1o Endpoint Research Articles

519 Rapid reduction in S. aureus & cytotoxins in dupilumab treated atopic dermatitis subjects

Atopic dermatitis (AD) severity correlates with S. aureus (SA) colonization and barrier dysfunction. To address the importance of IL-4&-13 on these parameters, the Atopic Dermatitis Research Network designed a 6wk, RDBPC trial (Dupilumab[DPL]:placebo/2:1) with sampling (at 0, 3, 7, 14, 21, 28 & 42 days [d]) to quantify SA, barrier and severity (EASI, NRS, IGA & SCORAD). Seventy-two moderate-severe adult AD subjects were randomized. There was a >7-fold reduction in SA (qPCR) on lesional (L) skin in DPL vs placebo group (1o endpoint [28d];P<0.001).

MDNA55 survival in recurrent glioblastoma (rGBM) patients expressing the interleukin-4 receptor (IL4R) as compared to a matched synthetic control.

2513 Background: MDNA55 is an engineered IL-4 fused to pseudomonas exotoxin A being developed for GBM, an aggressive, universally fatal disease. No curative therapy exists and 75% of patients are not eligible for resection at recurrence. MDNA55 targets IL4R overexpressed in GBM, the immunosuppressive tumor microenvironment, and high expression is associated with poor survival outcomes in GBM. A Ph 2b trial of MDNA55 was completed in rGBM using convection-enhanced delivery to bypass the BBB. Here we report results from the Ph 2b trial and comparison against a matched Synthetic Control Arm (SCA). Methods: MDNA55-05 is an open-label, single-arm study of intratumoral delivery of ≤ 240 μg MDNA55 as a single treatment via ≤ 4 catheters in de novo GBM without IDH1/2 mutation at 1st or 2nd recurrence not eligible for resection, tumors ≤ 4 cm, KPS ≥ 70. IL4R expression in GBM tissues was determined by H-Score using a validated IHC assay. 1o endpoint is median overall survival (mOS); 2o endpoint includes the impact of IL4R status on mOS. An eligibility-matched SCA was identified retrospectively from patient registries at major neurosurgery centers with access to GBM tumor tissue banks under IRB-approved protocols. Results: 44 subjects comprise the MDNA55 per protocol analysis population: median age 56 (35 - 77); median dose 177 mg (range 18 – 240 mg), 50% had KPS ≤ 80. No systemic toxicities observed, drug-related AEs were primarily neurological and characteristic of GBM, no deaths attributed to MDNA55. Median OS was 11.6 months (95% CI 7.9 – 15.2). When stratified by IL4R expression, mOS in IL4R High (n = 21) was 15 vs. 8.4 months in IL4R Low (n = 19); p = 0.2175. OS12 is 57% vs. 33%. When compared to the SCA (n = 81), MDNA55 subjects survived significantly longer: mOS 12.4 vs. 7.7 months; p = 0.0077. When comparing IL4R High groups, mOS in MDNA55 (n = 21) was 15.8 vs. 6.2 months in the SCA (n = 17); p = 0.0626. Subgroup analysis in unmethylated MGMT subjects also show better survival with MDNA55 (n = 23) than the SCA (n = 31); mOS 12.3 vs. 7.7 months (p = 0.0268), indicating that MDNA55 may be beneficial in patients resistant to temozolomide. Conclusions: MDNA55 subjects represent a difficult to treat population ( de novo GBM, IDH wild-type, not eligible for surgery at recurrence). Single treatment with MDNA55 prolongs survival by nearly 10 months in a subset of rGBM expressing high levels of IL4R when compared to a matched SCA, providing an unprecedented outcome for this highly lethal disease. Clinical trial information: NCT02858895 .

Primary results from a randomized (1:1), open-label phase II study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected stage IIIB- IV melanoma.

