Phase I/II study of 131I-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma

Background:

¹³¹I-metaiodobenzylguanidine (MIBG) is an active radiopharmaceutical in neuroblastoma. A previous study demonstrated that MIBG could be combined with vincristine and prolonged irinotecan, although 25% of first courses had grade 3 diarrhoea. The current phase I/II study evaluated MIBG with vincristine and 5 days of higher-dose irinotecan.

Methods:

Patients 1–30 years old with advanced neuroblastoma were eligible. Patients received cefixime on days −1 to +6, irinotecan (50 mg m⁻² per dose IV) on days 0–4, vincristine (2 mg m⁻²) on day 0, MIBG (555 or 666 MBq kg⁻¹) on day 1, and peripheral blood stem cells on day 13. UGT1A1 genotyping was performed in consenting patients.

Results:

Thirty-two patients (12 phase I ; 20 phase II) received 42 courses. No dose-limiting toxicities were seen during dose escalation and the recommended administered activity was 666 MBq kg⁻¹. Myelosuppression and diarrhoea were the most common toxicities, with grade 3 diarrhoea in 6% of first courses. Patients homozygous for UGT1A1*28 had more grade 4 thrombocytopenia (80% vs 37% P=0.14). Responses (five complete and four partial) occurred in 9 out of 32 (28%) patients.

Conclusions:

MIBG (666 MBq kg⁻¹) with vincristine and this irinotecan schedule is tolerable and active, with less severe diarrhoea compared with a regimen using more protracted irinotecan.     

Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer

Background:

This randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer.

Methods:

Patients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day⁻¹ based on body surface area (BSA), orally, days 1–28, every 6 weeks) or SOX (S-1 80/100/120 mg day⁻¹ based on BSA, orally, days 1–14, plus oxaliplatin 100 mg m⁻², intravenously, day 1, every 3 weeks). The primary end point was PFS.

Results:

Between January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65–1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79–1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%).

Conclusions:

Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.     

Phase I/II trial of a biweekly combination of S-1 plus docetaxel in patients with previously treated non-small cell lung cancer (KRSG-0601)

Background:

Combination of S-1, an oral fluorouracil derivative, plus docetaxel against non-small cell lung cancer (NSCLC) showed promising efficacy but clinically problematic emesis. A phase I/II study utilising a new schedule for this combination was conducted.

Methods:

A biweekly regimen of docetaxel on day 1 with oral S-1 on days 1–7 was administered to previously treated NSCLC patients. Doses of docetaxel/S-1 were escalated to 30/80, 35/80, and 40/80 mg m⁻², respectively, and its efficacy was investigated at the recommended dose below maximum tolerated dose (MTD).

Results:

In phase I study employing 13 patients, dose-limiting toxicities were febrile neutropenia and treatment delay, with the respective MTDs for docetaxel 40 mg m⁻²/S-1 80 mg m⁻². In the phase II study, 34 patients were treated with docetaxel 35 mg m⁻²/S-1 80 mg m⁻² for a median cycle of 6. The response and disease control rates were 34.3% (95% confidence interval (CI), 18.6–50.0%) and 62.9% (95% CI, 46.8–72.9%), respectively. Median progression-free survival was 150.5 days. Haematologic grade 4 toxicities were observed in neutropenia (11.8%) and thrombocytopenia (2.9%). Regarding non-haematologic toxicities, including emesis, there were no grade 3/4 side effects.

Conclusion:

Combination of 1-week administration of S-1 with biweekly docetaxel is safe and active for NSCLC.     

A phase I dose-escalation study of eribulin and S-1 for metastatic breast cancer

Background:

We evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, recommended dose for phase II (P2RD), and preliminary anticancer activity of a combination eribulin and S-1 therapeutic in metastatic breast cancer patients pretreated with anthracycline and taxane.

Method:

Patients aged 20–74 years were recruited. In level 1, patients received S-1 (65 mg m⁻²) from day 1 to 14, and eribulin (1.1 mg m⁻²) on day 1 and 8 in a 21-day cycle. In level 2, eribulin was increased to 1.4 mg m⁻². In level 3, S-1 was increased to 80 mg m⁻².

