A phase I, randomized, open-label study of the multiple-dose pharmacokinetics of vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma

Purpose

This study characterized the multiple-dose pharmacokinetics of vemurafenib 240–960 mg twice daily (bid) in BRAF ^V600E mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets).

Methods

Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2.

Results

Vemurafenib concentration increased with multiple doses to steady state at day 15; C _max, AUC_0–8h, and AUC_0–168h increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240–960 mg bid. Day 15 mean accumulation ratios (ratio of AUC_0–8h on day 15/AUC_0–8h on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration–time profile throughout the bid dosing interval. During dose interruption (days 15–22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5–38.4 h.

Conclusions

Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C _max) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.     

Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors

Purpose

The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites.

Methods

In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day.

Results

Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration–time curve 24 h post-dose (AUC_(0–24)) and mean maximum observed concentration (C _max) of pazopanib increased by 66 and 45 %, respectively; mean AUC_(0–24) and C _max for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC_(0–24) and C _max decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased.

Conclusions

Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.     

A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy

Purpose

We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).

Methods

Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients.

Results

Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels ?1 and ?2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation ≥50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment.

Conclusions

The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.     

Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours

Purpose

To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours.

Methods

In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib.

Results

In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C _ss,max, 36 for AUC_ss. gMean AUC_ss and C _ss,max for cediranib 20 mg increased by 21 % (94 % CI 9–35 %) and 26 % (94 % CI 10–43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C _ss,max and 41 for AUC_ss. gMean AUC_ss and C _ss,max for cediranib 45 mg decreased by 39 % (90 % CI 34–43 %) and 23 % (90 % CI 16–30 %), respectively, in the presence of rifampicin. gMean ratios for AUC_ss and C _ss,max were >1 for ketoconazole and <1 for rifampicin and CIs were outside the pre-specified equivalence boundaries, indicating a statistically significant effect. Significant inter-patient variability in cediranib AUC_ss and C _ss,max was observed. The safety profile of cediranib was similar to that reported previously.

Conclusions

Co-administration of ketoconazole or rifampicin had statistically significant effects on steady-state pharmacokinetics of cediranib in patients with advanced solid tumours. Therefore, caution is advised when administering cediranib with potent enzyme inhibitors or inducers.     

Phase 1 first-in-human clinical study of S-trans, trans-farnesylthiosalicylic acid (salirasib) in patients with solid tumors

Purpose

This phase I first-in-human trial evaluated salirasib, an S-prenyl derivative of thiosalicylic acid that competitively blocks RAS signaling.

Methods

Patients with advanced cancers received salirasib twice daily for 21 days every 4 weeks. Doses were escalated from 100 to 200, 400, 600, and 800 mg.

Results

The most common toxicity was dose-related diarrhea (Grade 1–2, 79% of 24 patients). Other toxicities included abdominal pain, nausea, and vomiting. No Grade 3–4 toxicity was noted. Nineteen (79%) patients had no drug-related toxicity >Grade 1. Dose-limiting toxicity (DLT) was not reached, but all three patients treated with 800 mg experienced Grade 1–2 diarrhea, abrogating dose escalation. Six patients were treated at a dose of 600 mg with no DLTs. Seven (29%) patients had stable disease on salirasib for ≥4 months (range 4–23+). The salirasib pharmacokinetic profile was characterized by slow absorption and a rapid elimination phase following oral administration. Salirasib exposure (C _max; day 1 AUC_inf vs. day 15 AUC_0–12 h) was similar between days 1 and 15 (P > 0.05). The T _1/2 (mean ± SD) was 3.6 ± 2.2 h on day 1.

Conclusions

Salirasib therapy was well tolerated. The recommended dose for phase II studies is 600 mg twice daily.     

Effects of famotidine or an antacid preparation on the pharmacokinetics of nilotinib in healthy volunteers

Purpose

This study evaluated the effects of either famotidine or antacid on the pharmacokinetics of nilotinib in healthy subjects, with the specific focus to explore different dosing separation schemes leading to a minimized drug–drug interaction.

