Preclinical study of prolonged administration of trastuzumab as combination therapy after disease progression during trastuzumab monotherapy

2009 ◽  
Vol 66 (2) ◽  
pp. 269-276 ◽  
Author(s):  
Kaori Fujimoto-Ouchi ◽  
Fumiko Sekiguchi ◽  
Kaname Yamamoto ◽  
Masatoshi Shirane ◽  
Yoriko Yamashita ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Disease Progression ◽  
Preclinical Study ◽  
Prolonged Administration ◽  
Trastuzumab Monotherapy

Antitumor Efficacy of Combination Therapy Consisting of S-1, Leucovorin, and Oxaliplatin against Human Gastric Cancer Xenografts

Chemotherapy ◽  
2018 ◽  
Vol 63 (1) ◽  
pp. 46-52
Author(s):  
Hideki Nagase ◽  
Fumio Nakagawa ◽  
Junji Uchida
Keyword(s):  
Gastric Cancer ◽  
Combination Therapy ◽  
Tumor Volume ◽  
Preclinical Study ◽  
Antitumor Efficacy ◽  
Human Gastric Cancer ◽  
Antitumor Activities ◽  
Once Daily ◽  
Xenograft Models

Background/Aim: A phase 3 trial of S-1, leucovorin (LV), and oxaliplatin for treating gastric cancer is now underway. However, the antitumor efficacy of the combination has not yet been examined in an in vivo preclinical study. This study examined the antitumor efficacy of combination therapy consisting of S-1, LV, and oxaliplatin against 4 human gastric cancer xenografts: NUGC-4, St-40, SC-2, and SC-4. Methods: The antitumor efficacy was evaluated using human gastric cancer xenograft-bearing nude mice. S-1 and LV were administered orally once daily on days 1-7 at doses of 6.9 and 10 mg/kg, respectively. Oxaliplatin was administered intravenously at a dose of 8.3 mg/kg on day 1. The tumor volume was measured on day 15, and the relative tumor volume (RTV) was calculated. Results: In all 4 xenograft models, S-1 alone and oxaliplatin alone, but not LV alone, had significant antitumor activities (p < 0.001). Combination therapy consisting of S-1 and LV resulted in a significantly smaller RTV than S-1 alone (p < 0.001). Combination therapy consisting of S-1 and oxaliplatin also resulted in a significantly smaller RTV than either S-1 alone (p < 0.001) or oxaliplatin alone (p < 0.001). Furthermore, combination therapy consisting of S-1, LV, and oxaliplatin resulted in the highest antitumor activity in these models (p < 0.001 vs. S-1 + LV; p < 0.001 or p = 0.003 vs. S-1 + oxaliplatin). Conclusion: Combination therapy consisting of S-1, LV, and oxaliplatin administered according to a 1-week-on/1-week-off schedule may be useful for the treatment of patients with gastric cancer.

scholarly journals Impact of early vs. delayed initiation of dutasteride/tamsulosin combination therapy on the risk of acute urinary retention or BPH-related surgery in LUTS/BPH patients with moderate-to-severe symptoms at risk of disease progression

2020 ◽  
Author(s):  
Salvatore D’Agate ◽  
Chandrashekhar Chavan ◽  
Michael Manyak ◽  
Juan Manuel Palacios-Moreno ◽  
Matthias Oelke ◽  
...  
Keyword(s):  
At Risk ◽  
Combination Therapy ◽  
Disease Progression ◽  
Urinary Retention ◽  
Acute Urinary Retention ◽  
Treatment Algorithm ◽  
Phase Iii ◽  
Rank Test ◽  
Survival Curves ◽  
Risk Of Disease

Abstract Purpose To evaluate the effect of delayed start of combination therapy (CT) with dutasteride 0.5 mg and tamsulosin 0.4 mg on the risk of acute urinary retention or benign prostatic hyperplasia (BPH)-related surgery (AUR/S) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) at risk of disease progression. Methods Using a time-to-event model based on pooled data from 10,238 patients from Phase III/IV dutasteride trials, clinical trial simulations (CTS) were performed to assess the risk of AUR/S up to 48 months in moderate-to-severe LUTS/BPH patients following immediate and delayed start of CT for those not responding to tamsulosin monotherapy. Simulation scenarios (1300 subjects/arm) were investigated, including immediate start (reference) and alternative delayed start (six scenarios 1–24 months). AUR/S incidence was described by Kaplan–Meier survival curves and analysed using log-rank test. The cumulative incidence of events as well as the relative and attributable risks were summarised stratified by treatment. Results Survival curves for patients starting CT at month 1 and 3 did not differ from those who initiated CT immediately. By contrast, significant differences (p < 0.001) were observed when switch to CT occurs ≥ 6 months from the initial treatment. At month 48, AUR/S incidence was 4.6% vs 9.5%, 11.0% and 11.3% in patients receiving immediate CT vs. switchers after 6, 12 and 24 months, respectively. Conclusions Start of CT before month 6 appears to significantly reduce the risk of AUR/S compared with delayed start by ≥ 6 months. This has implications for the treatment algorithm for men with LUTS/BPH at risk of disease progression.

