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

336s Gynecologic Cancer
5038 General Poster Session (Board #17F), Sun, 8:00 AM-12:00 PM
Phase Ib study of AMG 386 in combination with paclitaxel (P) and carboplatin
(C) in high-risk stage I and stages II-IV epithelial ovarian, primary peritoneal, or
fallopian tube cancers. Presenting Author: Antonio Casado, Hospital Clínico San
Carlos, Madrid, Spain
Background: AMG 386 is a first-in-class investigational peptibody that inhibits
angiopoietin-1/-2 binding to Tie2. We report on an ongoing, 2-part, open-label
phase 1b study of AMG 386 � PC as first-line treatment of high-risk ovarian
cancer. Methods: Part 1 enrolled women, GOG performance status 0/1, with
newly diagnosed, FIGO high-risk stage I or stages II, IIIA-B (primary debulking
surgery; PDS) or IIIC & IV (PDS or interval debulking surgery; IDS) ovarian
cancer. Patients (pts) received AMG 386 at 15 mg/kg QW IV � P at 175 mg/m2 Q3W � C at AUC 6 Q3W for 6 cycles (or until disease progression or
unacceptable toxicity); AMG 386 was withheld 4 weeks pre-/post-debulking. Pts
completing 6 cycles continued AMG 386 QW as maintenance for up to 18
months. Part 1: incidence of dose-limiting toxicities (DLTs) dictated expansion
to 25 pts (part 2). Primary endpoint: DLT incidence; secondary: adverse events
(AEs), PK and efficacy measures. Results: At the time of analysis, 16 pts had
received �1 dose of AMG 386 � PC and completed �2 cycles of therapy (PDS,
n�8; IDS, n�8). No DLTs occurred in part 1. 15 pts continue on-study; 6 pts
have received a median of 6 doses of maintenance AMG 386. One pt
discontinued due to progression. AEs are tabulated below. One serious AE
(decreased appetite; maintenance phase) required hospitalization. AE incidence
and type were similar for PDS or IDS. Combination therapy did not affect the PK
of AMG 386 or PC. Non-neutralizing antibodies against AMG 386 were detected
in 2 pts. Conclusions: AMG 386 at 15 mg/kg QW � PC is tolerable in pts with
high-risk ovarian cancer. AMG 386 maintenance was tolerated and associated
with few AEs. Updated toxicity and efficacy data will be presented.
AEs
Any; n (%)
Of specific interest (grade 3
Neutropenia
Decreased appetite
Localized edema
Syncope
Thrombocytopenia
Anemia
Ascites
Hypertension
Hypokalaemia
Psoriasis
All grade >4
Neutropenia
Thrombocytopenia
Grade 5
AMG 386 � PC
n � 16
16 (100)
1(6)
1(6)
1(6)
8 (50)
5 (31)
0
0
2 (13)
2 (13)
1(6)
1(6)
1(6)
1(6)
1(6)
4 (25)
3 (19)
1(6)
0
AMG 386 maintenance
n � 6
4 (67)
0
0
0
2 (33)
0
1 (17)
1 (17)
0
0
0
0
0
0
0
0
0
0
0
5040 General Poster Session (Board #17H), Sun, 8:00 AM-12:00 PM
ESA use in women with cancer: Consequences of the 2008 FDA clinical
alert. Presenting Author: Kimberly M. Dickinson, Warren Alpert Medical
School of Brown University, Providence, RI
Background: Erythropoietin stimulating agents (ESA) are used clinically as
an alternative to blood transfusions in cancer patients suffering from
symptoms of anemia. However, more recent randomized controlled trials of
ESA usage concluded that its use is associated with an increased risk of
tumor progression and death. As a result, in July 2008 the FDA issued a
clinical alert restricting the use of ESA. A reduction in the prescribing of
ESA was immediately seen but changes in blood transfusion rates have not
been examined. Methods: A retrospective chart review was conducted
drawing from patients under treatment in the Program in Women’s
Oncology at Women and Infant’s Hospital from one year before the clinical
alert (August 2007-July 2008) to one year afterward (August 2008-July
2009). The primary outcomes were blood transfusion and ESA administration
rates compared across the two time periods. Results: The study
population (n�776) included patients with a cancer diagnosis who
received chemotherapy during one or both time periods. 165 (21.3%)
patients received ESA treatment. The total number of ESA treatments
administered in the study period of interest was 1,277, with the majority
(60%) given prior to the FDA alert. The mean number of ESA treatments in
the first time period was 6.39 per person as compared to 0.61 per person in
the second time period. Of the study population, 186 (23.8%) patients
received at least one blood transfusion. A total of 463 blood transfusions
were administered during the entire study period but a significant difference
was not observed in the proportion of those delivered prior to the FDA
alert (52%) versus after the FDA alert (48%). The average number of
transfusions given in the first time period was 2.34 per person, as
compared to 2.17 per person in the second period. Conclusions: Our results
indicate that despite a steep decline in the use of ESA for chemotherapyinduced
anemia, blood transfusion rates were not significantly different
between the two periods. Interestingly, a slight downward trend was
observed from before the FDA alert to after the alert. While more work is
needed to understand the implications of these findings, it suggests that
resource utilization did not increase despite the reduction in ESA use.
