A phase I dose-escalating study of combination S-1 and carboplatin (CBDCA) in patients with chemo-naïve advanced non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17055-17055
Author(s):  
K. Tamura ◽  
I. Okamoto ◽  
T. Ozaki ◽  
T. Shimizu ◽  
T. Kashii ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Eligibility Criteria ◽  
Level 3 ◽  
Adequate Organ Function ◽  
Level 1 ◽  
Ecog Ps ◽  
Level 2

17055 Background: S1, a novel oral fluoropyrimidine derivative, has promising results in the treatment of advanced gastric or colorectal carcinoma. Response rate/median survival time of single S1 and the combination S1 plus cisplatin for advanced NSCLC were 22.0%/309 days and 47.3%/335 days, respectively in the previous phase II. Platinum doublets including a novel active drug is a potent standard for advanced NSCLC as 1st line chemotherapy. Carboplatin has advantage of low gastrointestinal or renal dysfunction in comparison with cisplatin. The primary objective of this study was to determine the maximum tolerated dose (MTD) of combination S-1 and carboplatin, the toxicity profile and the recommend dose (RD) for a multi-center randomized trial of platinum doublets including S1. Methods: Eligibility criteria includes histologically diagnosed NSCLC stage IIIB/IV, no prior chemotherapy, ECOG PS 0–1, 75 > age >20, adequate organ function, and written informed consent. Pts receive carboplatin intravenously over 30 minutes on day 1, and S1 daily for 2 weeks, every 3 weeks. Results: Total 10 patients were registered (M/F: 6/4; median age:67 (37–73); Ad/Sq:7/3; IIIB/IV: 0/10 PS 0/1:3/7) Three patients were enrolled at the dose level 1 (CBDCA AUC = 5 and S1 65 mg/m2), 3 patients at level 2 (CBDCA AUC=5 and S1 80 mg/m2) and 4 patients at level 3 (CBDCA AUC=6 and S1 80 mg/m2), respectively. No DLTs (dose-limiting toxicities) occurred at both level 1 and 2. DLTs were observed in 2 out of 4 patients at level 3. One is significant delay starting of 2nd cycle caused by thrombocytopenia. One is G3 anorexia and vomiting at 1st cycle and results in stop the treatment. A total 27 courses were assessable for safety. Two pts with G3 neutropenia, 2 pts with G3 anorexia, 1 pts with G3 liver dysfunction and 1 pts with G3 infection were observed during total courses. Five out of 6 patients at Level 1 or 2 have completion of 4 cycle’s treatment. Objective response was obtained in three patients out of 10. Conclusions: MTD was level 3. RD for the future trial was Level 2 (CBDCA AUC = 5 and S1 80 mg/m2). This combination was well tolerated and produced an antitumor effect for advanced NSCLC. No significant financial relationships to disclose.

Safety and efficacy of AMG 655 plus modified FOLFOX6 (mFOLFOX6) and bevacizumab (B) for the first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4079-4079 ◽  
Author(s):  
L. Saltz ◽  
J. Infante ◽  
L. Schwartzberg ◽  
J. Stephenson ◽  
C. Rocha-Lima ◽  
...  
Keyword(s):  
Disease Progression ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Death Receptor ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Death Receptor 5 ◽  
Grade 3 ◽  
Ecog Ps

