in CTs involving biological treatments, the incidence of SAEs was not associated with the type or sponsor of CTs suggesting that use of biological agents in phase I studies may have similar risks to phase II/III trials. Further studies should be done in other types of malignancies to evaluate further the decrease frequency of FAEs seen in investigator-initiated trials. No significant financial relationships to disclose.

A phase I trial of a local delivery of siRNA against k-ras in combination with chemotherapy for locally advanced pancreatic adenocarcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4037-4037 ◽  
Author(s):  
Talia Golan ◽  
Ayala Hubert ◽  
Amotz Shemi ◽  
Amiel Segal ◽  
Alan Dancour ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Pancreatic Adenocarcinoma ◽  
Phase Ii ◽  
Locally Advanced ◽  
Primary Study ◽  
Open Label ◽  
Serious Adverse Events ◽  
Line Setting

4037 Background:K-Ras mutation G12D is most prevalent in pancreatic adenocarcinoma (PDAC). siRNA against the K-RasG12D(siG12D) mutant had showed significant preclinical anti-tumor effects. siG12D LODER - miniature biodegradable polymeric matrix that encompasses anti-K-RasG12D siRNA drug, is placed with Endoscopic US biopsy and designed to continuously release the drug regionally over a period of 4 months. Methods: Open label phase I study of patients with locally advanced non-operable PDAC in the first-line setting. Patients were assigned to receive siG12D LODERs in dose escalation cohorts: 0.025mg, 0.75mg and 3.0mg. Gemcitabine 1000 mg/m2IV was given weekly, following siG12D LODER insertion. The RP2D (recommended phase II dose) was further examined in 3.0 mg dose cohort in combination with modified Folfirinox (Oxaliplatin 85mg/m2, Irinotecan 150mg/m2, Fluorouracil infusion 2,400mg/m2 46 hours, every 2 weeks). Follow up period was 8 weeks and survival follow up until death. Primary study objectives were to determine the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Results:15 patients have been enrolled. 2 patients were omitted from study due to metastatic disease detected on day 1 post siG12D LODER implant imaging . Median age = 70 (range 52-85); male:female 8:7. Among 13 treated patients, the most frequent adverse events observed in the study were typically grade 1- 2 in severity; 4 patients experienced serious adverse events (SAE), one procedure related. No DLTs were observed. MTD was not reached. CT performed 8-10 weeks following the procedure showed stable disease in all patients. Reduction in tumor marker CA 19-9 was observed in 64% (7/11) of patients. The median survival of 13 patients was 16 months ( 8/13 patients still alive at analysis). Conclusions: The combination of siG12D LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in locally advanced PDAC with durable responses. Phamocodynamic endpoints are currently being examined in an expansion cohort in operable patients. A phase II randomized trial is planned in order to investigate efficacy of siG12D LODER in locally advanced non-operable PDAC. Clinical trial information: NCT01188785.

A Phase I Study To Investigate the Pharmacokinetics (PK) and Pharmacodynamics (PD) of an Oral Platelet Growth Factor (SB-559448) in Healthy Subjects.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1072-1072 ◽  
Author(s):  
Sheng-Fang Su ◽  
Bin Peng ◽  
Daphne Williams ◽  
Jung Wook Park ◽  
Malcolm L. Handel ◽  
...  
Keyword(s):  
Platelet Count ◽  
Adverse Events ◽  
Phase I ◽  
Healthy Subjects ◽  
Phase I Study ◽  
Pharmacokinetic Profile ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Orally Bioavailable

