A phase I study of daily afatinib,an irreversible ErbB family blocker,in combination with weekly paclitaxel in patients with advanced solid tumours

BackgroundThis phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2.MethodsOral afatinib was combined with intravenous paclitaxel (80 mg/m²; days 1, 8 and 15 every four weeks) starting at 20 mg once daily and escalated to 40 and 50 mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity.ResultsSixteen patients were treated. Dose-limiting toxicities with afatinib 50 mg were fatigue and mucositis. The MTD was determined as afatinib 40 mg with paclitaxel 80 mg/m², which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n = 3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6 months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination.ConclusionsThe MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80 mg/m² (days 1, 8 and 15 every four weeks) was 40 mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity.Trial registrationClinicalTrials.gov, NCT00809133.     

Phase Ib safety and pharmacokinetic study of volociximab,an anti-α5β1 integrin antibody,in combination with carboplatin and paclitaxel in advanced non-small-cell lung cancer

BackgroundThis phase Ib study evaluated volociximab, an anti-α5β1 integrin antibody, in combination with carboplatin (Eli Lilly and Co., Indianapolis, IN) and paclitaxel (Taxol) in advanced, untreated non-small-cell lung cancer (NSCLC).Patients and methodsThree cohorts were treated with volociximab (10, 20, or 30 mg/kg) for up to six 3-week cycles in combination with carboplatin–paclitaxel chemotherapy and continued as maintenance therapy for patients with stable disease (SD) or better. Dose-limiting toxic effects, adverse events (AEs), pharmacokinetics, and anti-volociximab antibodies were assessed.ResultsA maximum tolerated dose was not reached up to the maximum planned dose of 30 mg/kg. In 29 patients who received volociximab, the most common grade ≥3 AEs were neutropenia (24%), hyponatremia (17%), and fatigue (10%). Three patients experienced volociximab-related serious AEs. No hemorrhages were observed. Of 33 patients enrolled, 8 (24%) achieved a partial response and 17 (52%) had SD. The median progression-free survival was 6.3 months (95% confidence interval 5.5–8.1). Levels of potential biomarkers of angiogenesis or metastasis were reduced following six cycles of treatment.ConclusionsVolociximab combined with carboplatin and paclitaxel was generally well-tolerated and showed preliminary evidence of efficacy in advanced NSCLC.     

Health-related quality of life in women with recurrent ovarian cancer receiving paclitaxel plus trebananib or placebo (TRINOVA-1)

BackgroundTo evaluate the influence of treatment on health-related quality of life (HRQoL) in 919 women with recurrent ovarian cancer enrolled in the TRINOVA-1 study, a randomized, placebo-controlled phase III study that demonstrated that trebananib 15 mg/kg QW plus weekly paclitaxel significantly improved progression-free survival (PFS) compared with placebo plus weekly paclitaxel (7.2 versus 5.4 months; hazard ratio, 0.66; 95% confidence interval 0.57–0.77; P < 0.001).Patients and methodsHRQoL was assessed with the Functional Assessment of Cancer Therapy–Ovary [FACT-O; comprising FACT-G and the ovarian cancer–specific subscale (OCS)] and EuroQOL EQ-5D instruments before treatment on day 1 of weeks 1, 5, 9, 13, 17, and every 8 weeks thereafter and at the safety follow-up visit. A pattern-mixture model was used to evaluate the influence of patient dropout on FACT-O and OCS scores over time.ResultsOf 919 randomized patients, 834 (91%) had a baseline and ≥1 post-baseline HRQoL assessment. At baseline, scores for all instruments were similar for both arms. At 25 weeks, mean ± SD changes from baseline were negligible, with mean ± SD changes typically <1 unit from baseline: -2.4 ± 16.6 in the trebananib arm and -1.6 ± 15.2 in the placebo arm for FACT-O, -0.71 ± 5.5 in the trebananib arm and -0.86 ± 4.9 in the placebo arm for OCS, and -0.02 ± 0.22 in the trebananib arm and 0.02 ± 0.19 in the placebo arm for EQ-5D. Distribution of scores was similar between treatment arms at baseline and over the course of the study. In pattern-mixture models, there was no evidence that patient dropout affected differences in mean FACT-O or OCS scores. Edema had limited effect on either FACT-O or OCS scores in patients with grade ≥2 edema or those with grade 1 or no edema.ConclusionsOur results demonstrate that the improvement in PFS among patients in the trebananib arm in the TRINOVA-1 study was achieved without compromising HRQoL.ClinicalTrials.gov identifierNCT01204749.     

