Q21 Days Research Articles

Outcome prediction based on single nucleotide polymorphisms (SNPs) in DNA repair paths in patients (pts) with esophageal adenocarcinoma (EAC) treated with preoperative (preop) cisplatin (C)-based chemoradiation (CRT): Results from the Eastern Cooperative Oncology Group (ECOG)

4530 Background: EAC has eluded cure even with platin-based CRT. Stratifying pts by likelihood of success is one approach to improving outcomes. We assessed whether SNPs in DNA repair paths are associated with complete pathologic response (pCR) in EAC pts who received C-based CRT followed by surgery. Methods: Patients and specimens: Pretreatment biopsy or post-CRT resection samples were obtained from pts (EAC, stage II-IVa) treated on a randomized phase II trial, E1201 (n=86), of preop CRT (RT to 45 Gy). Arm A: Preop C 30 mg/m2 + irinotecan (I) 50 mg/m2 days (d) 1, 8, 22, 29 with RT. Post-op C 30 mg/m2 + I 65 mg/m2 d 1, 8 q21 days x 3. Arm B: Preop C 30 mg/m2 + paclitaxel (P) 50 mg/m2 d 1, 8, 15, 22, 29 with RT. Post-op C 75 mg/m2 + P 175 mg/m2 d 1 q21 days x 3. Clinical outcome - pCR: (A) 14% [95% CI 5.5%, 28.5%]; (B) 16% [95% CI 6.7%, 30.1%]. Median overall survival (OS): (A) 34.9 m (months) [90% CI 23.5, not reached]; (B) 20.9 m [90% CI 17.4, 46.7]. Experimental procedure: Normal tissue was microdissected from unstained sections of paraffin-embedded tissue. DNA was extracted (Qiagen). Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight (Sequenom) for all SNPs. Each SNP was dichotomized a priori into: (1) major homozygote vs (2) minor (heterozygote plus minor homozygote) allele groups. Data analysis was performed centrally, with lab investigators blinded to clinical data. Exact logistic regression was used to derive ORs for non-pCR, using the major homozygote as the reference (2-sided p values). Results: Germline DNA was available in 68 pts; 60 were eligible and began therapy ( Table ). Conclusions: In this homogenous, well-defined cohort, the XRCC1 Arg399Gln minor allele group was associated with lower pCR (p=0.06). Lab data on a panel of additional SNPs have been collected and are under analysis for presentation at the meeting. [Table: see text] [Table: see text]

A phase I trial of GMX1777, an inhibitor of nicotinamide phosphoribosyl transferase (NAMPRT), given as a 24-hour infusion

3581 Background: GMX1777 is a pro-drug which converts to GMX1778, a potent and specific small molecule inhibitor of NAMPRT, the rate-limiting enzyme in NAD+ synthesis. NAMPRT activity is increased in tumor cells dependent on the glycolytic pathway. The aims of this first-in-man study were to define a dose of GMX1777 administered by 24-hr infusion with acceptable safety for phase II studies, and to determine the pharmacokinetic (PK) parameters of both GMX1777 and GMX1778. Methods: GMX1777 was administered at ascending doses as a 24 hour IV infusion q21 days to successive cohorts of patients with advanced malignancies. Single patient cohorts were utilized until a toxicity >Grade (Gr) 1 was observed during cycle (C) 1; then a standard 3+3 dose escalation schema was used. PK samples were drawn during C1. Results: 19 patients (11 males; median age 57) received doses of 60, 120, 160, 200 or 140 mg/m2 over 24 hours. 49 doses were administered. There were no toxicities >Gr 1 during C1 at 60 mg/m2; however Gr 2 toxicities were observed at 120 mg/m2 and the cohort was expanded to 3 patients. Gr 4 GI hemorrhage and Gr 4 thrombocytopenia occurred at 200 mg/m2, leading to expansion of the 160 mg/m2 cohort. 3/6 patients at 160 mg/m2 had erythematous symmetrical Gr 3 rash occur during C2–5. Six patients enrolled at 140 mg/m2 had no Gr 3 rash and 140 mg/m2 was determined to be the MTD. Preliminary data indicate that the most common (>30%) adverse events of all grades were nausea (89%), diarrhea (79%), fatigue (68%), vomiting (58%), anorexia (42%), pruritis (42%), thrombocytopenia (42%), rash (37%), anemia (32%), constipation (32%), dyspnea (32%), and insomnia (32%). Lab findings include lymphopenia. Two patients had stable disease for > 4 cycles (6 & 4 mos), and 3 additional patients had SD for ≥ 3 mos. Preliminary PK data document rapid conversion of GMX1777 to GMX1778 at all dose levels. Conclusions: The MTD for GMX1777 administered as a 24 hour infusion q21 days is 140 mg/m2. Thrombocytopenia, GI hemorrhage, and skin rash (the last occurring after multiple cycles) were encountered at higher doses. Single-agent GMX1777 exhibited moderate clinical activity, suggesting that inhibition of NAMPRT should be explored in other schedules or in combination with other agents. [Table: see text]

