A randomized,controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma

BackgroundThe efficacy and safety of nab-paclitaxel versus dacarbazine in patients with metastatic melanoma was evaluated in a phase III randomized, controlled trial.Patients and methodsChemotherapy-naïve patients with stage IV melanoma received nab-paclitaxel 150 mg/m² on days 1, 8, and 15 every 4 weeks or dacarbazine 1000 mg/m² every 3 weeks. The primary end point was progression-free survival (PFS) by independent radiologic review; the secondary end point was overall survival (OS).ResultsA total of 529 patients were randomized to nab-paclitaxel (n = 264) or dacarbazine (n = 265). Baseline characteristics were well balanced. The majority of patients were men (66%), had an Eastern Cooperative Oncology Group status of 0 (71%), and had M1c stage disease (65%). The median PFS (primary end point) was 4.8 months with nab-paclitaxel and 2.5 months with dacarbazine [hazard ratio (HR), 0.792; 95.1% confidence interval (CI) 0.631–0.992; P = 0.044]. The median OS was 12.6 months with nab-paclitaxel and 10.5 months with dacarbazine (HR, 0.897; 95.1% CI 0.738–1.089; P = 0.271). Independently assessed overall response rate was 15% versus 11% (P = 0.239), and disease control rate (DCR) was 39% versus 27% (P = 0.004) for nab-paclitaxel versus dacarbazine, respectively. The most common grade ≥3 treatment-related adverse events were neuropathy (nab-paclitaxel, 25% versus dacarbazine, 0%; P < 0.001), and neutropenia (nab-paclitaxel, 20% versus dacarbazine, 10%; P = 0.004). There was no correlation between secreted protein acidic and rich in cysteine (SPARC) status and PFS in either treatment arm.Conclusionsnab-Paclitaxel significantly improved PFS and DCR compared with dacarbazine, with a manageable safety profile.     

Phase I–II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma

Background:

This phase I–II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma.

Methods:

The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m⁻² (n=20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m⁻² on days 1, 8 and 15 q4wk combined with DTIC 800 mg m⁻² q4wk (n=38).

Results:

The overall response rate with plitidepsin/DTIC was 21.4% all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ⩽1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug–drug pharmacokinetic interactions were found.

Conclusion:

This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m⁻² fortnightly and DTIC 800 mg m⁻² q4wk is recommended.     

Intracerebral injection of CpG oligonucleotide for patients with de novo glioblastoma—A phase II multicentric,randomised study

BackgroundImmunostimulating oligodeoxynucleotides containing unmethylated cytosine-guanosine motifs (CpG-ODN) have shown a promising efficacy in several cancer models when injected locally. A previous phase II study of CpG-ODN in patients with recurrent glioblastoma (GBM) has suggested some activity and has shown a limited toxicity. This multicentre single-blinded randomised phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with de novo glioblastomas.Patients and methodsPatients with a newly diagnosed glioblastoma underwent large surgical resection and CpG-ODN was randomly administrated locally around the surgical cavity. The patients were then treated according to standard of care (SOC) with radiotherapy and temozolomide. The primary objective was 2-year survival. Secondary outcomes were progression free survival (PFS), and tolerance.ResultsEighty-one (81) patients were randomly assigned to receive CpG-ODN plus SOC (39 patients) or SOC (42 patients). The 2-year overall survival was 31% (19%; 49%) in the CpG-ODN arm and 26% (16%; 44%) in the SOC arm. The median PFS was 9 months in the CpG-ODN arm and 8.5 months in the SOC arm. The incidence of adverse events was similar in both arms; although fever and post-operative haematoma were more frequent in the CpG-ODN arm.ConclusionsLocal immunotherapy with CpG-ODN injected into the surgical cavity after tumour removal and followed by SOC, although well tolerated, does not improve survival of patients with newly diagnosed GBM.     

VEGF-SPECT with ¹¹¹In-bevacizumab in stage III/IV melanoma patients

Purpose

A feasibility study was performed to investigate the presence of VEGF in melanoma lesions by VEGF-SPECT with ¹¹¹In-bevacizumab. In addition the effect of a single therapeutic bevacizumab dose on ¹¹¹In-bevacizumab uptake was compared with VEGF levels in resected melanoma lesions.