Methods

Fifty-two subjects were randomized to receive the following treatments in a crossover manner: (A) single oral nilotinib 400 mg alone; (B) famotidine 20 mg twice a day for 3 days, followed by a single administration of nilotinib 400 mg and famotidine 20 mg on Day 4, where famotidine was given 2 h after nilotinib; (C) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h before nilotinib; (D) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h after nilotinib.

Results

Comparing Treatment B to Treatment A, the geometric mean ratios of nilotinib C _max, AUC_0-tlast, and AUC_0-inf were 0.966, 0.984, and 0.911, respectively (90 % confidence intervals (CIs), 0.875–1.066, 0.905–1.069, and 0.798–1.039, respectively). Nilotinib pharmacokinetic parameters following Treatment C or Treatment D were similar to those after Treatment A; the corresponding 90 % CIs of the geometric mean ratios of C _max, AUC_0-tlast, and AUC_0-inf all fell within the bioequivalence range of 0.8–1.25.

Conclusions

Neither famotidine nor antacid significantly affected nilotinib pharmacokinetics. When concurrent use of an H2 blocker or an antacid is necessary, the H2 blocker may be administered 10 h before and 2 h after nilotinib dose, or the antacid may be administered 2 h before or 2 h after nilotinib dose.     

A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation

Purpose

We undertook a phase I/II study of the EGFR/erbB2 inhibitor lapatinib in patients with recurrent glioblastoma multiforme (GBM) to determine response rate, pharmacokinetics (PK) and recommended dose in patients taking enzyme-inducing anti-epileptic drugs (EIAEDs) and to explore relationships of molecular genetics to outcome.

Methods

Recurrent GBM patients taking EIAEDs were enrolled on the phase I portion (starting dose of lapatinib 1,000 mg po bid). In the absence of dose-limiting toxicity (DLT), escalation continued in cohorts of three patients. Patients not on EIAEDs enrolled in the phase II arm (lapatinib 750 mg bid po). Immunohistochemical and quantitative RT PCR studies were performed on tumor to determine PTEN and EGFRvIII status, respectively. Lapatinib PK was analyzed using HPLC with tandem mass spectrometry.

Results

Phase II: Of 17 patients, 4 had stable disease and 13 progressed. Accrual ceased because of no responses. Phase I: Four patients received 1,000 mg bid and three, 1,500 mg bid. No DLT occurred, but escalation stopped because of lack of phase II efficacy. Lapatinib apparent oral clearance in patients taking EIAEDs was 106.9 L h^?1 m^?2 in comparison to 12.1 L h^?1 m^?2 in those not on EIAEDs. In 16 phase II patients, PTEN loss was seen in 6 and EGFRvIII expression in 4. No correlation was seen with outcome and molecular results.

Conclusions

Lapatinib apparent oral clearance increased by approximately tenfold when given with EIAEDs. In this small sample, EGFRvIII expression and PTEN loss did not predict a favorable subtype. Overall, lapatinib did not show significant activity in GBM patients.     

The effect of rifampicin,a prototypical CYP3A4 inducer,on erlotinib pharmacokinetics in healthy subjects

Purpose

Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine is approved for the treatment for non-small cell lung cancer and pancreatic cancer. Because erlotinib is metabolized predominately by CYP3A4, co-administration of compounds that increase CYP3A4 activity may alter the efficacy and safety of erlotinib therapy. Two phase I studies were conducted in healthy male subjects to evaluate the effect of pre- or co-administered rifampicin, a CYP3A4 inducer, on the pharmacokinetics of erlotinib.

Methods

Study 1 included Groups A (erlotinib 150 mg days 1 and 15, rifampicin 600 mg days 8–14) and B (erlotinib 150 mg days 1 and 15) in a parallel group study design. Study 2 subjects received erlotinib 150 mg day 1, erlotinib 450 mg day 15, and rifampicin 600 mg days 8–18. The primary endpoint in each study was the ratio of exposure (AUC_0–∞ and C _max) between days 1 and 15. Urinary cortisol metabolic induction ratios were determined in Study 1 for Group A subjects only.

