Pharmacokinetic/pharmacodynamic modelling-based optimisation of administration schedule for the histone deacetylase inhibitor abexinostat (S78454/PCI-24781) in phase I

Abexinostat, an oral pan-histone deacetylase inhibitor (HDACi), was evaluated in patients with advanced solid tumours in two single agent phase I studies (PCYC-402 and CL1-78454-002). In PCYC-402 study testing four different administration schedules, the maximum tolerated dose (MTD) was established at 75 mg/m² BID (twice daily) and the recommended dose at 60 mg/m² BID regardless of the schedule tested. The dose limiting toxicity (DLT), consistently observed across all these schedules, was reversible thrombocytopenia.The CL1-78454-002 study was initially investigating an additional schedule of 14 days on/7 days off. While testing two first cohorts, thrombocytopenia was observed without reaching DLT. To address this issue, a pharmacokinetic/pharmacodynamic (PK/PD) model was used to predict the optimal schedule allowing higher doses with minimal thrombocytopenia. Several administration schedules were simulated using this model. A 4 days on/3 days off schedule was associated with the smallest platelet decrease. Accordingly, the CL1-78454-002 study was amended. After reaching MTD1 (75 mg/m² BID) with the initial schedule, subsequent cohorts received abexinostat on a revised schedule of 4 days on/3 days off, starting at one dose level below MTD1 (60 mg/m² BID). As expected, the dose-escalation continued for two more dose levels beyond MTD1. The MTD2 reached for this optimised schedule was 105 mg/m² BID and the recommended dose 90 mg/m² BID.In conclusion, early understanding of toxicities and PK determination allowed us to build a PK/PD model of thrombocytopenia, which predicted the optimal administration schedule. This optimised schedule is currently used in the trials in solid tumours with abexinostat.     

Phase I study of temozolomide combined with oral etoposide in children with recurrent or progressive medulloblastoma

BackgroundThe prognosis of recurrent or progressive medulloblastoma (MB) is still poor. This study was designed to investigate the potential therapeutic benefit of combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with progressive or relapsed MB. Given the oral administration of both drugs the regimen was administered outpatient.MethodsA phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by classical 3 + 3 design. Cohorts of patients were enrolled at four different levels: (1) TMZ 120 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (2) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (3) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–10; (4) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–12. Therapy was administered in 28-d courses. A total of 66 courses were administered to 14 patients with a median age of 5.7 years.ResultsNone of the 3 patients at dose levels 1 and 2 had dose-limiting toxicity (DLT). Of the 6 patients at dose level 3, 1 patient had DLT. At dose level 4, grade 4 thrombocytopaenia and neutropaenia were observed in the first 2 patients enrolled. Therefore, the MTD was established at dose level 3.ConclusionThe recommended phase II dose in children is TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–10 every 28 d. The combination was well tolerated and demonstrated antitumour activity.     

Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group

AimPatients with metastatic osteosarcoma (OS) have a poor outcome with conventional therapies. Zoledronic acid (ZA) is a third-generation bisphosphonate that reduces skeletal-related events in many adult cancers, and pre-clinical data suggest a possible benefit in OS. This study assessed the maximum tolerated dose (MTD) and the feasibility of ZA when combined with chemotherapy in patients with metastatic OS.Patients and MethodsPatients with a histological diagnosis of OS were eligible if they were <40 years of age, had initially metastatic disease and met organ function requirements. Treatment combined surgery and a conventional chemotherapy regimen. ZA was given concurrent with chemotherapy for a total of eight doses over 36 weeks. Three dose levels of ZA were tested: 1.2 mg/m² [max 2 mg], 2.3 mg/m² [max 4 mg] and 3.5 mg/m² [max 6 mg]. The MTD was determined during induction. Six patients were to be treated at each dose level, with an additional six patients treated with the MTD to help assess post-induction feasibility.ResultsTwenty-four patients (median age 13.5 years [range, 7–22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5 mg/m². DLTs included hypophosphatemia, hypokalemia, hyponatremia, mucositis, limb pain and limb oedema. There were no reports of excessive renal toxicity or osteonecrosis of the jaw. The MTD was defined as 2.3 mg/m² (max 4 mg).ConclusionsZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m² (max 4 mg) for patients with metastatic osteosarcoma.     

