24.12.2012 Views

Annual Meeting Proceedings Part 1 - American Society of Clinical ...

Annual Meeting Proceedings Part 1 - American Society of Clinical ...

Annual Meeting Proceedings Part 1 - American Society of Clinical ...

SHOW MORE
SHOW LESS

You also want an ePaper? Increase the reach of your titles

YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.

Developmental Therapeutics—<strong>Clinical</strong> Pharmacology and Immunotherapy<br />

2593 General Poster Session (Board #8B), Mon, 8:00 AM-12:00 PM<br />

Phase I and pharmacokinetic (PK) study <strong>of</strong> pazopanib (P) in combination<br />

with two schedules <strong>of</strong> ifosfamide (I) in patients (pts) with advanced solid<br />

tumors (STs). Presenting Author: Paul Hamberg, Erasmus University<br />

Medical Center, Daniel den Hoed Cancer Center, Rotterdam, Netherlands<br />

Background: P is a tyrosine kinase inhibitor <strong>of</strong> PDGFR, VEGFR and KIT. This<br />

study aimed to determine the recommended phase II dose (RP2D) <strong>of</strong> P<br />

combined with I. To assess the impact <strong>of</strong> scheduling on tolerability, two I<br />

schedules were explored. Methods: Pts with progressive ST, no standard<br />

therapy available, PS 0-1 and good organ function were eligible. Pts<br />

received daily P with 3-weekly I, 9 g/m2 /cycle, either continuously (Iciv) or<br />

as 3 hrs boluses (Ibolus) for 3 days. P was escalated in serial cohorts <strong>of</strong> 3-9<br />

pts per I-schedule. If in 3-6 pts dose-limiting toxicity (DLT) <strong>of</strong> 33.3%<br />

within 1st cycle was seen 3 more pts at that dose level (DL) were enrolled.<br />

RP2D was exceeded if in � 1/3 pts, � 2/6 pts or � 3/9 pts DLT occurred. P<br />

was maximized at 1000 mg/day. At RP2D, an expansion cohort <strong>of</strong> 6-9 pts<br />

was studied to confirm safety. PK samples <strong>of</strong> P and I were collected in all<br />

pts. Sampling allowed intra-individual comparison <strong>of</strong> I-PK with or without P<br />

and vice versa. Results: 47 pts were studied. For Iciv (25 pts), RP2D was<br />

the maximum dose <strong>of</strong> P (1000 mg), higher than the single agent RP2D. At<br />

RP2D 2 DLTs in 15 pts occurred: 1 febrile neutropenia (FN); 1 encephalopathy.<br />

With Ibolus (22 pts), P 400 mg with or without GCSF was not tolerated<br />

(5 DLTs in 10 pts: 3*FN, 1 encephalopathy; 1 proteinuria). At RP2D (P<br />

200 mg � Ibolus � GCSF) 3 DLTs in 12 pts (FN; encephalopathy, renal<br />

insufficiency) were observed. Toxicity occurring in �30% <strong>of</strong> pts in Iciv (all<br />

grades/grade 3-4,%) were neutropenia (92/92) anemia (92/8); thrombocytopenia<br />

(35/12), elevated ASAT, ALAT, alkaline phosphatase (73/4; 73/0;<br />

62/2), nausea (58/0), vomiting (73/0), diarrhea (54/0) and hypertension<br />

(31/12). 4/25 pts in Iciv evaluable for response had PR (2 sarcoma, 2<br />

ovary) and 10 prolonged (�3 mths) SD. In Ibolus, 6/20 pts had PR (2<br />

urothelial, 1 sarcoma, 1 ovary, 1 CUP, 1 mesothelioma) and 3/20<br />

prolonged SD. Preliminary PK analysis showed no effect <strong>of</strong> P on I-exposure,<br />

neither <strong>of</strong> Ibolus or Iciv on P. Conclusions: P is tolerated at a higher dose<br />

combined with Iciv compared to Ibolus (1000 vs 200 mg). PK cannot<br />

explain this difference. This study underlines the impact <strong>of</strong> scheduling on<br />

the tolerability <strong>of</strong> VEGFR-TKI and cytotoxic drug combinations.<br />