4079 Background: AMG 655 is an investigational fully human monoclonal antibody (IgG1) agonist of human death receptor 5 (DR5). AMG 655 activates caspases and induces apoptosis in sensitive tumor cells. The primary objective of this phase 1b study was to determine the maximum tolerated dose (up to a target dose of 10 mg/kg IV every 2 weeks) of AMG 655 that can be safely administered in combination with mFOLFOX6-B to mCRC pts. Methods: Eligible pts were ≥ 18 years old with previously untreated mCRC, ECOG PS of 0 or 1, and adequate hematologic, hepatic, and renal function. Pts were enrolled into sequential cohorts of 3- or 10-mg/kg AMG 655 + mFOLFOX6-B administered on day 1 of each 14-day cycle. Study endpoints included incidence of dose-limiting toxicities (DLT), adverse events (AE), pharmacokinetic (PK) parameters of AMG 655, and objective response rate (by modified RECIST). Results: As of 09/08, 12 pts (6 per cohort) were enrolled and received ≥ 1 cycle of treatment; 8 were female. Median (range) age was 54 (37–75), median (range) time on AMG 655 treatment was 6.9 (1.6 to 11.4+) months; 8 pts continue on study treatment. There were no DLTs in the first 28 days of treatment. Eight pts had grade 3–4 AE; the most common were diarrhea, febrile neutropenia, peripheral neuropathy, neutropenia, DVT, and pulmonary embolism (2 pts each). Post baseline laboratory parameters grade ≥ 3: no ALT and AST; 1 grade 3 bilirubin (due to disease progression), and 3 grade 3 lipase (asymptomatic). No anti-AMG 655 antibodies were detected. AMG 655 PK values (Cmax, Cmin) were similar to those observed with single-agent AMG 655 (LoRusso JCO 2007; 25: abstract 3534). AMG 655 did not appear to affect PK of oxaliplatin or bevacizumab. Best overall tumor response: 5 partial responses (2 unconfirmed, both underwent resection); 6 stable disease; 1 pt had non-measurable disease at baseline. Time to disease progression (3 patients): 8, 42, and 44 weeks. Conclusions: The addition of AMG 655 does not appear to substantially alter the safety profile of mFOLFOX6-B. The randomized phase 2 part of the trial (mFOLFOX6-B ± AMG 655) is in progress. [Table: see text]

A dose-escalation study of docetaxel, oxaliplatin and S-1 (DOS) as a first-line therapy for patients with unresectable metastatic gastric cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 174-174
Author(s):  
Yasushi Sato ◽  
Tamotsu Sagawa ◽  
Yasuo Takahashi ◽  
Hiroyuki Ohnuma ◽  
Kyoko Hamaguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Febrile Neutropenia ◽  
Complete Response ◽  
Metastatic Gastric Cancer ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Promising Alternative ◽  
Level 3 ◽  
Level 1 ◽  
Level 2

174 Background: Although the triplet regimen of docetaxel/cisplatin/S-1 (DCS) has shown promising activity and conversion rate in patients with unresectable metastatic gastric cancer (UMGC) in Japan, it was accompanied by severe adverse events. Recent studies suggested that oxaliplatin was almost as active, and relatively less toxic, than cisplatin in combination regimens for UMGC and can therefore replace cisplatin. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended dose (RD), and preliminary efficacy of docetaxel/oxaliplatin/S-1 (DOS) instead of DCS in patients with UMGC. Methods: Previously untreated 16 patients with histologically proven UMGC were enrolled. Docetaxel and oxaliplatin were administered intravenously on day 8. S-1 was administered orally twice a day on days 1-14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first cycle of treatment. Three dose-escalations of DOS were used in this study namely, level 1 (50/100/80 mg/m2), level 2 (50/130/80 mg/m2), and level 3 (60/130/80 mg/m2). Results: Among the six patients, one patient each experienced DLTs (febrile neutropenia and diarrhea) at level 1 and 2 doses, respectively. While two more patients experienced DLTs (febrile neutropenia and diarrhea) after administration of level 3 doses. Therefore, two additional patients were enrolled into the study at level 2. However, both these patients subsequently exhibited DLTs (febrile neutropenia and diarrhea). Therefore, we concluded that the MTD and RD with this regimen were level 2 and level 1, respectively, and that the DLT were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) of the patients with measurable lesions, consisting of two complete response and five partial responses. Five patients underwent conversion surgery. Conclusions: The RD of the 3-weekly DOS regimen in patients with UMGC was docetaxel at 50 mg/m2 and oxaliplatin at 100 mg/m2 on day 8 and S-1 at 80 mg/m2 on days 1-14. The efficacy and ease of administration make the regimen a promising alternative to DCS. A phase II study using this RD regimen is currently underway. Clinical trial information: 000015849.