Activity of bortezomib (B) in plasma cell dyscrasia (PCD) with POEMS-like syndrome

e19564 Background: POEMS (polyneuropathy, organomegaly, endocrinopathy, m-protein, and skin changes) syndrome is a rare multi-system disorder associated with PCD. Although several reports revealed significant clinical benefit of IMIDs in POEMS syndrome cases that are not transplant candidates, no such published reports of B in this disease were found. Methods: We report the first case of PCD with POEMS like syndrome in addition to pulmonary hypertension, secondary right heart failure, and membranoproliferative glomerulonephritis that was successfully treated with single agent B. After presenting with the aforementioned signs and symptoms, a 64 year old white man, was diagnosed with PCD (bone marrow plasma cells 15%, IgG-λ, mild-moderate anemia, normal PET/CT, normal Cr and Ca) with ISS stage III. Due to being high risk for thromboembolic events, he was started on single agent B at 1.3mg/m2 days 1,4,8,11 Q21 days (cycles 1–4) which was reduced to 1.0mg/m2 days 1,4,8,11 Q21 days (cycles 5–6) due to grade 1 thrombocytopenia and neuropathy. This was followed by 3 maintenance cycles of 4 out of 5 weekly 1.0mg/m2. Results: Patient's breathing was subjectively better after cycle#1 despite experiencing side-effects from his pulmonary hypertension medications which had to be held and subsequently improved back to his baseline by cycle#4. By cycle#2, he was found to be in nCR with complete normalization of his bone marrow and serum electrophoresis by the end of therapy. He has been in nCR for almost 12 months so far. By cycle#3 his Raynaud's syndrome was significantly better with less dysesthesia which completely resolved by cycle#6. Conclusions: This case demonstrates for the first time the significant activity of B as a single agent in PCD with POEMS like syndrome. Further evaluation of the role of B as a first line agent in this disease, whether as single agent or in combination, is warranted. [Table: see text]

A multicenter phase II study of pemetrexed (P), cisplatin (C), and bevacizumab (B) in patients (pts) with advanced malignant mesothelioma (MM)

7578 Background: Vascular endothelial growth factor (VEGF) is a key growth factor for MM. In pre-clinical models, anti-VEGF antibodies inhibit MM proliferation. Standard chemotherapy for MM, pemetrexed + cisplatin, yields a response rate of 41%, progression-free survival (PFS) of 5.7 months (mo) and median overall survival (OS) of 12.1 mo. We added the anti-VEGF antibody B to PC in an ongoing phase II multi-center study in MM pts. Methods: Eligible pts have unresectable, histologically-confirmed MM, no prior chemotherapy, and PS 0–1. Pts receive C 75 mg/m2, P 500 mg/m2 and B 15 mg/kg Q21 days for 6 cycles, then B Q21 days until progression. CT scans are obtained Q 2 cycles. Primary endpoint: Progression-fere survival (PFS). Correlative studies include IHC for the VEGF/KDR complex and PCR for simian virus 40 (sv40) T antigen. Results: 43 pts enrolled at 4 centers from 3/06 to 12/08; currently, 34 are evaluable for PFS and 36 for toxicity. Pt characteristics: male 88%; median age 66 (range 24–81); histology: epithelial 62%, sarcomatoid 15%, biphasic 20%, unknown 3%; site of origin: pleural 85%, peritoneal 12%, tunica vaginalis 3%; PS 0 32%, PS 1 68%; thrombocytosis (>400) 32%. Cycles administered 229 (median 4, range 1–18). Grade 3/4 toxicity (%pts): neutropenia 8%; anemia 0%; thrombocytopenia 3%; thrombosis 11%; hypertension 8%; vomiting 8%; mucositis 6%; CVA 3%; proteinuria 0%; perforation 0%. Partial response: 41%, stable disease: 35%. Median PFS: 5.6 mo (95% CI: 4.1, 7.2). Median OS 11.5 mo (95% CI: 9.4, 24). Conclusions: These data suggest that the addition of B to PC does not improve PFS when compared with historical controls of PC in advanced MM pts. Correlative studies evaluating the VEGF/KDR complex and sv40 T antigen are pending. [Table: see text]

