A phase II trial of thalidomide plus tegafur/uracil for patients with advanced/metastatic hepatocellular carcinoma (HCC): Final report

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15533-e15533 ◽  
Author(s):  
C. Hsu ◽  
Z. Lin ◽  
K. Lee ◽  
K. Yeh ◽  
C. Hsiao ◽  
...  
Keyword(s):  
Disease Control ◽  
Local Treatment ◽  
Metronomic Chemotherapy ◽  
Progression Free Survival ◽  
Disease Control Rate ◽  
Final Report ◽  
Moderate Activity ◽  
Advanced Hcc ◽  
First Line Therapy ◽  
Grade 3

e15533 Background: Thalidomide (T) is an anti-angiogenic agent with modest activity in advanced/metastatic HCC. Tegafur/uracil (UFT) is an oral prodrug of 5-fluorouracil with activity against various gastrointestinal cancers. Metronomic chemotherapy has been shown to have anti-angiogenic and anti-cancer effect in preclinical and clinical models. This study evaluated the efficacy and safety of the combination of T and metronomic UFT as first-line therapy for advanced HCC. Methods: Patients (Pts) with advanced HCC not treatable by surgery or other loco-regional therapies received T 100mg bid and UFT 125mg/m2 (based on tegafur) bid continuously. Treatment was continued in the absence of disease progression or unacceptable toxicity. Primary endpoint was response rate (RR) by RECIST; secondary endpoints were disease control rate (CR+PR+SD), progression-free survival (PFS), overall survival (OS), and safety. Results: Between Jul 2006 and Jul 2008, 43 intent-to-treat pts (M/F 41/2, median age 55) were enrolled. Baseline characteristics were HBsAg(+)/anti-HCV(+)/both(+) /both(-) 31/6/1/7; AJCC stage II/III/IV 2/18/23; BCLC stage B/C 1/42; CLIP score ≤3/4 27/16; portal vein thrombosis 65%; extrahepatic metastasis 58%; prior local treatment 72%. There were 4 PR (9.3%) and 10 SD (23.3%), with a disease control rate of 32.6%. Median OS was 4.6 (95% CI, 3.5–7.3) months and median PFS was 1.9 (95% CI, 1.8–2.6) months. The OS and PFS for pts with CLIP score ≤3 were 7.6 and 2.6 months, respectively. Grade 3 leucopenia developed in 1 (2.3%) pt. The most common treatment-related grade 3 non-hematologic toxicities were somnolence (n=4, 9.3%), GI bleeding (n=3, 7.0%), and elevated transaminase (n=2, 4.7%). No grade 4 toxicities occurred. Conclusions: The combination of T with metronomic UFT is a well-tolerated regimen with moderate activity for advanced HCC, and worth further exploration in pts with CLIP score ≤3. [Table: see text]

151 A RANDOMIZED,OPEN CLINICAL TRIAL TO COMPARE THE EFFICACY AND SAFETY OF ANLOTINIB PLUS IRINOTECAN VERSUS IRINOTECAN IN PATIENTS WITH ESCC

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Feng Wang ◽  
Xiangrui Meng ◽  
Hangrui Liu ◽  
Qingxia Fan
Keyword(s):  
Disease Control ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Progression Free Survival ◽  
Thyroid Stimulating Hormone ◽  
Disease Control Rate ◽  
Control Group ◽  
Trial Group ◽  
Grade 3

