X-TRAP: Phase I/II study of capecitabine (X) plus ziv-aflibercept (TRAP) in metastatic colorectal cancer (mCRC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 687-687 ◽  
Author(s):  
John H. Strickler ◽  
Fatima A. Rangwala ◽  
Christel Rushing ◽  
Donna Niedzwiecki ◽  
Ivy Altomare ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Oral Mucositis ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Clinical Activity ◽  
Combination Methods ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Expansion Cohort

687 Background: Patients (pts) with chemotherapy refractory mCRC have a poor prognosis, with a median survival of approximately 6 months (mos). Ziv-aflibercept is FDA-approved in combination with FOLFIRI for the 2nd line treatment of mCRC, but its tolerability and activity in pts with chemotherapy refractory disease is unknown. We designed a phase I/II study of X+TRAP to define the recommended phase II dose (RPTD), and assess the safety, tolerability, and clinical activity for the combination. Methods: Eligible pts with refractory, advanced solid tumors were enrolled in a 3+3 dose escalation cohort (ESC) to identify the RPTD. Cycle length was 21 days. Radiographic assessment occurred every 3 cycles. X was administered po bid on days 1-14. The dose of X was 850 mg/m2 bid in ESC cohort 1 and 1,000 mg/m2 bid in ESC cohort 2. TRAP was administered on day 1 of each cycle (6 mg/kg IV). Pts with mCRC that had progressed on all standard therapies were then enrolled in a single-arm, phase II expansion cohort (EXP) and treated at the RPTD. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Results: As of 6/19/2015, 55 pts were evaluable for toxicity (13 ESC; 42 EXP) and 47 pts were evaluable efficacy (12 ESC; 35 EXP). In the phase I ESC cohorts, 3 DLTs occurred (1/6 cohort 1; 2/6 cohort 2): GI perforation (1), oral mucositis (1), and fatigue (1). The RPTD was X (850 mg/m2 po bid, days 1-14) and TRAP (6 mg/kg IV, day 1). In the ESC and EXP cohorts, there were no treatment related grade 4/5 adverse events (AEs). The most frequently reported treatment related AEs (grades 2+3; grade 3) were palmar-plantar erythrodysesthesia (36%; 5%), hypertension (29%; 20%), and oral mucositis (18%; 4%). Median follow up in the phase II EXP cohort was 9.3 mos (95% C.I., 6.5–11.1). Median PFS was 4.1 mos (95% C.I., 2.3-4.8). Response assessment in 35 pts (n; %): partial response (PR) (2; 6%); stable disease (SD) (12; 34%); SD > 6 mos (2; 6%). Median OS was 9.3 mos (95% C.I., 6.2–n/a). Conclusions: The combination of X+TRAP demonstrated an acceptable safety profile, with encouraging clinical activity at the RPTD. Recruitment for the phase II EXP cohort is now complete. Clinical trial information: NCT01661972.

Phase I/II docetaxel, oxaliplatin, and 5-fluorouracil combination chemotherapy in patients with advanced gastric cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 162-162
Author(s):  
Sung Rok Kim ◽  
Sung-En Park ◽  
Young Jin Yuh ◽  
Byeong Seok Sohn ◽  
Hye Ran Lee ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