Maximum Tolerated Dose and Early Response — Results of a Phase I Trial of Paclitaxel and Cisplatin with Radiation Therapy in Carcinoma of the Cervix1

AimsCisplatin-based chemotherapy with radiotherapy is currently the standard treatment for locally advanced carcinoma of the cervix. Recent studies have shown a better response with the addition of newer chemotherapeutic agents. The aim of this phase I study was to establish the maximum tolerated dose (MTD) of paclitaxel in combination with cisplatin as a radiosensitiser along with radiation therapy in the treatment of carcinoma of the cervix and to analyse the toxicity profile of the combination regimen.Materials and methodsIn total, 21 newly diagnosed patients with squamous cell carcinoma of the cervix, International Federation of Gynecology and Obstetrics stage IB to IIIB were included in this trial. All patients received external beam radiation therapy to the pelvis (50 Gy in 25 fractions) delivered by conventional four-field box technique followed by low dose rate brachytherapy. Concurrent chemotherapy was administered with weekly cisplatin (30 mg/m²) and an escalating dose of weekly paclitaxel starting at 10 mg/m² up to 50 mg/m² (according to the modified Fibonacci series).ResultsThe MTD of weekly paclitaxel was found to be 40 mg/m². The dose-limiting toxicity that occurred in our patients at a dose of 50 mg/m² weekly paclitaxel was grade 3 proctitis and vaginitis.ConclusionIn this phase I trial of concurrent radiation and combination chemotherapy with weekly paclitaxel and cisplatin (30 mg/m²/week), the MTD of paclitaxel was found to be 40 mg/m². This combination was feasible, with an acceptable toxicity profile.     

Combined chemoradiotherapy with gemcitabine in patients with locally advanced inoperable transitional cell carcinoma of the urinary bladder and/or in patients ineligible for surgery: a phase I trial

BackgroundWe conducted a phase I trial of gemcitabine (gem) with concurrent radiotherapy in patients with muscle-invasive bladder cancer (BC) ineligible for surgery or cisplatin or refusing organ loss.Patients and methodsPatients with urothelial cancer, cT2-T4, cN0-1, M0, ineligible for surgery due to local tumor extension, PS, age or co-morbidities or who refused surgery were included. After maximal transurethral resection, the treatment schedule included: twice-weekly i.v. infusion of gem [dose levels (DL) 1–6: 20, 27, 30, 33, 50 and 40 mg/m², respectively] for 30 min and concurrent radiotherapy (RT) to the bladder with 55.5 Gy. The primary end point was to determine the maximum-tolerated dose (MTD) and the dose recommended (RD) for further studies of this gem schedule. The secondary end point was late toxicity. The MTD was defined by dose-limiting toxicity (DLT) in 2 or more of 6 patients, discontinuation of RT and/or gem for >1 week in 2 or more of 6 patients due to grade (G) 3/4 acute and/or late toxicity in more than 2 of 18 patients.ResultsThirty-five of 44 patients were assessable for toxicity and thus the primary end point. DLTs occurred in two of five patients at dose level 5: one G3 alanine aminotransferase elevation and one G3 fatigue. The MTD, therefore, was 50 mg/m² gem twice weekly. At DL 6 with 40 mg/m², the RD was established: only one of six patients developed G3 fatigue and diarrhea. Late toxicity was rare and of low grade (only G1-2). The 2-year locoregional failure rate was 32% (9/28); 10 of 28 patients (38%) were alive with an intact bladder and no evidence of recurrent disease, 9 patients developed distant metastases and 6 died of their disease.ConclusionsGemcitabine in combination with RT is well tolerated in BC patients ineligible for surgery and/or cisplatin. The RD of gemcitabine for subsequent trials is 40 mg/m² twice weekly with concurrent radiation.     

