Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study)

Background:

The conventional treatment options for advanced gastric patients remain unsatisfactory in terms of response rate, response duration, toxicity, and overall survival benefit. The purpose of this phase II study was to evaluate the activity and safety of cetuximab combined with cisplatin and docetaxel as a first-line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma.

Methods:

Untreated patients with histologically confirmed advanced gastric or gastro-oesophageal adenocarcinoma received cetuximab at an initial dose of 400 mg m⁻² i.v. followed by weekly doses of 250 mg m⁻², cisplatin 75 mg m⁻² i.v. on day 1, docetaxel 75 mg m⁻² i.v. on day 1, every 3 weeks, for a maximum of 6 cycles, and then cetuximab maintenance treatment was allowed in patients with a complete response, partial response, or stable disease.

Results:

Seventy-two patients (stomach 81.9% and gastro-oesophageal junction 18.1%; locally advanced disease 4.2%; and metastatic disease 95.8%) were enrolled. The ORR was 41.2% (95% CI, 29.5–52.9). Median time to progression was 5 months (95% CI, 3.7–5.4). Median survival time was 9 months (95% CI, 7–11). The most frequent grades 3–4 toxicity was neutropenia (44.4%). No toxic death was observed.

Conclusions:

The addition of cetuximab to the cisplatin/docetaxel regimen improved the ORR of the cisplatin/docetaxel doublet in the first-line treatment of advanced gastric and gastro-oesophageal junction adenocarcinoma, but this combination did not improve the TTP and OS. The toxicity of cisplatin/docetaxel chemotherapy was not affected by the addition of cetuximab.     

Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours

Background:

This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours.

Methods:

Patients received intravenous aflibercept 4, 5, or 6 mg kg⁻¹ with docetaxel and cisplatin (75 mg m⁻² each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination.

Results:

During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg⁻¹). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg⁻¹ and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs.

Conclusion:

Aflibercept 6 mg kg⁻¹ with docetaxel and cisplatin 75 mg m⁻² every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.     

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

Background:

Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer.

Methods:

Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m⁻² at first infusion followed by weekly infusions of 250 mg m⁻² combined with FUFOX (oxaliplatin 50 mg m⁻², 5-FU 2000 mg m⁻², and DL-folinic acid 200 mg m⁻² d1, 8, 15 and 22 qd36). The primary endpoint was tumour response.

Results:

Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50–79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0–10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9–11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed.

Conclusion:

Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum–fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.     

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study

Background:

Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer.

Methods:

Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m⁻² plus irinotecan 250 mg m⁻² (Day 1)) or 3-weekly DF (docetaxel 85 mg m⁻² (Day 1) followed by 5-fluorouracil 750 mg m⁻² per day as a continuous infusion (Days 1–5)).

Results:

A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3–4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively).

Conclusion:

Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.     

Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial

Background:

We assessed the effectiveness of cetuximab plus chronomodulated irinotecan, 5-fluorouracil (5-FU), leucovorin (FA) and oxaliplatin (L-OHP) (chrono-IFLO) administered as neoadjuvant chemotherapy to increase the resectability of colorectal liver metastases.

Methods:

This was a phase II prospective trial with rate of liver metastases resection as primary end point. Forty-three patients with unresectable metastases were enroled: 9 with metastases >5 cm; 29 with multinodular (>4) disease; 1 with hilar location; 4 with extrahepatic lung disease. Treatment consisted of cetuximab at day 1 plus chronomodulated irinotecan 5-FU, FA and L-OHP for 2–6 days every 2 weeks. After the first 17 patients, doses were reduced for irinotecan to 110 mg m⁻², 5-FU to 550 mg m⁻² per day and L-OHP to 15 mg m⁻² per day.

Results:

Macroscopically complete resections were performed in 26 out of 43 patients (60%) after a median of 6 (range 3–15) cycles. Partial response was noticed in 34 patients (79%). Median overall survival was 37 months (95% CI: 21–53 months), with a 2-year survival of 68% in the entire population, 80.6% in resected patients and 47.1% in unresected patients (P=0.01). Grade 3/4 diarrhoea occurred in 93% and 36% of patients before and after dose reduction.

Conclusion:

Cetuximab plus chrono-IFLO achieved 60% complete resectability of colorectal liver metastases.     

A phase 1 trial of recombinant human IL-21 in combination with cetuximab in patients with metastatic colorectal cancer

Background:

Pre-clinical data indicate enhanced anti-tumour activity when combining recombinant human interleukin-21 (rIL-21), a class 1 cytokine, with cetuximab, a monoclonal antibody, targeting the epidermal growth factor receptor. This phase 1 trial assessed the safety and tolerability of escalating doses of rIL-21 in combination with cetuximab in chemo-naïve patients with stage IV colorectal cancer.