Efficacy of protracted dose-dense temozolomide (TMZ) in patients with progressive high-grade glioma

e13018 Background: The study was aimed to evaluate the efficacy of TMZ on a protracted dose-dense schedule after standard 5-day TMZ regimen in patients with progressive high-grade glioma. Methods: In this phase II prospective study, patients who had progression on standard 5-day TMZ for recurrence (group 1) or recurrence after concurrent radiotherapy+TMZ and ≥ 2 cycles of adjuvant TMZ (group 2) for high-grade glioma received TMZ 100 mg/m2× 21 q28 days until progression according to MacDonald's criteria. Patients were included in the study after ethical committee approval and written informed consent. The primary end-point was 6 months PFS. Secondary end-points were OS and toxicity. Results: Between October 2006 and October 2008, 25 patients were included in the study. Nine of the patients were group 1 and 16 of them were group 2. Male/female ratio was 18/7. The median age was 50 (range, 18–70) and median KPS score was 80 (range, 50–100). The histopathology was glioblastoma in 18 and grade 3 glioma (anaplastic astrocytoma, anaplastic oligoastrocytoma or anaplastic oligodendroglioma) in 7. The median cycles of 5-day TMZ received before study entry was 6 (range, 2–18) in group 1 and 6 (2–7) in group 2. With a median follow up of 6 months (1–14 months) the median number of 21-day TMZ cycles received was 2 (range, 1–8). Radiological evaluation could not be performed in 5 patients because of early clinical progression. The best response during treatment was partial response in 2 (8%), stable disease in 9 (36%), and progression in 9 (36%) out of 20 patients assessed. The median time to progression was 2 months (1–8 months) and 6 months PFS rate was 11%. The median OS time was 8 months and 1 year OS rate was 38%. Out of 80 cycles received there was no anemia; 5 (6%) grade 1, 8 (10%) grade 2, 2 (3%) grade 3 leucopenia; 1 (1%) grade 1, 2 (3%) grade 2, 1 (1%) grade 3, 1 (1%) grade 4 thrombocytopenia; 9 (11%) grade 1, 7 (9%) grade 2, 32 (40%) grade 3, and 11 (14%) grade 4 lymphopenia. Study was terminated in 2 patients (one with grade 4 thrombocytopenia and the other with grade 4 hepatic toxicity). There was no dose reduction in the study drug due to toxicity. Conclusions: Protracted dose-dense TMZ after 5-day schedule for recurrent or progressive disease has modest efficacy with tolerable toxicity. No significant financial relationships to disclose.

Final results of a FNCLCC French Sarcoma Group multicenter randomized phase II study of gemcitabine (G) versus gemcitabine and docetaxel (G+D) in patients with metastatic or relapsed leiomyosarcoma (LMS)

10527 Background: An objective response rate (RR) of 8% and 17% with G and G+D were respectively reported in metastatic soft tissue sarcomas (Maki, J Clin Oncol. 2007). We previously reported a 5% RR in 41 evaluable patients (pts) with ‘non uterus‘ LMS randomized to each arm of this randomized phase II study (Duffaud, ASCO. 2008). We present here the results of G vs G+D in uterine and all LMS. Methods: Patients had histologically proven metastatic or unresectable LMS, one prior anthracycline- based regimen, age ≥18, measurable disease (RECIST), PS ≤ 2. Treatment was G 1,000 mg/m2(over 100 minutes, d1+d8+d15) q28 days (d) or G 900 mg/m2(over 90 min, d1+d8) and docetaxel 100 mg/m2 (over 60 min, d8) q21 days; in the G+D arm, pts received lenograstim d9–15, 25% dose reductions were employed for prior pelvic radiation. The primary endpoint was the objective RR (CR+PR), evaluated every 2 cycles. Stratification was by primary tumor location (uterus vs. non-uterus). The Simon method was used: for “uterus” study, 20 pts per arm for a 74% probability of selecting the arm with a real RR of 50%, expected baseline RR was 40%; for the “non-uterus” study, 20 pts per arm for a 92% probability of selecting the arm with a real RR of 40%, expected baseline RR was 20%. Results: From 02/06 to 12/08, 44 pts were enrolled in the “non-uterus” study, 40 pts in the “uterus” study. Currently 76/82 pts are evaluable for response (41/44 in the “non uterus” and 35/38 in the “uterus” study) and 80/84 for toxicity. In the uterus group the median age is 57 (range 41–80), 24 pts received prior pelvic radiotherapy, the median number of cycles was 5 (range 0–8) and dose received/dose planned (%) were 69% in G arm, 88% of G and 86% of D in G+D arm. No differences in toxicity were observed between both LMS locations: in the G arm, toxicity was moderate except for one pulmonary gr4; in the G+D arm one toxic death was related to gr5 thrombocytopenia and there were 2 non-haemathologic gr4 toxicities; 11 pts stopped for intolerable toxicity (3 in G and 8 in G+D arm) and 1 pt for hypersensitivity (G+D arm). Conclusions: Final tumor response for uterine LMS and updated toxicity and PFS data for all the LMS will be presented during the meeting. [Table: see text]