2595 General Poster Session (Board #8D), Mon, 8:00 AM-12:00 PM<br />

Pharmacokinetic modeling and simulation (PK M&S) supported dose<br />

escalation <strong>of</strong> PF-03446962, a monoclonal antibody (mAb) against activin<br />

receptor like kinase 1, in patients with solid tumors. Presenting Author:<br />

Erjian Wang, Pfizer Inc., San Diego, CA<br />

Background: PF-03446962 is a first in class mAb. The PK <strong>of</strong> mAbs is<br />

complex, as their clearance (CL) can be linear or non-linear, besides<br />

extremely slow. Caution must be exercised when designing mAbs’ dose<br />

escalation schemes. Along with safety and activity evaluation, we used PK<br />

M&S in real time to ensure that subsequent recommended doses did not<br />

expose too many patients to subtherapeutic levels while preserving safety.<br />

Methods: The model incorporated both Michaelis-Menten approximation<br />

and linear components. A prespecified target exposure was defined by<br />

preclinically projected therapeutic and toxic concentrations. The PK M&S<br />

results were used to make dose escalation decisions. Results: Eight dose<br />

levels (0.5, 1, 2, 3, 4.5, 6.75, 10, and 15 mg/kg) were studied in 44<br />

patients. CL <strong>of</strong> PF-03446962 exhibited nonlinear characteristics at low<br />

doses and linear at high doses. CL was saturated at dose levels <strong>of</strong> 3 mg/kg<br />

and above. Mean half-life was 2.6 days for the first dose level and 12-15<br />

days after CL saturation. The dose ratio <strong>of</strong> 15 to 0.5 mg/kg was 30, while its<br />

corresponding Cmax and AUC ratios were 46 and 97, respectively.<br />

However, the PK M&S accurately predicted exposure following each dose.<br />

95% <strong>of</strong> the observed drug concentrations across all dose levels were within<br />

the predicted values. Concentrations at the 4.5 mg/kg dose exceeded the<br />

predicted efficacious level over the dosing period. None <strong>of</strong> 44 patients in<br />

the study were exposed to the toxic level derived from a study in monkeys.<br />

PK data also implied a biologically active dose at 2 mg/kg dose and above,<br />

confirmed by observing target toxicities (ie, telangiectasia) and clinical<br />

tumor responses. One patient with PR was at the 2 mg/kg dose and 2<br />

patients with PR were at the 10 mg/kg. The PK M&S well predicted the drug<br />

exposure following multiple doses in patients, indicating that patients did<br />

not develop antidrug immunogenicity. Conclusions: The PK M&S based<br />

approach ensured that the majority <strong>of</strong> patients were treated at or near the<br />

therapeutic dose. It can be readily implemented in the conduct <strong>of</strong> dose<br />

escalation trials <strong>of</strong> antitumor mAbs, while minimizing risk to patients and<br />

maximizing efficiency.<br />

165s<br />

2594 General Poster Session (Board #8C), Mon, 8:00 AM-12:00 PM<br />

Modeling the combined efficacy <strong>of</strong> rilotumumab (R; AMG 102) plus<br />

epirubicin/cisplatin/capecitabine (ECX) for the treatment <strong>of</strong> locally advanced<br />

or metastatic gastric or esophagogastric junction (G/EGJ) cancer.<br />

Presenting Author: Sameer Doshi, Amgen Inc., Thousand Oaks, CA<br />

Background: R is an investigational, fully human monoclonal antibody to<br />

hepatocyte growth factor/scatter factor (HGF/SF) that inhibits signaling<br />

though the MET receptor. In a double-blind, placebo-controlled, phase 2<br />

trial <strong>of</strong> 121 patients with G/EGJ cancer, R (7.5 or 15 mg/kg) � ECX showed<br />

trends for improved progression-free survival (PFS) and overall survival<br />

compared to ECX alone. The combined effects <strong>of</strong> R and ECX on tumor<br />

reduction and PFS were modeled using the phase 2 data. Methods: A<br />

population pharmacokinetic (PK) model was used to estimate R PK<br />

parameters and individual R concentrations (C) over time. A tumor dynamic<br />

model was developed to characterize the combined effects <strong>of</strong> R with ECX on<br />

tumor growth and cell death and to evaluate the impact <strong>of</strong> baseline patient<br />

characteristics and lab values on model parameters. A discrete timesurvival<br />

model was developed with PFS and C data to evaluate the effect <strong>of</strong><br />