Appropriate schedule of oral tegafur / uracil (UFT) in combination with irinotecan (CPT-11) and bolus 5-FU / l-leucovorin (LV) in patients (pts) with metastatic colorectal cancer (MCRC): A phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14538-14538
Author(s):  
N. Chayahara ◽  
T. Tamura ◽  
I. Miki ◽  
T. Okuno ◽  
T. Kamigaki ◽  
...  
Keyword(s):  
Gastrointestinal Toxicity ◽  
Treatment Schedule ◽  
Oral Fluoropyrimidine ◽  
Early Dropout ◽  
Level 3 ◽  
Adequate Organ Function ◽  
Grade 3 ◽  
Ecog Ps ◽  
Level 2 ◽  
Dose Limiting Toxicity

14538 Background: FOLFIRI is one of the standard regimens for MCRC. Considering the burden of continuous 5-FU administration, oral fluoropyrimidine-based therapy has been proposed in several clinical trials; however, gastrointestinal toxicity makes it difficult to perform successive oral chemotherapy. Therefore, no previous study could confirm whether to replace FOLFIRI with oral regimen. In order to find an appropriate schedule of oral fluoropyrimidine with safety and efficacy instead of continuous infusion of 5-FU, clinical trial using CPT-11, bolus 5-FU / l-LV and oral UFT / LV was conducted in pts with MCRC. Methods: Pts with MCRC, age > 18 years, ECOG PS 0–2, adequate organ function, and no or 1 prior chemotherapy were eligible. Pts received CPT-11 (100mg/m2) / 5-FU (500mg/m2) / l-LV (15mg/m2) i.v. on day 1 and UFT (300mg/m2) / LV (75mg/body) p.o. on days 1–5 (level 1), days 1–7 (level 2), or days 1–10 (level 3). Each course was repeated every 14 days. After determining feasible UFT / LV schedule, CPT-11 was dose-escalated (level 4: 125 mg/m2; level 5: 150mg/m2). Results: Nineteen pts were enrolled. A dose-limiting toxicity (DLT) of grade 4 neutropenia lasting for > 4 days was observed in 1 pt at level 2. Additional 3 pts at this level showed no toxicity of grade 3 or 4. A DLT of treatment delay (>8 days) was observed in 1 pt at level 3 because of prolonged neutropenia. Other 2 pts at level 3 refused to continue treatment within 4 cycles because of prolonged grade 2 anorexia. Obvious difference in toxicity was observed between level 2 and level 3. Therefore, 7-day-administration of UFT / LV was recommended. No DLT was observed at level 4 and 5, and the recommended dose of CPT-11 was 150mg/m2. The overall response rate was 66.7%. The median time to disease progression was 8.0 months. Conclusions: This oral fluoropyrimidine-based regimen is considered feasible and effective. The treatment schedule of UFT might be a key to prevent an early dropout due to gastrointestinal toxicity. Further study will be needed to confirm toxicity and efficacy of this regimen compared to FOLFIRI profile. No significant financial relationships to disclose.

A phase I/Ib study of crenolanib with ramucirumab (RAM)/paclitaxel (PTX) as second-line therapy (2L tx) for advanced esophagogastric adenocarcinoma (EGA).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 116-116
Author(s):  
Megan Greally ◽  
Sujata Jha ◽  
Sam S. Yoon ◽  
Jia Li ◽  
Avni Mukund Desai ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Objective Response ◽  
Study Drug ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Serious Adverse Events ◽  
Ecog Ps ◽  
Higher Doses