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 I clinical and pharmacokinetic study of trabectedin and cisplatin in solid tumours

Aim of the studyTo define the maximum tolerated dose (MTD) and toxicity of trabectedin (T) and cisplatin (C) given on days 1 and 8 every 3 weeks to adult patients with advanced solid tumours. Plasma pharmacokinetics at cycle 1 and a preliminary anti-tumour activity assessment in ovarian and non-small cell lung cancer (OC, NSCLC) were secondary objectives.MethodsIn the dose finding part (DFP) of the study the dose of T given at each administration was escalated by 100 μg/m² increments from 300 μg/m² up to the MTD, with a fixed dose of C of 40 mg/m². The recommended dose (RD) was assessed in the previously treated and untreated OC and NSCLC patients in the expansion of the RD (ERD) part of the study.T was administered with corticosteroids pre-medication as 3-h infusion and C as 30-min infusion.ResultsThirty-nine patients were treated in the DFP and 10 in the ERD. The MTD of T was 700 μg/m² due to dose-limiting neutropaenia and the RDs in the previously treated/untreated patients were 500 and 600 μg/m², respectively. Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%). Time to recovery from myelosuppression was dose-dependent and treatment could be repeated after ?4 weeks in the majority of patients at 600 μg/m². Confirmed partial responses were observed in 4 of 13 evaluable OC patients and in 1 with uterine leiomyosarcoma. No pharmacokinetic interaction was observed.ConclusionThe administration of T and C on days 1 and 8 resulted in prolonged neutropaenia requiring treatment delay. The evaluation of a single every 3 week schedule is worthwhile because of the hints of anti-tumour activity observed in OC.     

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.     

Phase I study of dose dense induction and consolidation with gemtuzumab ozogamicin and high dose cytarabine in older adults with AML

ObjectiveOlder adults with acute myeloid leukemia (AML) tend to have worse complete remission (CR) rates and overall survival compared to their younger counterparts. At least one reason for this is increased expression of the multidrug resistance gene (MDR1). Dose dense, high intensity chemotherapy may overcome the MDR1 effect, possibly when combined with anti-CD33 monoclonal antibody gemtuzumab ozogamicin (GO,Mylotarg?), which has been studied in older adults with relapsed AML. This phase I study was aimed at establishing safety by defining a maximum tolerated dose (MTD) by treating older AML patients with two cycles of dose-dense therapy with high dose cytarabine (HiDAC) combined with targeted therapy using GO.Materials and methodsNine patients ≥60 years with newly diagnosed, untreated CD33+ AML with adequate renal and hepatic function, and ECOG PS 0-2 were eligible. HiDAC was administered at two dose levels: 3000 mg/m² every 12 h for 6 doses (cohort 1), or 9 doses (cohort 2). GO was administered at 6 mg/m² on days 1 and 8.ResultsThe MTD was HiDAC 3000 mg/m² for six doses along with GO 6 mg/m². All patients had grades 3–4 pancytopenia, and two patients developed reversible grade 2 neurotoxicity. There were no cases of veno-occlusive disease. Seven of nine patients had a complete response (CR or CRp).ConclusionsThere was no difference in relapse-free survival in our patients when compared to historical data. However, despite high toxicity, two of nine patients treated in this dose-dense fashion remained in CR for > 60 months.     

Cabazitaxel in patients with advanced solid tumours: Results of a Phase I and pharmacokinetic study

