Downstaging of unresectable intrahepatic or hilar cholangiocellular carcinoma by selective intra-arterial floxuridine and systemic cisplatin and gemcitabine. A dose finding single center phase IIa study.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 478-478 ◽  
Author(s):  
Heike Pietge
Keyword(s):  
Systemic Chemotherapy ◽  
Hepatic Arterial Infusion ◽  
Progression Free Survival ◽  
Response Rates ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Fixed Dose ◽  
Pet Ct ◽  
Tract Infections ◽  
Palliative Systemic Chemotherapy

478 Background: Patients with unresectable cholangiocarcinomas (CCC) have a poor prognosis even if palliative systemic chemotherapy is offered. A combined approach of systemic and intrahepatic chemotherapy may improve local control rates and allow downstaging. The aim of the study was to determine the maximum tolerated dose (MTD) of systemic intravenous gemcitabine in combination with intravenous cisplatin and hepatic arterial infusion with floxuridine in patients with unresectable intrahepatic or hilar CCC. Safety, toxicity, response rates and resectability rates after 3 months of combination treatment are reported. Methods: 12 patients were treated within a 3+3 dose escalation algorithm with 600, 800 or 1000 mg/m2 gemcitabine and a fixed dose of cisplatin 25 mg/m2 systemic chemotherapy on day 1, 8 every 3 weeks for 4 cycles and floxuridine 0,2 mg/kg on day 1-14 continous hepatic intra-arterial chemotherapy every 4 weeks for 3 cycles. PET/CT and/or CT scan was performed after 12 weeks. Results: The MTD of gemcitabine was 800 mg/m2 in this setting. Dose-limiting toxicities were recurrent biliary tract infections (n = 1) and neutropenic fever (n = 1). Response rates were: 27% partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, 3-year-overall survival (OS) was 33%, median OS 21,9 months (1-49) and median progression-free survival 10,5 months (2-40). Conclusions: Combination of systemic gemcitabine and cisplatin plus intraarterial floxuridine is feasible and appears effective in disease control, but achievement of resectability seems challenging. Randomized trials comparing this combination to gemcitabine/cisplatin alone are warranted. Clinical trial information: NCT01692704.

scholarly journals Combination of HAI-FUDR and Systemic Gemcitabine and Cisplatin in Unresectable Cholangiocarcinoma: A Dose Finding Single Center Study

Oncology ◽  
2021 ◽  
Vol 99 (5) ◽  
pp. 300-309
Author(s):  
Heike Pietge ◽  
Patricia Sánchez-Velázquez ◽  
Dilara Akhoundova ◽  
Alexander Siebenhüner ◽  
Thomas Winder ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Data ◽  
Treatment Options ◽  
Hepatic Arterial Infusion ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Free Survival ◽  
Single Center Study ◽  
Tract Infections

Background: Unresectable cholangiocarcinoma has a poor prognosis and treatment options are limited. Combined systemic and intrahepatic chemotherapy may improve local control and enable downsizing. The aim of this study was to determine the maximum tolerated dose (MTD) of intravenous gemcitabine combined with intravenous cisplatin and hepatic arterial infusion (HAI) with floxuridine (FUDR) in patients with unresectable intrahepatic or hilar cholangiocarcinoma. Methods: Twelve patients were treated within a 3 + 3 dose escalation algorithm with 600, 800, or 1,000 mg/m2 gemcitabine and predefined doses of cisplatin 25 mg/m2 on days 1 and 8, q21, for 4 cycles, and FUDR 0.2 mg/kg on days 1–14 as continuous HAI, q28, for 3 cycles. Safety and toxicity as well as resectability rates after 3 months and preliminary survival data are reported. Results: The determined MTD for gemcitabine was 800 mg/m2. Dose limiting toxicities were neutropenic fever and biliary tract infections. In total, 27% of the patients showed partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, the 3-year overall survival rate was 33%, median overall survival 23.9 months (range 1–49), and median progression-free survival 10.1 months (range 2–40). Conclusions: Intravenous gemcitabine/cisplatin plus HAI-FUDR is feasible and appears effective for disease control. Larger prospective studies evaluating this triplet combination are warranted.