116 Background: PTX/RAM as 2L tx for patients (pts) with EGA is a standard-of-care based on the RAINBOW trial (Lancet Oncol 2014;15:1224). However, benefit is modest. Upregulation of the platelet-derived growth factor (PDGF)/PDGF receptor-β (PDGFR-β) pathway causes resistance to VEGF inhibition. Crenolanib is a selective inhibitor of PDGFR-β. We report initial results of the dose escalation phase of a study of crenolanib plus RAM/PTX in pts with previously treated advanced EGA. Methods: This phase I/Ib study is enrolling ECOG PS 0-1 EGA pts with progression on first-line chemo. PTX 80 mg/m2/ day on day 1, 8, 15 and RAM 8mg/kg q 14 days were administered with escalating doses of crenolanib (60, 80, 100 mg BID) after a 7 day “run-in” of crenolanib to assess crenolanib-related toxicities. The primary objective was to determine the maximum tolerated dose (MTD) of crenolanib plus RAM/PTX. Safety and preliminary efficacy were examined. Results: 15 pts were treated; 12 male, median age 58 (32-73), 66% were ECOG PS 1. Primary site was gastric in nine pts, GEJ in 4 pts and esophageal in two pts. Three pts each received crenolanib 60mg BID and 80mg BID, six pts received 100mg BID and three pts received higher doses. At data cutoff, eight pts continued on treatment. 12 pts have completed the DLT evaluation period across 3 dose levels (60 to 100 mg BID). Median treatment duration was 76 days (35-191). The combination was well tolerated, with no DLTs or serious adverse events (SAEs) attributed to study drug. Treatment related adverse events occurred in two pts (17%), all grade 1. These were fatigue, nausea, vomiting and hypertension. Disease progression was the most common reason for treatment discontinuation; no pt discontinued due to study drug related AEs. Nine pts were evaluable for response. One pt had objective response; the disease control rate was 78%. Median PFS and OS were 4.1 and 11.9 months respectively. Conclusions: Crenolanib plus RAM/PTX appears well tolerated at a dose level of 100mg BID. Further evaluation is needed to determine efficacy. Accrual is ongoing at higher doses. Once the MTD is defined, the dose expansion phase will enroll 25 pts. Updated data with pharmacokinetics and biomarkers will be presented. Clinical trial information: NCT03193918.

Phase I study of intravenous (IV) milataxel in adult patients with advanced malignant tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2037-2037 ◽  
Author(s):  
E. Bourbouloux ◽  
M. Campone ◽  
J. B. Vermorken ◽  
M. Martin ◽  
C. Sessa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dose Escalation ◽  
Malignant Tumors ◽  
Metastatic Breast ◽  
Dose Intensity ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Eligibility Criteria ◽  
Ecog Ps

2037 Background: M (TL139, MAC-321) is a novel taxane with activity in human xenograft models against tumors resistant to paclitaxel. The maximum tolerated dose (MTD) when given IV every 3 weeks was 35 mg/m2. The current study was designed to determine if the dose intensity of M could be increased by a weekly IV schedule. Methods: The primary objective of the study was to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT) and the recommended dose (RD) for phase II. Secondary objectives were pharmacokinetic (PK)/pharmacodynamic (PD) parameters of M given IV weekly and a preliminary estimate of efficacy in an expanded cohort at the RD. Key pt eligibility criteria included in adult pts with refractory malignant tumors, ECOG PS <3 and adequate hematologic, hepatic and renal function. Patients were not allowed concurrent strong inhibitors of cytochrome p450 3A4. Dose escalation was based on Fibonacci method. At the RD, additional pts with tumors that typically respond to taxane treatment were added. PK data were obtained on day 1 and 15. Results: A total of 32 pts were treated, 15 (6 females, 9 males) in the dose escalation part and 17 (15 females, 2 males) in the MTD confirmation part. The median number of doses was 11 (range 1–18). In the dose escalation phase, 3, 4, and 3 pts were treated at 8, 12, and 16 mg/m2 IV weekly without DLT. At 20 mg/m2, 2 of 5 pts developed DLT (1 pt - myalgia and neuropathy, 1 pt grade 4 neutropenia > 5 days in duration). The RD was 16 mg/m2 weekly. 17 more pts were treated at the RD. The most frequent grade 3 or 4 adverse events were asthenia (19%), nausea (9%), parethesia (9%) and neuropathy (9%). Of the 10 pts with breast cancer who were evaluable for response, one had a PR. Another breast cancer pt with a PR was a protocol violation and was not evaluable. In 20 pts at the MTD, the Tmax was 4 hr, the Cmax was 51.97 ng/mL, AUC 2711 ng*hr/mL, and the Vss was 1496 L/m2. Conclusions: Milataxel had an RD of 16 mg/m2 IV per week. Objective responses were observed in pts with metastatic breast cancer. No significant financial relationships to disclose.