162 Background: The results of recent studies with duo- or triple regimen for the advanced gastric cancer are still not satisfactory and the optimal doses of combinations with taxanes, fluorouracil and platinum analogues were not determined yet. The aim of this study is to determine the optimal dose of docetaxel and oxaliplatin in combination with 5-fluorouracil(FU) [DOF], with the efficacy and toxicity in patients (pts) with advanced gastric cancer. Methods: The pts with unresectable, metastatic, or relapsed gastric cancer were enrolled for a phase I/II study. The dose of docetaxel and oxliplatin was escalated from 50 mg/m2 and 80 mg/m2 day 1, respectively by traditional 3+3 design, and 5-FU was fixed at 850 mg/m2/day 24 hour continuous infusion day 1-4, all every 3 weeks. All pts had measurable disease and were assessable for toxicity. Results: A total of 50 pts including 12 patients from phase I study were enrolled. The recommended phase II dose of docetaxel and oxaliplatin were 60mg/m2 and 100mg/m2 on day 1 (cohort 2), respectively. A total of 335 cycles of chemotherapy was administrated (median: 6, range 1–24) and the dose intensity of docetaxel, oxaliplatin, and 5-FU were 96.3%, 96.2% and 98.5%, respectively. Twenty two (44.0%) of 50 patients showed partial response, 22 (44.0%) stable disease, and 1 (2.0%) complete response. The overall response rate was 46.0% (95% confidence interval [CI]: 32.2–60.0%) and the disease control rate 90.0% (95% CI: 81.7–98.3%). The median progression free survival was 6.5 months (95% CI, 3.3–9.8) and the overall survival 10.7 month (95% CI, 7.0–14.3). Grade 3/4 neutropenia and thrombocytopenia occurred in 81 (24.1%) and 3 cycles (0.9%), respectively [27 (56%) and 3 (6%) in 50 pts, respectively]. Grade 3/4 stomatitis, diarrhea and neuropathy occurred in 2 (0.6%), 6 (1.8%) and 6 cycles (5.7%), respectively. Conclusions: The recommended phase II dose of docetaxel and oxaliplatin was 60mg/m2 and 100mg/m2, respectively. This DOF combination chemotherapy has no better efficacy than reference regimen. The toxicities were substantial in some pts, but generally manageable.

A phase I dose escalation study of pharmacobiologically based scheduling of capecitabine and mitomycin C (MMC) in patients with gastrointestinal solid malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15154-15154 ◽  
Author(s):  
M. E. Hill ◽  
A. Campbell ◽  
K. Kosuri ◽  
J. Thomas ◽  
M. Villalona ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Therapeutic Index ◽  
Dose Escalation Study ◽  
Gastrointestinal Malignancies ◽  
Combination Methods ◽  
Phase Ii Studies ◽  
Solid Malignancies ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

15154 Background: A principal determinant of the therapeutic index of capecitabine-based treatment is the grade of thymidine phosphorylase(dThdPase) activity in malignant tissues. MMC, an agent that is active in gastrointestinal malignancies, produces significant upregulation of the dTHdPase starting 4–6 days after treatment and persisting for at least 10 days. On the basis of the time-dependency and transience of this upregulation, we performed a phase I study of capecitabine in combination with MMC. The aim was to determine the maximally tolerated dose of this combination. Methods: In this ongoing study, patients with advanced gastrointestinal solid malignancies received MMC on day 1 and capecitabine twice daily on days 8 and 21, every 4 weeks. The MMC dose was fixed at 6mg/m2, whereas capecitabine was escalated in successive patient cohorts. Patients were allowed to have had a maximum of 2 prior therapies for metastatic disease. The total cumulative dose of MMC was capped at 36 mg/m^2 to reduce the risk of cumulative toxicity. Results: So far 23 patients with a median age of 62 received capecitabine doses from 1000 to 2000 mg/m^2/d. The majority of the patients had at least 1 prior treatment (86%). Four patients were considered non-evaluable. No dose-limiting toxicities were observed as we reached our final dose level. Toxicities were generally mild with only 7 patients experiencing grade 3 toxicities and two experiencing grade 4 toxicities. The most common toxicities were fatigue (67%), nausea (43%), diarrhea (33%), and anemia (29%), and all toxicities were reversible. There were no objective responses; however, 32% of evaluable patients had prolonged stable disease (43% colorectal, 29% pancreas, 14% esophageal, and 14% gastric). Conclusions: Capecitabine in combination with MMC in the proposed schedule is well tolerated and has promising preliminary activity in various gastrointestinal malignancies. Recommended doses for phase II studies are capecitabine 1000 mg/m^2 twice daily and MMC 6 mg/m^2. This study is ongoing with 2 more patients being entered at the recommended phase II dose. No significant financial relationships to disclose.