Increased incidence of adverse events after concomitant hepatic arterial infusion plus systemic chemotherapy and bevacizumab for colorectal cancer with liver metastasis.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 591-591
Author(s):  
S. Sadahiro ◽  
T. Suzuki ◽  
Y. Maeda ◽  
A. Tanaka ◽  
K. Okada ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Adverse Events ◽  
Phase I ◽  
Systemic Chemotherapy ◽  
Response Rate ◽  
Hepatic Arterial Infusion ◽  
Progression Free Survival ◽  
Arterial Infusion ◽  
Grade 3

591 Background: FOLFOX+bevacizumab (BEV) is the standard systemic chemotherapy for metastatic colorectal cancer (CRC). We investigated the combination of FOLFOX4 and hepatic arterial infusion (HAI) in patients who had isolated liver metastasis from CRC. We also compared efficacy and safety between this combination therapy and its concomitant use with BEV. Methods: Twenty-five patients entered a phase I/II trial of HAI (5-FU 250 mg/d, leucovorin 25 mg/d; d1-7, q2w) combined with FOLFOX4. Fourteen other patients with a similar background received HAI + FOLFOX4 combined with BEV and the two regimens were compared. Results: In the phase I/II study, the recommended doses for FOLFOX were as follows: L-OHP, 85 mg/m2; l-LV, 100 mg/m2; 5-FU (bolus), 400 mg/m2; and 5-FU (infusion), 600 mg/m2. Sixteen patients who received this regimen showed a response rate of 93.8% (2 CR and 13 PR), a median progression-free survival of 323 days, and a one-year survival rate of 93.7%. In the subsequent phase II trial of HAI + FOLFOX4 with BEV, 14 patients were enrolled and the response rate was 78.6% (2 CR and 9 PR). The outcome was inferior when BEV was used concomitantly. The median numbers of doses were 10 (range: 1-27) for FOLFOX4 and 9 (1-27) for HAI without BEV, whereas the corresponding numbers with BEV were 8 (1-12) and 2 (0-9), respectively. There was a marked decrease in the number of HAI procedures when BEV was used. Thrombosis occurred in 8 patients who received concomitant BEV, which was the most common reason for cessation of HAI. Other adverse events (≥Grade 3) were neutropenia (n=7; 43.8%) and thrombocytopenia (n=2; 12.5%) without BEV or neutropenia (n=7; 43.8%) and diarrhea (n=1; 7.1%) with BEV, and no marked difference was seen between the two regimens. Both regimens were well tolerated. Severe neuropathy was only observed in 1 patient (6.3%; Grade 3) who received concomitant BEV. Conclusions: In the present study, HAI + FOLFOX combined with BEV caused thrombosis and disturbance of wound healing, thereby increasing the incidence of complications and making it difficult to continue treatment. These findings suggest that BEV should not be administered with HAI therapy. No significant financial relationships to disclose.

Activity and safety of Nab-FOLFIRI and Nab-FOLFOX as first-line treatment for metastatic pancreatic cancer (phase II NabucCO study).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 351-351 ◽  
Author(s):  
Elisa Giommoni ◽  
Evaristo Maiello ◽  
Vanja Vaccaro ◽  
Ermanno Rondini ◽  
Caterina Vivaldi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Phase Iii ◽  
Metastatic Pancreatic Cancer ◽  
First Line ◽  
Open Label ◽  
Grade 3

