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

154s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2549 General Poster Session (Board #2E), Mon, 8:00 AM-12:00 PM
Recommendation of dose banding of cytotoxics according to pharmacokinetic
criteria. Presenting Author: Etienne Chatelut, Institut Claudius
Regaud, Toulouse, France
Background: Dose-banding has been recently suggested in order to optimize
chemotherapy preparation. Ranges (or bands) of body surface area (BSA)
are predefined. The individual dose of a particular patient is calculated
according to a single BSA value per band, usually the mid-point of the BSA
band in which the actual BSA of the patient lies. Thanks to this simple
procedure, chemotherapy provision can be rationalized and chemotherapies
can be prepared in advance for drugs with sufficient long-term drug
stability. The primary purpose of dose-banding is to reduce patient waiting
time and improve capacity planning of the pharmacy production, but
additional benefits can also be found, such as reduced potential for
medication errors, reduced drug wastage, and prospective quality control of
preparations. The objective of this analysis was to compare dose-banding to
individual BSA-dosing (current practice) according to pharmacokinetic
(PK) criteria. Methods: Dose-banding was defined according to three bands
of BSA: BSA�1.7m², 1.7m²�BSA�1.9m², and BSA�1.9m² for which the
values of 1.55m², 1.80m², and 2.05m² were allocated, respectively. By
using individual actual values of clearance of six drugs (cisplatin, docetaxel,
paclitaxel, doxorubicin, topotecan, and irinotecan) from a total of
1,206 adult cancer patients, the AUCs corresponding to the two dosing
methods were compared to a target value of AUC for each drug. Results:
Over all 6 drugs, by using dose-banding the percent change of individual
dose in comparison with BSA dosing ranged between -14% and �22%. In
terms of capacity to attain the target AUC, there was no significant
difference in precision when using dose-banding as compared to BSAdosing
for all drugs except paclitaxel (precision of 23.2% versus 21.8%,
respectively). For all drugs including paclitaxel, distributions of AUC values
were very similar with both dosing methods. Conclusions: For these 6 drugs
and maybe others, dose-banding may be implemented without any risk of
increasing interindividual plasma exposure. Dose-banding would make it
possible to anticipate chemotherapy preparation and analytical control
without any delay for the patients.
2551 General Poster Session (Board #2G), Mon, 8:00 AM-12:00 PM
Thymidylate synthase genotype specific dosing of capecitabine: Proof of
concept phase I study. Presenting Author: Ross A. Soo, National University
Cancer Institute, Singapore
Background: Thymidylate synthase (TYMS) is the target of fluoropyrimidines
(FP). TYMS 3R3R is the predominant genotype in East Asian (EA) patients
and is associated with increased TYMS expression, reduced FP related
toxicity and relative FP resistance. Dose finding studies for FP were
developed in Caucasians, a population that typically harbors TYMS 2R2R
and 2R3R genotypes. We hypothesize the recommended phase II dose
(RP2D) of capecitabine is higher in 3R3R and similar for 2R allele carriers
compared to the FDA approved dose. Objectives 1) To determine the
maximal tolerated dose (MTD) and RP2D of capecitabine in EA patients
with advanced stage malignancy 2) To determine the safety and toxicity of
this regimen and 3) To perform plasma pharmacokinetics (PK) of capecitabine
and its metabolites. Methods: EA patients with advanced stage
cancer were prospectively allocated into two cohorts: Group A (3R3R) and
Group B (2R3R, 2R2R). In each cohort, dose escalation followed a
standard phase I 3�3 design. Additional patients were treated at the R2P2
dose level (DL). Initial dose was 1250/m2 bd for 14 days q3w (DL 1) with
125 mg/m2 bd increments subsequently. Pharmacokinetics (PK) of capecitabine
and its metabolites were performed using a LC-MS/MS method.
Results: 23 patients (Group A�18; group B�5) received 94 cycles (median
2.5, range 1-8). Median age was 58 (range 34-74) years. Median
turnaround time for TYMS genotyping was 1 day. In group A, grade 3-4
DLTs were seen in 3 patients: diarhoea, neutropenic fever, hand-foot
syndrome, and mucositis. MTD was at DL 4 (1625mg/m2 bd) and the RP2D
was 1500mg/m2 bd (DL 3). DL 3 was expanded to n�9. At DL 3, day 1
mean (� SD) capecitabine and 5FU Cmax was 12.3 � 9.9 and 0.91 � 0.73
�g/mL, respectively and AUC0 – twas 9.84 � 5.53 and 1.21 � 0.54
h*�g/mL, respectively. Compared with DL1, Cmax for capecitabine and 5FU
was 2 and 2.02 fold higher and AUC 0-t was 1.49 and 1.59 fold higher at
DL3. Accrual in group B was ceased at DL2 due to lack of patient
enrolment; no DLT was seen. By ROC analysis, day 1 5FU AUC0–tof 1.74
h*�g/mL predicted for DLT (p�0.022, sensitivity 100%, specificity 90%).
Conclusions: In EA patients with TSER 3R3R, the RP2D was 1500 mg/m2 bd. The D1 5FU AUC0–tat RP2D was 59% more than the FDA approved
dose (DL1).