A phase I/II trial of trifluridine/tipiracil in combination with irinotecan in patients with advanced gastric cancer refractory to fluoropyrimidine, platinum, and taxane.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 210-210
Author(s):  
Hiroki Hara ◽  
Takuro Mizukami ◽  
Keiko Minashi ◽  
Tomohiro Nishina ◽  
Naoki Takahashi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Recommended Phase Ii Dose

210 Background: Trifluridine/tipiracil (FTD/TPI) or irinotecan is a treatment option in the heavily pretreated patients with advanced gastric cancer (AGC) with the limited efficacy. Thus, we investigated the recommended dose of trifluridine/tipiracil (FTD/TPI) and irinotecan for these patients. Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used a escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on Days 1 and 15 of a 28-day schedule] with 2 dosage schedules of FTD/TPI:35 mg/m2/dose, twice daily (bid), on days 1-5 and 8-12 of a 28-day cycle (Level A) or on days 1-5 and days 15-19 of a 28-day cycle (Level B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) for phase I part and the evaluation of disease control rate (DCR) targeting > 55% in all enrolled patients for phase II part. Results: Eleven patients were enrolled from 4 institutions in Japan; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A (Grade 3 gum infection and Grade 3 febrile neutropenia on Day 29, outside the 28-day DLT assessment period, determined equivalent to DLT), and 2/6 patients at Level 2B (Grade 3 mucositis oral and Grade 3 febrile neutropenia). Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively. Conclusions: The RP2D was determined to be Level 1B although further investigation to explore optimal regimen is needed. Clinical trial information: UMIN000031346.

Sequential Phase II Studies of Flavopiridol by 72-Hour Continuous Infusion and 1-Hour Intravenous Bolus for the Treatment of Relapsed B-Cell Chronic Lymphocytic Leukemia: Results from CALGB Study 19805.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3485-3485
Author(s):  
John C. Byrd ◽  
Bercedis L. Peterson ◽  
Janice L. Gabrilove ◽  
Olatoyosi M. Odenike ◽  
Michael R. Grever ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Phase Ii ◽  
Tumor Lysis Syndrome ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Intravenous Bolus ◽  
Phase Ii Studies ◽  
Grade 3

Abstract Flavopiridol has in vitro activity in CLL and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol administered using two different schedules has activity in CLL. Patients with previously treated CLL were enrolled on two sequentially performed phase II studies. Patients in the first trial received flavopiridol (50 mg/m2 daily) as a continuous infusion (CI) over 72-hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m2 as a 1-hour intravenous bolus (IVB) daily for three days repeated every 3 weeks. Patients received up to 6 (CI cohort) or 8 (IVB cohort) cycles of therapy. Fifteen patients enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate (Rai stage I or II) and 9 (60%) high (Rai stage III and IV) risk stages. No responses were noted in this group with 27% having stable disease (SD) and 73% progressive disease (PD). Thirty-six patients enrolled in the IVB study, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) SD, and 13 (36%) PD. The progression-free survivals for responders in the IVB study were 2.9, 3.2, 8.7, and 19.3 months. The median progression-free survival was 2.1 months (95% confidence interval [CI] 1.8 – 3.8) for patients in the CI study and 3.2 months (95% CI [2.5 – 7.4]) for the IVB study. The median overall survival was 27 months (95% CI [20–42]) for the CI study and 24 months (95% CI [18–31]) for the IVB study. Toxicity was manageable and included mainly myelosuppression (granulocytopenia and thrombocytopenia), infections, diarrhea and fatigue. Grade 3 and 4 toxicities were 20% and 27%, respectively, on the CI study and 39% and 33% on the IVB study. One patient on the IVB study had tumor lysis syndrome that was managed medically and did not require dialysis. There was one on-study death following a myocardial infarction on the IVB study. We conclude that flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.