351 Background: FOLFIRINOX is an approved regimen for metastatic pancreatic cancer (mPC). We performed a modification in FOLFIRINOX schedule, using nab-paclitaxel (nab-p) to obtain two regimens that could be as effective and less toxic than the original triplet. NabucCO study was a randomized phase II trial to assess activity and toxicity of nab-p instead of either oxaliplatin (Nab-FOLFIRI) or irinotecan (Nab-FOLFOX) in first line setting. Previous dose–finding NabucCO study defined that maximum tolerated dose of nab-p with FOLFIRI is 120 mg/m2, and with FOLFOX is 160 mg/m2. Methods: The study was a 1:1 parallel arm, open label, not comparative one to assess overall response rate (ORR) of Nab-FOLFIRI and Nab-FOLFOX as primary end-point. Patients (pts) with PS 0-1, untreated for mPC were randomized to receive leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2, irinotecan 180 mg/m2 plus nab-p 120 mg/m2 (arm A) or leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2 and oxaliplatin 85 mg/m2 iv plus nab-p 160 mg/m2 (arm B) every 2 weeks for up to 12 cycles. Secondary end points were clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), and safety. Results: From November 2015 to January 2017, 84 pts were treated (42 for each arm). Median age was 60 years (29-65) in arm A and 64 years (47-64) in arm B. The ORR was 31 % for both schedules, with a CBR of 69% and 71%, respectively. At a median follow-up of 11.4 months for arm A and 14.5 months for arm B (censored on august, 31th 2017), 1-year survival is 41% and 50%, respectively. For Nab-FOLFIRI PFS and mOS were 6 months (90% CI: 4.9-8.0) and 13.2 months (90% CI: 8.3-14.8), while in Nab-FOLFOX were 5.6 months (90% CI:4.9-7.2) and 10.8 months (90% CI: 8.4-12.8). Grade ≥3 toxicities in arm A were neutropenia (19%) and febrile neutropenia (12%). In arm B, main grade ≥3 toxicities were neutropenia (29%), fatigue (14%), peripheral neuropathy (7%). No toxic death were registered. Conclusions: Nab-FOLFIRI and Nab–FOLFOX demonstrated a similar activity to FOLFIRINOX, with better safety profile in terms of neutropenia, fatigue and neuropathy. These results could justify a future phase III evaluation. Clinical trial information: NCT02109341.

Updated results from a phase Ib trial of regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer (REGONIVO, EPOC1603).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 135-135
Author(s):  
Kohei Shitara ◽  
Hiroki Hara ◽  
Naoki Takahashi ◽  
Takashi Kojima ◽  
Akihito Kawazoe ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase 1 ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Significant Difference ◽  
One Year ◽  
Anti Tumor Activity

135 Background: In the phase 1 REGONIVO study, regorafenib of 80 mg/day plus nivolumab showed manageable safety profiles and encouraging anti-tumor activity for advanced colorectal cancer (CRC) or gastric cancer (GC) with objective response rate (ORR) of 36% in CRC and 44% in GC (Fukuoka, et al. ASCO 2019). Updated efficacy results are presented. Methods: Enrolled patients (pts) received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one to estimate the MTD and the recommended dose. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 28-8 antibody. Tumor mutation burden (TMB) was measured using Oncomine tumor mutation load assay. Results: Fifty pts were enrolled (25 CRC; 25 GC) until October 2018 with median prior treatment line of 3. Efficacy results were updated as of September 1st 2019. One CRC pt was with MSI-high but all other pts were with MSS or MMR-proficient. Among the 20 pts (9 CRC and 11 GC) with objective response (40%), responses are still ongoing in 13 pts (7 CRC and 6 GC) and the median duration of response was not reached (NR). Median progression free survival (PFS) was 7.8 months in CRC (95% CI, 2.8- NR) and 5.5 months (95% CI, 2.6-10.2 months) in GC. One-year PFS rate was 41.7% in CRC and 22.4% in GC. Median overall survival (OS) was not reached in CRC (95% CI, 9.7-NR) and 12.1 months (95% CI, 5.2-NR) in GC. One-year OS rate was 68% in CRC and 55.3% in GC. No significant difference of PFS and ORR was observed in CRC according to PD-L1 and TMB. Conclusions: Encouraging anti-tumor activity of the combination of regorafenib plus nivolumab had been maintained with long-term follow-up. A randomized study for MSS CRC is under planning. Clinical trial information: NCT03406871.