Patients and methods

Eligible were patients with stage III/IV melanoma who presented with nodal recurrent disease. VEGF-SPECT was performed after administration of 100 Mbq ¹¹¹In-bevacizumab (8 mg) at days 0, 2, 4 and 7 post injection. Tumour visualisation and quantification were compared with CT and FDG-PET. On day 7 a single dose of 7.5 mg/kg bevacizumab was administered intravenously. On day 21, a second tracer dose ¹¹¹In-bevacizumab was administered and scans were obtained on days 21, 25 and 28. Metastases were surgically resected within 2 weeks after the last VEGF-SPECT scan and immunohistological (IHC) VEGF tumour expression was compared with ¹¹¹In-bevacizumab tumour uptake.

Results

Nine patients were included. FDG-PET and CT detected both in total 12 nodal lesions which were all visualised by VEGF-SPECT. At baseline, ¹¹¹In-bevacizumab tumour uptake varied 3-fold between and 1.6 ± 0.1-fold within patients. After a therapeutic dose of bevacizumab there was a 21 ± 4% reduction in ¹¹¹In-bevacizumab uptake. The ¹¹¹In-bevacizumab tumour uptake in the second series positively correlated with the VEGF-A expression in the resected tumour lesions.

Conclusion

VEGF-SPECT could visualise all known melanoma lesions. A single dose of bevacizumab slightly lowered ¹¹¹In-bevacizumab uptake. Future studies should elucidate the role of VEGF-SPECT in the selection of patients and the individual dosing of bevacizumab treatment.     

A phase I study of larotaxel (XRP9881) administered in combination with carboplatin in chemotherapy-naïve patients with stage IIIB or stage IV non-small cell lung cancer

Purpose

This primary objective of this phase I dose-escalation study was to define the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of larotaxel administered in combination with carboplatin in chemotherapy-naïve patients with advanced/metastatic non-small cell lung cancer (NSCLC).

Methods

Eighteen patients with stage IIIB or IV NSCLC, in cohorts of three to six evaluable patients, were to receive every 3 weeks: larotaxel beginning at 45 mg/m² administered as a 1-h infusion, followed after 30 min by carboplatin (area under the concentration–time curve (AUC) = 6 mg/mL × min, later AUC = 5) as a 1-h infusion. Dose escalation of larotaxel up to 90 mg/m² was permitted according to DLT occurrence. Patients received ondansetron as prophylactic anti-emetic premedication.

Results

In view of the toxicity encountered, the carboplatin dose was decreased for the later part of the study to AUC = 5 mg/mL × min. Eight of 18 treated patients experienced DLTs in the first cycle, including neutropenia and associated complications, diarrhea and fatigue. The MTD of the combination was defined as larotaxel 60 mg/m² with a carboplatin AUC of 6 mg/mL × min. Neutropenia, reported at grade 3/4 in 15/18 patients (83%), was the most common severe adverse event, reaching grade 4 in 14 patients (78%). Eleven patients (61%) experienced grade 3/4 non-hematological toxicity, predominantly dehydration, fatigue, infection, nausea and vomiting. One patient (6%) achieved a partial response and 11 (61%) had stable disease.

Conclusions

The combination of larotaxel and carboplatin is feasible and shows modest activity in chemotherapy-naïve patients with advanced/metastatic NSCLC. The principal toxicity was grade 3/4 neutropenia.     

A phase II study of paclitaxel in chemona?ve patients with recurrent high-grade glioma

Background:The prognosis of malignant gliomas remains poor. Inrecurrent disease, chemotherapy can be considered. Patients and methods:In this phase II study we determined theanti-tumour efficacy of paclitaxel 200 mg/m² in a three-hourintravenous infusion every three weeks in chemonaïve patients withrecurrent high-grade glioma in terms of response, survival, and quality oflife. Results:In 17 patients (14 glioblastoma multiforme, 3 anaplasticastrocytoma) 69 paclitaxel cycles were administered. Partial or completeresponses were not observed. Stable disease for four to six months wasobserved in five patients (29%). Median time to progression and mediansurvival were two and 10 months, respectively. Toxicity due to paclitaxel wasas to be expected and minor in most cases. Quality of life and mood estimatesappeared rather stable over time. Conclusions:We conclude that three-weekly 200 mg/m²paclitaxel chemotherapy for patients with recurrent high-grade gliomas did notlead to major complications or adverse effects on quality of life and mood.However, this therapy is of only very limited value in terms of response andsurvival in such patients.     