9509 Background: T is a HSV-1-based oncolytic virus designed to selectively replicate in tumors and produce GM-CSF to stimulate antitumor immune responses. I is an anti-CTLA-4 Ab that blocks inhibition of activated T cells. This is the first randomized study to evaluate the addition of an oncolytic virus to a checkpoint inhibitor. Methods: The 1o endpoint was ORR by immune-related response criteria. Key 2o endpoints: duration of response, disease control rate (DCR), PFS, OS, and safety. Prior treatment was allowed but not required. Pts had unresected stage IIIB-IV melanoma with measurable/injectable tumor(s) and no evidence of immunosuppression. T was given at approved dosing until no injectable tumors, disease progression (PD), or intolerance. I was started at w6 in T+I and at w1 in I at 3 mg/kg IV q3w x 4. Primary analysis occurred 6 m after last pt enrolled. Results: 198 pts were randomized: 98 T+I; 100 I. Characteristics were similar: 54% stage IIIB-IVM1a, 46% IVM1b/c. Median follow up time was 68 w (T+I) and 58 w (I). ORR was 38.8% (T+I) and 18.0% I, P = 0.002, Odds ratio (OR) 2.9. 89% T+I and 83% I pts remain in response. Unconfirmed visceral lesion response was 35.5% T+I vs 13.6% I. OS is immature. Of 190 pts (safety set: 95 T+I, 95 I), most common adverse events (AEs) for T+I, I (%) were fatigue (59, 42), chills (53, 3), and diarrhea (42, 35). 28% T+I and 18% I pts had gr ≥3 tx-related AE. There were 3 deaths (all unrelated) in T+I: 1 myocardial infarction and 2 PD. Conclusions: The study met the 1o endpoint. ORR was significantly higher for T+I vs I; responses were not limited to injected lesions. Toxicity of T+I combination was tolerable with no unexpected AEs. Clinical trial information: NCT01740297. [Table: see text]

A Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

A Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

Abstract 4660: A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small cell lung cancer.

Abstract Tumor regrowth after chemotherapy may be driven by growth of tumor ‘stem cells’. Telomerase, required for indefinite replication, is upregulated in tumor progenitor cells. Imetelstat is a 13-mer oligonucleotide which is a potent and specific telomerase inhibitor. Progression-free survival (PFS) and the duration of responses after 1st-line chemotherapy for non-small-cell lung cancer (NSCLC) are short, which has led to an interest in developing active maintenance therapies. A randomized phase II study was conducted to assess whether imetelstat, given as maintenance therapy, prolongs PFS in NSCLC. Pts were eligible with advanced NSCLC not progressing after completing 4-6 cycles of platinum-based doublet induction chemotherapy, any NSCLC histology, performance status (PS) ECOG 0 or 1, and not scheduled to receive maintenance with pemetrexed or erlotinib. Pts were randomized 2:1 to imetelstat 9.4 mg/kg (d1 and 8 of a 21d cycle) or observation until progressive disease or unacceptable toxicity (concomitant use of bevacizumab was permitted). The 1o endpoint was PFS; safety/tolerability and objective response rate were 2o endpoints. 116 pts were enrolled between Jul 2010 to Apr 2012, with 114 completing a first visit (i.e. efficacy population). Baseline characteristics of age, gender, PS and number of induction cycles were well balanced. 18.4% had squamous histology; 31.6% received concomitant bevacizumab (bev). The median number of imetelstat maintenance cycles was 3. In the overall analysis of PFS, a non significant improvement in favor of the imetelstat arm was observed (HR = 0.77, P=0.295, 95% CI 0.48 - 1.25). Median PFS was 2.8m for imetelstat and 2.6m for control. In the subgroup of patients who did not receive bevacizumab, the HR was 0.59 (vs. 1.07 for the bevacizumab subgroup; interaction P=0.15). The objective response rate was 4.3% in the imetelstat arm and 2.8% in the control arm. Six month overall survival was 80% for imetelstat and 72% for control (HR = 0.86, P=0.642, 95% CI 0.44 - 1.66). Imetelstat was generally well tolerated although hematologic toxicity, predominantly neutropenia and thrombocytopenia, was increased in the imetelstat arm (grade 3/4 neutropenia 18% for imetelstat vs 0% for control, grade 3/4 thrombocytopenia 37% for imetelstat vs 0% for control). The most frequent non-hematologic toxicities were fatigue (imetelstat 42.1% vs control 18.4%), nausea (43.4% vs 7.9%), vomiting (25.0% vs 5.3%) and anaemia (19.7% vs 5.3%). The overall findings suggest that imetelstat has modest, but not clinically meaningful, activity as a maintenance therapy in pts with NSCLC. A pre-specified exploratory subgroup analysis of PFS by tumor telomere length is reported separately. Citation Format: Alberto Chiappori, Tatjana Kolevska, Bart Burington, David Spigel, Steven Hager, Mark Rarick, Shirish Gadgeel, Normand Blais, Joachim Von Pawel, Lowell Hart, Martin Reck, Joan Schiller. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4660. doi:10.1158/1538-7445.AM2013-4660