Open-Label, Uncontrolled, Multicenter Phase II Study to Evaluate the Efficacy and Toxicity of Cetuximab As a Single Agent in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck Who Failed to Respond to Platinum-Based Therapy

2007 ◽  
Vol 25 (16) ◽  
pp. 2171-2177 ◽  
Author(s):  
Jan B. Vermorken ◽  
José Trigo ◽  
Ricardo Hitt ◽  
Piotr Koralewski ◽  
Eduardo Diaz-Rubio ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Combination Therapy ◽  
Disease Control ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Disease Progression ◽  
Response Rate ◽  
Single Agent ◽  
Open Label ◽  
Metastatic Squamous Cell Carcinoma

PurposeTo evaluate the efficacy and safety of the epidermal growth factor receptor–directed monoclonal antibody cetuximab administered as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) who experience disease progression on platinum therapy.Patients and MethodsAn open-label multicenter study in which patients with disease progression on two to six cycles of platinum therapy received single-agent cetuximab (initial dose 400 mg/m2followed by subsequent weekly doses of 250 mg/m2) for ≥ 6 weeks (single-agent phase). Patients who experienced disease progression could receive salvage therapy with cetuximab plus platinum (combination-therapy phase). From June 2001 to December 2002, 103 patients were enrolled and treated with cetuximab, 53 of whom subsequently received combination therapy.ResultsIn the single-agent phase, response rate was 13%, disease control rate (complete response/partial response/stable disease) was 46%, and median time to progression (TTP) was 70 days. During the combination-therapy phase, the objective response rate was zero, disease control rate was 26%, and TTP was 50 days. Median overall survival was 178 days. Treatment was well tolerated. The most common cetuximab-related adverse events in the single-agent phase were skin reactions, particularly rash (49% of patients, mainly grade 1 or 2). There was one treatment-related death due to an infusion-related reaction.ConclusionSingle-agent cetuximab was active and generally well tolerated in the treatment of recurrent and/or metastatic SCCHN that progressed on platinum therapy. Response was comparable to that seen with cetuximab plus platinum combination regimens in the same setting.

REGARD: A phase III, randomized, double-blinded trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. LBA5-LBA5 ◽  
Author(s):  
Charles S. Fuchs ◽  
Jiri Tomasek ◽  
Jae Yong Cho ◽  
Filip Dumitru ◽  
Rodolfo Passalacqua ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Disease Progression ◽  
Gastroesophageal Junction ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Vegf Receptor ◽  
First Line ◽  
Double Blind ◽  
Cancer Pathogenesis ◽  
Line Therapy

LBA5 Background: VEGF and VEGF receptor-2 mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab (RAM; IMC-1121B) is a fully human IgG1 monoclonal antibody targeting VEGF-receptor 2. We conducted a placebo-controlled, double-blind, phase III international trial to evaluate the safety and efficacy of RAM in pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidine containing combination therapy. Methods: Pts were randomized 2:1 to receive RAM (8 mg/kg IV) plus BSC or placebo (PL) plus BSC every 2 weeks (wks) until disease progression, unacceptable toxicity, or death. Eligible patients had disease progression within 4 months (m) after 1st-line therapy for metastatic disease or within 6 m after adjuvant therapy. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), 12-wk PFS rate, overall response rate (ORR) and safety. Results: From 10/09 to 01/12, 355 pts were randomized (RAM: 238; PL: 117). Baseline characteristics were well balanced between arms. The Hazard Ratio (HR) for OS was 0.776 (95% CI, 0.603-0.998; p = 0.0473). Median OS was 5.2 m for RAM and 3.8 m for PL. The HR for PFS was 0.483 (95% CI, 0.376-0.620; p < 0.0001). Median PFS was 2.1 m for RAM and 1.3 m for PL. 12-wk PFS was 40% for RAM and 16% for PL. ORR was 3.4% for RAM and 2.6% for PL. Disease control rate was 49% for RAM and 23% for PL (p < 0.0001). Use of anti-cancer therapy post-study: 32% RAM; 39% PL. The most frequent of grade ≥ 3 adverse events (AEs) were: hypertension (7.2% RAM; 2.6% PL), anemia (6.4% RAM; 7.8% PL), abdominal pain (5.1% RAM; 2.6% PL), ascites (4.2% RAM; 4.3% PL), fatigue (4.2% RAM; 3.5% PL), decreased appetite (3.4% RAM; 3.5% PL) and hyponatremia (3.4% RAM; 0.9% PL). Conclusions: Ramucirumab conferred a statistically significant benefit in OS and PFS compared to PL in metastatic gastric or GEJ adenocarcinoma following progression on 1st-line therapy with an acceptable safety profile. Clinical trial information: NCT00917384.