A randomised,phase II trial of the DNA-hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent,partially platinum-sensitive ovarian cancer

Background:

Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2′-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer.

Methods:

Patients progressing 6–12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma.

Results:

After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%).

Conclusions:

With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.     

Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized,multicenter, open-label,phase III study of gemcitabine–cisplatin plus necitumumab versus gemcitabine–cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer

BackgroundSQUIRE demonstrated addition of necitumumab to gemcitabine and cisplatin significantly improved survival in patients with stage IV sq-NSCLC. Here, we report additional outcomes for the subpopulation of patients with tumor epidermal growth factor receptor (EGFR) protein expression.Patients and methodsPatients with pathologically confirmed stage IV sq-NSCLC were randomized 1:1 to receive a maximum of six 3-week cycles of gemcitabine (1250 mg/m² i.v., days 1 and 8) and cisplatin (75 mg/m² i.v., day 1) chemotherapy with or without necitumumab (800 mg i.v., days 1 and 8). Patients in the chemotherapy plus necitumumab group with no progression continued on necitumumab alone until disease progression or intolerable toxicity. SQUIRE included mandatory tissue collection. EGFR protein expression was detected by immunohistochemistry (IHC) in a central laboratory. Exploratory analyses were pre-specified for patients with EGFR protein expressing (EGFR > 0) and non-expressing (EGFR = 0) tumors.ResultsA total of 982 patients [90% of intention-to-treat (ITT)] had evaluable IHC results. The large majority of these patients (95%) had tumor samples expressing EGFR protein; only 5% had tumors without detectable EGFR protein. Overall survival (OS) for EGFR > 0 patients was significantly longer in the necitumumab plus gemcitabine–cisplatin group than in the gemcitabine–cisplatin group {stratified hazard ratio (HR) 0.79 [95% confidence interval (CI) 0.69, 0.92; P = 0.002]; median 11.7 months (95% CI 10.7, 12.9) versus 10.0 months (8.9, 11.4)}. Additionally, an OS benefit was seen in all pre-specified subgroups in EGFR > 0 patients. However, OS HR for EGFR = 0 was 1.52. Adverse events of interest with the largest difference between treatment groups in EGFR > 0 patients (Grade ≥3) were hypomagnesemia (10% versus <1%) and skin rash (6% versus <1%).ConclusionsIn line with SQUIRE ITT, addition of necitumumab to gemcitabine–cisplatin significantly prolonged OS and was generally well tolerated in the subpopulation of patients with EGFR-expressing advanced sq-NSCLC. The benefit from addition of necitumumab to chemotherapy was not apparent in this analysis for the small subgroup of patients with non-EGFR-expressing tumors.Clinical TrialNCT00981058.     

A phase II randomized study of vinorelbine alone or with cisplatin against chemo-naïve inoperable non-small cell lung cancer in the elderly

PURPOSE: Our aim here was to determine whether or not the addition of cisplatin into vinorelbine (V) treatment is an appropriate regimen for physically fit chemo-na?ve non-small cell lung cancer (NSCLC) patients aged 70 or older. PATIENTS AND METHODS: Patients were randomized into vinorelbine (V) or vinorelbine plus cisplatin (VP) treatment arms. Treatment consisted of vinorelbine 25 mg/m(2) intravenous infusion (i.v.) on days 1 and 8 every 3 weeks (V arm), or vinorelbine 22.5 mg/m(2) i.v. on days 1 and 8 plus cisplatin 50 mg/m(2) i.v. on day 1 every 3 weeks (VP arm). RESULTS: Sixty-five patients were enrolled from May 2005 to December 2006, including 31 who received V treatment and 34 who received VP treatment. Objective response rates were 16.1% in V and 32.4% in VP (p=0.009). Control rates were 51.6% in V and 82.4% in VP (p=0.008). Myelosuppression was more common and severe in the VP arm. Any grade of anemia and neutropenia was significantly higher in the VP arm (p=0.001 and 0.009, respectively). Fatigue sensation was more common and severe in the VP arm (p=0.032). Median time to disease progression was 3.1 months in the V arm and 5.2 months in the VP arm (p=0.0303). The 1-year survival rate was 50.9% in the V arm and 47.2% in the VP arm. CONCLUSIONS: Adding cisplatin to vinorelbine treatment is feasible in elderly patients, and has a better response rate and longer median time to disease progression. However, both statistically significantly higher toxicity and no survival advantage for the combination treatment was observed.     