Patients and methods:

Sequential cohorts of PS 0–1, asymptomatic patients, were treated weekly with cetuximab 250 mg m⁻² intravenously (i.v.) plus escalating i.v. doses of rIL-21 following an initial loading dose of cetuximab 400 mg m⁻². Initial treatment period was 8 weeks, with extension permitted in patients without disease progression.

Results:

In all, 15 patients were included in this study. Adverse events related to rIL-21 or rIL-21 plus cetuximab included lethargy, nausea/vomiting, stomatitis, lymphopenia and pyrexia and were mainly ⩽ grade 2. One dose limiting toxicity occurred (grade 3 diarrhoea). Maximum tolerated dose was not determined because of the premature study closure. Maximum administered dose was 100 μg kg⁻¹ rIL-21 weekly. In all, 60% of the patients had stable disease. Immune activation was confirmed by various T- and NK-cell activation biomarkers, including dose-dependent increases in serum sCD25.

Conclusion:

rIL-21 weekly combined with cetuximab is well tolerated at doses up to 100 μg kg⁻¹ and results in activation of immune response biomarkers.     

Correlation of capecitabine-induced skin toxicity with treatment efficacy in patients with metastatic colorectal cancer: results from the German AIO KRK-0104 trial

Background:

The AIO KRK-0104 randomised phase II trial investigated the efficacy and safety of two capecitabine-based regimens: combination of capecitabine and irinotecan (CAPIRI) plus cetuximab (CAPIRI-C) and combination of capecitabine with oxaliplatin (CAPOX) plus cetuximab (CAPOX-C) in the first-line treatment of metastatic colorectal cancer (mCRC). Treatment-related skin toxicity (ST) was evaluated separately for capecitabine and cetuximab. The present analysis investigates the correlation of capecitabine-attributed ST (Cape-ST) and parameters of treatment efficacy.

Methods:

Patients with mCRC were randomised to cetuximab (400 mg m⁻², day 1, followed by 250 mg m⁻² weekly) plus CAPIRI (irinotecan 200 mg m⁻², day 1; capecitabine 800 mg m⁻², twice daily, days 1–14, every 3 weeks), or cetuximab plus CAPOX (oxaliplatin 130 mg m⁻², day 1; capecitabine 1000 mg m⁻², twice daily, days 1–14, every 3 weeks).

Results:

Of 185 recruited patients, 149 (CAPIRI-C, n=78; CAPOX-C, n=71) received study treatment beyond the first tumour assessment and were evaluable for efficacy. Capecitabine-attributed ST, predominantly hand–foot syndrome, was observed in 32.2% of patients. Capecitabine-attributed ST grade 1–3 was associated with a significantly higher disease control rate (DCR) (97.9 vs 86.1%, P=0.038) compared with grade 0 toxicity. Moreover, Cape-ST grade 1–3 related to a markedly longer progression-free survival (PFS) (9.9 vs 5.6 months, P<0.001) and overall survival (OS) (32.8 vs 22.4 months, P=0.008). Separate analyses of treatment arms indicated that the effect of Cape-ST on PFS remained significant for both arms, whereas the effect on OS remained apparent as a strong trend.

Conclusion:

This analysis supports the hypothesis that for the evaluated regimens, a correlation exists between Cape-ST and treatment efficacy regarding DCR, PFS, and OS.     

Docetaxel and capecitabine for advanced gastric cancer: investigating dose-dependent efficacy in two patient cohorts

Background:

No comparisons of different doses of docetaxel-capecitabine in patients with advanced gastric cancer have been performed.

Methods:

Patients with previously untreated metastatic/locally advanced gastro-oesophageal or gastric adenocarcinoma were enrolled in a prospective multicentre phase II trial. Two sequential cohorts received docetaxel 75 mg m⁻² (day 1) plus capecitabine 1000 mg m⁻² twice daily (days 1–14) (cohort I) or docetaxel 60 mg m⁻² (day 1) plus capecitabine 800 mg m⁻² twice daily (days 1–14) (cohort II) every 3 weeks. The primary end point was confirmed overall response rate.

Results:

In all, 91 patients were enrolled (cohort I, n=40; cohort II, n=51) and 87 were evaluable for efficacy (n=38, 49, respectively). Overall response rate was 50.0% in cohort I and 23.5% in cohort II (exploratory analysis, P=0.014). Median times to tumour progression and overall survival were 5.6 and 10.1 months in cohort I and 3.7 and 7.2 months in cohort II, respectively. Dose reductions for docetaxel and capecitabine were required in 50.0% and 57.5% of patients in cohort I and 11.8% and 15.7% in cohort II, respectively.

Conclusion:

Starting treatment with full doses and reducing promptly seems to be the more promisingly effective strategy than starting cautiously with lower doses. Docetaxel/capecitabine 75/2000 mg m⁻² is a manageable, convenient outpatient combination with promising efficacy against advanced gastric cancer.     