Abstract Introduction: SB-559448, is an orally bioavailable, non peptide, small molecule thrombopoietin receptor agonist that induces proliferation and differentiation of megakaryocytes and progenitor cells, ultimately increasing the production of platelets. Method: In a randomized, single blind, placebo-controlled, parallel group, phase I study in healthy subjects, SB-559448 was administered as oral capsules once daily for 1 day and, after a 7-day washout, for 10 days at doses of 160 to 640 mg. In this dose escalation study, subjects were randomized into 4 groups of 9 subjects to receive either active or placebo medication in a ratio of 6:3. Serial blood samples were collected to determine SB-559448 concentrations and estimate PK parameters following single- and repeat-dosing. PD assessments were performed every 4 to 5 days up to 31 days following initiation of repeat dosing. Results: The preliminary results showed that SB-559448 was well tolerated in the study, there were no serious adverse events, no significant changes in laboratory or cardiovascular safety parameters and there was no observed relationship between the incidence or severity of adverse events and dose. Most adverse events were mild in intensity and self-limiting. SB-559448 was also shown to be orally bioavailable in humans with a pharmacokinetic profile suitable for a once daily oral dosing. When administered at oral doses of 160 mg and above for 10 days, a dose dependent increase in the platelet count was observed with maximum platelet count observed on days 14 to 15 following initiation of repeat dosing. Conclusion: The results suggest that SB-559448 is an orally administered agent that increased platelet counts in healthy subjects. Additional studies will be needed to evaluate its effects in individuals with thrombocytopenia.

scholarly journals A phase I study of a dual PI3-Kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Serious Adverse Events ◽  
Efficient Treatment

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single centre open lable study was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia.Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort -1/1)) to assess safety, tolerability, preliminary efficacy and pharmakokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3+3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n=11) or AML (n=12) or CML-BP (n=1) were enrolled. All patients had failed one (n=5) or more lines of therapy (n=5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. registered 19th Decembre 2012, https://clinicaltrials.gov/ct2/show/NCT01756118

scholarly journals A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Open Label ◽  
Serious Adverse Events ◽  
Efficient Treatment ◽  
Link Type

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

scholarly journals OC 8521 PRELIMINARY REPORT ON SAFETY OF CO-ADMINISTERED HUMAN HOOKWORM VACCINE CANDIDATES NA-APR-1 (M74)/ALHYDROGEL® AND NA-GST-1/ALHYDROGEL® IN GABONESE CHILDREN

2019 ◽  
Vol 4 (Suppl 3) ◽  
pp. A12.1-A12
Author(s):  
Jeannot Fréjus Zinsou ◽  
Josiane Honpkehedji ◽  
Dejon Agobe Jean Claude ◽  
Bayodé R Adegbite ◽  
Jean Ronald Edoa ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Clinical Laboratory ◽  
School Age Children ◽  
Public Health Issue ◽  
Double Blind ◽  
Middle Income ◽  
Vaccine Candidates ◽  
Grade 3 ◽  
Randomised Controlled

BackgroundHuman hookworm infection is a major public health issue in tropical low and middle-income countries with severe consequences. To date, improvement of water supply, sanitation, and hygiene is the major contributor to disease control, and additional control tools are needed. Here, we assess a phase I trial of a new hookworm vaccine candidate Na-APR-1 (M74)/Alhydrogel and Na-GST-1/Alhydrogel in Gabonese school-age children.MethodsA double-blind, randomised, controlled, dose-escalation phase I clinical trial that aims to evaluate safety, reactogenicity and immunogenicity of Na-APR-1 (M74)/Alhydrogel co-administered with Na-GST-1/Alhydrogel hookworm vaccines in children aged 6 to 10 years living in hookworm-endemic area of Lambaréné, compared to the hepatitis B vaccine (ENGERIX-B). Children received three doses of assigned vaccines, delivered intramuscularly (deltoid) on Days 0, 56, and 112 or 180. Safety is measured from Day 0 through Day 14 by the occurrence of solicited injection site and systemic reactogenicity events. Clinical laboratory evaluations were performed approximately 14 days after each immunisation. Unsolicited adverse events were collected from Day 0 through approximately 1 month after each vaccination.ResultsA total of 135 children were screened, and 60, aged 6 to 10 years old, were randomised into 3 groups and received 10 µg, 30 µg or 100 µg of Na-APR-1 (M74)/Alhydrogel and Na-GST-1 Alhydrogel, respectively, compared to ENGERIX-B. At baseline, the mean age of the study population was 7.4 years and the sex ratio 1.3 (male: female). From Day 0 up to Day 14 after vaccination, the main solicited adverse events were pain and swelling at injection sites with 135 (26 of grade 2 and 1 of grade 3) and 9 events, respectively. Regarding systemic adverse events, 3 occurrences of grade 1 headache were recorded. Immunogenicity analyses are underway.ConclusionThe preliminary results confirm that co-administration of the two hookworm vaccine candidates is safe and well-tolerated in Gabonese children.