A phase 1b,open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours

Background

To examine the angiopoietin pathway inhibitor trebananib IV plus the anti-VEGF agents bevacizumab or motesanib in advanced solid tumours.

Methods

In this open-label phase 1b study, patients received IV trebananib 3 mg kg⁻¹ QW plus bevacizumab 15 mg kg⁻¹ Q3W (cohort 1) or motesanib orally 75 mg (cohort 2); or trebananib 10 mg kg⁻¹ plus bevacizumab 15 mg kg⁻¹ (cohort 3) or motesanib 125 mg (cohort 4). If <33% of patients had dose-limiting toxicities (DLTs), dose escalation occurred. Endpoints were treatment–related adverse events (AEs) incidence and pharmacokinetics (primary); anti-trebananib antibodies, biomarkers, and tumour response (secondary).

Results

Thirty-six patients received ≥1 dose of trebananib (cohorts 1, 2, 3, 4; n = 6, 8, 19, 3). DLT of G3 intestinal perforation and G3 tumor haemorrhage occurred in cohorts 2 and 3, respectively (both n = 1). Across both trebananib plus bevacizumab cohorts, the most common AEs included fatigue (n = 8), diarrhoea (n =4), constipation (n = 3), nausea (n = 3), and epistaxis (n = 3). Three patients across those cohorts had grade ≥3 AEs. Across the trebananib plus motesanib cohorts, the most common AEs included hypertension (n = 4), diarrhoea (n = 4), nausea (n = 3), fatigue (n = 3), vomiting (n = 2), and decreased appetite (n = 2). Two patients had grade ≥3 AEs. Trebananib did not markedly affect motesanib pharmacokinetics. Across the trebananib plus bevacizumab cohorts, two patients had a partial response; 11 patients had stable disease lasting >6 months. Across the trebananib plus motesanib cohorts, one patient had a partial response; five patients had stable disease lasting >6 months.

Conclusion

Trebananib IV 3 mg kg⁻¹ or 10 mg kg⁻¹ plus bevacizumab or motesanib in advanced solid tumours may be associated with less severe toxicities relative to those emerging when combining two anti-VEGF agents.     

Long-term results of weekly paclitaxel carboplatin induction therapy: An effective and well-tolerated treatment in patients with platinum-resistant ovarian cancer

BackgroundWeekly paclitaxel/cisplatin is effective in platinum-resistant epithelial ovarian cancer (EOC). To reduce toxicity, paclitaxel/cisplatin was replaced by paclitaxel/carboplatin.Patients and methodsPatients with progressive EOC after prior 3-weekly paclitaxel/carboplatin were treated with six cycles weekly paclitaxel 90 mg/m² and carboplatin area under the curve (AUC) 4 mg/ml/min, followed by six cycles 3-weekly paclitaxel/carboplatin. End-points were progression free survival (PFS), overall survival (OS), response rate (RR) and toxicity.ResultsMedian progression free interval after last platinum was 9 (0–81) months in 108 patients; 43 were platinum-resistant, of whom 13 started weekly paclitaxel/carboplatin <6 months after progression. During 633 weekly cycles grade 3/4 toxicity included; thrombocytopenia 8%, neutropenia 30%, febrile neutropenia 0.5%. Non-haematologic toxicity was low. Treatment was delayed in 16%, and dose reduced in 2% of cycles. RR was 58% for platinum-resistant and 76% for platinum-sensitive patients, median PFS were 8 (range 1–21) and 13 (1–46) months, median OS 15 (1–69) and 26 (4–93) months, respectively. The 13 platinum-resistant patients with a platinum-therapy free interval <6 months had a significant shorter PFS (4 versus 10 months, p = 0.035) and OS (9 versus 15 months, p = 0.002).ConclusionSix cycles weekly paclitaxel/carboplatin followed by six 3-weekly cycles is well-tolerated and highly active in platinum-resistant and platinum-sensitive patients.     