5039 General Poster Session (Board #17G), Sun, 8:00 AM-12:00 PM
The combination of intravenous bevacizumab and metronomic oral cyclophosphamide
for recurrent platinum-resistant ovarian cancer. Presenting
Author: Emma L. Barber, Northwestern University, Department of Gynecologic
Oncology, Chicago, IL
Background: This study was undertaken to determine the progression free
survival and overall survival in heavily pre-treated patients with recurrent
ovarian carcinoma treated with bevacizumab and metronomic oral cyclophosphamide.
Methods: An IRB-approved retrospective review was performed
for all patients with recurrent ovarian, fallopian tube or primary
peritoneal carcinomas treated with intravenous bevacizumab 10mg/kg
every 14 days and oral cyclophosphamide 50mg daily between January
2006 and December 2010. Response to treatment was determined by
change in disease status according to RECIST criteria and/or CA-125
levels. Results: Sixty-six eligible patients were identified with a median age
of 58 years. Fifty-five patients (83%) originally had optimal cytoreduction
and all were platinum resistant. Median time from diagnosis to beginning
bevacizumab and cyclophosphamide was 36 months. Median number of
prior chemotherapy treatments was 7.5 (range 3-16). Eight patients
(12.1%) had side effects which required discontinuing bevacizumab and
cyclophosphamide, most common were hypertension, proteinuria, and
fatigue. There was one bowel perforation (1.5%). A complete response was
noted in 7 patients (10.6%), partial response was seen in 21 patients
(31.8%) with an overall response rate of 42.4%. Fifteen patients (22.7%)
had stable disease and 23 (34.8%) had disease progression. Median
progression free survival (PFS) for responders was 5 months (range 2-14)
and 11 months (range 4-14) for those with a complete response. Median
overall survival (OS) from start of bevacizumab and cyclophosphamide for
responders was 20 months (range 2-56) and 9 months (range 1-51) for
nonresponders. Conclusions: Bevacizumab and cyclophosphamide is an
effective, well-tolerated chemotherapy regimen in heavily pre-treated
patients with recurrent ovarian carcinoma which significantly improves PFS
and OS in responders. Response rates were significantly better than the
rates we have reported in this same group of patients receiving topotecan
(22%) or liposomal doxorubicin (25%) and were superior to reported rates
for single agent bevacizumab (18%) in patients with only 2-3 prior
regimens.
5041 General Poster Session (Board #18A), Sun, 8:00 AM-12:00 PM
Carboplatin dosing in the treatment of epithelial ovarian cancer (EOC): A
Gynecologic Oncology Group (GOG) study. Presenting Author: Roisin Eilish
O’Cearbhaill, Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Optimal carboplatin dosing (CPRx) for patients (pts) with renal
dysfunction or low creatinine (Cr) values in the setting of malnutrition and
ascites is unknown. Multiple methods have been utilized to estimate Cr
clearance (CrCl) but these perform differently in pts with abnormal Cr
values. We sought to determine 1) the relationship between adverse events
(AE) and baseline CrCl used for CPRx; 2) the effect on CPRx of using
Cockcroft-Gault (CG) �/- the NCI/CTEP recommended limits (CGL), Modification
of diet in renal disease (MDRD) or Jelliffe Formula (J) renal function
estimates. Methods: Retrospective data were drawn from pts treated on
GOG 182, a phase III trial of carboplatin doublet vs triplet or sequential
doublet combinations in stage III/IV EOC. For patient safety, the protocol
was amended to assign the lower limit of Cr at 0.6mg/dl for CPRx. Area
under the receiver operating characteristic curve (AUC) was used to
describe associations between CrClJ and various AE. Sensitivity and
positive predictive values (PPV) described the AE rate in pts with CrClJ �60ml/min. CPRx for each pt was calculated using J, CG, CGL and MDRD.
Results: 3830 evaluable pts had a mean age 58.7yrs, mean BMI 26.8kg/m2 and mean baseline CrClJ 81.9ml/min (range 23.4-239). The AUC statistics
(range 0.52-0.64) show that the log(CrClJ) was not a good predictor of
grade �3 AE (anemia, thrombocytopenia, febrile neutropenia, auditory,
renal, metabolic, neurologic). A cutoff value of CrClJ �60 ml/min would
have deemed 15% of pts treated on GOG182 ineligible. The range of PPV
for the above AEs in pts with CrClJ �60 ml/min was 1.8-15%. Using CG,
CGL, MDRD instead of J for CPRx would have resulted in �10% decrease
in CPRx in 21%, 32% and 12% of pts, respectively. Using CG, CGL, MDRD
instead of J for CPRx would have resulted in �10% increase in CPRx in
45%, 9.6% and 5.2% of pts, respectively. Conclusions: Our data do not
support excluding patients with CrClJ �60ml/min from clinical trials. The
new GOG guidelines replacing J with CGL affect CPRx. The clinical
significance of this change with regards to toxicity, particularly in pts with
abnormally low Cr values, is yet to be determined.
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