Phase I study of irinotecan (Ir) and cisplatin (DDP) in combination with thoracic radiotherapy (RT), either twice daily (45 Gy) or once daily (70 Gy), in patients with limited (Ltd) small cell lung carcinoma (SCLC): Early analysis of RTOG 0241

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7058-7058 ◽  
Author(s):  
C. J. Langer ◽  
S. Swann ◽  
M. Werner-Wasik ◽  
R. Lilenbaum ◽  
W. Curran ◽  
...  
Keyword(s):  
Survival Data ◽  
Small Cell Lung Carcinoma ◽  
Maximum Tolerated Dose ◽  
Early Analysis ◽  
Cell Lung Carcinoma ◽  
Once Daily ◽  
Level 3 ◽  
Extensive Stage ◽  
Level 1 ◽  
Level 2

7058 Background: Ir in combination with DDP has proven superior to DDP & VP-16 in extensive stage SCLC (Noda et al NEJM 1/02), with marked increase in 2 yr survival (19.5%, vs 5.2%). Hence, it is critical to determine if Ir can be safely & effectively integrated with concurrent RT and DDP in earlier stage, Ltd SCLC. Methods: 1° endpoint: Determine maximum tolerated dose (MTD) of Ir d 1 & 8 plus DDP 60 mg/m2 q 3 wks & either BID RT (45 Gy) or QD RT (70 Gy). Eligibility stipulated Tx-naïve patients (pts) with Ltd SCLC, PS 0–1, adequate heme (ANC ≤ 1500/mL; plts ≥ 120,000/mL) hepatic (bili ≤ 1.5/dL) & renal (creat ≤ 1.5gr/dL) function, & baseline FEV1 of ≥ 1 liter. Ir was escalated in sequential (seq) cohorts from 40 mg/m2 (level 1) to 50 mg/m2 (level 2) & then to 60 mg/m2 (level 3) d 1 & 8 q 3 wks during each cycle of treatment. Ir & DDP were given concurrently with RT for cycle 1 in seq A (45 Gy) & during cycles 1 & 2 in seq B (70 Gy). 36 pts were targeted for accrual. DLT was defined as gr 4 esophagitis, pneumonitis, or diarrhea; gr 4 neutropenic fever, or any attributable gr 5 toxicity Results: As of 12/05, 36 pts were accrued, (21 - seq A; 15 - seq B). Median age was 64 (range 49–79) Of 33 eval pts, 18 (55%) were female; 24 (73%) PS 0; 67% had ≤ 5% wt loss. Attributable DLT was not seen in seq A, but was observed in seq B (70 Gy) at 50 mg/m2 with 1 episode each of gr 4 diarrhea & esophagitis, necessitating hospitalization. In addition, 1 pt in seq B had non-attributable gr 4 cardiovascular AEs. There has been no acute gr 5 toxicity. 1 pt experienced late gr 3 pulm toxicity, another gr 3 constitutional toxicity, including wt loss. The overall incidence of gr 3 esophagitis was 34%. Conclusions: In Ltd SCLC, I at 60 mg/m2 d 1 & 8 is safe & feasible in combination with DDP 60 mg/m2 q 3 wks & BID RT (45 Gy). The MTD for I in combination with RT (70 Gy) & DDP 60 mg/m2 is 40 mg/m2 d 1 and 8. Response, progression, survival data remain immature. [Table: see text] [Table: see text]

Phase I trial of ixabepilone and vorinostat in metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1070-1070
Author(s):  
Thehang H. Luu ◽  
Suzette Blanchard ◽  
Jan Hendrik Beumer ◽  
Bean N. Anyang ◽  
George Somlo ◽  
...  
Keyword(s):  
Dose Level ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Drug Clearance ◽  
Clinical Activity ◽  
Heavily Pretreated ◽  
Her 2 ◽  
Level 1 ◽  
Ecog Ps ◽  
Level 2