Results

In Study 1, the geometric mean ratios of AUC_0–∞ and C _max were 33 and 71 %, respectively, and the mean cortisol metabolic index increased from 7.4 to 27.0, suggesting cytochrome P450 (CYP) enzyme induction. In Study 2, the geometric mean ratios for AUC_0–∞ and C _max were 19 and 34 % (when dose adjusted from 450 to 150 mg erlotinib), respectively, a greater relative decrease than observed in Study 1.

Conclusions

Erlotinib exposure (AUC_0–∞ and C _max) was reduced after pre- or concomitant dosing with rifampicin. Doses of ≥450 mg erlotinib may be necessary to compensate for concomitant medications with strong CYP3A4 enzyme induction effect.     

Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer

Purpose

To translate promising preclinical data on the combination of vorinostat and ixabepilone for metastatic breast cancer (MBC) into clinical trials.

Methods

We conducted a randomized two-arm Phase IB clinical trial of ascending doses of vorinostat and ixabepilone in prior -treated MBC patients. To determine the maximum tolerated dose (MTD), 37 patients were randomized to schedule A: every-3-week ixabepilone + vorinostat (days 1–14), or schedule B: weekly ixabepilone + vorinostat (days 1–7; 15–21) Pharmacokinetics were assessed. Nineteen additional patients were randomized to schedule A or B and objective response rate (ORR), clinical benefit rate (CBR), toxicity, progression-free survival (PFS), and overall survival (OS) were assessed.

Results

The schedule A MTD was vorinostat 300 mg daily (days 1–14), ixabepilone 32 mg/m² (day 2); 21-day cycle 27% dose-limiting toxicities (DLTs). The schedule B MTD was vorinostat 300 mg daily (days 1–7; 15–21), ixabepilone 16 mg/m² (days 2, 9, 16); 28-day cycle; no DLTs. Vorinostat and ixabepilone clearances were 194 L/h and 21.3 L/h/m², respectively. Grade 3 peripheral sensory neuropathy was reported in 8% (A) and 21% (B) of patients. The ORR and CBR were 22 and 22% (A); 30 and 35% (B). Median PFS was 3.9 (A) and 3.7 (B) months. OS was 14.8 (A) and 17.1 (B) months.

Conclusions

We established the MTD of vorinostat and ixabepilone. This drug combination offers a novel therapy for previously treated MBC patients. The potential for lower toxicity and comparable efficacy compared to current therapies warrants further study.

     

Comparison of pharmacokinetics and safety profiles of two capecitabine tablet formulations in patients with colon, colorectal or breast cancer

Purpose

The objective of this study was to compare the pharmacokinetics and safety of two tablet formulations containing 500 mg of capecitabine (CAS number 154361-50-9) in patients with colon, colorectal or breast cancer.

Methods

The study was a multicentric, open label, randomized, two-treatment, two-period, two-sequence, single dose, crossover bioequivalence study in patients of either sex with colon, colorectal or breast cancer. Eligible patients received each treatment in a crossover manner under fed conditions according to the randomization schedule. The pre-dose blood sample was taken within 90 min prior to dosing, and serial blood sampling was done up to 10.00 h post-dose under monochromatic light. The analysis of plasma samples for concentrations of capecitabine and 5′-deoxy-5-fluorocytidine (5′-DFCR) was carried out using a validated liquid chromatography mass spectrometry method. Bioequivalence was to be concluded if the confidence intervals so constructed were within the range of 80–125 % for C_max, AUC_0?t and AUC_0?∞ of capecitabine and 5′-DFCR. Patients were monitored for safety and tolerability throughout the study.

Results

The 90 % confidence intervals for the “test/reference” mean ratios of the ln-transformed pharmacokinetic variables C_max, AUC_0?t and AUC_0?∞ were clearly within the conventional bioequivalence range of 80–125 %. Both the formulations were reasonably tolerated after a single oral dose in patients.

Conclusions

Both the capecitabine tablet formulations demonstrated equivalent rate and extent of systemic absorption, and hence were considered bioequivalent. Therefore, the two formulations can be considered as equivalent in terms of pharmacokinetics and safety profiles.     

Phase I and pharmacokinetic study of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, by twice daily oral administration between meals in patients with advanced solid tumors

Purpose

A single-agent dose-escalating phase I and pharmacokinetic study on TSU-68, a novel multiple receptor tyrosine kinase inhibitor, was performed to determine the safety profile, maximum-tolerated dose for Japanese patients with advanced solid tumors and to define the recommended dose of phase II studies.