Phase I dose-finding study of paclitaxel with panitumumab,carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck

BackgroundPanitumumab has the potential to improve the therapeutic ratio of concurrent chemoradiotherapy for squamous cell carcinoma of the head and neck (SCCHN).Patients and methodsThis phase I dose-finding study investigated escalating doses of paclitaxel (Taxol) given concurrently with panitumumab, carboplatin and intensity-modulated radiotherapy (IMRT) for stage III–IVB SCCHN. Untreated patients with oral cavity, oropharynx, larynx, hypopharynx or unknown primaries were eligible. Additional eligibility criteria included measurable disease, good performance status and no contraindication to therapy. Patients received weekly fixed doses of panitumumab and carboplatin plus escalating doses of paclitaxel with IMRT.ResultsNineteen patients were enrolled on to two dose levels (DLs): weekly paclitaxel 15 mg/m² (n = 3) and 30 mg/m² (n = 16). One dose-limiting toxicity occurred in DL 2, which was declared the maximum tolerated dose. All patients experienced mucositis, primarily grade 3 or more. Oral pain, xerostomia, dysphagia, weight loss, dermatitis, nausea and acneiform rash were frequent. All patients had partial response according to RECIST, whereas the overall complete clinical response rate was 95%. At median follow-up of 21 months, 18 of 19 patients (95%) remained disease free.ConclusionsPanitumumab, carboplatin, paclitaxel and IMRT are well tolerated and appear highly active in the treatment of SCCHN. Further study of this regimen in SCCHN is warranted.     

Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG,phase I,open-label dose-escalation study (IND 179)

BackgroundThe purpose of the study was to assess the safety, tolerability, recommended phase II dose (RPTD), and preliminary antitumor activity of the combination of carboplatin–paclitaxel (Taxol)–temsirolimus.Materials and methods: Patients with solid malignancies suitable for carboplatin–paclitaxel (CP) chemotherapy and two or less prior lines of chemotherapy received 15, 20, or 25 mg of temsirolimus per week with CP given every 21 days. Thirty-eight eligible patients were entered into six dose levels with the first two levels administering temsirolimus on days 8 and 15 and the subsequent four dose levels switching to days 1 and 8 temsirolimus administration.ResultsDays 8 and 15 administration of temsirolimus was not feasible due to myelosuppression on day 15. CP on day 1 with temsirolimus on days 1 and 8 was well tolerated. Dose-limiting toxicity (DLT) was grade 4 thrombocytopenia (n = 2) and grade 3 fatigue (n = 1). Relative dose intensities for carboplatin, paclitaxel, and temsirolimus at the RPTD were 92%, 82%, and 56%, respectively. Non-DLT treatment-related adverse events occurring in >20% of patients included fatigue, mucositis, alopecia, neuropathy, nausea, neutropenia, thrombocytopenia, and infection. Grade 3/4 non-hematological toxicity was rare. Partial responses (PRs) and disease stabilization were seen in 46% and 49% of patients, respectively. Nine of 11 (82%) endometrial cancer patients had objective PRs.Conclusions:Carboplatin–paclitaxel–temsirolimus is well tolerated and the RPTD is carboplatin area under the curve 5 mg/ml/min, paclitaxel 175 mg/m², both given on day 1 with temsirolimus 25 mg on days 1 and 8.     

Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized,double-blind,multicenter phase 2 trial

BackgroundIpilimumab, an anti-CTLA4 monoclonal antibody, demonstrated survival benefit in melanoma with immune-related (ir) adverse events (irAEs) managed by the protocol-defined guidelines. This phase 2 study evaluated ipilimumab + paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer (ED-SCLC).DesignPatients (n = 130) with chemotherapy-naïve ED-SCLC were randomized 1: 1: 1 to receive paclitaxel (175 mg/m²)/carboplatin (area under the curve = 6) with either placebo (control) or ipilimumab 10 mg/kg in two alternative regimens, concurrent ipilimumab (ipilimumab + paclitaxel/carboplatin followed by placebo + paclitaxel/carboplatin) or phased ipilimumab (placebo + paclitaxel/carboplatin followed by ipilimumab + paclitaxel/carboplatin). Treatment was administered every 3 weeks for a maximum of 18 weeks (induction), followed by maintenance ipilimumab or placebo every 12 weeks. End points included progression-free survival (PFS), irPFS, best overall response rate (BORR); irBORR, overall survival (OS), and safety.ResultsPhased ipilimumab, but not concurrent ipilimumab, improved irPFS versus control [HR (hazard ratio) = 0.64; P = 0.03]. No improvement in PFS (HR = 0.93; P = 0.37) or OS (HR = 0.75; P = 0.13) occurred. Phased ipilimumab, concurrent ipilimumab and control, respectively, were associated with median irPFS of 6.4, 5.7 and 5.3 months; median PFS of 5.2, 3.9 and 5.2 months; median OS of 12.9, 9.1 and 9.9 months. Overall rates of grade 3/4 irAEs were 17, 21 and 9% for phased ipilimumab, concurrent ipilimumab and control, respectively.ConclusionThese results suggest further investigation of ipilimumab in ED-SCLC.     