Raltitrexed in the management of metastatic colorectal cancer: The COMET study.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 677-677
Author(s):  
Jérôme Desramé ◽  
Louis-Marie Dourthe ◽  
Philippe Debourdeau ◽  
Dominique Mille ◽  
Pascal Artru ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Combination Therapy ◽  
Treatment Failure ◽  
Folinic Acid ◽  
Disease Progression ◽  
Cardiac Toxicity ◽  
Tumour Progression ◽  
Single Agent ◽  
Patient Consent

677 Background: Raltitrexed, indicated for palliative treatment of advanced colorectal cancer (CRC), may be useful for patients (pts) with cardiovascular (CV) risk factors, or cardiotoxicity/disease progression with prior chemotherapy (CT). The COMET study, conducted in France, described the characteristics of pts with metastatic CRC (mCRC) treated with raltitrexed, focusing on pts with cardiotoxicity or disease progression with prior 5-fluorouracil (5FU)/folinic acid. Methods: A national, multicentred, cross-sectional, non-interventional study to describe the profiles of pts with mCRC treated with raltitrexed. Pts (≥18 years) with mCRC, treated with raltitrexed as a single agent or in combination therapy, were included. Following patient consent, retrospective data were recorded during a single inclusion visit based on pt medical files; during the study, data were recorded prospectively. Results: 414 pts with mCRC were analysed; 84.8% had ≥1 prior CT, 60.9% had CV risk factors and 35.2% had CV history (angina: 11.8%; myocardial infarction: 11.8%). Overall, 79.5% of pts had received a prior 5FU-based CT. Reasons for switching to raltitrexed included short 15-min infusion duration (34.8%), treatment failure (49.8%) and acute cardiotoxicity with 5FU (8.9%). After switching, 57.2% of pts received raltitrexed as combination therapy. Mean initial dosage of raltitrexed was 2.6±0.6 mg/m2. Of those who had CV risk factors (n=73) or CV history (n=67), 69.0% and 72.7% received raltitrexed after CV toxicity, respectively. Of the pts treated with second-line raltitrexed and assessed with prior acute CV events (45/414), 88.9% (40/45) had no cardiac toxicity during treatment with raltitrexed. Of those (n=206) receiving raltitrexed due to treatment failure, 62.7% had received 5FU/folinic acid during their last CT. Of the pts assessed for tumour response (183/206), tumour progression was controlled with raltitrexed in 25.7% of cases (stable disease: 18.0%; partial response: 7.7%; progressive disease: 56.3%). Conclusions: Raltitrexed appears to be effective in heavily pretreated pts with mCRC and tumour progression after 5FU therapy and could be a safe therapeutic alternative to 5FU for pts with mCRC and prior cardiac toxicity.

scholarly journals Complete Response Associated With Combination Treatment Regorafenib and Sintilimab in a Sorafenib-refractory Hepatocellular Carcinoma Patient

2020 ◽  
Author(s):  
Erlei Zhang ◽  
Zunyi Zhang ◽  
Lei Zhang ◽  
Shuai Xiang ◽  
Xiaoping Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Resection ◽  
Combination Therapy ◽  
Disease Progression ◽  
Combination Treatment ◽  
Lung Metastases ◽  
Complete Response ◽  
Advanced Hcc ◽  
Liver Recurrence ◽  
Short Period

Abstract Background Most of patients diagnosed with Hepatocellular carcinoma (HCC) have advanced diseases and many are not eligible for curative therapies. There is a growing evidence suggesting that combination treatment of PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors (TKIs) becomes a prospective trend for advanced HCC. For those HCC patients with sorafenib resistance, the efficacy of regorafenib combined with PD-1/PD-L1 inhibitors remains unclear. Case presentation: Herein, we represent a case of HCC with lung metastasis in the setting of HBV-induced liver cirrhosis responding dramatically to the combination treatment of sorafenib-regorafenib sequential and PD-1 inhibitor after initial liver resection. A 56-year-old man diagnosed with AFP-negative HCC underwent liver resection in September 2015, and was found to have solitary liver recurrence and lung metastases in March 2017. He received microwave coagulation therapy and trans-arterial chemoembolization (TACE) for liver tumor and treatment was started with sorafenib 400 mg twice daily for controlling lung metastases. In December 2018, abdominal computerized tomography (CT) scan showed two new lesions in liver. In March 2019, disease progression of lung metastases was measured and he received 160 mg regorafenib once daily. After a short period of partial response, he started treatment with regorafenib 160 mg in combination with sintilimab (200 mg, 3 weeks as a cycle) in December 2019 due to disease progression. Surprisingly, after 5 cycles of sintilimab injection, it showed complete response in target lesions. There is no clinical evidence of disease progression and the side effects were mild and well tolerated. The current overall survival is 57 months. Conclusion Data from this clinical case report suggests that combination therapy of regorafenib and PD-1 inhibitor is a promising therapeutic option for the treatment of advanced HCC. This is the first article reporting the complete response to regorafenib combination therapy with PD-1inhibitor for sorafenib-regractory HCC.

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