Docetaxel in combination with radiation in prostate cancer: A phase I dose-finding study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14649-14649 ◽  
Author(s):  
W. R. Berry ◽  
R. K. Fairbanks ◽  
R. H. Gersh ◽  
S. M. Mull ◽  
D. Ilegbodu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Phase Ii Trials ◽  
Effects Of Radiation ◽  
Definition Of ◽  
Ecog Ps ◽  
Dose Levels

14649 Background: Docetaxel (D), one of the more active agents against prostate cancer, also enhances the effects of radiation therapy (XRT). However, there is little information on the tolerability of the addition of D to pelvic XRT. This Phase I multicenter study was conducted to determine the maximum tolerated dose (MTD) and toxicities of D when given in combination with pelvic XRT. Methods: Patients (pts) with PSA levels >4.0 and <8.0 ng/mL after radical prostatectomy who were referred for salvage XRT were treated at 3 dose levels of D: 10 mg/m2, 16 mg/m2, and 22 mg/m2. One treatment course consisted of D given on Day 1 of each 1-week cycle for 7 cycles with daily XRT administered at 180 cGy Monday–Friday. The 3+3 standard Phase I escalation rule was used to establish the MTD. Results: A total of 9 pts were treated, 3 in each cohort at 3 dose levels. Median doses in the 3 cohorts were 22 mg, 35 mg, and 46 mg. Of the 9 pts, 89% were white, 89% had ECOG PS of 0, and 56% had Stage III disease. The median age was 56 years (range, 48–71). Eight patients completed all 7 weeks of D and XRT; 1 pt went off study after Week 4 due to a fall and fractured arm; 3 other pts subsequently went off study due to PD. In the 3rd cohort, 1 pt had Grade 3 diarrhea (a predefined dose-limiting toxicity [DLT]). The cohort was not expanded by 3 additional pts, and the study was closed to enrollment. The MTD of D with concurrent XRT was not determined. The most frequent adverse events (AEs) were fatigue and diarrhea (67% each), nausea and proctitis (44% each), and anorexia and insomnia (22% each). Except for fatigue, the incidences of these AEs were as expected for treatment with D. Four patients (44%) had a CR (1 CRu). There were 4 PR (1 PRu; 44%) and 1 SD (11%). The median time to response was 1.88 mo. (range, 1.8–7); the overall survival was 27.5 mo.; and the median progression-free survival was 17.7 mo. (range, 1.8–27.5). All patients are currently alive. Conclusions: This Phase I study did not allow definition of the MTD of weekly D with XRT before the trial was terminated. The maximum dose tested was 22 mg/m2/week for 7 weeks. D with pelvic XRT to the prostate was well-tolerated and showed promising responses. It thus deserves further study in Phase II trials. Supported in part by sanofi-aventis, Bridgewater, NJ. [Table: see text]

Clofarabine Combinations in Acute Myeloid Leukemia (AML) Salvage: A Dose-Finding Phase I Study of Clofarabine Plus Idarubicin and Clofarabine/Idarubicin Plus Cytarabine (ara-C).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2803-2803
Author(s):  
Stefan Faderl ◽  
Alessandra Ferrajoli ◽  
William Wierda ◽  
Farhad Ravandi ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Response Rates ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Unrelated Donor ◽  
Acute Leukemias ◽  
First Relapse ◽  
Dose Levels