The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 388-388 ◽  
Author(s):  
Gautam Borthakur ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Low Dose ◽  
Response Rate ◽  
Median Number ◽  
Highly Active ◽  
Flt3 Inhibitor ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Low Dose Cytarabine

Abstract Background: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity. In a phase I and II studies the composite response rate (CRR) was approximately 50% among patients with FLT3-ITD. There is in-vitro synergy between quizartinib and 5-AZA or LDAC. We hypothesize that adding quizartinib to a hypomethylating agent such as 5-azacitidine (AZA) or cytarabine may improve the response rate expected from the use of either agent alone. Objectives: The primary objective of phase I part is to determine the dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of the combination of quizartinib (AC220) with either AZA or low-dose cytarabine (LDAC); for phase II is to determine the clinical activity of both combinations. This planned interim analysis reports on the recommended phase II dose (RP2D) and first futility analysis. Methods: For phase I, patients with relapsed/refractory high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or AML were eligible irrespective of FLT3 mutation and salvage status. For phase II, presence of FLT3-ITD is a requisite. Phase II enrollment is limited to patients >60 years with untreated MDS/CMML/AML, or any age receiving first salvage treatment. Additional eligibilities include performance status ECOG ≤2, adequate organ function, normal electrolytes (potassium, calcium and magnesium). Important exclusions include QTcF> 450 mSec, concomitant drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers with the exception of antibiotics, antifungals, and antivirals that are used as standard of care. Treatment cycle is defined as 28 days. Treatment comprises of AZA 75 mg/m2 subcutaneously (SQ) or intravenously (IV) for 7 days of every cycle (Days 1-7), or cytarabine 20 mg SQ twice daily for 10 days of every cycle (Days 1-10) along with quizartinib at two planned dose levels: 60 mg (dose level 1) or 90 mg orally daily (dose level 2) uninterrupted. Patients are assigned to AZA or LDAC arm by physician choice or slot availability. Planned accrual for each arm in phase 2 is 26 pts each and an ORR of ≥50% will be considered favorable. Accrual of 26 pts will give a 95% credible interval for overall response rate of (0.32, 0.68). The study will be stopped for toxicity (>30%) and/or futility (ORR <50%) at interim analysis for each arm. Results: Twenty-six (Phase I=12, phase II=14) pts have been enrolled: 18 to AZA arm and 8 to LDAC arm. Median age is 62 years (range, 25-79 years), 7 (27%) are female. Cytogenetics are diploid=14, +8=2, -7=2, miscellaneous=6, 11q and t(8;21)= 1 each. Median number of prior therapies is 2 (range, 0-7), 7 patients received prior FLT3 inhibitor. For both schedules quizartinib 60 mg daily was identified as the recommended phase II dose (RP2D) based on emerging results from separate dose-finding study. Eighteen [5 in LDAC arm (63%) and 13 (72%) in AZA arm; all with FLT3-ITD mutation without D835 mutation] of 26 total pts (69%) have responded (CR=1/ CRp=3/ CRi=2/ MLFS=10/PR=1/HI=1). Among patients with FLT3-ITD (N=22), ORR is 82%. Four of 7 (57%) patients with prior FLT3 inhibitor exposure responded. Median number of days to respond is 57 days (range, 25-102 days). Among responders two patients died (MLFS=1, PR=1): one with gastro-intestinal bleeding and other with progressive pneumonia. Three additional responders have discontinued therapy for stem cell transplant (1), withdrawal of consent (1), and loss of response with emergence of D835 mutation (1). Nine responders (CR=1, CRi=1, CRp=1, PR=1, MLS=5) had >50% reduction of FLT3-ITD allelic burden and 2 additional pts (CR=1, CRi=1) had no detectable FLT3-ITD at response. Number of pts with treatment emergent grade 3/4 toxicities irrespective of attribution include hypokalemia (15), hypophosphatemia (5), hyponatremia (4), hypocalcemia (4), hyperbilirubinemia (3), increase in ALT (1), hypernatremia (1hyperglycemia (1), hypotension (1), QTcF prolongation (1, grade 3). Conclusion: Combination of quizartinib and AZA or LDAC is highly active among patients with AML/MDS/CMML with FLT3-ITD . Response rates appear higher than expected with either agent alone. Clinically significant QTcF prolongation is infrequent. Accrual to both arms of the current trial continues. Disclosures Cortes: Ambit Biosciences: Research Funding.

