A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non–small cell lung cancer

AimThe phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non–small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC.Patients and methodsA 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1–14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination.ResultsAll 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a ‘14 days on, 7 days off’ schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients.ConclusionCombining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.     

Safety,tolerability and antitumour activity of LY2780301 (p70S6K/AKT inhibitor) in combination with gemcitabine in molecularly selected patients with advanced or metastatic cancer: a phase IB dose escalation study

BackgroundLY2780301, a dual inhibitor of protein kinase B (AKT) and the downstream effector p70 ribosomal protein S6 kinase (p70S6K), may inhibit progression in tumours relying on phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling pathway activation. This phase IB trial investigated the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, pharmacokinetics (PK) and antitumour activity of LY2780301 plus gemcitabine in patients with advanced/metastatic solid tumours.MethodsThis was a non-randomised, open-label, dose escalation and dose expansion trial. Patients harbouring molecular alterations of the PI3K/AKT/mTOR pathway received once daily (QD) oral LY2780301 (400 or 500 mg) in combination with intravenous gemcitabine (750 or 1000 mg/m²) on days 1, 8 and 15 of a 28-d cycle. Dose escalation followed a 3 + 3 design. Assessments included adverse events (AEs), PK and preliminary antitumour activity.ResultsFifty patients (median age, 53 years; 74% female) predominantly with mutations/amplifications of PI3K (60%) and phosphatase and tensin homologue (PTEN) gene/protein inactivation (42%) were treated for up to 14 cycles. The MTD was LY2780301 500 mg QD with gemcitabine 750 mg/m². DLTs during cycle 1 were grade IV thrombocytopenia, grade III skin rash and grade III increase in alkaline phosphatase, gamma glutamyltransferase and alanine aminotransferase, occurring in one patient each. Most common AEs were anaemia (84%), fatigue (84%), transaminase increase (74%), thrombocytopenia (74%), nausea/vomiting (70%), neutropenia (68%) and lymphopenia (56%). Among the efficacy-evaluable population, two patients (5%) had a partial response; the disease control rate was 74% at cycle 2.ConclusionsAddition of LY2780301 to gemcitabine showed manageable toxicity and encouraging antitumour activity in patients with molecular alterations of the PI3K/AKT/mTOR pathway.Clinical trial registration numberNCT02018874.     

PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer

BackgroundPhosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.Patients and methodsPIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.ResultsA total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug–drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57–92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12–51%]).ConclusionCombining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.Trial registration IDNCT01589861.     

A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer

BackgroundPoly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648).MethodsCediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed.Results28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia ?4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) >24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for >24 weeks.InterpretationThe combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients.     

Radiation Dose-escalated Chemoradiotherapy Using Simultaneous Integrated Boost Intensity-Modulated Radiotherapy for Locally Advanced Unresectable Thoracic Oesophageal Squamous Cell Carcinoma: A Single-institution Phase I Study

AimsAbout 80% of cases of locally advanced unresectable thoracic oesophageal squamous cell carcinoma recur within the irradiation fields after chemoradiotherapy. Radiation dose escalation using advanced radiotherapy techniques is expected to improve clinical outcomes by reducing local and regional recurrence. The current study aimed to determine the recommended escalated radiation dose for these patients.Materials and methodsPatients with locally advanced unresectable thoracic oesophageal squamous cell carcinoma with good performance status underwent chemoradiotherapy using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) with elective nodal irradiation. SIB-IMRT was delivered in five fractions per week. The radiation dose to the unresectable gross tumour was escalated from 66 Gy to a planned maximum dose of 72 Gy in 3 Gy increments in a standard 3 + 3 design. The doses to the resectable component, superficial tumours and elective nodal regions were fixed as 60, 51 and 48 Gy, respectively. Cisplatin and 5-fluorouracil were concurrently administered. Dose-limiting toxicity (DLT) was defined as acute grade 3 oesophagitis, grade 2 pneumonitis, grade 2 cardiac toxicity and a failure to complete planned radiotherapy within 60 days. Locoregional control and overall survival were estimated using the Kaplan–Meier method. Nine patients were enrolled.ResultsDLTs occurred in one of six and two of three patients at doses of 66 and 69 Gy, respectively. All DLTs were grade 3 oesophagitis. The recommended dose was determined as 66 Gy delivered in 30 fractions based on the predefined criteria. With a median follow-up period of 23 months, the 1-year locoregional control and overall survival rates were 67 (95% confidence interval = 19–90) and 78% (95% confidence interval = 36–94), respectively.ConclusionThe recommended radiation dose in chemoradiotherapy using SIB-IMRT with elective nodal irradiation was 66 Gy delivered in 30 fractions.     