Results:

Twelve patients were enrolled into three cohorts. Planned dose escalation was completed, with one case exhibiting dose-limiting toxicity (grade 3 hypokalaemia) at level 3, without reaching the MTD. The P2RD was determined to be level 2 (eribulin 1.4 mg m⁻² and S-1 65 mg m⁻²). The most common grade 3 or 4 toxicity was neutropenia (83.3%), followed by febrile neutropenia (25.0%). Five of eleven patients (41.7%) with measurable disease had a partial response. Pharmacokinetics were characterised by dose-dependent elimination and nonlinear exposure.

Conclusion:

Dose level 3 was not tolerated owing to febrile neutropenia development. Thus, intermediate dose level 2 was recommended for further evaluation. Preliminary antitumour activity warrants further investigation in this setting.     

Phase II study of gemcitabine,oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer

Background:

Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.

Methods:

Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0–2 were treated with panitumumab 6 mg kg⁻¹, GEM 1000 mg m⁻² (10 mg m⁻² min⁻¹) and OX 85 mg m⁻² on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.

Results:

Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5–24 months) and median overall survival 20.3 months (95% CI 9–25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.

Conclusions:

The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.     

Phase II and UGT1A1 genotype study of irinotecan dose escalation as salvage therapy for advanced gastric cancer

Background:

To assess the efficacy and safety of individualised dose optimisation of irinotecan monotherapy as salvage treatment for advanced gastric cancer (AGC).

Methods:

A total of 43 patients were enrolled. Intravenous irinotecan (350 mg m⁻²) was administered every 3 weeks. The dose was increased (425 mg m⁻² and 500 mg m⁻²) or decreased (250 mg m⁻²) depending on patient tolerance. UGT1A1 genotypes were determined by direct sequencing of genomic DNA extracted from peripheral blood.

Results:

A total of 183 cycles of irinotecan were administered, with a median of four cycles per patient. The overall response rate was 9.3%, and the disease control rate was 62.8%. Median time to disease progression was 2.8 months, and median overall survival was 8.0 months. Grade 3–4 neutropenia was the most common toxicity (53.5%), and febrile neutropenia was the least common toxicity (4.6%). Compared with defective allele groups, UGT1A1 *1/*1 was associated with a lower incidence of grade 3–4 neutropenia during the first cycle (P=0.018).

Conclusion:

Individualised irinotecan dose escalation based on patient tolerance was not associated with increased toxicity and shows modest activity as salvage chemotherapy for AGC. The role of UGT1A1 genotype in clinical toxicity requires further evaluation.     

First-line bevacizumab and capecitabine–oxaliplatin in elderly patients with mCRC: GEMCAD phase II BECOX study

Background:

Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC.

Methods:

Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg⁻¹ and oxaliplatin 130 mg m⁻² on day 1, plus capecitabine 1000 mg m⁻² bid orally on days 1–14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP).

Results:

The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%).

Conclusions:

Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.     

Docetaxel plus cetuximab as second-line treatment for docetaxel-refractory oesophagogastric cancer: the AGITG ATTAX2 trial

Background:

Cetuximab can reverse chemotherapy resistance in colorectal cancer. This study evaluated the efficacy and safety of the combination of docetaxel and cetuximab as a second-line treatment in docetaxel-refractory oesophagogastric cancer.

Methods:

Patients received docetaxel 30 mg m⁻² on days 1 and 8, every 3 weeks and cetuximab 400 mg m⁻² on day 1, then 250 mg m⁻² weekly. Biomarker mutation analysis was performed.

Results:

A total of 38 patients were enrolled. Response rates were PR 6% (95% CI 2–19%), s.d. 43% (95% CI 28–59%). Main grade 3/4 toxicities were febrile neutropenia, anorexia, nausea, diarrhoea, stomatitis, and acneiform rash. Median progression-free and overall survival were 2.1 and 5.4 months, respectively. A landmark analysis showed a trend to improved survival times with increased grade of acneiform rash. No KRAS, BRAF or PIK3CA mutations were observed.