BackgroundAlthough the taxanes paclitaxel and docetaxel are among the most active agents for the treatment of a wide range of cancers, tumours often develop resistance to these treatments. Cabazitaxel is a novel taxane active in both preclinical models of chemotherapy-sensitive and -resistant human tumours and patients with advanced prostate cancer that progressed following docetaxel treatment.AimTo establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel.Patients and methodsCabazitaxel was administered every 3 weeks to patients with advanced solid tumours. The design allowed intrapatient dose escalation. The primary objective was to determine the MTD. Secondary objectives were to describe the safety profile, establish an appropriate dose, determine the pharmacokinetic (PK) profile of cabazitaxel, and assess antitumour activity.ResultsTwenty-one patients were recruited. The MTD was reached at 30 mg/m², at which three of five patients experienced haematologic DLTs during the first cycle. DLTs during subsequent cycles were mainly haematologic and reported at 25 and 30 mg/m² dosing levels. Nail disorders and severe alopecia were not reported, and neurotoxicity, fluid retention and hypersensitivity were mild and infrequent. Cabazitaxel demonstrated linear PK, a triphasic elimination profile, with a long half-life and high clearance. Of the 19 patients evaluable for response, one unconfirmed partial response and six occurrences of stable disease were reported.ConclusionsThe 25 mg/m² dose of cabazitaxel was recommended for use in future clinical studies. In this study, cabazitaxel had an acceptable tolerability profile and activity in cervical, colorectal, endometrial and lung cancers.     

Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours

PurposeTo evaluate maximum tolerated dose and recommended dose (RD) for phase II studies of topotecan (TPT) combined with temozolomide (TMZ) (TOTEM) in children and adolescents with relapsed or refractory solid malignancies.Patients and methodsMulticentre, phase I study with a standard ‘3 + 3’ design in five dose increments. Eligible patients: aged 6 months to 21 years, diagnosis of a solid malignancy failed at least 2 previous lines of therapy. TMZ was administered orally, starting at 100 mg/m²/d, and TPT intravenously over 30 min, starting at 0.75 mg/m²/d over 5 consecutive days every 28 d. A pharmacokinetics analysis was performed on Day 1 and Day 5 of cycle 1.ResultsBetween February and October 2007, 16 patients were treated. The median age was 8.5 years (range, 3–19 years). Dose-limiting toxicity (grade 4 neutropenia and/or thrombocytopenia lasting more than 7 d) during the first cycle occurred in 2 of 3 patients at level 3 (TMZ 150 mg/m²/d and TPT 1.0 mg/m²/d) and was always manageable. Confirmed complete and partial responses were observed in 4 patients (25%), three with metastatic neuroblastoma and one with high-grade glioma. Seven patients had a stable disease. Pharmacokinetic data show a wide inter-individual variability. No significant differences were observed between plasma TMZ and TPT concentrations on Day 1 and Day 5 indicating the absence of pharmacokinetic interaction between the drugs.ConclusionsThe RD for the combination is TMZ 150 mg/m²/d and TPT 0.75 mg/m²/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies.     

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.     

Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study

BackgroundTrastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1 + docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1 + docetaxel ± pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC).Patients and methodsPhase Ib (part 1) explored dose escalation, with T-DM1 + docetaxel administered for greater than or equal to six cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered less than or equal to six cycles of T-DM1 + docetaxel or T-DM1 + docetaxel + pertuzumab. Phase IIa explored the MTDs identified in phase Ib.ResultsAdministered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m² in MBC. In LABC, the MTD was 100 mg/m² docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony-stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg) + pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m² with G-CSF support. Neutropenia was the most common grade 3–4 adverse event (AE; MBC, 72% and LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced AEs requiring dose modification. In MBC (median prior systemic agents = 5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3–93.2) and the median progression-free survival was 13.8 months (range, 1.6–33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1–71.5). Pharmacokinetic analyses indicated a low risk of drug–drug interaction between T-DM1 and docetaxel.ConclusionsT-DM1 combined with docetaxel ± pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced AEs requiring dose reductions with these T-DM1 combinations.ClinicalTrials.gov identifierNCT00934856.     

Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma

BackgroundPatients with severe depletion of skeletal muscle (sarcopenia) are prone to dose-limiting toxicity (DLT) during fluoropyrimidine therapy. We hypothesized that sarcopenia may also predict toxicity of targeted therapy drugs.Materials and methodsMetastatic renal cell cancer (RCC) patients (n = 55) received sorafenib 400 mg b.i.d. Weight, height and skeletal muscle cross-sectional area at the third lumbar vertebra were measured by computed tomography (CT). Toxicity was assessed.ResultsDLT occurred in 22% of patients overall, of which three-quarters were dose reductions to 400 mg and the remainder entailed termination of treatment. DLT was most common (41%) in sarcopenic patients whose body mass index (BMI) was <25 kg/m² and least common (13%) in patients who were not sarcopenic and/or overweight or obese (P = 0.03). Toxicity was especially prevalent in sarcopenic male patients with BMI < 25, with 71% of men with these characteristics being unable to continue treatment at 800 mg/day. By contrast, only 5% of male patients whose muscle index was above the cut-off for sarcopenia and only 11% of male patients whose BMI was >25 experienced a DLT.ConclusionBMI < 25 kg/m² with diminished muscle mass is a significant predictor of toxicity in metastatic RCC patients treated with sorafenib.     

Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor,in patients with advanced malignancies

AimPhase I study of seliciclib (CYC202, R-roscovitine), an inhibitor of cyclin-dependent kinases 2, 7 and 9, causing cell cycle changes and apoptosis in cancer cells.Patients and methodsThis phase I trial aimed at defining the toxicity profile, the maximum tolerated dose (MTD), the recommended phase II dose (RD) and the main pharmacokinetic and pharmacodynamic parameters of oral seliciclib. Three schedules were evaluated: seliciclib given twice daily for 5 consecutive days every 3 weeks (schedule A), for 10 consecutive days followed by 2 weeks off (schedule B) and for 3 d every 2 weeks (schedule C).ResultsFifty-six patients received a total of 218 cycles of seliciclib. Dose-Limiting Toxicities (DLT) consisting of nausea, vomiting, asthenia and hypokalaemia occurred at 1600 mg bid for schedule A and in schedule C, DLT of hypokalaemia and asthenia occurred at 1800 mg bid. The evaluation of longer treatment duration in schedule B was discontinued because of unacceptable toxicity at lower doses. Other adverse events included transient serum creatinine increases and liver dysfunctions. Pharmacokinetic data showed that exposure to seliciclib and its carboxylate metabolite increased with increasing dose. Soluble cytokeratin 18 fragments allowed monitoring of seliciclib-induced cell death in the blood of patients treated with seliciclib at doses above 800 mg/d. One partial response in a patient with hepatocellular carcinoma and sustained tumour stabilisations were observed.ConclusionsThe MTD and RD for seliciclib are 1250 mg bid for 5 d every 3 weeks and 1600 mg bid for 3 d every 2 weeks, respectively.     

Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy

BackgroundNeratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer.Patients and methodsPhase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m²; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR).ResultsIn phase I (n = 12), neratinib (240 mg) plus vinorelbine (25 mg/m²) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine.ConclusionNeratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients.Trial registrationClinicalTrials.gov #NCT00706030.     

Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexol®-PM) in patients with solid tumors

BackgroundThe aim of this study was to determine the maximum tolerated dose (MTD) and the pharmacokinetic profile of Genexol-PM in Asian cancer patients.Materials and methodsPatients (N = 24) refractory to previous chemotherapy received Genexol-PM as an 1-h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80 mg/m² and the maximum administered dose was 200 mg/m².ResultsThe majority of patients had lung, nasopharyngeal and breast cancers and in eleven patients (46%), taxane-based chemotherapy had previously failed. The MTD was defined at 180 mg/m². The most common grade 3 non-hematologic adverse events in cycle 1 were fatigue (4%) and neuropathy (4%) occurring mainly at 200 mg/m². Five (21%) patients had partial response, nine (38%) had stable disease and seven (29%) had disease progression. Five of 11 previously taxane-refractory patients showed clinical benefit to Genexol-PM. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both the maximum concentration (C_max) and the area under the concentration-time curve from zero to infinity (AUC_0–∞) increasing by approximately four- and threefold, respectively, as the dose of Genexol-PM was escalated from 80 to 200 mg/m². The median total-body clearance of Genexol-PM for all patients was 43.9 l/h.ConclusionThe weekly regimen of Genexol-PM was well tolerated and responses were observed in patients with refractory tumors, including patients who had failed taxane-based chemotherapy previously.     