scholarly journals Risk assessment based on the Risk Index for Serious Adverse Events (SAEs) in Phase I trials

2017 ◽  
Vol 28 ◽  
pp. ix108
Author(s):  
Sigehiro Koganemaru ◽  
Yasutoshi Kuboki ◽  
Kohei Shitara ◽  
Shogo Nomura ◽  
Hideaki Takahashi ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Adverse Events ◽  
Phase I ◽  
Risk Index ◽  
Phase I Trials ◽  
Serious Adverse Events

scholarly journals Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Henglin Yang ◽  
Jingyan Wang ◽  
Hui Liu ◽  
Xingliang Li ◽  
Renhua Nie ◽  
...  
Keyword(s):  
Adverse Events ◽  
Southeast Asia ◽  
Clinical Laboratory ◽  
Protective Efficacy ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Prophylactic Efficacy ◽  
Content Type ◽  
Double Blind Placebo ◽  
Intention To Treat

ABSTRACTNew prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for 2 months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated, without any serious adverse events. Four adverse events (transient and slight elevations of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, againstPlasmodium falciparuminfections, whereas both offered 100% prophylactic efficacy againstPlasmodium vivaxandPlasmodium ovale. These trials showed that NQAZ had a good safety profile, and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.

Fludarabine-Based Conditioning for Allogeneic Marrow Transplantation From Unrelated Donors in Severe Aplastic Anemia (SAA): Serious and Unexpected Adverse Events in Pre-Defined Cyclophosphamide (CY) Dose Levels

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3009-3009
Author(s):  
Jakub Tolar ◽  
H. Joachim Deeg ◽  
Sally Arai ◽  
Mitchell Horwitz ◽  
Joseph H. Antin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Marrow Transplantation ◽  
Graft Failure ◽  
Marrow Transplant ◽  
The Other ◽  
Unrelated Donor ◽  
Dose Levels

Abstract Abstract 3009FN2 Objective: To determine toxicity and efficacy of adding fludarabine (FLU) to a regimen of total body irradiation (TBI), anti-thymocyte globulin (ATG) and cyclophosphamide (CY), with de-escalation of the CY dose. The goal is to minimize CY-related toxicities while preserving (or improving) engraftment and survival in patients with SAA receiving an unrelated donor marrow transplant. Patients and Methods: Since May 2006, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), sponsored by the NHLBI and NCI, has conducted a prospective Phase I/II clinical trial of unrelated donor marrow transplantation in SAA (BMT CTN 0301). Patients with SAA are eligible if they are < 65 years, have adequate organ function, and have an available unrelated marrow donor matched 7 of 8 HLA-A, B, C, DRB1 loci. Patients with Fanconi anemia and other marrow failure syndromes are excluded. All patients receive TBI 200 cGy, ATG (either thymoglobulin: 3 mg/kg IV or ATGAM 30 mg/kg IV daily × 3, days –4 to –2), FLU (30 mg/m2 IV daily × 4, days –5 to –2). The Phase I portion of the trial sequentially tested four CY dose levels: 150 mg/kg (administered days –4 to –2); 100 mg/kg (days –3 to –2); 50 mg/kg (day –2); and, 0 mg/kg, and allowed enrollment of up to six patients at each CY dose level unless toxicity or graft failure boundaries were crossed. In the Phase II portion of the trial, patients enroll onto the optimal CY dose level, which is chosen using adaptive Bayesian criteria to rank desirability of the CY doses. All patients are followed for two years after transplantation. Early stopping guidelines are used to monitor for graft failure and early transplant-related mortality through day 100. Results: Twenty-one patients accrued to the Phase I portion of the trial. CY dose level 0 mg/kg was closed after all three enrolled patients developed secondary graft failure. All received a second allograft. One patient remains alive at 23 months after the first transplantation. The other two died from adult respiratory distress syndrome (ARDS) at 114 days after the first transplant and idiopathic pneumonia at 200 days after the first transplant. Review of Phase I results for the other three dose levels suggested CY dose 150 mg/kg as the optimal dose level for Phase II testing. However, after an additional eight patients were treated at this dose, the level was closed to further accrual because of excess toxicity. Seven of the 14 patients receiving 150 mg/kg of CY (and 7 of the last 8 enrolled) died. Causes of death were cardiac/pulmonary/multi-organ failure (n=4), ARDS (n=2), and parainfluenza virus type 3 pneumonia (n=1). Bayesian evaluation of the two remaining dose levels indicates very similar desirability scores and accrual continues at both the CY 100 mg/kg and 50 mg/kg levels. As of July 15, 2011, a total of 61 patients have been enrolled, 17 on the two closed levels, 33 on the 100 mg/kg level and 11 on the 50 mg/kg level. Conclusions: Early analysis of this trial, made necessary by these unexpected severe adverse events, revealed two important findings among patients receiving low-dose TBI, ATG, and FLU at the doses outlined: 1) CY dose 0 mg/kg is associated with higher than expected graft failure; and, 2) CY dose 150 mg/kg is associated with excess transplant-related toxicity. Neither CY dose level should be tested further in the context of the regimen used in this trial. To date, the two intermediate CY dose levels (100 mg/kg and 50 mg/kg) have not crossed the graft failure or fatality stopping boundaries and accrual is in progress. Disclosures: Pulsipher: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