Phase 2 study of adjuvant chemotherapy with docetaxel,capecitabine, and cisplatin in patients with curatively resected stage IIIB–IV gastric cancer

Gastric Cancer - Postoperative chemotherapy with S-1 or capecitabine plus oxaliplatin is a standard treatment for resectable gastric cancer (GC). However, survival outcomes of stage IIIB–IV...     

A phase II study of epirubicin, cisplatin and raltitrexed combination chemotherapy (ECT) in patients with advanced oesophageal and gastric?adenocarcinoma

Background:The aim of this study was to evaluate theefficacy of the combination of epirubicin, cisplatin and ralitrexed(Tomudex), ECT, in patients with advanced oesophageal or gastricadenocarcinoma. Efficacy was assessed primarily as response rate andsecondarily in terms of toxicity, time to progression and survival. Patients and methods:Twenty-one patients withhistologically and/or cytologically proven unresectable (7) ormetastatic (14) gastro-oesophageal adenocarcinoma, who hadbi-dimensionally measurable disease, with ECOG performance status 2,with adequate haematological, hepatic and renal function receivedfirst-line chemotherapy with epirubicin (50 mg/m²), cisplatin(60 mg/m²) and Tomudex (2.5 mg/m²), ECT, atthree-weekly intervals. Treatment consisted of three cycles ofchemotherapy, with a further three cycles if there was disease responseor stabilisation. Results:ECT is an active regimen inthe treatment of advanced gastro-oesophageal adenocarcinoma with anoverall intention-to-treat response rate of 29% (95%confidence intervals (CI): 11%–52%). In addition, 4(19%) patients had stable disease. Median time to progression was19 weeks (95% CI: 7–31 weeks). Median overall survival was18 weeks (95% CI: 11–24 weeks). Seventeen patients failedto complete the six cycles of treatment due to disease progression (5),toxicity (3), non-toxic death (1 pulmonary embolism, 1 cardiac), severeallergy to epirubicin (1), patient decision (1) and five patients afterthe study was discontinued early due to toxicity. There were three toxicdeaths: two due to sepsis complicating neutropaenia and one due tocardiorespiratory failure following drug induced enteritis. Ninepatients experienced grade 3 or 4 neutropaenia, two patients experiencedgrade 3 or 4 nausea and vomiting and one patient had grade 4diarrhoea. Conclusions:The combination of epirubicin,cisplatin and tomudex is active against advanced gastro-oesophagealadenocarcinoma but the toxicity suggests that further evaluation in arandomised comparison to ECF is not appropriate.     

A randomised phase II trial of 1 month versus 1 year of adjuvant high-dose interferon α-2b in high-risk acral melanoma patients

Background

High-dose Interferon-α-2b (HD-IFN) is an adjuvant treatment for melanoma. However, clinical trials for HD-IFN have not been reported in acral melanoma (AM), the predominant subtype of cutaneous melanoma in Asian population.

Methods

Patients with resected high-risk (stage IIb-IIIc) AM were randomly assigned to a regimen of 4-week (arm A: 15 × 10⁶ U/m² d1-5/w × 4w) or 1-year adjuvant HD-IFN (arm B: 15 × 10⁶ U/m² d1-5/w × 4w + 9 × 10⁶ U tiw × 48w), respectively. The endpoints were relapse-free survival (RFS), overall survival (OS) and toxicities.