Abstract   The benefit of systemic treatment in esophageal squamous cell carcinoma (ESCC) which has progressed after chemotherapy is still uncertain. Anlotinib (AL3818) is a novel multi-target TKI, inhibiting tumor angiogenesis and proliferation. A phase II trial (NCT02649361) has demonstrated that anlotinib has a durable antitumor activity with a manageable adverse event profile in refractory metastatic ESCC. This study (NCT03387904) aimed at comparing the effects and safety of Anlotinib Plus Irinotecan versus Irinotecan in patients with ESCC. Methods We conducted a prospective randomized, multicenter, phase II trial to compare the efficacy of Anlotinib Plus Irinotecan with Irinotecan in recurrent ESCC patients who had resistance to platinum or taxane-based chemotherapy. Eligible patients were adults with pathologically confirmed recurrent ESCC, and 82 patients were randomized 1:1 to Irinotecan (65 mg/m2/day 1 and day 8) with or without anlotinib (12 mg qd day 1 to 14) of a 21-day cycle till progression or intolerable. The primary endpoint is the disease control rate (DCR) and progression-free survival (PFS) and the secondary end points are objective response rate (ORR) and overall survival (OS). Results Between 13/1 2019 and 20/1 2020, a total of 43 patients were enrolled and randomly assigned to either the anlotinib plus irinotecan (n = 22) or the irinotecan group (n = 21).The mPFS was longer in trial group than in control group (89 days vs 66 days, HR = 0.447, P = 0.055). The Disease control rate (DCR) was 54.5% in trial group and 38.1% in the control group. The treatment-related adverse events (>10%) were fatigue (59.1%), nausea (50.0%), decreased appetite (36.4%), hoarseness (27.3%), thyroid-stimulating hormone elevation (22.7%), diarrhea (9.1%), and decreased lymphocytes count(9.1%) in trial group. Grade 3 AEs included fatigue (4.5% vs 4.8%), nausea (4.5% vs 0%) and diarrhea (4.5% vs 0%) in two groups. Conclusion Anlotinib plus irinotecan was similarly tolerable but prolonged PFS compared to irinotecan monotherapy as a second-line treatment in patients with recurrent ESCC.

Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 520-520 ◽  
Author(s):  
Scott Kopetz ◽  
Shannon L McDonough ◽  
Van Karlyle Morris ◽  
Heinz-Josef Lenz ◽  
Anthony Martin Magliocco ◽  
...  
Keyword(s):  
Disease Control ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Disease Control Rate ◽  
Free Survival ◽  
Type 1 Error ◽  
Braf Inhibition ◽  
Grade 3 ◽  
Ecog Ps

520 Background: BRAF V600 mutations are associated with rare objective responses to the mutated BRAF inhibitor vemurafenib in patients with mCRC. Blockade of BRAFV600 by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. In murine models of BRAFV600 mCRC, the combination of irinotecan, cetuximab, and vemurafenib leads to greater anti-tumor activity, as suggested by a prior Phase 1B study. Methods: Patients (pts) with BRAFV600 mutated and extended RAS wild-type mCRC were randomized to irinotecan (180 mg/m2 IV every 14 days) and cetuximab (500 mg/m2 IV every 14 days) with or without vemurafenib (960 mg PO twice daily). Patients had received 1 or 2 prior regimens, with no prior anti-EGFR agents, although prior irinotecan was allowed. Crossover from the control arm to the experimental arm was allowed after documented progression. The primary endpoint was progression-free survival (PFS, investigator assessed), with 90% power to detect a HR of 0.5, with two-sided type 1 error of 5%. Results: 106 patients were enrolled (54 in the experimental arm) from 12/2014 to 4/2016, with ECOG PS ≤ 1. Median age of 62 years, 59% female, and prior irinotecan therapy in 39%. PFS was improved with the addition of vemurafenib (HR = 0.42, 95% confidence interval [CI] of 0.26 to 0.66, P < 0.001) with median PFS of 4.4 (95% CI: 3.6 – 5.7) months vs 2.0 (95% CI: 1.8 – 2.1). Response rate was 16% vs 4% (P = 0.09), with disease control rate of 67% vs 22% (P < 0.001). Grade 3/4 adverse events higher in the experimental arm included neutropenia (28% vs 7%), anemia (13% vs 0%), and nausea (15% vs 0%). There was no increase in skin toxicity or fatigue. No new safety signal was observed. Approximately 50% of patients in the control aim crossed over at the time of progression. Overall survival and efficacy at cross-over data remain immature. Conclusions: The addition of vemurafenib to the combination of cetuximab and irinotecan resulted in a prolongation of progression-free survival and a higher disease control rate, indicating that simultaneous EGFR and BRAF inhibition is effective in BRAFV600 mutated CRC. Clinical trial information: NCT02164916.

scholarly journals Association between Low-Grade Chemotherapy-Induced Peripheral Neuropathy (CINP) and Survival in Patients with Metastatic Adenocarcinoma of the Pancreas