Phase II study of nedaplatin and irinotecan with concurrent thoracic radiotherapy in patients with locally advanced non-small-cell lung cancer

Background:

Current international guidelines recommend the use of platinum-based chemotherapy with thoracic radiotherapy (TRT) for patients with locally advanced non-small-cell lung cancer (NSCLC).

Methods:

Patients with unresectable stage IIIA or IIIB NSCLC were treated with nedaplatin (NP) at 50 mg m⁻² and irinotecan (CPT) at 60 mg m⁻² on days 1 and 8 every 4 weeks for two to four cycles with concurrent TRT (2 Gy per day, total 60 Gy).

Results:

All 35 patients were able to receive a total of 60 Gy. Adverse effects and events in chemotherapy with TRT were grade 3 or 4 anaemia, neutropenia and thrombocytopenia, which occurred in 3.0%, 32.8% and 6.0% of patients, respectively. There was no grade 3 pneumonitis or oesophagitis. Adverse effects and events in chemotherapy alone were mild. There was no treatment-related death. An overall response rate was 94.3%. The median progression-free and overall survivals were 13.0 and 36.0 months, respectively. The 5-year disease-free and overall survival rates were 25.7% and 40.0%, respectively.

Conclusion:

NP and CPT treatment with concurrent TRT is effective and safe for patients with unresectable, locally advanced NSCLC.     

A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours

Background:

To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.

Methods:

Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg⁻¹ in combination with fixed doses of pemetrexed (500 mg m⁻²) plus cisplatin (75 mg m⁻²) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.

Results:

Eighteen patients were enrolled. One patient dosed at 4 mg kg⁻¹ experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg⁻¹ cohort or the 6 mg kg⁻¹ dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ⩾3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.

Conclusion:

The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg⁻¹, to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.     

A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer

Background:

Only a few clinical trials have been conducted in patients with advanced pancreatic cancer after failure of first-line gemcitabine-based chemotherapy. Therefore, there is no current consensus on the treatment of these patients. We conducted a randomised phase II study of the modified FOLFIRI.3 (mFOLFIRI.3; a regimen combining 5-fluorouracil (5-FU), folinic acid, and irinotecan) and modified FOLFOX (mFOLFOX; a regimen combining folinic acid, 5-FU, and oxaliplatin) regimens as second-line treatments in patients with gemcitabine-refractory pancreatic cancer.

Methods:

The primary end point was the 6-month overall survival rate. The mFOlFIRI.3 regimen consisted of irinotecan (70 mg m⁻²; days 1 and 3), leucovorin (400 mg m⁻²; day 1), and 5-FU (2000 mg m⁻²; days 1 and 2) every 2 weeks. The mFOLFOX regimen was composed of oxaliplatin (85 mg m⁻²; day 1), leucovorin (400 mg m⁻²; day 1), and 5-FU (2000 mg m⁻²; days 1 and 2) every 2 weeks.

Results:

Sixty-one patients were randomised to mFOLFIRI.3 (n=31) or mFOLFOX (n=30) regimen. The six-month survival rates were 27% (95% confidence interval (CI)=13–46%) and 30% (95% CI=15–49%), respectively. The median overall survival periods were 16.6 and 14.9 weeks, respectively. Disease control was achieved in 23% (95% CI=10–42%) and 17% patients (95% CI=6–35%), respectively. The number of patients with at least one grade 3/4 toxicity was identical (11 patients, 38%) in both groups: neutropenia (7 patients under mFOLFIRI.3 regimen vs 6 patients under mFOLFOX regimen), asthaenia (1 vs 4), vomiting (3 in both), diarrhoea (2 vs 0), and mucositis (1 vs 2).

Conclusion:

Both mFOLFIRI.3 and mFOLFOX regimens were tolerated with manageable toxicity, offering modest activities as second-line treatments for patients with advanced pancreatic cancer, previously treated with gemcitabine.     

A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

Background:

This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel.

Methods:

A total of 22 patients received paclitaxel (135–175 mg m⁻²) intravenously, administered once every three weeks for up to six cycles, with oral tosedostat (90–240 mg) daily.

Results:

One DLT (grade 3 dyspnoea) was observed in one patient with tosedostat 180 mg combined with paclitaxel 175 mg m⁻². A high number of paclitaxel infusion reactions was noted during the second administration (59%) and this prompted interruption of tosedostat dosing for 5 days around every second and subsequent paclitaxel infusion. No formal MTD was determined because of the high frequency of paclitaxel infusion reactions that may have been influenced by tosedostat. Most frequently observed drug-related adverse events were alopecia, fatigue (95% each), peripheral sensory neuropathy (59%), paclitaxel hypersensitivity (59%) and rash (55%). One patient died because of eosinophilic myocarditis, possibly related to study medication. There was no PK interaction between tosedostat and paclitaxel. In all, 3 patients had a partial response and 12 patients had stable disease lasting >3 months.