Efficacy results from a multicenter phase II noncomparative two-arm pilot trial of bevacizumab with anastrozole or fulvestrant as first-line endocrine therapy for metastatic breast cancer

1091 Background: Estrogen modulates angiogenesis via effects on endothelial cells with subsequent induction of vascular endothelial growth factor (VEGF). VEGF promotes tumor growth and is associated with poor response to antiestrogen therapy. This trial was designed to evaluate the progression-free survival (PFS) of bevacizumab (B) in combination with anastrozole (A) or fulvestrant (F) as first-line endocrine therapy (ET) in metastatic breast cancer (MBC). Methods: Eligibility criteria: no prior hormonal or chemotherapy for MBC, measurable or evaluable disease, normal LVEF, post-menopausal. Treatment: Arm A: anastrozole 1 mg po QD in pts who were a) ET naïve, b) ≥ 12 months from adjuvant ET, and c) intolerant of or progressed on prior tamoxifen. Arm B: fulvestrant 500 mg D1 and 250 mg D15 IM loading dose followed by 250 mg q28 days in pts who were a) < 12 months from adjuvant aromatase inhibitors (AIs), b) intolerant of or progressed on AIs, and c) MD's discretion. Bevacizumab 10 mg/kg IV D1 q2 weeks was given in both arms. Trastuzumab permitted in HER-2+ pts only. Response assessments were q8 weeks; pts were treated until disease progression or toxicity. Results: 79 pts were enrolled fromNovember 2006 to November 2008. 42 pts are evaluable for response and toxicity, Arm A - 25 pts and Arm B - 17 pts. Median age was 64, ECOG PS 0 - 55%, 1- 43 %, adjuvant chemo 27%, adjuvant hormonal -38%, hormone receptor status: ER+/PR+ 80%, ER+/PR- 14%, ER-/PR+ 2 %. HER-2+ 5 pts, 31% had ≥ 2 metastatic disease sites predominately lung and bone only disease - 40%. Median # cycles - 4. 24% achieved a partial response and 57% stable disease; 7 pts progressed. G3 hypertension (12%) was the most common toxicity. Median PFS for Arm A was 16.3 months and has not yet been reached for Arm B. Conclusions: Bevacizumab in combination with anastrozole or fulvestrant is feasible and well tolerated with no unanticipated toxicities. The addition of bevacizumab resulted in prolongation of the median PFS to16.3 months with anastrozole as compared to the 7–9 month historical control PFS reported for first-line AI monotherapy in MBC. Further evaluation of bevacizumab endocrine combinations is warranted. [Table: see text]

Randomized phase II study of weekly versus every-3-week ixabepilone plus bevacizumab (ixa/bev) versus paclitaxel plus bev (pac/bev) as first-line therapy for metastatic breast cancer (MBC)

1029 Background: Pac/bev is superior to pac alone as first-line therapy for MBC. Ixa/bev has greater preclinical activity than pac/bev in human tumor models. The primary objective of this trial was to evaluate objective response rates (ORR) of ixa/bev given weekly or every 3 weeks relative to pac/bev as 1st line therapy for women with advanced breast cancer. Methods: Women with measurable disease and no prior chemotherapy for advanced breast cancer (locally advanced or MBC) were randomized in a 3:3:2 ratio to Arm A (ixa 16 mg/m2 IV on days 1, 8 & 15 q28 days/ bev 10 mg/kg IV q 2 wks), Arm B (ixa 40 mg/m2 IV q3 wks / bev 15 mg/kg IV q 3 wks) or Arm C (pac 90 mg/m2 IV, schedule/bev as in Arm A). Treatment was continued until disease progression or unacceptable toxicity. Results: Key efficacy and safety results from a pre-planned analysis of all randomized subjects after at least 24 weeks of follow-up are presented. Baseline characteristics were balanced between arms except for liver metastasis. Conclusions: The combination of ixa/bev weekly or q 3 wks demonstrated encouraging clinical activity and safety comparable to 1st line pac/bev in E2100. Final PFS will be provided when data is mature. These results support ongoing clinical trials of ixa given weekly or q 3wk in 1st line MBC, and in combination with bev. [Table: see text] [Table: see text]

