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

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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 />

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