A pooled analysis of phase II trials of gemcitabine (GEM)-containing doublets plus bevacizumab (BEV): Should combination chemotherapy serve as the backbone in clinical trials of advanced pancreatic cancer (APC)?

4038 Background: GEM has served as the chemotherapy platform for most phase III clinical trials in APC, inc. CALGB 80303 (GEM +/- BEV). However, GEM-based combination regimens may confer superior outcomes in select pts and represent a preferred backbone in clinical trial design testing targeted agents. Methods: Data was pooled from 5 phase II trials evaluating GEM-based cytotoxic doublets plus BEV in APC. 1o endpoint was OS. 2o endpoints included ORR, CA19-9 response, and adverse events (AEs). Kaplan-Meier methods estimated time-to-event endpoints. The Cox proportional hazard model estimated univariate hazard ratios (HR) of death. Results: Of 261 pts, 90.7% were Caucasian, 95.4% had an ECOG PS 0-1, and 91.6% had metastatic disease. Median age = 60y. Pooled OS data (in mos), stratified for PS and stage, is shown in the table. ORR across all trials: CR 1.6%, PR 22.9%, SD 50.8%, PD 20.2%, NA 4.7%. HR for pts who achieved disease control (CR/PR/SD) was 0.35 vs. those with PD (95% CI 0.23-0.54, p&lt;0.001). 76.5% of pts had elevated baseline CA19-9; of these, 62% achieved ≥50% reduction (HR 0.50; 95% CI 0.34-0.73, p&lt;0.001). BEV-related AEs ≥grade 3: HTN (10.6%), hemorrhage (9.5%), VTE (10.1%), cardiac events (3.4%), and bowel perforation (2.2%). Median OS in pts with grade 3-4 HTN was 13.4 mos vs. 9.8 mos in those without (HR 0.77; 95% CI 0.48-1.24, p=0.29). Conclusions: Recognizing the limitations of single-arm phase II trial design and cross-study comparisons, these results compare favorably to those from CALGB 80303. The standard paradigm of GEM +/- drug X in clinical trial development for APC needs to be reconsidered. Based on our data as well as the recent phase III FOLFIRINOX study, building on more intensive combination chemo regimens in future trials may represent a better strategy, especially for pts with good PS. [Table: see text]

A comparison of CR versus CRi response following CPX-351 treatment of newly diagnosed AML in elderly patients (pts).