Long-term results of a randomised phase III trial of weekly versus three-weekly paclitaxel/platinum induction therapy followed by standard or extended three-weekly paclitaxel/platinum in European patients with advanced epithelial ovarian cancer

BackgroundWeekly paclitaxel/carboplatin might improve survival in platinum-resistant epithelial ovarian cancer (EOC). We compared efficacy of first-line weekly to three-weekly paclitaxel/cis- or carboplatin (PCw and PC3w) induction therapy, followed by either three or six PC3w cycles.Patients and methodsIn this multicentre, randomised phase III trial with 2×2 design, patients with FIGO stage IIb–IV EOC were randomised to six cycles PCw (paclitaxel 90 mg/m², cisplatin 70 mg/m² or carboplatin AUC 4) or three cycles PC3w (paclitaxel 175 mg/m², cisplatin 75 mg/m² or carboplatin AUC 6), followed by either three or six cycles PC3w. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were response rate (RR) and toxicity.ResultsOf 267 eligible patients, 133 received PCw and 134 PC3w. The first 105 patients received cisplatin, after protocol amendment the subsequent 162 patients received carboplatin. Weekly cisplatin was less well tolerated than weekly carboplatin. All PC3w cycles were well tolerated. At the end of all treatments, RR was 90.8% with no differences between the treatment arms. After a follow-up of median 10.3 years (range 7.1–14.8), median PFS was 18.5 (95% confidence interval (CI) 15.9–21.0) months for PCw and 16.4 (95% CI 13.5–19.2) months for PC3w (p = 0.78). Median OS was 44.8 (95% CI 33.1–56.5) months for PCw and 41.1 (95% CI 34.4–47.7) months for PC3w (p = 0.98).ConclusionsThere was no benefit in terms of OS, PFS or RR for a weekly regimen nor for extended chemotherapy as first-line treatment for EOC in European patients.     

Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast,ovarian and other solid tumors

BackgroundTo establish the maximum tolerated dose, determine safety/tolerability and evaluate the pharmacokinetics and preliminary efficacy of olaparib in combination with cisplatin in patients with advanced solid tumors.Patients and methodsPatients aged ≥18 years with advanced solid tumors, who had progressed on standard treatment, were assigned to a treatment cohort and received oral olaparib [50–200 mg twice daily (bid); 21-day cycle] continuously or intermittently (days 1–5 or 1–10) in combination with cisplatin (60–75 mg/m² intravenously) on day 1 of each cycle.ResultsDose-limiting toxicities (DLTs) of grade 3 neutropenia (cisplatin 75 mg/m² with continuous olaparib 100 mg bid or 200 mg bid; n = 1 each) and grade 3 lipase elevation (cisplatin 75 mg/m² with olaparib 100 mg bid days 1–10 or 50 mg bid days 1–5; n = 1 each) were reported. Olaparib and cisplatin doses were subsequently reduced to 50 mg bid days 1–5 and 60 mg/m², respectively; no DLTs were reported for patients receiving this regimen. The most frequent grade ≥3 adverse events were neutropenia (16.7%), anemia (9.3%) and leucopenia (9.3%). Thirty patients (55.6%) received colony-stimulating factors for hematologic support. The overall objective response rate was 41% for patients with measurable disease, and 43% and 71% among patients with a BRCA1/2 mutation who had ovarian and breast cancer, respectively.ConclusionsOlaparib in combination with cisplatin 75 mg/m² was not considered tolerable; intermittent olaparib (50 mg bid, days 1–5) with cisplatin 60 mg/m² improved tolerability. Promising antitumor activity in patients with germline BRCA1/2 mutations was observed and warrants further investigation.     