1070 Background: VOR, an HDAC inhibitor, induces acetylation of tubulin, and decreases resistance by attenuating downstream activation of AKT, c-Raf and HER-2. Patients (pts) with MBC treated with VOR had a TTP of 8.5 months (range 4-14) and stable disease in 29% (Luu et al., 2008). Our preclinical data showed synergistic effect of IXA and VOR in MDA-MB-231 and MCF7. Methods: The primary aims were to: 1) define the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT), and 2) describe the pharmacokinetics (PK) of 2 schedules of VOR and IXA. Secondary aims were to describe: 1) response rate (RR) and 2) clinical benefit rate (CBR). The study included: 1) pts with MBC; 2) ECOG PS 0-2; 3) adequate marrow and organ functions; 4) no prior IXA or VOR; and 5) < grade (gr) 1 neuropathy. Stable brain metastasis were allowed. Pts were randomized to schedule A: VOR (QDx14) + IXA (D2) Q21D; or B: VOR (D1-7 and 15-21) + IXA (D2, 9, 16) Q28D. A modified toxicity probability interval design (target toxicity rate= 0.2 and equivalence range +/- 0.05) (Ji et al, 2010) determined dose escalation guidelines. PK were assessed with LC-MS/MS assays. Results: Among 37 pts randomized, 36 were evaluable [median age (55 yrs); median prior chemotherapy regimens (3); ER and/or PR + (64%); HER2 + (19%)]. In cohort A, 16 pts were treated (1 inevaluable). The MTD was: VOR 300mg (QDx14) + IXA (32mg/m2 D2) Q21D (dose level 1). DLT was experienced by 27% (4/15) pts [gr 4 neutropenia, gr 3 fatigue/AST, hyponatremia and allergic reaction to IXA]. In cohort B, 21 pts were treated (dose level 1, n=15; dose level 2, n=6). The MTD was VOR 300mg QD (D1-7 and 15-21) + IXA 16mg/m2 (D2, 9, 16) Q28D (dose level 1), no DLTs were observed. Dose level 2 was closed with 50% (3/6) of pts experiencing DLTs [gr 3 neutropenia, hypertension, and hypokalemia]. Median cycles treated (cohort A: 6, cohort B: 4). Response in cohort A and B respectively was: 1 CR, 2 PR, 7 SD (RR: 20%, CBR: 67%) and 1 CR, 4 PR, 9 SD (RR: 33%, CBR: 93%). VOR and IXA PK were not influenced by the presence of the other drug, clearance values= 220 L/h and 20 L/h/m2, respectively. Conclusions: We established the MTD of VOR and IXA in pts with MBC. The combination demonstrated clinical activity in these heavily pretreated pts. Further studies are recommended.

SUNCAP, a phase II study with sunitinib and capecitabine in patients with metastatic colorectal cancer (MCRC) refractory to previous treatment with 5FU/irinotecan/oxaliplatin.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 545-545 ◽  
Author(s):  
B. Samson ◽  
J. Latreille ◽  
N. T. Nguyen ◽  
C. Sperlich ◽  
D. Berbiche ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Oral Treatment ◽  
Single Agent ◽  
Objective Response ◽  
Primary Objective ◽  
Primary Tumors ◽  
Phase Ii Studies ◽  
Level 1 ◽  
Level 2