2550 General Poster Session (Board #2F), Mon, 8:00 AM-12:00 PM
Phase I study of weekly oral docetaxel (ModraDoc001) plus ritonavir in
patients with advanced solid tumors. Presenting Author: Serena Marchetti,
Netherlands Cancer Institute, Amsterdam, Netherlands
Background: ModraDoc001 is a novel oral formulation containing docetaxel
as a solid dispersion. Oral administration of docetaxel is feasible in
combination with the CYP3A4 inhibitor ritonavir. Objectives were to
determine the safety, maximum tolerated dose (MTD) and pharmacokinetics
(PK) of weekly oral docetaxel (as ModraDoc001) in combination with
ritonavir. Methods: Patients with advanced solid tumors, WHO PS � 2, no
concomitant use of MDR or CYP3A modulating drugs, adequate bone
marrow (ANC � 1.5x109 /L), liver (bilirubin � 1.5xULN, ALAT/ASAT �
2.5xULN) and renal function (creatinine � 1.5xULN or clearance � 50
ml/min) were eligible. Docetaxel (ModraDoc001 10mg capsule) and
ritonavir (Norvir 100mg) were simultaneously given once weekly in a ‘3�3
cohort’ dose escalation design. MTD was defined as the highest dose
resulting in �1/6 probability of causing a dose limiting toxicity in the first 4
weeks of treatment. This cohort was expanded with 6 patients. PK was
determined on days 1 and 8. Results: 40 patients (25 male, 35 evaluable
for safety) were enrolled in 6 dose levels (30/100, 40/100, 60/100,
80/100, 60/200 and 80/200 mg docetaxel/ritonavir). Common treatment
related adverse events in the 4 highest dose levels were diarrhea (68%),
nausea (62%) and fatigue (62%), mostly CTC grade 1-2 (80%, 95% and
73% respectively). Five patients experienced a DLT (grade 3 diarrhea (4),
elevated ASAT/ALAT (1), grade 4 dehydration and grade 3 mucositis (1),
grade 3 fatigue (2)). The MTD was 60 mg/200 mg docetaxel/ritonavir.
Partial remission was seen in 4 patients (CUP, NSCLC, gastric and mamma
ca) and sustained stable disease in 15 patients (6x NSCLC). Both drugs
were rapidly absorbed after oral administration. Mean Tmax was 2.0 hours
(CV�73%) for docetaxel. Cmax and AUC of docetaxel increased less than
proportionally with dose to 162 ng/ml (CV� 67%) and 1615 ng/ml*hr
(CV� 81%), respectively, in 15 patients at the MTD. Conclusions: At the
MTD (once weekly 60 mg docetaxel and 200 mg ritonavir) ModraDoc001 is
safe, well tolerated and shows encouraging antitumor activity. The exposure
of docetaxel with this regimen is comparable to weekly intravenous
administration of 35 mg/m2 docetaxel. Phase II studies in solid tumors are
planned.
2552 General Poster Session (Board #3A), Mon, 8:00 AM-12:00 PM
A phase Ib dose-escalation study of eribulin mesylate in combination with
capecitabine in patients with advanced/metastatic cancer. Presenting
Author: Muhammad Yaser Nasim, Medical Oncology, The Beatson West of
Scotland Cancer Centre, Glasgow, United Kingdom
Background: Eribulin mesylate is a microtubule dynamics inhibitor approved by
FDA for patients (pts) with metastatic breast cancer after treatment with at
least two prior chemotherapeutic regimens. This Phase Ib, open-label doseescalation
study determined the maximum tolerated dose (MTD) of eribulin in
combination with capecitabine. Methods: Pts with advanced solid malignancies
refractory to standard therapies, adequate organ function and ECOG
performance status �2 received eribulin mesylate (2–5-min IV) by Schedule 1
(1.2, 1.6 or 2.0 mg/m2 on Day 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on
Days 1 and 8), in combination with twice-daily oral capecitabine 1000 mg/m2 Days 1-14 every 21 days. The MTD was defined as the highest dose in each
schedule where �1/6 pts experienced dose-limiting toxicity (DLT). Safety and
pharmacokinetics (PK) were assessed. Results: Of the 34 pts recruited, 19
(53% male; median age 62 years; 42% ECOG 0, 58% ECOG 1) and 15 (33%
male; median age 61 years; 33% ECOG 0, 60% ECOG 1, 7% ECOG 2) were
enrolled in Schedules 1 and 2, respectively. Most common tumor types were
large intestine (20.6%), lung/bronchus (17.7%) and breast (14.7%). DLTs are
shown in the table; there were no unexpected toxicities with the combination.
The MTD for eribulin mesylate was 1.6 and 1.4 mg/m2 for Schedules 1 and 2,
respectively, in combination with capecitabine 1000 mg/m2 twice-daily.
Eribulin PK were dose proportional and independent of schedule or capecitabine
co-administration. Combination with eribulin had no effect on the
disposition of capecitabine and its metabolites. Although sample size was
small, preliminary signs of efficacy were observed. Conclusions: The combination
of eribulin and capecitabine was well tolerated with no unexpected safety
findings. Schedule 2 MTD (1.4 mg/m2 Days 1 and 8) delivered a higher dose
intensity of eribulin than Schedule 1 and was selected for evaluation in an
ongoing Phase II breast cancer study.
Summary of DLTs.
Schedule
Dose
mg/m2 DLT
n (%) DLT DLT grade
1(N�19) 1.2 1 (5.3) Febrile neutropenia 3
1.6 1 (5.3) Neutropenia 4
2.0 2 (10.5) 1x Fatigue 3
1x Lethargy 3
2(N�15) 0.7 0 (0) NA NA
1.1 1 (6.7) Neutropenic sepsis 4
1.4 1 (6.7) Neutropenia 3
NA, not applicable
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