A prospective trial of stereotactic body radiation therapy for unresectable pancreatic cancer testing ablative doses

BackgroundWe explored the safety and efficacy of ablative doses of stereotactic body radiation therapy (SBRT) for unresectable pancreatic cancer.MethodsThis phase I/II trial included patients with unresectable pancreatic cancer previously treated with any number of cycles of induction chemotherapy. Patients were enrolled according to a 3+3 dose escalation design at 10, 12.5, and 15 Gy ×3, with subsequent patients at the maximally tolerated dose (MTD). Treatment was delivered to gross tumor delineated with MRI fusion using image-guidance to fiducial markers. Dose-limiting toxicity (DLT) was defined as grade 3+ toxicity within 30 days. Secondary endpoints included late gastrointestinal (GI) toxicity, freedom from local failure (FFLF), and survival.ResultsFifteen patients received a median 10 cycles of chemotherapy. There were no DLTs, and the MTD was 15 Gy ×3. Thirty-day toxicity included grade 2 nausea (46%) and grade 2 diarrhea (7%). Median survival after SBRT was 12.8 months (23 months after diagnosis) and median relapse-free survival was 7 months. At 1-year, FFLF was 80%. Four patients had grade 3+ GI bleeding after 30 days (median 6 months). Grade 3+ GI bleeding was associated with tumor volume (P=0.01), heterogeneity of dose within the planning target volume (PTV) (V120, P=0.03), and duodenal dose (V26–30 Gy, P<0.2).ConclusionsThis aggressive SBRT regimen demonstrated limited 30-day morbidity, a moderate degree of local control, and a moderate risk for late GI bleeding. Further work is necessary to define the most appropriate hypofractionated radiation therapy (RT) regimen in the ablative dose range.     

A phase II trial of pemetrexed and gemcitabine as first line therapy for poor performance status and/or elderly patients with stage IIIB/IV non-small cell lung cancer

Pemetrexed and gemcitabine are both active agents for the treatment of locally advanced or metastatic NSCLC. We tested a novel biweekly combination of pemetrexed and gemcitabine for tolerability and efficacy in 45 elderly and/or poor performance status patients (44% female, mean age of 72.4 years) with measurable stage IIIB/IV NSCLC. Patients received biweekly cycles of pemetrexed 500 mg/m² IV over 10 min followed by gemcitabine 1500 mg/m² IV with vitamin B12 1000 μg IM, and folic acid 1 mg po daily beginning 7 days before and continuing throughout treatment (median of 4 cycles). Ten patients experienced grade 3/4 neutropenia, two had grade 3 febrile neutropenia, and two had grade 3 anemia. Patients with ECOG PS 2 appeared poorly suited for the regimen, with 61.5% completing ≤2 cycles. The overall response rate was 17.8%, the clinical benefit rate (CR + PR + SD >24 weeks) was 26.7%, and the median progression free survival was 3.5 months. However, ECOG 0–1 patients had longer PFS and tended to have a better response rate than ECOG 2 patients.     

Outcomes in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for maximal volume (PCI 39) appendiceal tumours

BackgroundHigher Peritoneal Cancer Index (PCI) requires more extensive surgery and maybe associated with more limited outcomes. The aim of this study in a high-volume centre in Australia was to analyse the outcomes in PCI 39 patients regarding short and long term outcomes in appendiceal tumours.MethodsA retrospective analysis of prospectively maintained database of patients that underwent primary cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) with PCI 39 at St George Hospital, Sydney from 1996 to 2018. Patients with appendiceal tumours (inclusive of high and low grade) were analysed. Factors contributing to high grade (III/IV Clavien-Dindo) morbidity and mortality were assessed.ResultsOf the 1201 patients in the database, 58 patients had a PCI 39 from appendix tumours at their first operation. The overall survival rate at 1, 3 and 5 year was 91.2%, 79.5% and 62.9% respectively. The median survival was 87.2 months (96% CI 51.8-NR). The rate of major morbidity was 71%. The postoperative mortality incidence was 1.7%. The median hospital length of stay was 34 days (IQR:27–54 days).ConclusionsIn an experienced centre CRS + HIPEC is safe in selected patients with PCI 39. Despite the high morbidity, the overall survival for appendiceal tumours appear considerably better than debulking surgery.     