Methods

Study design was a dose escalation method on a three-patient cohort. TSU-68 was given orally twice daily (bid) between meals without interruption; the estimation of dose escalation was based on the toxicity within 4?week administration at each dose level.

Results

Fifteen patients were enrolled into the study. Dose levels studied were 200, 400, 800, and 1,200?mg/m² bid. Grade 3 arrhythmia and anemia/thrombocytopenia were observed in 1 patient each at 800?mg/m² bid. Three patients discontinued continuous oral administration for 4?weeks at 400 and 800?mg/m² bid. At 1,200?mg/m² bid, 2 patients discontinued the treatment over 4?weeks for intolerable fatigue and abdominal pain, respectively. No serious drug-related toxicities have been observed. Grade 1?C2 toxicity included urinary/feces discoloration, diarrhea, fatigue, anorexia, abdominal/chest pain, and edema. Tumor shrinkage was observed in 1 patient of NSCLC. In the pharmacokinetics, at any dose levels, C_max and AUC_0?Ct after repeated administration of TSU-68 on days 8 and 29 were ~2-fold lower that those after the first administration on day 1; these parameters are similar between days 8 and 28. In addition, no obvious dose-dependent increase in plasma exposure to TSU-68 repeatedly administered was observed over the four dose levels, including the higher dose levels.

Conclusions

The tolerable dose in this administration schedule for continuing treatment is thought to be 800?mg/m² or less bid.     

Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies.

PURPOSE: The primary objective of this study was to determine the recommended phase II doses of the novel histone deacetylase inhibitor vorinostat when administered in combination with carboplatin and paclitaxel. EXPERIMENTAL DESIGN: Patients (N = 28) with advanced solid malignancies were treated with vorinostat, administered orally once daily for 2 weeks or twice daily for 1 week, every 3 weeks. Carboplatin and paclitaxel were administered i.v. once every 3 weeks. Doses of vorinostat and paclitaxel were escalated in sequential cohorts of three patients. The pharmacokinetics of vorinostat, its metabolites, and paclitaxel were characterized. RESULTS: Vorinostat was administered safely up to 400 mg qd or 300 mg bd with carboplatin and paclitaxel. Two of 12 patients at the 400 mg qd schedule experienced dose-limiting toxicities of grade 3 emesis and grade 4 neutropenia with fever. Non-dose-limiting toxicity included nausea, diarrhea, fatigue, neuropathy, thrombocytopenia, and anemia. Of 25 patients evaluable for response, partial responses occurred in 11 (10 non-small cell lung cancer and 1 head and neck cancer) and stable disease occurred in 7. Vorinostat pharmacokinetics were linear over the dose range studied. Vorinostat area under the concentration versus time curve and half-life increased when vorinostat was coadministered with carboplatin and paclitaxel, but vorinostat did not alter paclitaxel pharmacokinetics. CONCLUSIONS: Both schedules of vorinostat (400 mg oral qd x 14 days or 300 mg bd x 7 days) were tolerated well in combination with carboplatin (area under the concentration versus time curve = 6 mg/mL x min) and paclitaxel (200 mg/m(2)). Encouraging anticancer activity was noted in patients with previously untreated non-small cell lung cancer.     

A phase IB dose-finding trial of liposomal doxorubicin in combination with capecitabine in patients with pretreated metastatic breast cancer

Purpose

Anthracyclines and fluoropyrimidines are very active in breast cancer, while liposomal doxorubicin has low cardiotoxicity. We conducted a dose-finding study of the combination of liposomal doxorubicin and capecitabine in patients with pretreated metastatic breast cancer.

Patients and methods

Patients received liposomal doxorubicin 60 mg/m² on day 1 plus capecitabine 825 mg/m² bid (level 0) or 1,000 mg/m² bid (level 1) on days 1–14 of each 21-day cycle to establish the maximum tolerated dose (MTD) and cardiac safety.