Phase I study of E7389/gemcitabine combination in patients with advanced solid tumors

e13509 Background: E7389 (E) is a synthetic analogue of halichondrin B, an investigational tubulin-based antimitotic drug. Gemcitabine (G) is a nucleoside analogue clinically active in several human tumours. These two drugs exhibit synergistic cytotoxic effects against the H522 non-small cell lung cancer (NSCLC) xenografts. Methods: A phase I study of these two drugs in combination was initiated in patients with advanced solid tumours. Two prior chemotherapy regimens for metastatic disease were allowed. Results: Patient characteristics: male 11/female 10; median age 59 (range 28–84); performance status 0 /1/2: n=1/13/7; prior chemotherapy 21, prior radiotherapy 7, prior immunotherapy 1; tumour types: ovarian cancer 3, endometrial cancer 3, NSCLC 3, gastric/esophageal adenocarcinoma 3, miscellaneous 9. Total number of cycles given 52, median cycles/patient (range) 2 (1, 8). Cohort (CT) 1: E/G given days 1,8,15 q28 days. Due to DLT, regimen changed in CT 2 with E/G given days 1, 8 q21 days. Cycles (C) given: median 2 range 1–8, total 52. Response: partial response 1 (ovarian cancer), stable 8 [minor response 4 (NSCLC 2, endometrial cancer 1, head and neck cancer 1)], progression 8, inevaluable 4. Conclusions: Further phase II investigation of this regimen should be considered at a dose of E 1.0 g/m2/G 1000 mg/m2 q 3 weeks. [Table: see text] No significant financial relationships to disclose.

Results of a multicenter pilot study of weekly nab-paclitaxel, carboplatin with bevacizumab, and trastuzumab as neoadjuvant therapy in HER2+ locally advanced breast cancer with SPARC correlatives

527 Background: The addition of targeted therapies to standard chemotherapy has resulted in improved outcomes in metastatic, neoadjuvant and early stage breast cancer. A phase III study in MBC demonstrated improved efficacy with nab paclitaxel (nab-P) compared with standard solvent-based paclitaxel. The secreted protein acidic rich in cysteine (SPARC) is a poor prognostic factor for survival and may mediate enhanced intratumoral accumulation of nab-P via an interaction with albumin. This multicenter phase II pilot study was designed to evaluate the feasibility, safety, and preliminary efficacy of dual VEGF and HER-2 monoclonal antibodies of bevacizumab (B) and trastuzumab (T) administered in with neoadjuvant nab-P and carboplatin (C) with SPARC tumor correlatives. Methods: Eligibility: clinical T1c-T4d and/or N0–3, M0 (T1N0M0 excluded) chemo naive, ECOG PS 0–2, normal LVEF, adequate organ function. Treatment: nab-P 125 mg/m2 D1, 8, 15 with C AUC 6 D1 q28 days plus T 4 mg/kg load followed by 2 mg/kg/wk and B 5 mg/kg/wk x 6 cycles followed by surgery. Post surgery T and B continued for 52 wks. SPARC tumor expression was measured by immunohistochemistry. Results: 29 pts are enrolled and evaluable for safety. Median age: 52 years (29–76), ECOG PS 0–93%, median tumor size 3.2 cm, 54% ER-/PR-, 72% node positive. G3/4 neutropenia was 38% with no febrile neutropenia. Nonheme toxicity: G3/4 hyperglycemia 10%, proteinuria and hypertension, each in 7%. 8 pts were hospitalized (infection-4, ↓LVEF-1, wound dehiscence-1 pt, other-2). 5 pts did not complete neoadjuvant therapy (↓LVEF-1, noncompliance-1, pt request-3) and 10 pts did not complete post op therapy ((pt request-2, toxicity-3, wound-2, unk-3). Pathologic responses are available for 20 pts. pCR was noted in 13/20 pts (65%) and PR was noted in 7/20 pts (35%). 77% of the pCR pts (10/13) and 86% of the PR pts (6/7) were positive for SPARC. Conclusions: Neoadjuvant B, T with nab-P and C is feasible and highly active with a remarkable pCR of 65%. SPARC tumor correlations with pathologic response data reveal a concordance between the high response rate and high incidence of SPARC positivity. [Table: see text]

Randomized phase II study of erlotinib (E) or intercalated E with carboplatin/paclitaxel (CP) in chemotherapy-naive advanced NSCLC: Correlation of biomarker status and clinical benefit

