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

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300s Genitourinary Cancer<br />

4593 General Poster Session (Board #3H), Sun, 8:00 AM-12:00 PM<br />

Activity <strong>of</strong> intravesical CG0070 in Rb-inactive superficial bladder cancer<br />

after BCG failure: Updated results <strong>of</strong> a phase I/II trial. Presenting Author:<br />

Terence W. Friedlander, University <strong>of</strong> California, San Francisco, San<br />

Francisco, CA<br />

Background: Loss <strong>of</strong> retinoblastoma (Rb) tumor suppressor activity occurs<br />

commonly in bladder cancer and leads to upregulation <strong>of</strong> the E2F-1<br />

transcription factor. CG0070 is a replication-competent oncolytic adenovirus<br />

genetically modified to express GMCSF under control <strong>of</strong> the human<br />

E2F-1 promoter. Updated results from a phase I study <strong>of</strong> CG0070 in<br />

patients with recurrent superficial bladder cancer (T1, Ta, Tcis) after BCG<br />

treatment are presented here. Methods: The V-0046 phase I/II study<br />

previously reported the safety and evidence <strong>of</strong> efficacy <strong>of</strong> single and<br />

multiple doses <strong>of</strong> intravesical CG0070. Efficacy was determined using<br />

quarterly cystoscopy, biopsy, and/or urine cytology. Tumor Rb status was<br />

assessed immunohistochemically in 18 tumors. Results: 35 patients were<br />

treated with either a single dose (n�13) <strong>of</strong> CG0070 ranging from 1x1012 to<br />

3x1013 viral particles (vp) or with weekly x6(n�9) or every 4 week x 3-6<br />

doses (n�13) ranging from 1x1012 to 1x1013 vp per dose. The most<br />

common adverse events regardless <strong>of</strong> schedule were flu-like illness,<br />

dysuria, hematuria, bladder spasm, and nocturia. No maximum tolerated<br />

dose was reached. Urine GMCSF and CG0070 levels were detectable in<br />

almost all patients suggesting in-vivo viral replication. The CR rate in the<br />

single dose cohort was 23% (3/13), and 64% (14/22) in the multi-dose<br />

cohorts. The CR rate for patients with either CIS or Ta tumors was 65%<br />

(15/23). Of all responders, 11 recurred with a remission duration ranging<br />

from 3.0 - 33.4 months and 6 patients, all in the multiple dose cohorts,<br />

remain in remission as <strong>of</strong> last follow-up with a remission duration ranging<br />

from 3.3 – 38.2 months. Phosphorylated (inactive) Rb was detected in 13<br />

<strong>of</strong> the 18 (72%) patients evaluated. Nine <strong>of</strong> these 13 patients (70%) had a<br />

complete response. All patients (5/5, 100%) with known phosphorylated<br />

Rb treated in the weekly cohort experienced a CR. Conclusions: CG0070<br />

was well tolerated with minimal toxicities. Complete responses were more<br />

frequently observed in the multiple-dose cohorts, including durable CRs in<br />

patients with inactive Rb and in patients with CIS. Further study in<br />

Rb-inactive superficial tumors is warranted.<br />

4595 General Poster Session (Board #4B), Sun, 8:00 AM-12:00 PM<br />

Late gastrointestinal (GI) complications in patients with stage I-II testicular<br />

seminoma treated with radiotherapy (RT). Presenting Author: Christopher<br />

Leigh Hallemeier, Mayo Clinic, Rochester, MN<br />

Background: For stage I-II testicular seminoma, RT is highly effective at<br />

eradicating disease in the abdominopelvic lymph nodes, but results in<br />

unnecessary exposure to normal tissues including the GI tract. The purpose<br />

<strong>of</strong> this study was to define the incidence and risk factors for late GI<br />

complications in this patient population. Methods: A retrospective review<br />

was performed <strong>of</strong> 251 patients with stage I-II testicular seminoma treated<br />

with curative intent RT at our institution from 1974-2009. All patients<br />

underwent orchiectomy and postoperative external beam RT to the involved<br />

and/or at-risk nodal basins. Potential late GI complications that were<br />

assessed included endoscopically-confirmed gastric or duodenal ulceration,<br />

small bowel obstruction (SBO), and biopsy-confirmed malignancy <strong>of</strong><br />

the GI tract. Risks were estimated using the Kaplan-Meier (KM) technique<br />

and univariate/multivariate analyses were performed using the Cox proportional<br />

hazards model. Results: Median age at diagnosis was 36 years (range<br />

18 – 80). <strong>Clinical</strong> stage was I (n�199) or II (n�52). Median abdominopelvic<br />