Randomised,double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29

IntroductionThis randomised double-blind placebo-controlled study evaluated the addition of cediranib, an inhibitor of vascular endothelial growth factor receptors 1–3, to standard carboplatin/paclitaxel chemotherapy in advanced non-small cell lung cancer.MethodsEligible patients received paclitaxel (200 mg/m²) and carboplatin (area under the concentration time curve 6) intravenously every 3 weeks. Daily oral cediranib/placebo 20 mg was commenced day 1 of cycle 1 and continued as monotherapy after completion of 4–6 cycles of chemotherapy. The primary end-point of the study was overall survival (OS). The trial would continue to full accrual if an interim analysis (IA) for progression-free survival (PFS), performed after 170 events of progression or death in the first 260 randomised patients, revealed a hazard ratio (HR) for PFS of ⩽0.70.ResultsThe trial was halted for futility at the IA (HR for PFS 0.89, 95% confidence interval [CI] 0.66–1.20, p = 0.45). A final analysis was performed on all 306 enrolled patients. The addition of cediranib increased response rate ([RR] 52% versus 34%, p = 0.001) but did not significantly improve PFS (HR 0.91, 95% CI 0.71–1.18, p = 0.49) or OS (HR 0.94, 95% CI 0.69–1.30, p = 0.72). Cediranib patients had more grade 3 hypertension, diarrhoea and anorexia.ConclusionsThe addition of cediranib 20 mg daily to carboplatin/paclitaxel chemotherapy increased RR and toxicity, but not survival.     

Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials

BackgroundAfatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials.Patients and methodsTreatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not.ResultsDose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}.ConclusionsTolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy.Clinical trial registrationClinicaltrials.gov identifiers: NCT00949650 and NCT0112393.     

Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours

BackgroundTo determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2).Patients and methodsIn this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks.ResultsTwo grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5 mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6 mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4 mg/kg. Twenty-two patients had stable disease (five with 4 mg/kg), lasting >3 months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4 mg/kg.ConclusionBased on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4 mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2 weeks.     

A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer

BackgroundThis study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m² given over 90 min i.v. and l-leucovorin 200 mg/m² given over 120 min on day 1, followed by 5-FU 400 mg/m² bolus and then 2400 mg/m² infused over 46 h) in untreated metastatic colorectal cancer (mCRC).Patients and methodsIn this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1–6. Efficacy was a secondary objective.ResultsThirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n = 1), grade 4 neutropenia (n = 4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n = 1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5–79.7).ConclusionsThe MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.     

A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors

BackgroundAxitinib and bevacizumab are targeted therapies against the vascular endothelial growth factor pathway.MethodsPatients with previously treated solid tumors received axitinib (starting dose 5 mg twice daily) combined with FOLFOX plus bevacizumab (1, 2, or 5 mg/kg, cohorts 1–3, respectively), FOLFIRI (cohort 4), or FOLFOX (cohort 5). Safety and pharmacokinetics were assessed.ResultsThirty patients were enrolled (n = 16, 8, and 6 for cohorts 1–3, 4, and 5, respectively). Plasma concentrations and pharmacokinetic (PK) parameters were similar when drugs were administered alone and in various combinations. Most treatment-emergent adverse events (AEs) were mild to moderate and clinically manageable (most common: nausea, fatigue, diarrhea, anorexia, hypertension). Two of the four patients receiving axitinib with FOLFOX plus 5 mg/kg bevacizumab experienced dose-limiting toxicity (DLT) of inability to resume treatment for 14 days following treatment interruption (associated AE: hypertension); the maximum tolerated dose of bevacizumab in this combination was 2 mg/kg. No DLTs occurred with axitinib plus FOLFIRI or FOLFOX. Ten patients had RECIST-confirmed partial tumor responses (objective response rate: 33.3%).ConclusionAxitinib is well tolerated in combination with FOLFOX, FOLFIRI, or FOLFOX plus 2 mg/kg bevacizumab. PK interactions appear to be absent.     

Phase III randomised clinical trial comparing primary surgery versus neoadjuvant chemotherapy in advanced epithelial ovarian cancer with high tumour load (SCORPION trial): Final analysis of peri-operative outcome