A phase I dose-finding,safety and tolerability study of AZD8330 in patients with advanced malignancies

ObjectiveThis is the first clinical study of the MEK1/2 inhibitor AZD8330 (ARRY-424704). This phase I study defined the maximum tolerated dose (MTD) and assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8330 in patients with advanced malignancies.MethodsPatients with refractory cancer or cancer with no standard therapy received either once-daily (OD) or twice-daily (BID) oral AZD8330 on day 1 followed by a 7-day washout period and continuous dosing from day 8. The starting dose was 0.5 mg with dose escalations in subsequent cohorts until a non-tolerated dose was reached.ResultsEighty-two patients received AZD8330 across 11 cohorts. The most frequent AZD8330-related adverse events were acneiform dermatitis (13/82, 16%), fatigue (11/82, 13%), diarrhoea (11/82, 13%) and vomiting (9/82, 11%). Four patients experienced dose-limiting toxicities: mental status changes (40 mg OD; 2/9 patients and 60 mg OD; 1/3) and rash (20 mg BID; 1/9). The MTD was defined as 20 mg BID. AZD8330 exposure increased approximately proportionally with dose across the dose range 0.5–60 mg OD. Dose-dependent modulation of phosphorylated ERK in peripheral blood mononuclear cells (PBMCs) was observed at doses ?3 mg. One patient had a partial response and thirty-two (39%) had stable disease, with a duration >3 months in 22 patients, assessed by Response Evaluation Criteria in Solid Tumors.ConclusionAZD8330 has a manageable toxicity profile at the MTD of 20 mg BID, and target inhibition was confirmed in PBMCs. One patient with malignant melanoma had a partial response.     

Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours

BackgroundThe phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K-AKT-mTOR) signalling pathway is aberrantly activated in several cancers. Notch signalling maintains cell proliferation, growth and metabolism in part by driving the PI3K pathway. Combining the mTOR inhibitor ridaforolimus with the Notch inhibitor MK-0752 may increase blockade of the PI3K pathway.MethodsThis phase I dose-escalation study (NCT01295632) aimed to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of combination oral ridaforolimus (rising doses starting at 20 mg, 5 days/week) and oral MK-0752 (1800 mg once weekly) in patients with solid tumours. No intrapatient dose escalation was permitted.ResultsTwenty eight patients were treated on study. Ridaforolimus doses were escalated from 20 to 30 mg/day. Among 14 evaluable patients receiving ridaforolimus 20 mg, one DLT (grade 2 stomatitis, second episode) was reported. Among eight evaluable patients receiving ridaforolimus 30 mg, three DLTs were reported (one each grade 3 stomatitis, grade 3 diarrhoea, and grade 3 asthenia). The MTD was 20 mg daily ridaforolimus 5 days/week + 1800 mg weekly MK-0752. The most common drug-related adverse events included stomatitis, diarrhoea, decreased appetite, hyperglycaemia, thrombocytopenia, asthenia and rash. Two of 15 (13%) patients with head and neck squamous cell carcinoma (HNSCC) had responses: one with complete response and one with partial response. In addition, one patient experienced stable disease ⩾6 months.ConclusionsCombined ridaforolimus and MK-0752 showed activity in HNSCC. However, a high number of adverse events were reported at the MTD, which would require careful management during future clinical development.     

A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas

PurposeTo estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ?21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG.Patients and methodsThree strata were identified: stratum 1A – BSG; stratum IB – incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II – incompletely resected STMG receiving EIACD. Dose escalation using a modified 3 + 3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100 mg/m²/d commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients.ResultsOf the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100 mg/m²/d, 1 of 10 at 250 mg/m²/d and 3 of 12 at 375 mg/m²/d. Subsequently a second patient at 250 mg/m²/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage (p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples.ConclusionThis trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m²/d was selected for the phase II trial.