A phase I/II study of biweekly XELIRI plus bevacizumab for patients with metastatic colorectal cancer as second-line chemotherapy (BIXER study): Reports of phase I part and interim analysis of phase II part.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 643-643
Author(s):  
Mitsukuni Suenaga ◽  
Satoshi Matsusaka ◽  
Eiji Shinozaki ◽  
Nobuyuki Mizunuma ◽  
Kiyohiko Hatake ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Interim Analysis ◽  
Japanese Patients ◽  
Recommended Dose ◽  
Grade 3 ◽  
Dose Limiting Toxicity

643 Background: Capecitabine is an oral fluoropyrimidine prodrug, which is converted to fluorouracil (5-FU) predominantly in the tumor cells. In Japan, capecitabine is mainly used in combination with oxaliplatin (XELOX) in treatment for metastatic colorectal cancer (mCRC) since its approval in 2009. The results of capecitabine plus Irinotecan (CPT) (XELIRI) with or without bevacizumab (BV) in EU or US patients were previously reported, but not in Japanese. Thus, we conducted this study to assess the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC. Methods: Patients with prior chemotherapy including oxaliplatin and BV for mCRC, wild or hetero type of UGT1A1 *6*28 were eligible for this study. This was a phase I study composed of two steps, and dose limiting toxicity (DLT) was assessed during the first treatment cycle. Treatment comprised capecitabine 1,000 mg/m2 twice daily from the evening of day 1 to the morning of day 8, intravenous CPT 180 mg/m2 on day 1, and BV 5mg/kg on day 1 every two weeks. To evaluate the initial safety, 3-6 patients received XELIRI+BV (CPT 150mg/m2) in step 1, and 6 patients received XELIRI+BV (CPT 180mg/m2) in step 2. If DLT occurred in 1 patient in step1, 3 patients would be newly added to step 1, and if in none of 3 or 1-2 of 6 patients, the step 2 would be started. If DLT occurred in less than or equal to 2 of 6 patients in step 2, phase II study would be proceeded, and if In more than 2 of 6 patients, phase II would be conducted at the recommended dose of step 1. Results: In step 1 and 2 of phase I, initial safety of 9 patients was confirmed without occurrence of DLT. Adverse events observed in step 1 and 2 were: neutropenia in 2 and 1; anorexia in 1 and 1; diarrhea in 1 and 1; stomatitis in 1 and 1; alanine or aspartate aminotransferase increased in 1 and 3, respectively. There was no grade 3 or greater adverse events. Conclusions: In mCRC patients with wild or hetero of UGT1A1*6*28 genotype, safety of biweekly XELIRI+BV was confirmed and recommended dose of CPT-11 was determined as 180mg/m2. Interim analysis of safety of phase II part will be reported at the meeting.

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