The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1642-1642 ◽  
Author(s):  
Waleed Abdelall ◽  
Hagop M. Kantarjian ◽  
Gautam Borthakur ◽  
Guillermo Garcia-Manero ◽  
Keyur P. Patel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Highly Active ◽  
Flt3 Inhibitor ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Low Dose Cytarabine

Abstract Background: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with early relapse and poor survival. Quizartinib inhibits FLT3 kinase activity potently and selectively. In phase I and II studies, the composite response rate (CRR) was approximately 50% among patients with FLT3-ITD. There is in-vitro synergy between quizartinib and 5-AZA or LDAC. We hypothesize that adding quizartinib to a hypomethylating agent- such as 5-azacitidine (AZA) -or to cytarabine may improve the response rate expected from the use of either agent alone. Objectives: The primary objective of phase I is to determine dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of combination of quizartinib with either AZA or low-dose cytarabine (LDAC); for phase II is to determine the clinical activity of both combinations. This planned interim analysis reports on the recommended phase II dose (RP2D) and first futility analysis. Methods: For phase I, pts with relapsed/refractory high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) or AML were eligible irrespective of FLT3 mutation and salvage status. For phase II: presence of FLT3-ITD is a requisite, pts must be >60 years with untreated MDS/CMML/AML or any age receiving first salvage treatment. Other requisites: performance status ECOG ≤2, adequate organ function and normal electrolytes (potassium, calcium and magnesium). Important exclusions include: QTcF> 450 msec, administration of drugs that prolong QT/QTc interval or strong CYP3A4 inhibitors or inducers; with the exception of antibiotics, antifungals, and antivirals that are used as standard of care. Treatment cycle is 28 days and comprises of AZA 75 mg/m2 subcutaneously (SQ) or intravenously (IV) for 7 days of every cycle, or cytarabine 20 mg SQ twice daily for 10 days of every cycle along with quizartinib at two planned dose levels: 60 mg (dose level 1) or 90 mg orally daily (dose level 2), uninterrupted. Patients are assigned to AZA or LDAC arm by physician choice or slot availability. Planned accrual for each arm in phase II is 26 pts each and an ORR of ≥50% will be considered favorable. Accrual of 26 pts will give a 95% credible interval for ORR of (0.32, 0.68). The study will be stopped for toxicity (>30%) and/or futility (ORR <50%) at interim analysis for each arm. Results: Fifty-two (Phase I=12, phase II=40) pts have been enrolled: 38 to AZA arm and 14 to LDAC arm. Median age is 67 years (range, 23-83 years), 24 (46%) are female. Cytogenetics are diploid=24, +8=5, monosomy 7=3, miscellaneous=17, 11q=2 and t(8;21)= 1. Median number of prior therapies is 1 (range, 0-7); 7 patients had received prior FLT3 inhibitor: sorafenib (5), crenolanib (1), quizartinib (1). For both combinations quizartinib 60 mg daily was identified as the recommended phase II dose (RP2D). Thirty-five Pts [8 in LDAC arm (23%) and 27 in AZA arm (77%)] of total 52 have responded with ORR 67 % (CR=8, CRp=7, CRi=18, PR=2); all with FLT3-ITD mutation without D835 mutation. ORR is 73% among pts with FLT3-ITD (N=48). Three of eight pts (38%) with prior FLT3 inhibitor exposure responded. Median time to response is 35 days (range, 14-187days). Among responders, two pts died (in CRi=1, PR=1): one with GI bleed and one with progressive pneumonia. Twelve responders discontinued therapy: 11 to receive a SCT and 1 due to loss of response with emergence of D835 mutation. Fifteen responders (CR=2, CRi=8, CRp=3, PR=2) had >50% reduction of FLT3-ITD allelic burden and eight additional pts (CR=5, CRi=1, CRp=2) had no detectable FLT3-ITD at response. The median survival was: 14.8 mo for the total study group: 7.5 mo for LDAC arm and not reached for AZA arm; median EFS has not been reached for either arm (Figure). Treatment emergent grade 3/4 toxicities irrespective of attribution include hypokalemia (15), hypotension (7), hypophosphatemia (7), hyponatremia (7), hypocalcemia (7), hyperbilirubinemia (1), elevated ALT (5), hypernatremia (2) hyperglycemia (1), QTcF prolongation (1, grade 3). Conclusion: Combination of quizartinib and AZA or LDAC is highly active among patients with AML/MDS/CMML with FLT3-ITD mutation in absence of D835 mutation. Response rates appear higher than expected with either agent alone. Clinically significant QTcF prolongation is infrequent. Accrual to the study continues. Figure Figure. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Docetaxel, oxaliplatin, and capecitabine (TEX regimen) for patients with metastatic gastric cancer: Interim results from a phase II trial by the German AIO Group