A Phase I Trial of the PI3K Inhibitor Buparlisib Combined With Capecitabine in Patients With Metastatic Breast Cancer

Background

Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer.

A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer

BackgroundSRC plays an important role in the pathogenesis of metastatic breast cancer (MBC). In preclinical models, paclitaxel and the oral SRC inhibitor dasatinib showed greater antitumor activity than either agent. To determine the maximum tolerated dose of this combination, we conducted a phase I study.Patients and methodsPatients with MBC; Eastern Cooperative Oncology Group performance status of zero to one; normal hepatic, renal and marrow function were eligible. Paclitaxel 80 mg/m² was given 3 weeks of 4. The starting dasatinib dose was 70 mg and was increased, using a standard 3 + 3 dose-escalation scheme.ResultsFifteen patients enrolled (median age 54 years, range 35–74). No dose-limiting toxic effects (DLTs) occurred at dasatinib doses of 70–120 mg. One DLT (grade 3 fatigue) occurred in the dasatinib 150-mg cohort, which was expanded (six patients) with no further DLTs. However, due to cumulative toxic effects (rash, fatigue, diarrhea), the recommended phase II dose is dasatinib 120 mg. Of 13 assessable patients, a partial response was seen in 4 patients (31%), including 2 patients previously treated with taxanes; all received ≥120 mg dasatinib. An additional five patients (29%) had stable disease.ConclusionIn combination with weekly paclitaxel, the recommended phase II dose of dasatinib is 120 mg daily and preliminary activity has been seen in patients with MBC.     

Phase I dose‐escalation study of buparlisib (BKM120), an oral pan‐class I PI3K inhibitor,in Japanese patients with advanced solid tumors

Buparlisib (BKM120) is an oral pan‐phosphatidylinositol 3‐kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ and δ). This open‐label Phase I dose‐escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose‐limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first‐in‐man study of buparlisib in non‐Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment‐related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose‐proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non‐Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.     

Phase‐1 study of abiraterone acetate in chemotherapy‐naïve Japanese patients with castration‐resistant prostate cancer

Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration‐resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase‐1, open‐label and dose‐escalation study. Chemotherapy‐naïve Japanese CRPC patients (N = 27) received one of four AA daily doses (250 mg [n = 9], 500 mg [n = 6], 1000 [1 h premeal] mg [n = 6] and 1000 [2 h postmeal] mg [n = 6]) continuously through 28‐day treatment cycles. In the first cycle, AA monotherapy was given on days 1–7 for pharmacokinetics, and AA plus prednisone (5 mg twice daily) from days 8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut‐off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median t_max 2–3 h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day 8 regardless of the dose. At least 3 patients from each dose‐group experienced ≥50% prostate‐specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well‐tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000 mg oral dose under modified fasting conditions (at least 1 h premeal or 2 h postmeal). This study is registered at ClinicalTrials.gov : NCT01186484.     

Application of prolonged microdialysis sampling in carboplatin-treated cancer patients

Purpose  To determine the dose-limiting toxicity (DLT) and activity of combination with docetaxel and S-1 on unresectable gastric cancer. Patients and methods  Docetaxel was administered intravenously on day 1 and S-1 was administered orally on days 1–14, every 3 weeks. Doses of each drug in phase I study were docetaxel 60–75 mg/m² and S-1 60–80 mg/m². A phase II study was conducted with the recommended dose (RD) based on phase I. Results  Sixty-five patients (median age 54 years) were enrolled. The DLTs were neutropenia with fever or stomatitis. The RD was docetaxel 75 mg/m² and S-1 60 mg/m². Two patients (aged 66 and 64 years) developed septic shock during the initial part of phase II study. A phase I study at lower dose (docetaxel 60 mg/m² and S-1 80 mg/m²) was conducted for patients older than 60 years, and this dose was determined as the RD for these patients. In the phase II study, frequent grade 3/4 toxicities were neutropenia (47%) and febrile neutropenia (26%). The overall response rate was 50% (95% CI, 35–66%) and median survival was 15.3 months (95% CI, 10.0–20.6 months). Conclusions  Combination with docetaxel and S-1 was active against advanced gastric cancer and gave manageable toxicities. Supported in part by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (0412_CR01_0704_0001).     