Conclusion:

Cetuximab and docetaxel achieve modest responses rates, but maintain comparable survival times to other salvage regimens with low rates of toxicity.     

A randomised,double-blind,placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer

Background:

The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer.

Methods:

We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1 : 1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m⁻² as a 90-min infusion, leucovorin at 200 mg m⁻² as a 2-h infusion, and a bolus injection of 5-FU 400 mg m⁻² followed by a 46-h continuous infusion of 5-FU at 2400 mg m⁻². The XELIRI regimen consisted of irinotecan at 250 mg m⁻² as a 90-min infusion with capecitabine 1000 mg m⁻² twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity.

Results:

Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5–7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4–8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade ⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively).

Conclusions:

The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.     

UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy

Background:

The impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU.

Methods:

Genotyping of TYMS (5′TRP and 3′UTR), UGT1A1^*28, UGT1A9^*22 and UGT1A7^*3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study. Their association with response, toxicity and survival was investigated by univariate and multivariate statistical analysis.

Results:

TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response (OR=5.87, 95% confidence interval (CI)=1.68–20.45; P=0.005). UGT1A1^*28/^*28 was predictive for haematologic toxicity (OR=6.27, 95% CI=1.09–36.12; P=0.04), specifically for neutropenia alone (OR=6.40, 95% CI=1.11–37.03; P=0.038) or together with diarrhoea (OR=18.87, 95% CI=2.14–166.67; P=0.008). UGT1A9^*1/^*1 was associated with non-haematologic toxicity (OR=2.70, 95% CI=1.07–6.82; P=0.035). Haplotype VII (all non-favourable alleles) was associated with non-haematologic toxicity (OR=2.11, 95% CI=1.12–3.98; P=0.02).

Conclusion:

TYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients. A genetic-based algorithm to optimise treatment individualisation is proposed.     

Neoadjuvant FOLFIRI+bevacizumab in patients with resectable liver metastases from colorectal cancer: a phase 2 trial

Background:

Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting.

Methods:

Patients aged 18–75 years, PS 0–1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg⁻¹ followed by irinotecan 180 mg m⁻², leucovorin 200 mg m⁻², 5-fluorouracil 400 mg m⁻² bolus and 5-fluorouracil 2400 mg m⁻² 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required.

Results:

From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8–80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6–76.6). Median PFS and OS were 14 (95% CI: 11–24) and 38 (95% CI: 28–NA) months, respectively.

Conclusion:

Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance.     

Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205

Background:

Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer.

Methods:

Two dose levels (I/II) were defined: capecitabine 850/1000 mg m⁻² twice daily on days 1–14; oxaliplatin 100/130 mg m⁻² on day 1; bevacizumab 7.5 mg kg⁻¹ on day 1; imatinib 300 mg day⁻¹ on days 1–21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS).

Results:

Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities.

Conclusion:

The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.     

Phase II study of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1)

Background:

S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC.

Methods:

Patients with HER2-positive AGC received S-1 (80–120 mg per day) orally on days 1–14, cisplatin (60 mg m⁻²) intravenously on day 1, and trastuzumab (course 1, 8 mg kg⁻¹; course 2 onward, 6 mg kg⁻¹) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events.

Results:

A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54–80%), and the disease control rate was 94% (95% CI=84–99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%).

Conclusions:

Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC.     

Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201)

Background:

This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer.

Patients and methods:

A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II–IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m⁻², followed by oral doxifluridine 460–600 mg m⁻² per day for 3 months) or MFP (MMC 20 mg m⁻², followed by oral doxifluridine 460–600 mg m⁻² per day for 12 months with 6 monthly infusions of 60 mg m⁻² of cisplatin) chemotherapy.

Results:

With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89–1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89–1.39); P=0.33).

Conclusion:

Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.     

Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre Phase I/II trial

Background:

This trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy.

Methods:

In Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m⁻² every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity.