RT dose was 26 Gy (interquartile range 25 – 30). Median follow-up was<br />

15 years (range 0.1 – 38). KM estimates for any GI complication (ulcer,<br />

SBO, or GI malignancy) at 10, 20, and 30 years were 7, 10 and 24%,<br />

respectively. Four patients died as result <strong>of</strong> a GI complication. KM<br />

estimates for ulcer at 10, 20, and 30 years were 4, 7, and 9%, respectively.<br />

Age at RT (Hazard Ratio [HR] 1.05, 95% Confidence Interval [CI] 1.00 –<br />

1.10, p�0.03) and RT total dose (per Gy, HR 1.20, 95% CI 1.09 – 1.31,<br />

p�0.01) were associated with risk <strong>of</strong> ulcer. KM estimates for SBO at 10,<br />

20, and 30 years were 2%, 2%, and 3%, respectively. History <strong>of</strong><br />

inflammatory bowel disease was associated with risk <strong>of</strong> SBO (HR 43, 95%<br />

CI 7-325, p�0.01). KM estimates for GI malignancy at 10, 20, and 30<br />

years were 0.5, 3 and 16%, respectively. Age at RT was associated with risk<br />

<strong>of</strong> GI malignancy (HR 1.07, 95% CI 1.02-1.14, p�0.01). Conclusions: In<br />

patients with stage I-II testicular seminoma treated with RT, late GI<br />

complications were a relatively uncommon, but clinically significant source<br />

<strong>of</strong> late morbidity. Use <strong>of</strong> low dose, limited field, and/or proton RT may<br />

reduce these risks.<br />

4594 General Poster Session (Board #4A), Sun, 8:00 AM-12:00 PM<br />

Utilization and predictors <strong>of</strong> neoadjuvant chemotherapy for muscleinvasive<br />

bladder cancer in the Veterans Health Administration. Presenting<br />

Author: Gurdarshan Singh Sandhu, Washington University School <strong>of</strong><br />

Medicine, St. Louis, MO<br />

Background: The survival benefit with neoadjuvant chemotherapy for<br />

bladder cancer was established in 2003. However, adoption <strong>of</strong> this<br />

paradigm in clinical practice has been slow. We explored the use <strong>of</strong><br />

neoadjuvant chemotherapy and identified predictors <strong>of</strong> its use in a<br />

contemporary cohort in the Veterans Health Administration (VA). Methods:<br />

Using the national VA <strong>Clinical</strong> Cancer Registry, all patients diagnosed with<br />

clinical stage T2-4, N0 or Nx, M0 bladder cancer from 1997 to 2007 were<br />

stratified into surgically (radical cystectomy [RC], n�1,211) and nonsurgically<br />

managed groups (n�2,125). Receipt <strong>of</strong> neoadjuvant chemotherapy<br />

was defined as chemotherapy treatment up to 6 months before RC as well<br />

as initial treatment only with chemotherapy (without subsequent surgery or<br />

radiation) in the nonsurgical group. Temporal trends in neoadjuvant<br />

chemotherapy use were evaluated with a chi square test. Predictors <strong>of</strong><br />

neoadjuvant chemotherapy were examined using a multivariable logistic<br />

regression model incorporating demographic, socioeconomic, comorbid,<br />

pathologic and hospital factors. Results: 6.3% and 8.3% <strong>of</strong> patients<br />

received neoadjuvant chemotherapy in the surgical and non-surgical group,<br />

respectively. Analysis <strong>of</strong> temporal trends in chemotherapy use demonstrated<br />