6601 Background: A Phase 2b study randomized untreated elderly AML pts to CPX-351 or 7+3. CPX-351 improved leukemia clearance (88% v 71%, &lt;5% marrow blasts), CR+CRi rate (67% v 51%), and was particularly effective in pts with adverse karyotype and antecedent hematologic disorders (sAML). Survival following CRi is usually inferior compared to CR. CPX-351 markedly prolongs plasma drug levels and maintains the 5:1 molar ratio for optimal leukemic cell killing potentially delaying hematologic recovery among CRi patients. Consequently, we compared the characteristics and outcomes of pts achieving CR v CRi. Methods: Untreated AML pts, aged 60-75, PS= 0-2, SCr &lt; 2.0 mg/dL, total bilirubin &lt;2.0 mg/dL, ALT/AST &lt;3 x ULN, and LVEF ≥50% were eligible. Pts were randomized 2:1 to receive up to 2 inductions and 2 consolidations with CPX-351 (100 u/m2; D 1, 3, 5; 90 min infusion) or 7+3 (cytarabine=100 mg/m2 and daunorubicin=60 mg/m2). Consolidation with stem cell transplantation (SCT) was permitted. The 1o endpoint was CR+CRi rate. The 7+3 control arm had only a single CRi among 21 responders. The CPX-351 arm had 15 CRi (27%) and 41 CR (73%) allowing a CR v CRi comparison to be made. Results: CR and CRi pts were balanced by age, race, and PS. The CRi group had more males (87% v 51%), more baseline WBC&gt;20K (27% v 15%), and more adverse karyotype (40% v 27%) and sAML (47% v 29%). A smaller proportion of CRi pts received post-remission chemotherapy (47% v 73%) but had similar rates of SCT (13% v 20%). Most CRi pts had delayed platelet recovery (80%). By 1-year more CRi pts had relapsed (54% v 39%) and more had died (54% v 34%). Contributing causes included: relapsed AML (7 CRi v 10 CR pts), complications post SCT (1 CRi v 1 CR pt), chemotherapy complications (0 CRi v 2 CR pts) and unknown causes (0 CRi v 1 CR pt). The survival curves were not significantly different (p=0.39). Conclusions: More CRi patients had adverse karyotype and sAML and most (53%) received no post remission chemotherapy. Survival was not significantly different compared to CR patients but was markedly better than that of non-responders. These data suggest that CRi following CPX-351 provides clinically meaningful benefit, a finding that needs to be confirmed in a larger randomized study.

Neoadjuvant capecitabine, oxliplatin, and bevacizumab (CAPOX-B) in intermediate-risk rectal cancer (RC) patients defined by magnetic resonance (MR): GEMCAD 0801 trial.

3586 Background: Retrospective data suggest that RT might not be needed in all patients with stage II/III RC. Modern systemic therapy might have local efficacy similar to chemoradiation (CRT). Methods: A multicenter phase II trial was undertaken to evaluate safety and efficacy of neoadjuvant CAPOX-B in patients with T3 middle third rectal adenocarcinoma. Eligible patients (pts) had measurable disease at the baseline and candidate for R0 total mesorectal escision (TME) with intermediate-risk defined by pelvic MR a) T3 with distal border of tumor &gt; 5 cm from the anal verge and below the sacral promontory. b) tumor ≥2 mm from the mesorectal fascia. Pts received 4 cycles of Cap 2000 mg/m2 (d1-14), Ox 130 mg/m2 (d1) and B 7.5 mg/kg (d1) every 3 weeks (last cycle without B). Pts undergo re-staging with MR. One radiologist reviewed all pre- and post-treatment MR scans independently. Pts without progression proceed to TME 4-6 weeks from the last cycle. If progression, pts were to be referred for pre-op cap/RT followed by TME. 1º Endpoint: Tumor Response (RECIST). Design: Simon 2-stage; 28 pts 1st stage and 46 pts 2nd stage. We report data on the planned analysis of pts included for 1st stage. Results: 28 eligible pts (10F/18M) were enrolled from 7/09-5/11. Tumor response, compliance and toxicity details are shown in table below. Two pN2 pts received postop Cap/RT. Conclusions: Neoadjuvant CAPOX-B is active and safe. Early parameters of efficacy are encouraging and seem similar to those observed with CRT. [Table: see text]

Phase 2B Randomized Study of CPX-351 Vs. Cytarabine (CYT) + Daunorubicin (DNR) (7+3 Regimen) In Newly Diagnosed AML Patients Aged 60–75