8026 Background: E plus chemotherapy showed no additive effects in NSCLC but preclinical studies suggested that intercalation of E and chemotherapy could give synergy. Clinical studies suggested that EGFR mutations could aid in pt selection. KRAS mutation status of tumors was also evaluated. We conducted a randomized phase II study of E and E intercalated with CP in pts with chemonaive NSCLC. Methods: Stage IIIB/IV EGFR+ NSCLC pts were randomized to E 150 mg/d or CP d1 plus E days 2–15 q21 days (ECP). After 4 cycles, E continued until PD. Tumor tissue was evaluated by IHC (EGFR), FISH (EGFR gene copy number), and PCR amplification followed by DNA sequencing (EGFR and KRAS mutations). Results: Among 143 pts randomized 53% EGFR FISH+; 13% activating EGFR mutations and 8% non-activating EGFR mutations (evaluable samples=114); and 22% KRAS mutations (evaluable samples=130). No pt had both EGFR and KRAS mutations. EGFR-activating mutations were higher among females (19% vs 6% males), adenocarcinoma histology (17% vs 0% others), Asians (45% vs 7% non-Asian), and never smokers (29% vs 7% former and 0% current); KRAS mutations were higher in current smokers (41% vs 27% former and 0% never) and adenocarcinoma histology (22% vs 18% squamous). In the E arm, 6-mo PFS probability for the efficacy evaluable population (n=69) was significantly higher in pts with EGFR activating mutations vs no mutations (89% vs 25%, HR=0.17, P=0.001), numerically higher in pts with EGFR FISH+ vs FISH- (40% vs 22%, HR=0.61, P=0.07), and with KRAS wild type vs mutation+ (38% vs 12%, HR=0.56, P=0.10). Response rates, PFS and OS by type of EGFR/KRAS mutation will be presented. In the ECP arm, 6-mo PFS probability for the efficacy evaluable population (n=68) was numerically higher in pts with EGFR activating mutations (42% vs 29%, HR=0.72, P=0.53), numerically higher in pts with wild type KRAS (32% vs 9%, HR=0.57, P=0.08), and numerically lower in pts with EGFR FISH+ vs FISH- (23% vs 30%, HR=0.93, P=0.78). Conclusions: Activating EGFR mutations correlate with increased 6 mo PFS probability in 1st line therapy with E. EGFR FISH + and absence of KRAS mutation trend towards increased 6 mo PFS rate with E. [Table: see text]

Correlation of surface expression of CD11b or CD32 in polymorphonuclear cells (PMNs) and CD69 in natural killer cells (NK) with progression-free survival (PFS) following chemoimmunotherapy with rituximab and liposomal doxorubicin (LD) in patients (pts) with relapsed or refractory B-cell lymphoma

8583 Antibody dependent cellular citotoxicity (ADCC) play a significant role in rituximab's anti-tumor activity. FcγRIIIa polymorphisms have been associated with clinical responses to rituximab. The predictive value of FcγRIIIa polymorphisms is lost when rituximab is combined with chemotherapy. Alternative assays to assess the immune system had not been studied in patients treated with rituximab plus chemotherapy. To this end, we prospectively studied the pre-treatment quality and function of PMNs and NK cells from pts with refractory/relapsed B-cell lymphomas in a Phase I/II trial. Forty-two B-cell lymphoma patients pts completed treatment. Demographics: 22M:20F; Median age = 61.8 (range 35–83); Patients received R (375 mg/m2/dose) on day 1 and LD (30 mg/m2/dose) on day 3 q21 day × 6 cycles. Pre-treatment flow cytometry was performed to assess surface expression of CD11b, CD62, CD69, CD16, CD32 and CD64 in PMNs or NKcells was performed. Serum or PBMC's were isolated from each patient and used 51Cr release assays to study rituximab-associated complement mediated cytotoxicity (CMC) or ADCC. To correlate laboratory parameters with response rate, and PFS patients were divided in tertiles. Overall, R+LD was very well-tolerated. Overall response rate (ORR) = 68% (39% CR, 19% PR); median time-to-progression (TTP) = 12 m. Surface expression of CD32 in PMNs, and CD69 in NKcells correlated with better response rates. Surface expression of CD11b and CD32 in the PMN's correlated with a longer PFS (P = 0.040 and P = 0.015, respectively).There was a non-statistically significant trend towards an improved in PFS in those patients whom their PBMC's exhibited a higher degree of ex-vivo rituximab ADCC. Our data suggest that R+LD is a safe and effective regimen and that the quality of the immune system prior to a chemo-immunotherapy regimen may play a role in clinical outcomes, specifically the expression of CD11b and CD32 in PMNs or CD69 in NKcells. Our data supports further research in seeking ways to enhance the quality of the immune system to improve responses to rituximab ± chemotherapy. [Table: see text]

Preliminary progression free survival and SPARC tumor correlatives from a phase II neoadjuvant trial of gemcitabine, epirubicin, and nab paclitaxel.