2021 ◽  
Vol 10 (9) ◽  
pp. 1846
Author(s):  
Martina Catalano ◽  
Giuseppe Aprile ◽  
Monica Ramello ◽  
Raffaele Conca ◽  
Roberto Petrioli ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Disease Control ◽  
Progression Free Survival ◽  
Disease Control Rate ◽  
Low Grade ◽  
First Line ◽  
First Line Therapy ◽  
Kaplan Meier ◽  
Adenocarcinoma Of The Pancreas

The combination of nab-paclitaxel and gemcitabine demonstrated greater efficacy than gemcitabine alone but resulted in higher rates of chemotherapy-induced peripheral neuropathy (CINP) in patients with metastatic pancreatic cancer (mPC). We aimed to evaluate the correlation between the development of treatment-related peripheral neuropathy and the efficacy of nab-P/Gem combination in these patients. mPC patients treated with nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 as a first-line therapy were included. Treatment-related adverse events, mainly peripheral neuropathy, were categorized using the National Cancer Institute Common Toxicity Criteria scale, version 4.02. Efficacy outcomes, including overall survival (OS), progression-free survival (PSF), and disease control rate (DCR), were estimated by the Kaplan–Meier model. A total of 153 patients were analyzed; of these, 47 patients (30.7%) developed grade 1–2 neuropathy. PFS was 7 months (95% CI (6–7 months)) for patients with grade 1–2 neuropathy and 6 months (95% CI (5–6 months)) for patients without peripheral neuropathy (p = 0.42). Median OS was 13 months (95% CI (10–18 months)) and 10 months (95% CI (8–13 months)) in patients with and without peripheral neuropathy, respectively (p = 0.04). DCR was achieved by 83% of patients with grade 1–2 neuropathy and by 58% of patients without neuropathy (p = 0.03). In the multivariate analysis, grade 1–2 neuropathy was independently associated with OS (HR 0.65; 95% CI, 0.45–0.98; p = 0.03). nab-P/Gem represents an optimal first-line treatment for mPC patients. Among possible treatment-related adverse events, peripheral neuropathy is the most frequent, with different grades and incidence. Our study suggests that patients experiencing CINP may have a more favorable outcome, with a higher disease control rate and prolonged median survival compared to those without neuropathy.

Sorafenib-Regorafenib Sequential Therapy in Advanced Hepatocellular Carcinoma: A Single-Institute Experience

2017 ◽  
Vol 35 (6) ◽  
pp. 611-617 ◽  
Author(s):  
Kazuomi Ueshima ◽  
Naoshi Nishida ◽  
Masatoshi Kudo
Keyword(s):  
Hepatocellular Carcinoma ◽  
Objective Response ◽  
Progression Free Survival ◽  
Sequential Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Open Label ◽  
Effective Treatment Option ◽  
Sorafenib Treatment ◽  
Advanced Hcc ◽  
Grade 3

Objectives: Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Methods: Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. Results: The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Conclusion: Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC.

scholarly journals Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy

Blood ◽  
2019 ◽  
Vol 134 (4) ◽  
pp. 353-362 ◽  
Author(s):  
Emanuele Zucca ◽  
Stephanie Rondeau ◽  
Anna Vanazzi ◽  
Bjørn Østenstad ◽  
Ulrich J. M. Mey ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Complete Response ◽  
Clinical Cancer Research ◽  
International Prognostic Index Score ◽  
First Line Therapy ◽  
Phase 2 Trial ◽  
Grade 3

Abstract The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.

scholarly journals Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 909 ◽  
Author(s):  
Achyut Ram Vyakaranam ◽  
Joakim Crona ◽  
Olov Norlén ◽  
Dan Granberg ◽  
Ulrike Garske-Román ◽  
...  
Keyword(s):  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Favorable Outcome ◽  
First Line ◽  
Ki 67 ◽  
First Line Therapy ◽  
Line Therapy ◽  
Radiological Response ◽  
Low Toxicity ◽  
Grade 3