AbstractAbstract 655 Introduction:CPX-351 is a liposomal formulation encapsulating CYT and DNR at a 5:1 molar ratio that maximizes synergy. CPX-351 was well tolerated and demonstrated markedly prolonged plasma half-life for CYT (t1/2=31.1 hours) and DNR (t1/2=21.9 hours) in Phase 1. Responses (CR + CRp) were noted in patients with prior 7+3 exposure including some with multiple relapses and primary induction failure. A Phase 2 study using 2:1 randomization to demonstrate efficacy and safety of CPX-351 versus conventional 7+3 regimen is summarized here. Methods:Subjects with de novo or 2o AML (based on history of MDS, MPD, or prior chemotherapy exposure), ECOG PS of 0–2, SCr <2.0 mg/dL, total bilirubin <2.0 mg/dL, ALT/AST <3xULN, and LVEF >50% by echo or MUGA were eligible. Subjects with acute promyelocytic leukemia [t(15;17)], known favorable cytogenetics including t(8;21) and inv(16), prior DNR-equivalent exposure >368 mg/m2, myocardial impairment resulting in heart failure (NYHA Class III/IV), uncontrolled infection, and prior treatment for AML, save hydroxyurea, were excluded. Subjects with active CNS leukemia or unable to give informed consent were also excluded. The investigational arm was CPX-351 100 units/m2 on Day 1, 3, and 5 and the control arm was CYT 100 mg/m2/d × 7 day continuous infusion + DNR 60 mg/m2/d Days 1, 2, 3. The 1o endpoint was CR + CRi rate with 2o endpoints of survival at 1-year, response duration, EFS, and 30 and 60-day mortality. Results:From 13Nov2008 to 14Oct2009 126 patients were treated, 125 of whom were eligible (84 with CPX-351 and 41 with 7+3 Control). All patients have had ≥6 months follow-up at time of abstract submission. Both study arms were well balanced for sex, age, race, time from diagnosis to treatment, de novo vs. 2o AML, presence of extramedullary disease, WBC at baseline, ECOG PS, prior anthracycline exposure and cytogenetic risk category.All of the CRi patients had delayed platelet recovery and met the definition for CRp. CPX-351 increased the rate of response (CR + CRp, 66.7% vs. 51.2%); largely due to a higher CRp rate (Table 1). Higher response rates were observed particularly for those with adverse risk cytogenetics, age >70, and 2o AML.Table 1:Primary Response and Early Mortality Results for CPX-351 vs. 7+3 Therapy in Newly Diagnosed Elderly AML PatientsPercent ResponseCPX-3517+3nCRCRpTotalnCRCRpTotalAll Patients8440.526.266.74139.012.251.2Chromosomal AbnIntermediate Risk5438.922.261.12642.315.457.7Adverse Risk2142.933.376.21330.87.738.5Age60–65 yo2634.638.573.11330.823.153.866–70 yo3056.76.763.31353.8053.8>70 yo2828.635.764.31533.313.333.3AML TypeDe novo5545.529.174.5265015.465.42o AML293120.751.715206.726.7Percent Early MortalityDay 30Day 60Day 30Day 60All Patients853.54.7417.314.6Cytopenia-associated adverse event rates were higher in the CPX-351 treatment arm: febrile neutropenia (64.7% vs. 51.2%), infections of all grades (84.7% vs. 68.3%), bacteremia (40% vs. 22%), petechiae (32.9% vs. 12.2%) and ecchymoses (11.8% vs. 2.4%). Median time to count recovery after induction was longer after CPX-351, 38 vs. 34 days for ANC>1000 and 44 vs. 33 days for Plt>100K. CPX-351 was associated with reduced early mortality compared to 7+3 (4.7% vs. 14.6% at 60 days, p= 0.053, Chi Square). Complete analysis of adverse events will be presented.Kaplan Meier analysis reveals a hazard ratio for CPX-351 for overall survival after a minimum of 6 months follow-up to be 0.83 (95%CI: 0.62–1.13; p=0.24). The estimated mean difference within the first year was 2.2 months. Response (CR + CRp) was highly predictive of prolonged survival with the hazard ratio of responders vs. non responders of 0.55 (95% CI: 0.41–0.73; p<0.0001). Data for 1 year survival, EFS, and response duration will be presented. Conclusions:CPX-351 induction therapy in elderly patients with newly diagnosed AML was associated with a higher response rate (66.7% vs. 51.2%) and a strong trend towards reduced 60-day mortality (4.7% vs. 14.6%) compared to the 7+3 regimen. Response (CR + CRp) predicts for prolonged survival and early analyses suggest a first year difference of 2 months favoring CPX-351. In view of these positive results, a Phase 3 trial comparing CPX-351 vs. 7+3 regimen in newly diagnosed elderly AML patients is warranted. Disclosures:Lancet:Celator: Compensation donated to H. Lee Moffitt Cancer & Research Center, Membership on an entity's Board of Directors or advisory committees. Cortes:Celator: Consultancy, Membership on an entity's Board of Directors or advisory committees. Louie:Celator: Employment. Feldman:Celator: Membership on an entity's Board of Directors or advisory committees.