Results

Nine patients were enrolled and a total of 52 courses were delivered (median 6 cycles per patient [range 4–7]). Grade 4 neutropenia occurred in 15% of cycles, with one episode of febrile neutropenia; most nonhematological toxicities were mild or moderate. No formal MTD was established, and the study was closed because two cardiac events were observed at dose level 1 and another at dose level 0 in patients pretreated with epirubicin ≥ 560 mg/m².

Conclusions

The recommended dose for phase II studies is liposomal doxorubicin 60 mg/m² on day 1 plus capecitabine 825 mg/m²/bid on days 1–14 of each 21-day cycle. Despite the lower cardiotoxicity of liposomal doxorubicin, the risk of cardiac damage persists in anthracycline-pretreated individuals and mandates close cardiac monitoring and careful evaluation of the overall cumulative dose.     

A phase I study of sorafenib in combination with S-1 plus cisplatin in patients with advanced gastric cancer

Background

Sorafenib inhibits several receptor tyrosine kinases involved in tumor progression and angiogenesis. S-1, an oral fluorouracil antitumor drug, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase I study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP.

Methods

Patients with histologically confirmed previously untreated AGC were evaluated for eligibility and treated with sorafenib (400 mg bid, days 1–35), S-1 (40 mg/m² bid, days 1–21), and CDDP (60 mg/m², day 8). Treatment was continued until disease progression or unacceptable toxicity. Pharmacokinetics for sorafenib, 5-FU, and CDDP were investigated in cycle 1.

Results

Thirteen patients were enrolled and received at least one dose of the study treatment. No specific or serious adverse event was newly reported in this study. Five patients had partial response and 8 had stable disease as the best response. Pharmacokinetic analysis showed no significant differences in the exposures of sorafenib when administered alone or in combination with S-1 and CDDP.

Conclusions

The present phase I study demonstrates the acceptable toxicity and preliminary efficacy of combined treatment with S-1, CDDP, and sorafenib.     

Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors

Purpose

To describe the pharmacokinetics of orally administered ABT-751 and its conjugated metabolites in children with neuroblastoma and other solid tumors and to relate pharmacokinetic parameters to toxicity and therapeutic outcomes.

Methods

Patients (median age, 11 years) with neuroblastoma (n = 37) or other solid tumors (n = 25) had pharmacokinetic sampling after the first dose of ABT-751 (75–250 mg/m²/day) on a 7-day or 21-day schedule. ABT-751 and its glucuronide and sulfate metabolites were quantified with an HPLC/MS/MS assay. Pharmacokinetic parameters were derived with non-compartmental methods. The relative bioavailability of more water soluble capsule and suspension formulations was assessed.

Results

ABT-751 peaked in plasma at 2 h and declined monoexponentially with a t _1/2 of 5.1 h. The apparent clearance was 33 ml/min/m² and was age-independent. The AUC_0–∞ increased in proportion to the dose, and at 200 mg/m² the median AUC_0–∞ was 91 mcg h/ml and the C _ave was 3.9 mcg/ml. Inter-and intra-patient variability was low. The metabolites were detected in plasma 30 min post-dose and peaked 3–5 h after the dose. The glucuronide:sulfate molar AUC_0–∞ ratio was 0.57. Less than 1% of the dose was excreted in urine as parent drug; 13% of the dose was excreted as sulfate metabolite and 10% as glucuronide metabolite. The relative bioavailability of the water soluble capsule and suspension formulations was 105 and 93%, respectively. AUC_0–∞ was higher in patients experiencing dose-limiting toxicity.

Conclusions

Oral ABT-751 pharmacokinetics was dose-proportional and age-independent with minimal intra- and inter-patient variability in children.     

Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma

Purpose

To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies.

Methods

Using a 3 + 3 dose-escalation design, patients received oral sunitinib (37.5 or 50 mg) qd on a continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off treatment) plus pemetrexed (400 or 500 mg/m² IV) and cisplatin (75 mg/m² IV) q3w up to 6 cycles.