Abstract Clofarabine is a second-generation nucleoside analog with single agent activity in acute leukemias. To try and improve efficacy, various combination trials are being conducted. In studies of clofarabine plus ara-C we reported overall response rates of 41% (CR 24%) in AML salvage and 60% (CR 52%) in untreated elderly AML with acceptable toxicity profile. To explore additional clofarabine combinations in AML we conducted a phase I study of clofarabine (C) with idarubicin (I) [CI] alone and with ara-C (A) [CIA] in pts with relapsed AML and high-grade MDS. Dose-limiting toxicities (DLT) were defined as ≥ grade 3 drug-related toxicities. Maximum tolerated dose (MTD) was determined by “3+3” method. Thirty-three patients (18 on CI and 15 on CIA) have been treated and are evaluable. Of 18 pts on CI, 6 were primary refractory and 12 in first relapse (median first remission duration [CRD1] 2 mos. [range 0–9]. Eleven pts had abnormal cytogenetics. Fourteen pts received prior ara-C-based regimens, 2 relapsed from allogeneic transplant (SCT). Median age: 57 yrs (range 24–71). Four dose levels have been explored. When C was given at 22.5mg/m2 i.v. daily x 5d and I at 12mg/m2 i.v. daily x 3d, 2 ≥ gr. 3 toxicities (diarrhea, rash, ↑ bili) occurred necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d/I at 8mg/m2 x 3d (6 pts, 1 ≥ gr.3 toxicity [↑ bili]), C at 18 mg/m2 x 5d, I at 10mg/m2 x 3 d (3 pts, no DLT), and C at 22.5mg/m2 x 5d, I at 10mg/m2 x 3d (3 pts, no DLT). Three (17%) responses (2 CRp, 1 CR) occurred. Of 15 pts on CIA, 4 were primary refractory and 11 in first relapse. Median CRD1 was 9 mos (0–24). Eight pts had an abnormal karyotype. Seven pts received prior ara-C-based regimens and 2 failed unrelated donor SCT. Median age: 58 yrs (23–78). Three dose levels were evaluated. At C 22.5mg/m2 i.v. daily x 5d, I 8mg/m2 i.v. daily x 3d, A 1g/m2 i.v. daily x 5d, 2 of 3 pts developed ≥ gr.3 toxicities (↑ bili, diarrhea) necessitating dose de-escalation. Subsequent levels included C at 15mg/m2 x 5d, I at 6mg/m2 x 3d, A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 rash, ↑ bili), and C at 22.5mg/m2 x 5d, I at 6mg/m2 x 3d, and A at 0.75g/m2 x 5d (6 pts, 1 with ≥ gr. 3 ↑ bili). Nine (60%) responses (8 CR, 1 CRp) occurred. Further dose escalation of clofarabine is planned in both trials. The preliminary results indicate feasibility of the combinations. The higher response rates with CIA need to be evaluated in view of different pt. characteristics between the two trials.

Phase I trial of biweekly S-1, leucovorin, oxaliplatin, and gemcitabine (the SLOG regimen) in metastatic pancreatic adenocarcinoma (mPDAC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 369-369
Author(s):  
Nai-Jung Chiang ◽  
Kelvin K. Tsai ◽  
Jen-Shi Chen ◽  
Shih-Hung Yang ◽  
Chiun Hsu ◽  
...  
Keyword(s):  
Dose Level ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Common Grade ◽  
Frontline Treatment ◽  
Fixed Dose Rate Infusion ◽  
Grade 3

369 Background: Gemcitabine and S-1 had been approved as the frontline treatment for mPDAC in Taiwan and Japan. Our previous study showed biweekly gemcitabine plus modified FOLFOX4 (the GOFL regimen) was a moderate active and well-tolerated regimen in mPDAC. To explore whether oral S-1/LV can be a substitute for infusion 5-FU/LV in combination with gemcitabine and oxaliplatin as “the SLOG regimen” to improve treatment efficacy and convenience. To define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and preliminary anti-tumor efficacy of SLOG in patients with chemo-naïve mPDAC. Methods: Enrolled patients would receive intravenous infusion of 800 mg/m2 gemcitabine (fixed-dose rate infusion, 10 mg/m2/min) followed by 85mg/m2 oxaliplatin (2 hours) on D1 and escalating dose of oral S-1 and 20 mg/m2 leucovorin, twice daily D1-D7, every 14 days. DLTs were evaluated during the first 2 cycles of treatment. The treatment was continued until disease progression, unacceptable toxicity or withdrawal of informed consent. Results: 19 patients were enrolled into four dose levels of S-1, 20 mg/m2 (three), 30 mg/m2 (seven), 35 mg/m2 (six) and 40 mg/m2 (three). At 30 mg/m2 dose level, one patient who withdrew consent after one cycle treatment was replaced with another one. DLTs were observed in three patients, one at 30 mg/m2 (grade 3 diarrhea) and two at 40 mg/m2 (grade 3 hypersensitivity reaction and diarrhea in one each). MTD of S-1 was determined as 35 mg/m2. The median treatment duration was 8 cycles (ranged, 1-26). Of the 16 evaluable patients, the objective response rate and disease control rate were 37.5% (6 partial response, PR) and 81.3% (6 PR + 7 stable disease, SD), respectively. The median progression-free survival (PFS) was 4.6 months. At MTD dose level, there were 4 PR and 2 SD, with 6.7 months of PFS. The most common grade 3-4 adverse events included neutropenia (26.4%), diarrhea (15.8%), ALT increased (10.5%) and anemia (10.5%). Conclusions: The MTD of S-1 was 35 mg/m2 in the SLOG regimen. Extension phase II study in mPDAC is ongoing. Clinical trial information: NCT 01415713.