an increase in neoadjuvant chemotherapy use over time (p�0.0001);<br />

from 3% (2003 and before) to 14% annually (2007). On multivariable<br />

analysis <strong>of</strong> both groups, older age and more recent diagnosis were<br />

predictive <strong>of</strong> neoadjuvant chemotherapy use (Table). Other covariates did<br />

not predict receipt <strong>of</strong> neoadjuvant chemotherapy. Conclusions: While<br />

overall use <strong>of</strong> neoadjuvant chemotherapy in the VA population with bladder<br />

cancer remains low, use there<strong>of</strong> is slowly increasing, with a more recent<br />

diagnosis most strongly predicting its use.<br />

Multivariable predictors <strong>of</strong> neoadjuvant chemotherapy in bladder cancer.<br />

OR 95% CI P value<br />

Age (per year older)<br />

Year <strong>of</strong> diagnosis (reference 2003 and before)<br />

1.02 1.00-1.04 �.0001<br />

2004 1.56 0.98-2.47 0.06<br />

2005 1.23 0.76-2.00 0.39<br />

2006 1.66 1.09-2.52 0.02<br />

2007 2.38 1.59-3.57 �0.0001<br />

4596 General Poster Session (Board #4C), Sun, 8:00 AM-12:00 PM<br />

Interim results <strong>of</strong> phase II trial <strong>of</strong> the cyclin-dependent kinase 4/6 inhibitor<br />

PD-0332991 in refractory retinoblastoma protein positive germ cell<br />

tumors. Presenting Author: David J. Vaughn, Abramson Cancer Center at<br />

the University <strong>of</strong> Pennsylvania, Philadelphia, PA<br />

Background: Deregulation <strong>of</strong> the retinoblastoma pathway in germ cell<br />

tumors (GCT) has been well documented. We previously reported that<br />

PD-0332991, a selective oral inhibitor <strong>of</strong> cyclin-dependent kinase 4/6, led<br />

to prolonged disease control in 3 patients (pts) with unresectable growing<br />

teratoma syndrome (NEJM, 2009). For these reasons, we initiated a phase<br />

II trial <strong>of</strong> PD-0332991 in pts with refractory retinoblastoma protein (Rb)<br />

positive (�) GCT. Methods: Pts with incurable refractory GCT that expressed<br />

Rb by immunohistochemistry were treated with PD-0332991 125 mg<br />

orally daily for 21 days followed by a 7 day break (cycle � 28 days). Tumor<br />

assessments were performed every 2 cycles. The primary endpoint was<br />

6-month progression-free survival (PFS) rate. Results: As <strong>of</strong> 1/12/2012,<br />

archived tumors from 36 pts with refractory GCT were stained for Rb and 35<br />

had � 1� staining. 18 <strong>of</strong> planned 24 pts have been enrolled and treated.<br />

Pt characteristics: 17 male, 1 female; median age, 31 years (range,<br />

17-56); median ECOG performance status, 1 (range, 0-1); median number<br />

<strong>of</strong> prior chemotherapy regimens, 2 (range, 1-6); median number prior<br />

surgeries, 3 (range, 1-6). Pt pathology: mature teratoma (MT), 7; teratoma<br />

with malignant transformation (TMT), 7; mixed GCT, 2; late relapse (LR),<br />

2. 16 pts are evaluable; 2 pts are too early to evaluate. 5 <strong>of</strong> 16 evaluable pts<br />

achieved 6-month PFS (3 MT, 1 TMT, 1 LR). Median PFS was 2 months<br />

(range, 0-17). No objective radiological responses were observed; 7<br />

patients had best response <strong>of</strong> stable disease by RECIST criteria (3 MT, 3<br />

TMT, 1 LR). Grade 3 toxicity included neutropenia (4 pts), thrombocytopenia<br />

(3 pts), anemia (1 pt), mucositis (1 pt). No grade 4 toxicity was seen.<br />

Analysis <strong>of</strong> archival tumor for predictive biomarkers including Rb and p16<br />

expression is being performed. Conclusions: PD-0332991 has resulted in<br />

6-month PFS in pts with refractory Rb � GCT, including pts with incurable<br />

teratomas.<br />

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