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4554-4554 ◽  
Author(s):  
M. H. Moehler ◽  
P. Thuss-Patience ◽  
D. Arnold ◽  
W. Grothe ◽  
A. Stein ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Distant Metastases ◽  
Response Assessment ◽  
Metastatic Gastric Cancer ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Ecog Ps

4554 Background: Combination regimens of 3 drugs have shown promising activity as treatment for patients (pts) with metastatic gastric cancer (GC). Docetaxel combined with cisplatin and 5-FU (CF) improved overall survival and response rates when compared to standard CF. However, the identification of less toxic and more convenient variants of this regimen is still important. We have previously established a regimen with docetaxel (T) combined with oxaliplatin (E) and capecitabine (X) in a phase I trial [Grothe et al., Proc. ASCO 2006]. Results of a preplanned interim analysis of subsequent multicenter phase II trials of the TEX regimen are presented here. Methods: Pts with metastatic or locally advanced GC, adequate organ function, ECOG PS 0–2, and no prior chemotherapy for advanced disease (adjuvant allowed) were enrolled. TEX regimen was administered as defined: T 35 mg/m2 and E 70 mg/m2 on days (d) 1 and 8, with X 800 mg/m2 bid on d1–14 every 22 days Toxicity assessment was done 3-weekly while CT scans were repeated 9-weekly. Results: 35 of 48 pts were enrolled until 06/08: 28 male / 7 female, median age 59 (36–81) years, ECOG PS 0/1/2 69%/31%/0%, gastric / gastroesophageal cancer 60%/40%, distant metastases 96%, tumor in situ 37%. The most common toxicities reported were (CTC grade [gr] 3/4): diarrhea 20%/3%, vomiting 11%/3%, asthenia and neurotoxicity each 9%/0%. Mucositis and hand-foot-syndrome were observed in (grade 1+2 / grade 3) 29%/0% and 26%/3%, respectively. Hematoxicity was mild with grade 3 anemia in 10% and no other grade 3/4 toxicity except one episode of febrile neutropenia . Of 25 pts evaluable so far, first tumor response assessment revealed (RECIST criteria) partial response in 36% and stable disease in 40% of patients. Conclusions: TEX is a safe and tolerable regimen for patients with metastatic gastric cancer. Preliminary efficacy results indicate promising activity. Mature data including progression free survival will be presented at the meeting. [Table: see text]

Irinotecan plus temozolomide in children with recurrent or refractory neuroblastoma: A phase II Children's Oncology Group study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10011-10011
Author(s):  
R. Bagatell ◽  
L. M. Wagner ◽  
S. L. Cohn ◽  
J. M. Maris ◽  
C. P. Reynolds ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Bone Marrow Aspirate ◽  
Response Rate ◽  
Objective Response ◽  
Response Assessment ◽  
Stage Design ◽  
Combination Methods ◽  
Grade 3 ◽  
Experienced Grade