Phase I study of hepatic arterial infusion (HAI) therapy with floxuridine (FUDR) combined with systemic gemcitabine and oxaliplatin in patients with locally advanced intrahepatic cholangiocarcinoma (ICC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 417-417
Author(s):  
Patrick Grierson ◽  
Aabha Oza ◽  
Maria Majella Doyle ◽  
Kathryn Fowler ◽  
Ryan Fields ◽  
...  
Keyword(s):  
Systemic Chemotherapy ◽  
Phase 1 ◽  
Locally Advanced ◽  
Hepatic Arterial Infusion ◽  
Standard Of Care ◽  
High Rate ◽  
Grade 3 ◽  
Palliative Systemic Chemotherapy ◽  
Age Range ◽  
Rate Of Response

417 Background: The standard of care for unresectable ICC is palliative systemic chemotherapy with cisplatin and gemcitabine. HAI therapy with FUDR in ICC resulted in high response rates [Kemeny 2011]. The use of HAI FUDR with systemic chemotherapy may improve outcomes. We conducted a phase 1 study of HAI FUDR with systemic gemcitabine and oxaliplatin. Methods: We enrolled patients in 3 cohorts: FUDR 0.16mg/kg/day x 14 days (Cohort 1), FUDR 0.12 mg/kg/day x 14 days with gemcitabine 1000mg/m2 on days 1, 8, 15 (Cohort 2), and FUDR 0.10 mg/kg/day x 14 days with gemcitabine 800mg/m2 days 1, 15 and oxaliplatin 85mg/m2 days 1, 15 (Cohort 3). The primary endpoint was the recommended phase 2 dose (RP2D) for Cohort 3. DLTs were assessed during cycle 1. Secondary objectives were response rate and survival. Results: We enrolled 24 patients, 6 male, age range 42-81 years (median 64). No DLTs were observed in Cohort 1 (FUDR). In Cohort 2 (FUDR + Gem), the addition of gemcitabine at 1000mg/m2 days 1, 8, 15 resulted in grade 3 LFT elevation in 2 patients; for subsequent patients, the gemcitabine dose was reduced to 800mg/m2, and no further DLT were noted. No DLT were observed in Cohort 3 (FUDR + GemOx). 10 patients experienced partial responses and conversion to resectable disease occurred in all cohorts. No other significant toxicities occurred. Conclusions: FUDR via HAI with systemic gemcitabine and oxaliplatin is well-tolerated in patients with unresectable cholangiocarcinoma, with a high rate of response and disease control, allowing for resection in some patients. Our RP2D is FUDR 0.10 mg/kg/day x 14 days, with gemcitabine 800mg/m2 days 1, 15 and oxaliplatin 85mg/m2 days 1, 15. Collaboration with MSKCC is ongoing. Clinical trial information: NCT01525069. [Table: see text]

Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study.