545 Background: Patients (pts) with MCRC refractory/resistant to Irinotecan and Oxaliplatin have a poor prognosis. Sunitinib is an oral TKI that selectively inhibits the VEGFR 1, 2, 3, PDGFR and FLT3, CSF-1R, RET. Phase II studies with single agent sunitinib in patients with MCRC did not demonstrate a meaningful ORR but showed acceptable safety profile and warranted further study. Methods: We conducted a phase II escalating dose of sunitinib (S) and capecitabine (C) to assess the efficacy of this oral treatment given on a 2 wks every 3 wks schedule, (level 0, S: 37,5 mg, C: 2,000mg/m2, level +1, S: 50 mg, C: 2,000 mg/m2, level +2, S: 50 mg, C: 2,500 mg/m2 and level -1:S: 25 mg, C: 1,500 mg/m2. Treatment was initiated at level 0 and increased at level +1 and +2 at cycle 3 and 5 if no grade 2/3 toxicity was observed. Between 02.2009 and 06.2010, 15 pts previously exposed to oxaliplatin/irinotecan/bevazizumab were enrolled, all of them had progressive disease at the time of study entry. Primary objective was ORR. Treatment was given until PD or unacceptable toxicity. Results: Pts characteristics were: sex: 12M/3F, median age: 65 years [41-75], primary tumors: colon: 13, rectum: 2, ECOG PS 0/1: 8/7, median nb of metastatic sites: 3, KRAS status: WT/MT/Unknown: 1/9/5. Escalating to level +1:53%, level +2: 7%. Median nb of cycles received/pt: 5. All pts were evaluable for toxicity (tox): SAEs: 40%, any tox. grade 1/2/3(%): 93/60/ 40. Neutropenia gr. 1/2/3(%): 13/13/7, thrombocytopenia gr.1/2/3(%): 13/20/7. Fatigue gr.1/2/3(%): 27/20/7. Nausea gr.1: 27%. Diarrhea gr.1: 13%. Hand foot syndrome gr. 1/2/3 (%): 13/13/27. Mucositis gr. 1/2/3(%): 7/20/7. Hypertension gr.2: 13%. Thyroïd gr.1: 27%. ORR (CR+PR): 0%, confirmed SD: 7/15: 47%, PD: 8/15: 53%. Median PFS: 137 days [95%CI: 112-162], median OS: 291 days [95%CI: 99-482]. Conclusions: In this heavily pretreated patients, sunitinib in combination with capecitabine appears feasible, with acceptable toxicity. 47% of patients had a confirmed stable disease. Although no objective response was observed, the high level of stable disease may suggest a role of this combination for maintenance therapy. [Table: see text]

Inotuzumab ozogamicin (INO) plus bosutinib (BOS) in R/R PH+ ALL or CML in lymphoid blast phase (CML LBP).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7512-7512
Author(s):  
Nitin Jain ◽  
Abhishek Maiti ◽  
Farhad Ravandi ◽  
Marina Konopleva ◽  
Yesid Alvarado ◽  
...  
Keyword(s):  
Median Time ◽  
Dose Level ◽  
Skin Rash ◽  
Maximum Tolerated Dose ◽  
Kinase Domain ◽  
Primary Objective ◽  
Molecular Response ◽  
Antibody Drug Conjugate ◽  
Level 3 ◽  
Level 2

7512 Background: Pts with R/R Ph+ ALL and CML LBP have poor outcomes. INO is an anti-CD22 antibody drug conjugate approved for R/R ALL. BOS is a 2nd generation BCR-ABL TKI approved for CML. Methods: This was a phase I/II study of INO + BOS for R/R Ph+ ALL and CML LBP. Primary objective was to determine safety and the maximum tolerated dose (MTD) of the combination. Secondary objective was to assess efficacy. Pts with T315I mutation were excluded. Pts needed to have adequate organ function (Cr ≤2 gm/dL, total bilirubin ≤2 mg/dL, ALT & AST ≤3xULN). BOS was dosed once daily starting on cycle 1 day 1, and 3 dose levels were evaluated (300, 400, 500 mg) in a standard 3+3 design. INO was given IV weekly during cycle 1 (0.8 mg/m2 day 1; 0.5 mg/m2 day 8; 0.5 mg/m2 day 15). In responding pts, INO was subsequently administered at 1 mg/m2 once every 4 weeks for a total of 6 cycles. Results: Between June 2015 and December 2019 we enrolled 18 R/R pts (16 Ph+ ALL, 2 CML LBP). The median age was 62 yrs (range 19-74), median no. of prior therapies was 1 (range 1-5) and 9 pts had ABL kinase domain mutations at screening. There were no early deaths (<30 days). 3 pts were treated at BOS dose level 1; 6 pts at dose level 2; 9 pts at dose level 3. 1 pt had a DLT at dose level 2 - G3 skin rash, and 2 pts had a DLT at dose level 3 - both G3 skin rash. First 3 pts at dose level 3 did not receive ≥80% BOS doses during cycle 1 due to issues unrelated to adverse events (AE). As 2/6 DLT evaluable pts at dose level 3 had DLTs thus exceeding the MTD, the dose level 2 was identified as the MTD. Most frequent AE were diarrhea in 50%, rash in 50%, and nausea in 39%. Grade 3 AEs were rash (3), reversible ALT elevation (1) and hyponatremia (1). No pts had veno-occlusive disease. Pts have received a median of 3 cycles (range 1-8) with a median of 1 cycle to response (range 1-2). Responses are shown in Table. Median time to response was 1 months (mo, range 0.8-2.1), median time to negative MRD by flow cytometry (FCM) was 6.9 mo (range 3.4-18) and median time to complete molecular response (CMR) was 9.1 mo (range 3.4-18). After a median follow-up of 32 mo, the median overall survival was 15.4 mo and median event-free survival censored at stem-cell transplantation (SCT) was 6.1 mo. 6 pts underwent SCT, 8 pts relapsed, 10 pts are alive and 2 pts continue therapy. Conclusions: INO + BOS was well tolerated and showed promising activity in R/R Ph+ ALL and CML LBP. Clinical trial information: NCT02311998 . [Table: see text]