Abstract Abstract #5116 Background: Neoadjuvant combinations of gemcitabine (G), anthracyclines and taxanes have demonstrated significant activity with pCR rates of 20-25% albeit with significant myelosuppression. Secreted protein acidic rich in cysteine (SPARC) is an albumin binding protein that mediates intratumoral accumulation of nab-paclitaxel (nab-P) via a SPARC-albumin specific binding activity. This study was designed to evaluate a biweekly schedule of neoadjuvant nab paclitaxel (nab-P) with gemcitabine and epirubicin (E). SPARC tumor assessments were performed in consenting patients (pts) with subsequent pathologic and survival correlatives.
 Methods: Eligibility: Clinical T1c-T4d and/or N0-3, M0 breast cancer (T1N0M0 excluded), ECOG PS 0-2, normal LVEF. ER/PR/HER2 obtained for all pts. Treatment: 6 cycles neoadjuvant G 2000 mg/m2, E 50 mg/m2, and nab-P 175 mg/m2 q14 days followed by surgery. Post operative therapy: 4 cycles G 2000 mg/m2 and nab-P 220 mg/m2 q14 days. Myeloid growth factors were mandated with all cycles. 2 antibody reagents were used to probe for SPARC expressions. For this study, level 3 immunohistochemical (IHC) SPARC staining was considered positive. Results: 123 pts have enrolled with pathologic responses available for 106. 82 pts consented to SPARC testing. Median age 51 (29-72). Median tumor size 4.5 cm. Histology: 81% ductal, 10% lobular, 9% other. 42% ER and PR negative. 55% clinical T3/T4 and 66% lymph node positive at presentation. G3/4 toxicity present in >5% of pts: neutropenia 16% (febrile neutropenia 1 pt), thrombocytopenia 9% with arthralgias 11%, fatigue 10%, and infection 7%. 20 pts did not complete study treatment for the following reasons: disease progression 7, toxicity 3, pt/MD request 5, and other 5. pCR was noted in 23 pts (22%) with PRs in 76 pts (71%), and 6 SD. SPARC IHC staining was available for 76 tumors. SPARC level 3 IHC staining was noted in 65 tumors (86%); 65% were associated with a PR or pCR. Median PFS was 23 months and overall survival at 24 months is 77%. Pts who relapsed ≤16 months from diagnosis were more likely to be triple negative (p = 0.04), or ER negative (p = 0.001), or PR negative (p = 0.0006). Conclusions: Neoadjuvant dose dense GEA is active and better tolerated than other gemcitabine/anthracycline/taxane combinations. The pCR rate of 22% compares favorably with other comparable neoadjuvant regimens albeit with minimal toxicity. Pts with early relapse defined as ≤16 months from diagnosis were more likely to demonstrate a triple negative phenotype or demonstrate estrogen or progesterone receptor negativity. SPARC tumor correlatives with progression free and overall survival are on ongoing and will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5116.

Preliminary safety results from a multicenter phase II noncomparative two arm pilot of bevacizumab with anastrozole or fulvestrant as 1st line metastatic breast cancer therapy.