ObjectiveTo establishing whether neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is superior primary debulking surgery (PDS) in terms of clinical outcome as well as peri-operative morbidity in advanced epithelial ovarian cancer (AEOC) endowed with high tumour load (HTL).Material and methodsThis is a single-Institution, superiority, randomised phase III trial enrolling supposed AEOC women. Patients considered pre-operatively eligible were triaged to staging laparoscopy to assess the predictive index (PI) of tumour load. All AEOC women with PI ≥ 8 or ≤ 12 (considered as HTL) were included. They were randomly assigned (1:1 ratio) to undergo either PDS followed by systemic adjuvant chemotherapy (arm A, standard), or NACT followed by IDS (NACT/IDS) (arm B, experimental). Co-primary outcome measures were postoperative complications (graded according to the Memorial Sloan Kettering Cancer Center surgical secondary events grading system) and progression free survival (PFS); secondary outcomes were overall survival, and quality of life (QoL). QoL was assessed using the EORTC QoL questionnaires. A sample size of 110 patients was required for the analysis of the first co-primary end-point (major peri-operative morbidity) whereas recruitment is still on-going to achieve the statistical power on PFS.ResultsBetween October 2011 and November 2014, we registered 280 AEOC. Of the 110 eligible women, 55 were assigned to arm A and 55 to arm B. Despite different extension of surgery, rates of complete residual disease (residual tumour = 0 cm) were superimposable between the groups (45.5% versus 57.7%; p = 0.206). Twenty-nine patients (52.7%) in arm A experienced early grade III–IV complications versus three patients (5.7%) in IDS (p = 0.0001). The most common complication was grade III and consisted of symptomatic pleural effusion requiring thoracic drainage (17/55 women (30.9%) in arm A versus 1/52 (1.9%) in arm B, p = 0.0001). Three grade IV (5.4%) (i.e., two re-operations for postoperative haemorrhage and one septic multi-organ failure), and two grade V (3.6%) (two deaths for acute cardiopulmonary failure) early complications were observed in arm A only.Mean QoL scores of several scales/items were shown to ameliorate over time in both arms. Emotional functioning, cognitive functioning, nausea/vomiting, dyspnoea, insomnia and hair loss were statistically and clinically better in NACT/IDS compared to PDS arm.ConclusionsPerioperative moderate/severe morbidity as well as QoL scores were shown to be more favourable in NACT/IDS arm than PDS in AEOC patients with very HTL. Completion of patient enrolment and analysis of survival data will clarify whether PDS with such a high rate of severe complications is an acceptable treatment in AEOC women with HTL.     

Phase I study of the HER3-targeted antibody patritumab (U3-1287) combined with erlotinib in Japanese patients with non-small cell lung cancer

ObjectivesHuman epidermal growth factor receptor 3 (HER3) is a key dimerization partner for HER family members and is associated with resistance to other HER family receptor-targeted therapeutics. This study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287), a fully human anti-HER3 monoclonal antibody, in combination with erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with previously treated advanced non-small cell lung cancer (NSCLC).Patients and methodsThis study enrolled patients with stage IIIB/IV NSCLC with Eastern Cooperative Oncology Group performance status 0–1, life expectancy >3 months and who had progressed after at least one prior course of chemotherapy (excluding erlotinib). This open-label study included two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, patients received intravenous patritumab 9 or 18 mg/kg every 3 weeks in addition to per-oral erlotinib 150 mg/day daily. In Part 2, patients received the recommended dose of patritumab as determined in Part 1. Adverse event rates, pharmacokinetics and tumor responses were determined.ResultsTwenty-four Japanese patients received patritumab at 9 mg/kg (n = 3) or 18 mg/kg (n = 21), and erlotinib. No dose-limiting toxicities were reported, indicating the maximum-tolerated dose was not reached. The most frequent adverse events were gastrointestinal or skin toxicities, which were generally mild and manageable. Patritumab pharmacokinetics were similar to those reported in previous studies. The median progression-free survival (95% confidence interval) was 44.0 (22.0–133.0) days for the EGFR wild-type group (n = 9) and 107.0 (74.0–224.0) days for the EGFR-activating mutation group (n = 13). Evaluation of biomarkers by immunohistochemical analysis did not indicate a relationship between efficacy and HER3 expression in tumor tissues.ConclusionPatritumab in combination with erlotinib was well tolerated and the efficacy of the combination was encouraging, especially in patients where prior gefitinib treatment failed.     