A phase I study of cetuximab (cet) in combination with S-1 and irinotecan (iri) (SIRC) in first-line treatment for metastatic colorectal cancer (mCRC) (JACCRO CC-10).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 735-735 ◽  
Author(s):  
Akihito Tsuji ◽  
Masato Nakamura ◽  
Toshiki Masuishi ◽  
Masahito Kotaka ◽  
Ken Shimada ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Dose Adaptation ◽  
Nonhematologic Toxicity ◽  
Level 1 ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Ecog Ps ◽  
Level 2

735 Background: S-1 combined with iri and cet are also effective treatments in patients (pts) with mCRC. However, diarrhea is one of the concerned toxicities overlapping of each 3 drugs. To evaluate the safety of this combination, we conducted a multi-center phase I study. Methods: The phase I trial was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) based on a 3+3 cohort expansion design. The cohort at the level of speculated RD was expanded to 10 pts. The main criteria for eligibility was as follows; histologically confirmed mCRC, ECOG PS 0-1, KRAS wild type. The dose adaptation schedule of iri was 125 mg/m2 for level 1 and 150 mg/m2 for level 2. Patients received cet (initial dose 400, and 250 mg/m2 weekly) followed by SIR (iri on day 1 and S-1 40 mg/m2 twice daily on days 1-14). The treatment was repeated every 3 weeks. Dose-limiting toxicity (DLT) was defined as any of the following findings during cycle 1:1) neutrophil count less than 500/mm3 for 4 days or more; 2) febrile neutropenia; 3) platelet count less than 50,000/mm3; 4) grade 3 or 4 diarrhea; 5) grade 3 or 4 of nonhematologic toxicity, excluding nausea, vomiting, diarrhea, anorexia, and skin toxicities; 5) the number of S-1 administration less than two-third; 6) the delayed start of the second course greater than 1-week as the drug-related toxicity. Results: The MTD was not determined, because DLT was not observed in level 1 (n=3) and level 2 (n=6). Level 2 was speculated to be the RD. Because 4 pts in the expansion cohort experienced no DLT, level 2 was determined as the RD. The completion rate of cycle 4 was 76.9%. Median dose intensities at the level 2 were 97%, 89%, and 91% for iri, S-1, and cet, respectively. During cycle 4 at level 2, grade 3 or worse adverse events were anorexia (20%) and dry skin (10%). The response rate according to RECIST criteria was 62.7% (95% CI, 50.4 to 75.1). Conclusions: We determined 150 mg/m2 of irinotecan as the RD for SIRC. This combination is tolerable at full doses of cet and SIR, with manageable toxicities. We are now planning the further phase II/III trial including SIRC as an experimental arm. Clinical trial information: UMIN000010639.

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