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.     

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 – REGOLD

BackgroundRegorafenib significantly increases overall survival (OS) in patients with metastatic colorectal cancer previously treated but gives toxicities.Objectivesto assess the efficacy and safety of regorafenib at it's approved dose in the older population.Patients and methodsThis multicenter single-arm phase II enrolled patients ≥70 years old after the failure of fluoropyrimidine-based chemotherapy, anti-VEGF, and anti-EGFR treatment. The primary endpoint was disease control rate (DCR) 2 months after initiation of regorafenib (160 mg/day, 3 weeks on/1 week off).ResultsForty-three patients were enrolled, with a median age of 77 years. The 2 months DCR was 31.4% in the 35 evaluable patients. For the 42 patients that received at least one dose of regorafenib, median progression-free survival and OS were 2.2 and 7.5 months. The median time to autonomy degradation and quality of life degradation was 3.1 and 3.2 months, respectively. A grade 3–4 treatment-related adverse events was observed in 35/42 patients, notably: fatigue (45.2%), hand-foot skin reaction (19.0%), hypertension (21.4%), and diarrhea (7.1%). There is a trend to achieve DCR in patients ≤80 years and a trend to discontinue the study due to toxicity in patients with ECOG ≥1, over 80 years and with impaired baseline autonomy.ConclusionTreatment with regorafenib in pretreated patients ≥70 years is feasible and demonstrate similar efficacy that was observed in previous studies in young patients. Fatigue is the most frequent severe adverse event. However, caution should be taken for older patients with ECOG ≥1, over 80 years, and with impaired baseline autonomy.     

A phase II trial of frontline capecitabine and bevacizumab in poor performance status and/or elderly patients with metastatic colorectal cancer

ObjectivesThis study aims to determine the efficacy and tolerability of capecitabine (CAP) plus bevacizumab (BEV) as treatment for frontline metastatic colorectal cancer (mCRC) in frail and/or elderly patients.Materials and MethodsThis was an open label, multi-site, single arm, phase II study in frontline mCRC. In this study, patients (pts) who were frail (ECOG 2) or older patients with ECOG 1 performance status (PS) received CAP (1000 mg/m² bid, 14 days of every 21 days) plus BEV (7.5 mg/kg iv once every 21 days). The primary objective was progression free survival (PFS). Secondary objectives were overall response rate (ORR) and toxicity.ResultsIn terms of patients: 50 were enrolled; 5 withdrew consent prior to treatment; 45 were treated, and 41 were evaluable. The mean age was 75.9 (range 54–93) and 62% had an ECOG 2 PS. The median PFS was 6.87 months (95% CI, 5.1–11.5 months) and median overall survival was 12.7 months (95% CI, 6.9–12.7 months). The most common grades 3–4 toxicities were: diarrhea (17.8%), fatigue (13.3%), hand–foot syndrome (13.3%), dehydration (8.9%), hypertension (6.7%) and vomiting (6.7%).ConclusionsThe results of this trial support the use of CAP plus BEV as first-line treatment for frail/elderly patients with metastatic CRC. The ORR (40%) is comparable to pooled data in elderly on fluorouracil (5-FU) + BEV. The median PFS (7.2 months) in this study is slightly lower than that seen with 5-FU + BEV but this study had a high percentage of ECOG PS 2 patients. Side effects were manageable with no new safety signals.     

Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer

BackgroundPhosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, pan-class I PI3 kinase inhibitor.MethodsThis was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel. The primary end-point was the rate of radiographic/clinical progression-free survival (PFS) at 6 months.ResultsThirty men were accrued: 67% post-docetaxel; median prostate specific antigen (PSA) was 70 ng/dl, 83% had ≥4 prior therapies for mCRPC; 43% received concurrent enzalutamide. The final 6 month PFS rate was estimated to be 10% (95% confidence interval 2.5–23.6%). Median PFS was 1.9 months and was 3.5 months with concurrent enzalutamide. Median overall survival was 10.6 months. Concurrent enzalutamide led to a five-fold reduction in buparlisib concentrations. PSA declines were observed in 23%; no patients achieved a ≥50% decline, and no radiographic responses were observed. Severe adverse events occurred in four men including respiratory infection and multi-organ failure, urinary tract obstruction, confusion and one seizure in the setting of a new central nervous system (CNS) metastasis. Grade III adverse events were seen in 43% of patients; common toxicities included grade I–II weight loss, diarrhoea, nausea, fatigue, anorexia, rash, hyperglycemia and anxiety/mood disorders.ConclusionsBuparlisib did not demonstrate significant activity in men with mCRPC, suggesting that PI3K inhibition is not sufficient to reverse resistant mCRPC progression. Future studies of PI3K pathway inhibitors with concurrent enzalutamide should develop optimal dosing and focus on selected patients more likely to benefit.     

Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer

To determine the feasible dose and schedule for everolimus, an oral mTOR inhibitor, combined with vinorelbine and trastuzumab for patients with HER2-overexpressing metastatic breast cancer pretreated with trastuzumab. In this phase Ib multicenter, Bayesian dose-escalation study, 50 patients received everolimus 5 mg/day, 20 mg/week, or 30 mg/week plus vinorelbine (25 mg/m² on day 1 and 8 every 3 weeks) and trastuzumab (2 mg/kg weekly). Endpoints included end-of-cycle-1 dose-limiting toxicity (DLT) rate (primary endpoint), safety, relative dose intensity, overall response rate (ORR), and pharmacokinetics. Grade 3/4 neutropenia was the most common end-of-cycle-1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg/day and 30 mg/week cohorts, respectively. Other end-of-cycle-1 DLTs included single cases of febrile neutropenia, grade 3 stomatitis with concomitant fatigue, grade 2 stomatitis, grade 3 anorexia, and grade 2 acneiform dermatitis, all in the 5-mg/day cohort. Based on the recorded DLTs and global safety, everolimus 5 mg/day and 30 mg/week were chosen as the optimal dose levels for the daily and weekly arms. Forty-seven patients were evaluable for efficacy. ORR was 19.1%, with a disease control rate of 83.0% and median progression-free survival of 30.7 weeks. No drug interaction was observed between everolimus and vinorelbine. Everolimus combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with HER2-overexpressing metastatic breast cancer that progressed on trastuzumab (NCT00426530).     

An European Organisation for Research and Treatment of Cancer phase I study of lapatinib and docetaxel as neoadjuvant treatment for Human Epidermal Growth Factor Receptor 2 (HER2) positive locally-advanced/inflammatory or large operable breast cancer

BackgroundLapatinib is an effective anti-HER2 therapy in advanced breast cancer and docetaxel is one of the most active agents in breast cancer. Combining these agents in pre-treated patients with metastatic disease had previously proved challenging, so the primary objective of this study aimed to determine the maximum tolerated dose (MTD) in treatment-naive patients, by identifying acute dose-limiting toxicities (DLT) during cycle 1 in the first part of a phases 1–2 neoadjuvant European Organisation for Research and Treatment of Cancer (EORTC) trial.Patients and methodsPatients with large operable or locally-advanced HER2 positive breast cancer were treated with continuous lapatinib, and docetaxel every 21 days for 4 cycles. Dose levels (DLs) were: 1000/75, 1250/75, 1000/85, 1250/85, 1000/100 and 1250/100 (mg/day)/(mg/m²).ResultsTwenty-one patients were included. Two DLTs occurred at dose level 5 (1000/100); one grade 4 neutropenia ?7 days and one febrile neutropenia. A further 3 patients were therefore treated at the same dose with prophylactic granulocyte-colony stimulating factor (G-CSF), and 3 patients at dose level 6. No further DLTs were observed.ConclusionsOur recommended dose for phase II is lapatinib 1000 mg/day and docetaxel 100 mg/m² with G-CSF in HER2 positive non-metastatic breast cancer. The dose of lapatinib should have been 1250 mg/day but we were mindful of the high rate of treatment discontinuation in GeparQuinto with lapatinib 1250 mg/day combined with docetaxel. No grade 3-4 diarrhoea was observed. Pharmacodynamics analysis suggests that concomitant medications altering P-glycoprotein activity (in addition to lapatinib) can modify toxicity, including non-haematological toxicities. This needs verification in larger trials, where it may contribute to understanding the sources of variability in clinical toxicity and treatment discontinuation.