1995 ◽  
Vol 13 (11) ◽  
pp. 2688-2699 ◽  
Author(s):  
L Gianni ◽  
E Munzone ◽  
G Capri ◽  
F Fulfaro ◽  
E Tarenzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Single Agent ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Antitumor Efficacy ◽  
Severe Neutropenia ◽  
Fixed Dose ◽  
Median Response

PURPOSE To define the maximum-tolerated dose (MTD) and better tolerated sequence of paclitaxel by 3-hour infusion plus bolus doxorubicin (DOX) and to evaluate antitumor efficacy. PATIENTS AND METHODS Thirty-five women with metastatic breast cancer (dominant visceral metastases in 56%, and involvement of > or = three sites in 67%) who never received chemotherapy of any type were studied. Paclitaxel every 3 weeks (125 mg/m2 starting dose) was increased by 25-mg/m2 steps in subsequent cohorts of patients. DOX (60 mg/m2 fixed dose) was administered 15 minutes before the start of or after the end of paclitaxel for a maximum of eight cycles. Subsequently, patients in continuous response could receive single-agent paclitaxel (175 to 200 mg/m2 every 3 weeks). The drug sequence was alternated in consecutive patients and in the first two cycles. RESULTS Severe neutropenia that lasted greater than 7 days (n = 4), febrile neutropenia (n = 7) and grade III oral mucositis (n = 6) defined the MTD of paclitaxel at 200 mg/m2 in 34 assessable patients. Grade II peripheral neuropathy occurred in 33% of patients. Six women (18%) developed clinically reversible congestive heart failure (CHF) after a median of 480 mg/m2 total DOX. Drug sequence had no effect on toxicities. High efficacy on all metastatic sites in 32 assessable patients accounted for a 41% complete response (CR) rate (95% confidence interval [CI], 24% to 59%) and 94% overall-response rate (95% CI, 79% to 99%). After a median follow-up of 12 months (range 3 to 18), the median response duration is 8 months (range, 2+ to 18+) for complete responders and 11 months (range 1+ to 15+) for partial responders. CONCLUSION The rate of CR and incidence of CHF may be an expression of therapeutic and toxic enhancement due to the schedule used in this trial. Until clarification of this possibility, this promising combination should be used in investigational trials.

Impact of KRAS on outcomes of patients with unresectable colorectal liver metastases (CRLM).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 510-510
Author(s):  
Celina Ang ◽  
Alexandra N. Gewirtz ◽  
Joanne F. Chou ◽  
Marinela Capanu ◽  
Efsevia Vakiani ◽  
...  
Keyword(s):  
Overall Survival ◽  
Liver Resection ◽  
Systemic Chemotherapy ◽  
Univariate Analysis ◽  
Hepatic Arterial Infusion ◽  
Progression Free Survival ◽  
Rank Test ◽  
Related Factors ◽  
Hazards Model ◽  
The Impact

510 Background: In patients with resected CRLM, mutant (MUT) KRAS may confer a worse prognosis than wild-type (WT) KRAS (Karagkounis et al., ASCO 2012, abs 3616; Kemeny et al., ASCO 2013, abs 3609). We analyzed the impact of KRAS on the outcomes of patients with unresectable CRLM treated with hepatic arterial infusion (HAI) + systemic chemotherapy. Methods: Median overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan Meier methods. The log rank test was used to examine the association of patient demographics and disease-related factors including KRAS mutation status with OS and PFS. Cox proportion hazards model was used to examine the association of liver resection with survival outcomes by treating liver resection as a time dependent covariate. Results: Of 93 patients: 59 male, 34 female; 77 Caucasian, 16 non-Caucasian; 66 were age < 60 years, 27 were age > 60 years; 70 were KRAS WT and 23 were KRAS MUT; 59 had chemotherapy pre-HAI pump placement and 53 subsequently underwent liver resection. Median PFS and OS were 13.3 months and 45.7 months, respectively. Age, sex and race were not associated with PFS or OS. Univariate analysis of the impact of KRAS, pre-HAI chemotherapy, and subsequent liver resection on PFS and OS is presented in the Table. Multivariate analysis including important variables did not change outcome. Conclusions: In patients with unresectable CRLM treated with HAI and systemic chemotherapy, overall survival tended to be improved in KRAS WT vs MUT patients. [Table: see text]

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