A phase I trial of LY2584702 tosylate,a p70 S6 kinase inhibitor,in patients with advanced solid tumours

BackgroundLY2584702 tosylate (hereafter referred to as LY2584702) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway which regulates cell proliferation and survival. LY2584702 exhibited anti-tumour activity in preclinical analysis.MethodsPatients with advanced solid tumours were treated with LY2584702 orally on a 28-day cycle until the criteria for maximum tolerated dose (MTD) were met. Skin biopsies were collected for pharmacodynamic analysis, and levels of phospho-S6 protein were examined. The primary objective was to determine a phase II dose and schedule with secondary objectives of observing safety and tolerability. Dose escalation was based upon Common Terminology Criteria for Adverse Events Version 3.0.ResultsThirty-four patients were enrolled onto this phase I study and treated with LY2584702 on a QD (once-daily) or BID (twice-daily) dosing schedule. Part A dose escalation (n = 22) began with 300 mg BID (n = 2). Due to toxicity, this was scaled back to doses of 25 mg (n = 3), 50 mg (n = 8), 100 mg (n = 3), and 200 mg (n = 6) QD. Part B dose escalation (n = 12) included 50 mg (n = 3), 75 mg (n = 3), and 100 mg (n = 6) BID. Seven patients experienced dose-limiting toxicity (DLT). All DLTs were Grade 3 and included vomiting, increased lipase, nausea, hypophosphataemia, fatigue and pancreatitis.ConclusionThe MTD was determined to be 75 mg BID or 100 mg QD. No responses were observed at these levels. Pharmacokinetic analysis revealed substantial variability in exposure and determined that LY2584702 treatment was not dose proportional with increasing dose.     

Venetoclax,bendamustine, and rituximab in patients with relapsed or refractory NHL: a phase Ib dose-finding study

BackgroundVenetoclax is a selective, potent inhibitor of the anti-apoptotic B-cell leukemia/lymphoma-2 protein approved for treatment of chronic lymphocytic leukemia. We conducted a dose-finding study of venetoclax in combination with bendamustine–rituximab (BR) in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL).Patients and methodsBR was given for six cycles at standard doses. Intermittent and continuous oral venetoclax administration was explored at 50–1200 mg daily doses. Co-primary objectives included safety, pharmacokinetics (PKs), maximum-tolerated dose (MTD), and recommended phase II dose (RP2D); secondary objective was preliminary efficacy.ResultsSixty patients were enrolled: 32 with follicular lymphoma, 22 with diffuse large B-cell lymphoma, and 6 with marginal zone lymphoma. Nausea (70%), neutropenia (68%), diarrhea (55%), and thrombocytopenia (52%) were the most frequent adverse events (AEs). Most common grade 3/4 AEs were neutropenia (60%) and lymphopenia (38%). Serious AEs were reported in 24 patients; the most frequent were febrile neutropenia and disease progression (8% each). Five patients died from either disease progression (n = 4) or respiratory failure (n = 1). MTD was not reached; RP2D for venetoclax-BR combination was established as 800 mg daily continuously. Venetoclax PK exposure with and without BR was comparable. For all patients, overall response rate was 65%. Median duration of overall response, overall survival, and progression-free survival was 38.3 months [95% confidence interval (CI) 10.4–NR], not yet reached, and 10.7 months (95% CI 4.3–21.0), respectively.ConclusionsThis study established the safety profile of venetoclax in combination with BR, and results demonstrated tolerability and preliminary efficacy of the combination. Additional follow-up is needed to better determine the future role of BR plus venetoclax in the treatment of relapsed/refractory B-cell NHL.Trial registeredClinicaltrials.gov, NCT01594229.     

First-line therapy for ovarian cancer with carboplatin followed by paclitaxel–gemcitabine (SCOTROC5): A feasibility study and comparative analysis of the SCOTROC series

BackgroundWe have conducted a series of four feasibility studies in stage Ic–IV ovarian cancer exploring six sequential first-line schedules with the same entry criteria in a total of 339 patients. Here we present the results of the sixth study, and an analysis of the overall series.MethodsIn this trial patients received 4 cycles of carboplatin AUC 7 every 3 weeks, followed by 4 cycles of concurrent paclitaxel 175 mg/m² (day 1) and gemcitabine 1000 mg/m² (days 1 and 8) every 3 weeks. The primary end-point of the trial was feasibility of administering all cycles of planned chemotherapy to >60% of patients.ResultsFifty-four patients were recruited to the trial between June 05 and June 06. A total of 40 (74.1%) patients received all 8 cycles of treatment. Reasons for early discontinuation included toxicity (n = 8) and disease progression (n = 4). The overall response rate was 73.7%, and the median progression free survival (PFS) was 14.2 months with a median follow-up of 24 months. A comparative analysis of all six regimens from the SCOTROC series suggests that the sequential schedule in which paclitaxel was given weekly (median PFS 19.5 m) is most effective.¹ConclusionThe sequential schedule explored in this trial is feasible, but comparative efficacy analysis suggests that trials involving weekly paclitaxel should be prioritised for further study.