Peptide receptor radiotherapy (PRRT) with 177Lu-DOTATATE has emerged as a promising therapy for neuroendocrine tumors (NETs). This retrospective cohort study aimed to assess the outcome of PRRT for 22 patients with histopathologically confirmed pheochromocytoma (PCC) and paraganglioma (PGL), of which two were localized and 20 metastatic. Radiological response utilized response evaluation criteria in solid tumors 1.1 and toxicity was graded according to common terminology criteria for adverse events version 4. Median 4 (range 3–11) 7.4 GBq cycles of 177Lu-DOTATATE were administered as first-line therapy (n = 13) or because of progressive disease (n = 9). Partial response (PR) was achieved in two and stable disease (SD) in 20 patients. The median overall survival (OS) was 49.6 (range 8.2–139) months and median progression-free survival (PFS) was 21.6 (range 6.7–138) months. Scintigraphic response >50% was achieved in 9/19 (47%) patients. Biochemical response (>50% decrease) of chromogranin A was found in 6/15 (40%) patients and of catecholamines in 3/12 (25%) patients. Subgroup analysis showed Ki-67 <15% associated with longer OS (p = 0.013) and PFS (p = 0.005). PRRT as first-line therapy was associated with increased OS (p = 0.041). No hematological or kidney toxicity grade 3–4 was registered. 177Lu-DOTATATE therapy was associated with favorable outcome and low toxicity. High Ki-67 (≥15%) and PRRT received because of progression on previous therapy could constitute negative predictive factors for OS.

A prospective multicenter phase II trial of capecitabine plus oxaliplatin (CapOx) in advanced biliary system adenocarcinomas: The final results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4136-4136 ◽  
Author(s):  
O. Nehls ◽  
H. Oettle ◽  
J. Hartmann ◽  
R. Hofheinz ◽  
H. Hass ◽  
...  
Keyword(s):  
Disease Control ◽  
Survival Data ◽  
Sensory Neuropathy ◽  
Complete Response ◽  
Biliary System ◽  
Disease Control Rate ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
Ecog Ps ◽  
Peripheral Sensory

4136 Background: To investigate the safety and efficacy of capecitabine and oxaliplatin combination therapy (CapOx) in unresectable or metastatic adenocarcinomas of the biliary system. Methods: 65 patients (pts) (27 male, and 38 female) were enrolled (median age, 61 yrs). Major eligibility criteria: histologically proven, measurable disease, age ≤ 75 yrs, ECOG PS 0–2. A total number of 364 cycles (median, 5; range, 1–16) of oxaliplatin (130 mg/m2, d1) plus capecitabine (2 g/m2, d 1–14) were administered 3 weekly for gallbladder carcinoma (GBC) (27 pts), extrahepatic (20 pts), and intrahepatic (18 pts) cholangiocarcinoma (CCC). Response rates were assessed according to WHO criteria. Clinical outcome was determined separately for pts with either GBC/extrahepatic CCC or intrahepatic CCC (mass-forming type). Results: Grade 4 toxicities (WHO): diarrhea in 1 pt (1% of cycles), thrombocytopenia in 1 pt (1%), leukocytopenia in 1 pt (1%), and fever in 2 pts (1%); grade 3 toxicities: nausea/vomiting in 1 pt (1%), diarrhea in 2 pts (1%), thrombocytopenia in 3 pts (2%), and fever in 1 pt (1%). Grade 3/4 peripheral sensory neuropathy (Lévis scale) was found in 13 pts (14% of cycles). Two pts were excluded from study because of oxaliplatin-related allergic reactions. One patient died due to sepsis and another due to cerebral insult during the first treatment cycle. The overall disease control rate in 47 pts with GBC or extrahepatic CCC was 72% (complete response (CR), n = 2 (4%); partial response (PR), n = 11 (23%); stable disease (NC), n = 21 (45%)), whereas progressive disease (PD) was found in 13 pts (28%). In 18 pts with intrahepatic mass-forming CCC, no CR or PR was observed, 5 pts (28%) had SD, and 13 pts (72%) experienced PD. Conclusions: The CapOx protocol is well tolerated and remarkably active for advanced GBC as well as extrahepatic CCC with a disease-control rate of 72%. However, activity appears to be limited in the subset of pts with intrahepatic mass-forming type tumors. Survival data will be presented at the meeting. No significant financial relationships to disclose.