Results

A total of 158 patients were enrolled in this study and 147 patients were eligible for survival analysis. With a median follow-up of 36.1 months, median RFS for arm A and arm B were 17.9 months and 22.5 months, respectively (P = 0.72). Stratified analysis showed that RFS curves of patients in stage IIIb-IIIc were statistically different between arm A and arm B (P = 0.02). The median RFS of patients with more nodal metastases (n ? 3) was shorter (P = 0.004) in arm A (3.3 months) than that in arm B (11.9 months). Grade 1/2 adverse effects were observed in both groups. However, patients in arm B showed higher incidence of reversible Grade 3/4 hepatotoxicity (P = 0.03).

Conclusions

The induction dose of 15 × 10⁶ U/m² and the maintenance dose of 9 × 10⁶ U were tolerable, which may be the optional dose intensity for adjuvant IFN-α-2b therapy in Chinese high risk AM population. No statistical significance was detected in RFS between the 4-week and 1-year regimen while a 1-year regimen may show clinical benefits in patients with stage IIIb-IIIc AM or with ?3 nodal metastases.     

A phase II study of oral eniluracil/fluorouracil in patients with anthracycline-refractory or anthracycline- and taxane-refractory advanced?breast cancer

Background:Eniluracil is an effective inactivator ofdihydropyrimidine dehydrogenase, the initial and rate limiting enzyme inthe catabolism of fluorouracil. The current study was done to determinethe objective tumour response of a 28-day oral regimen ofeniluracil–fluorouracil in patients with advanced breastcancer. Patients and methods:This was a multicentre, phase II studyin patients with anthracycline-refractory (AR) or anthracycline- andtaxane-refractory (ATR) advanced breast cancer. Oral eniluracil (10mg/m²) and fluorouracil (1 mg/m²) were taken twicedaily for 28 days of each 35-day treatment course. Results:In this study, 106 patients received treatment: 62patients in the AR stratum and 44 patients in the ATR stratum. Theobjective tumour response rate in the intent-to-treat population was18% (95% confidence intervals (CI):11%–27%), including three complete responses. Theresponse rate was similar in both strata: 19% in the AR and16% in the ATR stratum. The overall median duration of responsewas 23.6 weeks. The treatment was well tolerated with a low incidence ofgrade 3 or 4 toxicities that were considered attributable to studymedication. Conclusion:Treatment with oraleniluracil–fluorouracil was well tolerated by patients withadvanced breast cancer. The efficacy data were comparable with those ofother published studies in this group of refractory patients.     

A phase I study of olaratumab,an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody,in patients with advanced solid tumors

Purpose

The platelet-derived growth factor receptor (PDGFR) has an important role in tumorigenesis and tumor progression. Olaratumab (IMC-3G3) is a fully human monoclonal antibody that selectively binds human PDGFRα and blocks ligand binding. This phase I study assessed the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of olaratumab in patients with advanced solid tumors.

Methods

Patients were enrolled into five dose-escalating cohorts of 3–6 patients each. Olaratumab was administered intravenously weekly at 4, 8, or 16 mg/kg (cohorts 1–3) or once every other week at 15 or 20 mg/kg (cohorts 4–5), with 4 weeks/cycle.

Results

Nineteen patients were treated in five cohorts. There were no dose-limiting toxicities; the MTD was not identified with the doses studied. The most common olaratumab-related adverse events (AE) were fatigue and infusion reactions (10.5 % each). With the exception of 1 patient (20 mg/kg) experiencing two grade 3 drug-related AEs after the dose-limiting toxicity assessment period, all drug-related AEs were grade 1 or 2. The trough concentrations (C _min) for 16 mg/kg weekly and 20 mg/kg biweekly were higher than 155 μg/mL, and the concentration found to be efficacious in preclinical xenograft models. Twelve patients (63.2 %) had a best response of stable disease [median duration of 3.9 months (95 % CI 2.3–8.7)].

Conclusions

Olaratumab was well tolerated and showed preliminary antitumor activity. RP2Ds are 16 mg/kg weekly and 20 mg/kg biweekly. Phase II studies of olaratumab as monotherapy and in combination are ongoing in several tumor types.