10011 Background: Treatment of children with relapsed or refractory neuroblastoma (NB) remains a challenge. Responses to irinotecan (IRN) + temozolomide (TEM) were seen in NB xenograft-bearing mice, and objective responses were observed in patients with NB treated on a phase I study of this combination. Methods: A phase II study of IRN (10 mg/m2/dose IV daily × 5 days times; 2 weeks) + TEM (100 mg/m2/dose PO daily × 5 days) for children with relapsed or refractory NB was conducted. A one-stage design (endpoint: best overall response) required 5 or more responders out of the first 25 evaluable patients on each of two strata: 1) patients with disease measurable by CT or MRI; and 2) patients with disease detected only by bone marrow aspirate/biopsy and/or MIBG scan. Patients with stable disease or better after 3 cycles could receive an additional 3 cycles of study therapy. International Neuroblastoma Response Criteria were used for response assessment. Radiographic responses were centrally reviewed. Results: Fifty-five eligible and evaluable patients were enrolled, 28 on stratum 1 and 27 on stratum 2. Four responses were observed in the first 25 evaluable stratum 1 patients, and five responses were observed in the first 25 evaluable stratum 2 patients. Three patients had complete responses, but the overall objective response rate (CR+PR) was 16% (9/55). Eleven (stratum 1) and 13 (stratum 2) patients had stable disease. Less than 5% of patients experienced Grade 3 or 4 diarrhea. Although 18% of patients on stratum 1 and 35% of patients on stratum 2 experienced Grade 3 or 4 neutropenia during the first 3 cycles of therapy, <10% of all patients developed evidence of infection while neutropenic. Thrombocytopenia (Grade 3 or 4) was observed in only 7% of patients on stratum 1 and 12% on stratum 2. Conclusions: The combination of IRN+TEM was well tolerated in patients with recurrent or refractory NB. There were 9 objective responses, including 3 complete responses. The minimum desired response rate was attained within stratum 2, but not stratum 1. IRN+TEM may be an appropriate backbone for further study in the relapse setting in combination with novel, targeted agents. No significant financial relationships to disclose.

Phase I trial of docetaxel (D), cisplatinum (C), and continuous capecitabine (CAP) (TCX) in advanced esophagogastric cancer (AEC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14587-e14587
Author(s):  
Simon Gollins ◽  
Arwel Lloyd ◽  
Jackie Morris ◽  
Nick Smith ◽  
Brian Haylock ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Free Survival ◽  
Best Response ◽  
Esophagogastric Cancer ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

e14587 Background: This phase I study assessed the combination of D, C, and continuous CAP in AEC to develop a regimen of acceptable toxicity to take forward to phase II study. Methods: Patients with AEC were treated in cohorts of 3, at one of 3 dose levels (DL). DL0: D at 60 mg/m2 IV on day 1, C at 60 mg/m2 IV on day 1, CAP at 1,000 mg/m2 per day in two divided doses days 1-21, every 3 weeks. DL1: CAP increased to 1,250 mg/m2 per day. DL2: D increased to 75 mg/m2 IV day 1 and CAP to 1,250 mg/m2 per day. Prophylactic colony stimulating factors were not used. Patients received a maximum of 6 cycles. Blood counts and biochemistry were assessed twice weekly and daily for grade 3/4 abnormality. Results: Between 1.11.07 and 24.6.09 15 patients were enrolled: male/female:14/1, WHO PS:0/1:10/5, median age 63 yr (range 46-69), primary site oesophagus/GOJ/stomach:7/3/5, adeno/squamous:14/1, T2/3/4:2/9/4, N0/1/2:1/13/1, M0/1:1/14. 6 patients were treated at DL0, 6 at DL1 and 3 at DL2. All patients received 6 cycles apart from 2 at DL 1 who received 3 because of disease progression. Dose intensity: DL0: D 95%, C 100%, CAP 85%; DL1: D 91%, C 98.2%, CAP 79%; DL2: D 86%, C 100%, CAP 79%. There were no deaths on chemotherapy or within 30d of the last dose. The main dose limiting toxicity was febrile or infective neutropenia developing in 1/6 DL0, 2/6 DL1 and 3/3 DL2 (see table of most common treatment-related adverse events below: serious toxicity is gr 3 unless specified gr 4). The maximum length of gr 4 neutropenia was 5d. Best response (RECIST): 1 CR, 11PR, 2 SD and 1PD. 11 patients received second-line chemotherapy. Median and 1 yr overall survival: 17.5m and 60%. Median and 1 yr progression-free survival: 7m and 27%. Conclusions: TCX DLO is recommended for further study in a phase II trial. Encouraging response and survival were seen. [Table: see text]

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.

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