Randomized multicenter phase III trial of oxaliplatin plus raltitrexed compared to oxaliplatin plus fluorouracil and leucovorin treatment in recurrent and metastatic colorectal cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4102-4102
Author(s):  
J. Wang ◽  
J. Li ◽  
S. Qin ◽  
T. Liu ◽  
Z. Ye ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Median Number ◽  
Disease Control Rate ◽  
Phase Iii ◽  
Progression Of Disease ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Ecog Ps

4102 Purpose: To compare oxaliplatin (L-OHP) plus raltitrexed (RTX) with L-OHP plus fluorouracil and leucovorin (LV/5FU) for patients (pts) with recurrent and metastatic colorectal cancer(CRC). Methods: Eligible pts had to have histologically proven recurrent or metastatic CRC,not having previously received oxaliplatin as palliative chemotherapy,ECOG PS = 2,age:18∼70,and adequate hematological,renal and hepatic function.After written informed consent,pts were randomized to L-OHP:130 mg/m2 d1 + RTX: 3 mg/m2 d1 (Arm A) or + LV: 200 mg/m2 + 5FU:375 mg/m2 d1–5 (Arm B). Results: Between Jan 2005 and July 2006, 216 pts were enrolled at 15 centers in China.112 pts (mean age: 55.0 (19∼70), M/F: 57/46, PS 0/1/2: 46/53/13) were randomly assigned to A and 102 (mean age: 54.2(22∼70), M/F: 54/46, PS 0/1/2: 44/59/9) to B. 203 pts were eligible for response evaluation (A:103, B:100).The median number of cycles was 4 (1∼6) in A and 3 (1∼6) in B (P=0.1431).The RR was 29.1% (CR:2, PR:28, SD:50 , PD:23) in A and 17.0% (CR:2, PR:15, SD:46 , PD:37) in B (P=0.0437).The disease-control rate was 77.7% in A and 63.0% in B (P=0.0237). After a median follow-up of 10 months (4–16.5),92 pts had had progression of disease (40 in A and 52 in B); 73 deaths had occurred (35 in A and 38 in B), median time to progression was not reached. Following-up is ongoing.The median QoL scores for the two arms were comparable. 214 were included in the safety analyses (A:112, B:102). There was a higher incidence of neutropenia (48.2% verse 29.4%, P=0.005) and transaminase increase (49.1% verse 35.3%, P=0.041) among A. Grade 3 or 4 neutropenia was much common in pts in A than those in B (20.5% verse 4.9% , P=0.001), but was complicated by fever in only 3.6% of cases (4 pts) in A and in 2.9% of cases (3 pts) in B. No pts were dead or infectious due to neutropenia. There were similar rates of grade 3 or 4 transaminase elevation in the two groups. Vomitting and anorexia were much commoner with B. Conclusions: The L-OHP+RTX seems beneficial in recurrent and metastatic CRC, demonstrating better response rate and higher disease control rate with acceptable tolerability, maintenance of QoL and convenient administration schedule. No significant financial relationships to disclose.

Bevacizumab (BEV) plus capecitabine as maintenance therapy after initial treatment with BEV plus XELOX in previously untreated patients (pts) with metastatic colorectal cancer (mCRC): Mature data from STOP and GO, a phase III, randomized, multicenter study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3565-3565 ◽  
Author(s):  
Suayib Yalcin ◽  
Ruchan Uslu ◽  
Faysal Dane ◽  
Ugur Yilmaz ◽  
Nurullah Zengin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Maintenance Therapy ◽  
Objective Response ◽  
Progression Free Survival ◽  
Drop Out ◽  
Phase Iii ◽  
Significance Level ◽  
First Line Therapy ◽  
Significant Difference ◽  
Grade 3