A phase II study testing the safety and activity of AGS-003 as an immunotherapeutic in subjects with newly diagnosed advanced stage renal cell carcinoma (RCC) in combination with sunitinib.

4588 Background: AGS-003 is an autologous immunotherapy prepared from matured monocyte-derived dendritic cells co-electroporated with the subject's own amplified tumor and synthetic CD40L RNA. Based on previous trial results with AGS-003 and the emergence of tyrosine kinase inhibitors as the standard of care, AGS-003 was evaluated in combination with sunitinib for treatment of advanced RCC. Methods: AGS-003-006 is an open label phase II trial enrolling subjects with newly diagnosed clear cell RCC. Post-nephrectomy, subjects received sunitinib (4wk on, 2wk off) and then concomitant AGS-003 injections (every 3wk × 5 doses, then every 3mo until progressive disease [PD] or end of study). AGS-003 was dosed as 3 intradermal injections containing 1 × 107 cells (targeted to a single lymph node basin). The 1o endpoint was to evaluate clinical activity as measured by the complete response (CR) rate. 2o endpoints included safety; clinical activity via estimates of progression free survival (PFS), overall survival (OS), stable disease (SD), partial response (PR), and CR rates; and measurement of immune response. Results: 25 subjects were enrolled and 21 dosed (intent to treat [ITT]). 3 subjects discontinued before the first dose of AGS-003 and 8 discontinued during treatment due to PD. Baseline characteristics for ITT subjects included median age=56yr (22-68); ECOG performance status, 0=71%, 1=29%; and MSKCC, intermediate risk=15, poor risk=6. Interim results demonstrated that 62% (13/21 subjects) experienced clinical benefit (2 PR, 11 SD). Preliminary median PFS from registration date for the ITT population=12.5 months (95% confidence interval 7.2, N/A). Conclusions: AGS-003 is well tolerated with no immunotherapy-related SAEs or grade 3/4 AEs reported. Promising interim data indicate that AGS-003 in combination with sunitinib yields a median PFS of 12.5 months in subjects with intermediate or poor risk factors. Updated PFS and OS data will be presented. No significant financial relationships to disclose.

Use of melphalan (M)/dexamethasone (D)/bortezomib in AL amyloidosis.

8024^ Background: AL amyloidosis is a monoclonal plasma cell disorder with progressive organ dysfunction and short survival. Standard non-transplant AL therapy is melphalan (M) + dexamethasone (D). As adding bortezomib (Bz) to M+ Prednisone improved outcomes in myeloma, we sought to determine if adding Bz to MD improves outcomes in AL. Methods: Eligibility: ECOG PS ≤ 3, Cr ≤ 5 mg/dL, T.Bili ≤ 2.5 × IULN, ALT/AST ≤ 3 × IULN, ANC ≥ 1.0 K/mm3, PLT ≥ 80 K/mm3, peripheral neuropathy (PN) ≤ Gr 2 (≤ 1 if painful), no lower limit for LVEF. Design: Two-stage phase II study. Stage I: 16 pts with biopsy-proven AL, light chain deposition disease (LCDD) or smoldering myeloma with amyloid (SMM). 1o endpoint: complete hematologic responses (cHR). If ≥5 cHRs observed, then 2nd stage with 17 more pts, giving 90% power to detect a true cHR rate of 50%. 2o endpoints: overall HR, organ response (OrR), and survival. Therapy: M (9 mg/m2 PO d 1-4; 6 mg/m2 if Cr > 2.5 mg/dL), Bz (1.3 mg/m2 IV d 1, 8, 15, 22; 1.0 mg/m2 if baselin...