Conclusion:

The combination of tosedostat with paclitaxel was well tolerated except for the high incidence of paclitaxel-related infusion reactions.     

Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials

Background:

Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy.

Methods:

Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m⁻² over 30 min), oxaliplatin (65 mg m⁻²) and 5-FU (1500 mg m⁻² over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure.

Results:

Response rates were 19% (95% CI: 6–32%) and 23% (95% CI: 9–37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6–12.4) and 9.9 months (95% CI: 7.5–12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia.

Conclusion:

Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.     

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.     

Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

Background:

A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting.

Methods:

Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m⁻² twice daily) on days 1–14 plus paclitaxel (60 mg m⁻²) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m⁻² twice daily) on days 1–21 plus cisplatin (60 mg m⁻²) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Results:

A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin.

Conclusion:

S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials.     

Docetaxel and epirubicin compared with docetaxel and prednisone in advanced castrate-resistant prostate cancer: a randomised phase II study

Background:

This randomised phase II study compared the activity and safety of the combination docetaxel (D)/epirubicin (EPI) with the conventional treatment D/prednisone (P) in advanced castrate-resistant prostate cancer (CRPC) patients.

Materials and methods:

Patients were randomly assigned to D 30 mg m⁻² as intravenous infusion (i.v.) and EPI 30 mg m⁻² i.v. every week (D/EPI arm), or D 70 mg m⁻² i.v. every 3 weeks and oral P 5 mg twice daily (D/P arm). Chemotherapy was administered until disease progression or unacceptable toxicity.

Results:

A total of 72 patients were enrolled in the study and randomly assigned to treatment: 37 to D/EPI and 35 to D/P. The median progression-free survival (PFS) was 11.1 months (95% CI 9.2–12.6 months) in the D/EPI arm and 7.7 months (95% CI 5.7–9.4 months) in the D/P arm (P=0.0002). The median survival was 27.3 months (95% CI 22.1–30.8 months) in the D/EPI arm and 19.8 months (95% CI 14.4–24.8 months) in the D/P arm (P=0.003). Both regimens were generally well tolerated.

Conclusion:

The treatment of advanced CRPC with weekly D combined with weekly EPI was feasible and tolerable, and led to superior PFS than the treatment with 3-weekly D and oral P.     

Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma

Background:

Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.

Methods:

Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg^–1 on day 1 and capecitabine 800 mg m^–2 twice daily on days 1–14 every 3 weeks as first-line therapy.

Results:

A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.

Conclusion:

The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.     

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity

Background:

We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing.

Methods:

Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1–5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg⁻¹. DL5 alternated between bevacizumab 10 mg kg⁻¹-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg⁻¹ (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1–5 were analysed.

Results:

Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand–foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation ⩾4 months (53% median 6 (4–26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4–37 months.

Conclusion:

Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.     

Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours

Background:

Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumour sensitivity to retinoids. The objective of this study was to determine the safety, tolerability, and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor entinostat in combination with 13-cis retinoic acid (CRA) in patients with solid tumours.

Methods:

Patients with advanced solid tumours were treated with entinostat orally once weekly and with CRA orally twice daily × 3 weeks every 4 weeks. The starting dose for entinostat was 4 mg m⁻² with a fixed dose of CRA at 1 mg kg⁻¹ per day. Entinostat dose was escalated by 1 mg m⁻² increments. Pharmacokinetic concentrations of entinostat and CRA were determined by LC/MS/MS. Western blot analysis of peripheral blood mononuclear cells and tumour samples were performed to evaluate target inhibition.

Results:

A total of 19 patients were enroled. The maximum tolerated dose (MTD) was exceeded at the entinostat 5 mg m⁻² dose level (G3 hyponatremia, neutropenia, and anaemia). Fatigue (G1 or G2) was a common side effect. Entinostat exhibited substantial variability in clearance (147%) and exposure. CRA trough concentrations were consistent with prior reports. No objective responses were observed, however, prolonged stable disease occurred in patients with prostate, pancreatic, and kidney cancer. Data further showed increased tumour histone acetylation and decreased phosphorylated ERK protein expression.

Conclusion:

The combination of entinostat with CRA was reasonably well tolerated. The recommended phase II doses are entinostat 4 mg m⁻² once weekly and CRA 1 mg kg⁻¹ per day. Although no tumour responses were seen, further evaluation of this combination is warranted.     

Phase I study of BIBF 1120 with docetaxel and prednisone in metastatic chemo-naive hormone-refractory prostate cancer patients

Background:

BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1–3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients.

Methods:

This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m⁻², every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity.

Results:

Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ⩾50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone.

Conclusion:

Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m⁻² of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.