3565 Background: Colorectal cancer is one of the most frequent malignancies, second after breast cancer in women and third after lung cancer and prostate cancer in men. The aim of this study was to evaluate and compare the progression-free survival (PFS) between two arms: Arm A is a combination of BEV + XELOX; Arm B is a combination of BEV + XELOX for 6 cycles followed by maintenance BEV + capecitabine as first-line therapy in mCRC. Methods: BEV (7.5 mg/kg) + XELOX (capecitabine 1000 mg/m2 bid d1–14 + oxaliplatin 130 mg/m2 d1 q3w) were administered until progression (Arm A) or 6 cycles of BEV + XELOX followed by BEV + capecitabine were administered until progression (Arm B). PFS was the primary endpoint; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. A sample size of 118 pts was required to detect with 80% power an increase of 1.5 months in median PFS between two arms with a standard deviation of 3.9 months and significance level of 0.05 (10% drop-out rate). Results: A total of 123 pts were randomized. Demographic characteristics were balanced between the arms. Median treatment period was 7.5 (range 0.5–13.9) and 8.1 (range 0.1–20.7) months in Arms A and B, respectively. There was a statistically significant difference in median PFS between arms, although there was no significant difference in ORR and OS (see table). Tolerability was acceptable in both arms with the following grade 3/4 adverse events (AEs): Arm A 48.4%; Arm B 34.4% (p=0.116). Grade 3/4 diarrhoea occurred in 9.7% vs. 3.3%, weakness in 8.1% vs. 8.2%, hand-foot syndrome in 3.2% vs. 1.6%, and neuropathy in 4.8% vs. 3.3% of pts in Arms A and B, respectively. Conclusions: These findings suggest that maintenance therapy with BEV + capecitabine following induction with 6 cycles of BEV + XELOX may be superior to continuous BEV + XELOX until progression inpts with previously untreated mCRC. [Table: see text]

Investigation of the HDAC inhibitor resminostat in patients with sorafenib-resistant hepatocellular carcinoma (HCC): Clinical data from the phase I/II SHELTER study.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 262-262 ◽  
Author(s):  
Michael Bitzer ◽  
Marius Horger ◽  
Tom M Ganten ◽  
Jens T Siveke ◽  
Marcus A Woerns ◽  
...  
Keyword(s):  
Clinical Data ◽  
Hdac Inhibitor ◽  
Rest Period ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Open Label ◽  
First Line Therapy ◽  
Parallel Group ◽  
Term Tolerability ◽  
Grade 3

262 Background: Resminostat (4SC-201), an oral pan-HDAC inhibitor, is in clinical development in a variety of cancer indications. The SHELTER study aims to evaluate safety, tolerability and efficacy in HCC patients (pts) exhibiting progressive disease under sorafenib first-line therapy. Methods: Pts with advanced HCC, (BCLC B or C) are included in a multi-center, open-label, two-arm parallel group trial. Radiologic progression under sorafenib is determined acc. to RECIST by central review prior to study entry. For Arm A, dose escalation of resminostat and sorafenib is performed to determine the MTD. Resminostat is administered orally once-daily in a “5+9” schedule, consisting of 5 consecutive treatment days followed by a 9-day rest period resulting in 14 day cycles on dose levels of 200 (DL1), 400 (DL2) and 600 mg (DL3+4), either combined with continuously taken sorafenib at 400 (DL1-3) or 800 mg (DL4) (Arm A), or as resminostat monotherapy (600 mg, Arm B). Primary objective is to determine progression-free survival after 12 weeks (w) (6 cycles). Secondary objectives include safety, tolerability, tumor response, TTP, OS, PK, biomarkers. Results: To date, 39 pts were treated with 600 mg resminostat alone or on DL1-4 in combination with sorafenib. Up to now, no DLT occurred in 5 pts treated on DL4. Most frequently AE observed include CTC grade 1-2 gastrointestinal complaints such as nausea and vomiting and skin disorders like rash, pruritus and HFSR. CTC Grade 3-4 toxicity documented in SAE reports consisted mainly of no-hematological events and was mostly related to the tumor disease. Interim results revealed that 15 out of 27 pts (56%) assessed after 6 w of treatment, and 11 out of 24 pts after 12 w displayed SD. In one patient treated on DL2, SD persisted for more than 1 year along with good long-term tolerability. Conclusions: Preliminary clinical data show a favorable drug profile of resminostat either in mono or in combination treatment with sorafenib. No DLT was observed on the highest DL of the combination therapy up to now. Initial data on toxicity and therapeutic activity to overcome resistance to sorafenib are promising and will be updated for the meeting.

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