Phase II study of bevacizumab (B) plus cisplatin (C) plus intensity-modulated radiation therapy (IMRT) for locoregionally advanced head and neck squamous cell cancer (HNSCC): Preliminary results

6013 Background: For patients with locoregionally advanced HNSCC, concurrent high-dose cisplatin + radiation therapy is a historical standard of care. HNSCC tumors expressing high levels of VEGF have been associated with worse prognosis, and bevacizumab may sensitize tumors to cisplatin and radiation. Methods: Percutaneous gastrostomy (PEG) tube was placed pre-treatment for all patients. Planned treatment consisted of definitive IMRT (total, 70 Gy) with concurrent C (50 mg/m2 days 1, 2, 22, 23, 43, 44) and B (15 mg/kg days 1, 15, and 43). The initial version of the protocol called for an additional 6 months of maintenance B, but this was discontinued in an amendment after a G4 pulmonary hemorrhage event in subject 1 during maintenance treatment. 1o endpoint was 2-year PFS. Results: 42 previously untreated patients (34 M, 8 F), median age 55 (27–75), with stage III/IV, M0 HNSCC (oropharynx 39, larynx 3) enrolled. HPV status by ISH: 16 pos, 14 neg, 12 unknown). All patients have completed treatment. CTCAE v3.0 toxicities (% patients) have included: functional mucositis G3 (76 %); nausea G3 (24%); vomiting G3 (17%); neutropenia G3 (31%), G4 (10%); hemoglobin G3 (17%); hyponatremia G3 (14%). Median weight loss during treatment was 8.9 kg (2.1–26 kg). There were two deaths within 90 days of last treatment: 1 aspiration pneumonia, 1 sudden death. Median follow up is approximately 9 months (range, &lt;3 to 24 months). Locoregional control rate is 100%. Three patients have developed distant metastasis. Estimated one-year PFS is 83% (± 10%) and estimated 1 year OS is 88% (± 6%). At a median of 8 months after completion of radiation therapy, PSS-HN scores were 100 for eating, speech, and diet in respectively 88%, 76%, and 53% of surveyed patients (n = 17). Conclusions: The addition of B to C + IMRT did not appear to increase toxicity to unacceptable levels, and preliminary efficacy results are encouraging. [Table: see text]

Overall survival (OS) analysis of a phase II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer (mCRPC)

5013 Background: Therapeutic poxviral vaccines for prostate cancer are safe with preliminary evidence of clinical benefit in phase I/II studies. PROSTVAC-VF (PV) comprises 2 recombinant viral vectors (Vaccinia and Fowlpox), each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). PV is administered subcutaneously in a heterologous prime-boost regimen with concurrent low-dose GM-CSF. Methods: 122 patients (pts) were treated in a multi-center, double-blind, RCT of a vaccination series. Pts were randomized 2:1 to PV + GM-CSF vs. placebo empty vector + control saline injections (C). Vaccinia-based vector was used for priming followed by 6 planned Fowlpox-based vector boosts. The trial completed enrollment in July 2005. Eligible pts had metastatic disease, a rising PSA despite castrate testosterone levels, and a Gleason score of ≤7. Pts with a history of prior chemotherapy use, visceral metastasis, or narcotic use were excluded. The 1º endpoint was progression free survival (PFS), with progression defined as 2 new lesions on bone scan or RECIST-defined progression. Vaccination was discontinued after progression. Results: 82 pts received PV and 40 received C. Pt characteristics were similar (means): age (72PV/76C), PSA (134PV/188C), Alk-Phos (142PV/159C), LDH (207PV/218C), Hgb (13PV/13C), and number bone metastatic sites (5.3PV/6.5C). Mean number of vaccinations was 5.4 PV and 5.3 C. PFS was similar in the 2 groups (p = 0.56). However, at 3 years post study, PV patients had a better overall survival than C patients (25 alive, 30%, PV, versus 7 alive, 17%, C) and a longer median survival (24.5 months PV, versus 16 months C); estimated hazard ratio 0.6 (95% CI 0.4–0.9); stratified log rank p = 0.016. Conclusions: In a RCT, PV immunotherapy was associated with an 8.5 month improvement in median OS in men with mCRPC. These data provide evidence of prolonged anti-tumor activity, but need to be confirmed in a larger phase III study. [Table: see text]