Results:

Phase I included 10 patients (median age 63 (49–73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43–80) years) received irinotecan 180 mg m⁻² every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51–77). Median PFS and OS were 3.7 (95% CI, 3.2–4.7) and 8.0 (95% CI, 4.8–9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%).

Conclusion:

The NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00989469","term_id":"NCT00989469"}}NCT00989469).     

Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102)

Background:

A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival.

Methods:

Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m⁻² day 5, mitomycin 7 mg m⁻² day 5, cisplatin 14 mg m⁻² days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival.

Results:

A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80% P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85).

Conclusion:

Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.     

A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours

Background:

This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumour activity of the combination in solid tumours.

Methods:

Cohorts of three to six patients were treated with escalating doses of belinostat administered intravenously once daily, days 1–5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg m⁻²) were administered 2–3 h after the end of the belinostat infusion.

Results:

In all 23 patients received 600–1000 mg m⁻² per day of belinostat with carboplatin and/or paclitaxel. No DLT was observed. The maximal administered dose of belinostat was 1000 mg m⁻² per day for days 1–5, with paclitaxel (175 mg m⁻²) and carboplatin AUC 5 administered on day 3. Grade III/IV adverse events were (n; %): leucopenia (5; 22%), neutropenia (7; 30%), thrombocytopenia (3; 13%) anaemia (1; 4%), peripheral sensory neuropathy (2; 9%), fatigue (1; 4%), vomiting (1; 4%) and myalgia (1; 4%). The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration. There were two partial responses (one rectal cancer and one pancreatic cancer). A third patient (mixed mullerian tumour of ovarian origin) showed a complete CA-125 response. In addition, six patients showed a stable disease lasting ⩾6 months.

Conclusion:

The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.     

Gemcitabine–oxaliplatin plus prednisolone is active in patients with castration-resistant prostate cancer for whom docetaxel-based chemotherapy failed

Background:

There has been no previous study on the activity of gemcitabine in combination with oxaliplatin (GemOx) for castration-resistant prostate cancer (CRPC).

Methods:

The GemOx was preclinically tested for cytotoxic activity in human prostate cancer cell lines. Clinically, patients with CRPC who failed prior docetaxel were treated with gemcitabine 1000 mg m⁻² and oxaliplatin 100 mg m⁻² intravenously every 2 weeks and prednisolone 5 mg orally twice daily. The primary end point was the prostate-specific antigen (PSA) response rate.

Results:

The GemOx displayed synergistic effects based on Chou and Talalay analysis. In the phase II study, 33 patients were accrued. The median dose of docetaxel exposure was 518 mg m⁻². A total of 270 cycles were administered with a median of eight cycles per patient. A PSA response rate was 55% (95% CI, 38–72) and radiologic response rate was 82% (9 out of 11). With a median follow-up duration of 20.5 months, the median time to PSA progression was 5.8 months (95% CI, 4.4–7.2) and the median overall survival was 17.6 months (95% CI, 12.6–22.6). The most frequently observed grade 3 or 4 toxicities were neutropenia (13%) and thrombocytopenia (13%).

Conclusions:

The GemOx is active and tolerable in patients with metastatic CRPC after docetaxel failure ({"type":"clinical-trial","attrs":{"text":"NCT 01487720","term_id":"NCT01487720"}}NCT 01487720).     

A phase I,dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours

Background:

Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours.

Methods:

Sunitinib was initially administered once daily at 37.5 mg per day on days 1–14 of a 21-day cycle, in which irinotecan 250 mg m⁻² was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies.

Results:

In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug–drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1–14) with irinotecan 250 mg m⁻² (day 1), but no activity was observed at this dose.

Conclusion:

Although a higher sunitinib dose of 37.5 mg per day (days 1–14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.     

Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan

Background:

A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients.

Methods:

Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m⁻² plus gemcitabine 1000 mg m⁻² on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m⁻² on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks.

Results:

A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and γ-GTP increase (29.3%/35.7%).

Conclusions:

Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.