R, ECX, and the interaction between R and ECX on PFS within a given time<br />

interval. Results: R exhibited linear PKs with an estimated mean clearance<br />

<strong>of</strong> 0.216 L/d/70 kg. The tumor dynamic model suggested that R and ECX<br />

worked jointly to reduce tumor size from baseline via inhibition <strong>of</strong> the tumor<br />

growth rate constant (Kgrowth) and stimulation <strong>of</strong> the death rate <strong>of</strong> tumor<br />

cells (Kdeath). Assuming the maximal inhibition <strong>of</strong> Kgrowth is 100%, the<br />

estimated mean C that provided 50% maximal Kgrowth inhibition (EC50) was<br />

6.71 �g/mL. The mean (SD) estimated effect <strong>of</strong> 7.5 and 15 mg/kg R on<br />

K was 90.1% (3.8%) and 95.5% (1.9%) inhibition, respectively. None<br />

growth<br />

<strong>of</strong> the tested baseline factors appeared to significantly affect tumor<br />

reduction by R � ECX. In the discrete time-survival model, the R and ECX<br />

combination significantly improved PFS, and the model suggests that the<br />

magnitude <strong>of</strong> the effect <strong>of</strong> one treatment was dependent on the other.<br />

Conclusions: R and ECX appeared to work in combination to decrease tumor<br />

size and to improve PFS.<br />

2596 General Poster Session (Board #8E), Mon, 8:00 AM-12:00 PM<br />

Individual PK-guided sunitinib dosing: A feasibility study in patients with<br />

advanced solid tumors. Presenting Author: Nienke A.G. Lankheet, Slotervaart<br />

Hospital, Amsterdam, Netherlands<br />

Background: Sunitinib treatment shows a clear dose-efficacy relationship.<br />

However, due to large inter-individual variations in plasma exposure, target<br />

total trough levels (� 50 ng/mL) are frequently not reached with the current<br />

dosing schedule. Therefore, a prospective Phase I study was performed to<br />

determine the safety and feasibility <strong>of</strong> PK-guided dosing <strong>of</strong> sunitinib.<br />

Methods: Thirty patients with solid tumors with a potential benefit from<br />

sunitinib treatment were included. Patients were treated continuously with<br />

sunitinib 37.5 mg once daily. At day 15 and 29 <strong>of</strong> sunitinib treatment,<br />

plasma trough levels <strong>of</strong> sunitinib and its active metabolite (N-desethyl<br />

sunitinib) were measured. If the total trough level (TTL) was � 50 ng/mL<br />

and the patient did not show any � grade 3 toxicity (CTCAE 4.02), the daily<br />

sunitinib dose was increased by 12.5 mg. If the patient suffered from<br />

� grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg. After 8<br />

weeks a final TTL evaluation was performed. Results: All 30 patients started<br />

treatment and in 18 patients all 3 TTLs were measured at the time <strong>of</strong> this<br />

analysis. Given TTL � 50 ng/mL and � grade 3 toxicity, a first sunitinib<br />

dose increase could be applied in 10 patients and a second dose increase<br />

in 2 patients at day 15 and 29, respectively. At day 15, day 29 and 8 weeks<br />

<strong>of</strong> treatment, mean TTLs were 49.7 ng/mL (coefficient <strong>of</strong> variation (CV)<br />

27.7%), 62.4 ng/mL (CV 35.5%) and 56.7 ng/mL (CV 47.8%), respectively.<br />

At day 15, using the sunitinib standard dose <strong>of</strong> 37.5 mg, target TTLs<br />

were reached in 8 patients (44%). At 8 weeks, the mean sunitinib daily<br />

dose intensity was increased to 40.3 mg (standard deviation (SD) � 11.0).<br />

At the end <strong>of</strong> the 8 week study period, 5 out <strong>of</strong> 18 patients (28%) were still<br />

at an increased sunitinib dose level without additional side effects. In these<br />

patients the mean daily sunitinib dose was 55.0 mg (SD � 6.8) and their<br />

final TTLs were all � 50 ng/mL (mean: 70.8 ng/mL (CV 29.8%)). Using<br />

PK-guided sunitinib dosing, target TTLs were reached in 10 out <strong>of</strong> 18<br />

patients (56%) at the final TTL evaluation, compared to 44% at day 15<br />

before any dose adjustment. Conclusions: Individual PK guided dosing is<br />

feasible and enables a significant increase in sunitinib dose intensity<br />

without causing additional toxicity.<br />

Visit abstract.asco.org and search by abstract for the full list <strong>of</strong> abstract authors and their disclosure information.

Hooray! Your file is uploaded and ready to be published.

Saved successfully!

Ooh no, something went wrong!