A case for time to tumor progression (TTP) as the primary (1o) efficacy endpoint in 1st-line metastatic colorectal cancer (MCRC) therapy: Correlation of TTP and overall survival (OS)

3503 Background: OS has been the 1o endpoint for phase III MCRC registration trials. However, increasing numbers of efficacious agents have extended OS and added therapeutic complexity. Evaluation of new drugs based on OS may be impeded by larger sample sizes, longer study durations, and crossovers. Thus, FDA, ASCO and AACR, in a review of surrogate and clinical benefit endpoints, have asked if TTP could replace OS as the 1o endpoint because it measures an early treatment effect and is not confounded by later therapies. Methods: As part of this effort, we assessed the relationship of TTP to OS in the 1o patient data from the 2 large, FDA-reviewed phase III trials (NEJM, 343:905, 2001; Lancet 355:1041, 2001) that form the basis of irinotecan/5-FU/leucovorin (IFL) approval in previously untreated MCRC. Patients (pts) were randomized to: Study 1 (bolus IFL or FL or I) and Study 2 (infusional IFL or FL) and could receive 2nd-line I or FL; 2nd-line oxaliplatin was not widely available. Results: The linear regression of OS vs TTP (mo) was OS=1.2xTTP+8.3 (r=.56), showing an ≈1:1 correlation between TTP and OS improvement and that pts lived an average of ≈8 more mo after progression. The OS:TTP relationship (slope) was not altered by treatment or prognostic factors (PS, LDH), but post-study survival (y-intercept) was affected. In a Cox regression analysis, longer OS was better explained by longer (≥6 mo) TTP (p<0.0001, hazard ratio [HR] 0.31) than by PS=0 (p<0.0001, HR 0.47) or normal LDH (p<0.0001, HR 0.51). Conclusion: An irinotecan-induced improvement in TTP translates into a similar improvement in OS, supporting the use of TTP as the 1o endpoint in phase III MCRC trials. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Corp. Pfizer Corp. Pfizer Corp. Pfizer Corp. Aventis Pfizer Pfizer Corp.

A case for time to tumor progression (TTP) as the primary (1o) efficacy endpoint in 1st-line metastatic colorectal cancer (MCRC) therapy: Correlation of TTP and overall survival (OS)

3503 Background: OS has been the 1o endpoint for phase III MCRC registration trials. However, increasing numbers of efficacious agents have extended OS and added therapeutic complexity. Evaluation of new drugs based on OS may be impeded by larger sample sizes, longer study durations, and crossovers. Thus, FDA, ASCO and AACR, in a review of surrogate and clinical benefit endpoints, have asked if TTP could replace OS as the 1o endpoint because it measures an early treatment effect and is not confounded by later therapies. Methods: As part of this effort, we assessed the relationship of TTP to OS in the 1o patient data from the 2 large, FDA-reviewed phase III trials (NEJM, 343:905, 2001; Lancet 355:1041, 2001) that form the basis of irinotecan/5-FU/leucovorin (IFL) approval in previously untreated MCRC. Patients (pts) were randomized to: Study 1 (bolus IFL or FL or I) and Study 2 (infusional IFL or FL) and could receive 2nd-line I or FL; 2nd-line oxaliplatin was not widely available. Results: The linear regr...