Results

Sunitinib 37.5 mg/pemetrexed 400 mg/m²/cisplatin 75 mg/m² CDD (n = 5) was not tolerated. Lower doses on this schedule were not explored. The Schedule 2/1 MTD (n = 15) was sunitinib 37.5 mg/pemetrexed 500 mg/m²/cisplatin 75 mg/m², based on one dose-limiting toxicity (myocardial infarction) out of six patients. The MTD was further studied in an expansion cohort of 10 non-small cell lung cancer (NSCLC) patients and one mesothelioma patient. There were no clinically significant drug–drug interactions. Cumulative myelosuppression was problematic: the median relative dose intensity (% actual/intended) across all cycles was 61 % for sunitinib, 78 % for pemetrexed, and 74 % for cisplatin. Four of eight NSCLC patients in the dose-escalation and expansion cohorts at the Schedule 2/1 MTD who were evaluable for efficacy had stable disease ≥8 weeks, and the one patient with mesothelioma had a partial response.

Conclusions

In patients with advanced solid malignancies, sunitinib was not tolerated at 37.5 mg CDD with standard pemetrexed and cisplatin doses. Dose reductions were often needed due to cumulative myelosuppression following cycle 1. The MTD showed modest antitumor activity.     

Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects

Purpose

This study evaluated the effects of chronic hepatic impairment on the single-dose pharmacokinetics (PK) of the tyrosine kinase inhibitor ponatinib.

Methods

Subjects (n = 16) had Child-Pugh class A (mild, n = 6), B (moderate, n = 6), or C (severe, n = 4) hepatic impairment and were matched with healthy controls (n = 8). Each subject received a single oral dose of ponatinib 30 mg under fasting conditions, and PK parameters were assessed in blood samples collected through 96 h post-dose.

Results

Ponatinib maximum plasma concentrations (C _max) were observed after 5–6 h in Child-Pugh A, Child-Pugh B, and healthy subjects, and after ~3 h in Child-Pugh C subjects. The estimated  % geometric mean ratios for C _max, area under the plasma concentration–time curves from time zero to last observation (AUC_0–t ) and to infinity (AUC_0–∞) suggested a slightly lower exposure in Child-Pugh B (61.4, 89.1, and 90.6 %, respectively) and Child-Pugh C subjects (62.8, 77.1, and 79.4 %) versus healthy subjects. Child-Pugh A subjects had similar estimated % geometric mean ratio for C _max (106.7 %), and slightly greater estimated % geometric mean ratios for AUC_0–t (133.0 %) and AUC_0–∞ (122.8 %), versus healthy subjects. Mean elimination half-life was extended in subjects with hepatic impairment (43–47 vs 36 h). Ponatinib was generally well tolerated. A single serious AE (pancreatitis) in the Child-Pugh C group resolved with treatment.

Discussion

As no major differences in ponatinib single-dose PK were observed in patients with hepatic impairment versus healthy subjects, a reduction of ponatinib starting dose in these patients is not necessary, but caution is recommended when administering ponatinib to these patients.     

A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms

Purpose

To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations.

Methods

Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1–2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine “maintenance” doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22–27. The pharmacokinetics of perifosine with these schedules was characterized.

Results

Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 µg/mL. Four patients had stable disease ranging from 167 to 735 days.

Conclusions

Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.     

Microdialysis measurement of intratumoral temozolomide concentration after cediranib, a pan-VEGF receptor tyrosine kinase inhibitor, in a U87 glioma model

Background

Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas may affect the cytotoxic drug distribution by normalizing the blood–brain barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib.

Methods

Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation, TMZ (50 mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for 6 h following TMZ administration. Cediranib (6 mg/kg) was then given orally, and 12 h later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment.

Results

After dosing of oral TMZ only, ECF-TMZ mean-C _max and area under the concentration curve(AUC_0–∞) within the tumor were 0.59 μg/mL and 1.82 μg h/mL, respectively. Post-cediranib, ECF-TMZ mean-C _max and AUC_0–∞ were 0.83 μg/mL and 3.72 ± 0.61 μg h/mL within the tumor, respectively. This represented a 1.4-fold (p = 0.3) and 2.0-fold (p = 0.06) increase in the ECF-TMZ C _max and AUC_0–∞, respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB “normalization” profile following cediranib treatment.

Conclusions

In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to the treatment of TMZ alone with radiographic evidence of a normalized BBB.