Abstract Abstract #4113 Background: Estrogen modulates angiogenesis through effects on endothelial cells and by induction of vascular endothelial growth factor (VEGF) expression. Increased VEGF promotes tumor growth and is associated with a poor response to anti-estrogen therapy. This trial evaluates the impact of bevacizumab (B) combined with anastrozole (A) or fulvestrant (F) on progression free survival (PFS) as first line endocrine therapy in metastatic breast cancer (MBC).
 Methods: Study design: Two arm nonrandomized, noncomparative trial of A or F in combination with B. Eligibility: 0 prior hormonal or chemotherapy for MBC, measureable or evaluable disease, normal LVEF, postmenopausal, normal organ function. Treatment: Arm 1: Patients (pts) who either were endocrine therapy naïve, ≥ 12 months from adjuvant endocrine therapy, or who had intolerance to or progression on tamoxifen were treated with anastrozole 1 mg po daily. Arm 2: Patients who were ≤ 12 months from adjuvant aromatase inhibitors (AIs), intolerant of or progressed on adjuvant AIs, or at physician's discretion were treated with fulvestrant 500 mg IM loading dose, 250 mg D15 and every q28 days thereafter. B 10 mg/kg q2wks beginning day 1 was administered in both arms. Concurrent trastuzumab (T) was administered in HER2+ patients. Response assessments were performed q8 wks. Pts were treated until disease progression or toxicity.
 Results: 44 pts have been enrolled with data available for 29 pts. 18 pts (62%) were treated with anastrozole and 11 pts (38%) with fulvestrant. Median age: 64 yrs (range 44-88), ECOG PS 0-17 pts (59%) and PS 1 -12 pts (41%). 7 pts (24%) presented with de novo stage IV disease. 52% had 2 or more metastatic disease sites with bone metastases predominating 16 pts (55%), 7 pts (24%) with bone only disease. There were no G3/4 heme toxicities. G3/4 non-hematologic events consisted of G3 hypertension in 3 pts (10%), arthralgias 1 pt (3%), and CHF 1 pt (3%). This symptomatic LVEF of 40% occurred in arm 1 during cycle 3 and was noted to recover to 50-55% within 1 wk. This pt did not receive T. A median of 4.5 cycles have been administered. PRs were noted in 7 pts (24%) and 14 pts (48%) demonstrated SD. PD was noted in 3 pts and 5 pts were not yet evaluable. 73% of pts are progression free at 12 months. At a median follow up of 7.5 months, median PFS and overall survival has not been reached.
 Conclusions: The combination of bevacizumab with anastrozole or fulvestrant is feasible and well tolerated with adverse events as expected, reflecting standard bevacizumab related toxicities. Bevacizumab in combination with endocrine therapy is promising with early evidence of a high rate of clinical benefit at 72%. Further follow up is warranted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4113.

A Phase I/II Trial of the Kinesin Spindle Protein (KSP) Inhibitor SB- 743921 Administered on Days 1 and 15 Every 28 Days without and with Prophylactic G-CSF in Non-Hodgkin or Hodgkin Lymphoma.

Background: KSP is a mitotic kinesin essential for cell cycle progression. SB-743921 (SB-921), a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and cell death. Since neurons lack a mitotic spindle, neurotoxicty, common with anti-tubulins, is not expected. In the first-in-humans (FIH) trial, the maximum tolerated dose (MTD) was 4 mg/m2 q21 days (d), a dose density of 0.2 mg/m2/d. Since neutropenia was the major dose-limiting toxicity (DLT), with nadir at ~d8 and recovery by ~d15, a q14d schedule without (−GCSF) and with prophylactic G-CSF (+GCSF) is being explored in this trial.Methods: In Phase I of this Phase I/II trial, the MTD of SB-921 (−GCSF) and (+GCSF) will be determined. In Phase II, efficacy and safety of the MTD will be further explored. Eligible patients (pts) have relapsed or refractory Hodgkin (HL) or non-Hodgkin (NHL) lymphoma, aggressive (a) or indolent (i), have had at least 1 prior chemotherapy (CT) regimen, and have relapsed after or were not candidates for autologous stem cell transplant. SB-921 is given to cohorts of 3 on d1/d15 q28d, starting at 2 mg/m2 and escalating by 1 mg/m2. Cohorts expand to 6 if 1/3 pts have DLT. Once DLT (−GCSF) is identified, (+GCSF) dosing begins at the (−GCSF) MTD, escalating in 1 mg/m2 increments until (+GCSF) DLT is identified.Results: The (−GCSF) cohort included 39 pts treated at 6 dose levels (2–7 mg/m2) of SB-921. DLT was reported in 4 pts: 2/10 at 6 mg/m2 (both neutropenia with sepsis) and 2/7 at 7 mg/m2 (both Grade 4 neutropenia lasting >5d). MTD (−GCSF) was 6 mg/m2. Ten pts have been treated with SB-921 (+GCSF) at 6 (n=4), 7 (n=3) and 8 (n=3) mg/m2, with no DLT. Enrollment at 9 mg/m2 is ongoing. Among the first 39 pts treated with SB-921 (−GCSF), mean age was 47 yr, 49% were male, histology was 46% HL, 28% aNHL, and 26% iNHL, 67% had ≥3 prior CT regimens. The most common Grade 3/4 adverse event (AE) was neutropenia (42% of pts treated at or above MTD). Other Grade 3/4 AEs were uncommon. No neuropathy or alopecia >Grade 1 was reported. Demographics and AEs in the (+GCSF) cohort are similar with less Grade 3/4 neutropenia. Two partial responses (PRs) have been reported, both in elderly pts with HL, 1 at 6 mg/m2 (−GCSF) after 2 cycles and 1 at 8 mg/m2 (+GCSF) after 2 cycles.Conclusions: The MTD of SB-921 (−GCSF) on a d1/d15 q28d schedule was 6 mg/m2 (dose density = 0.42 mg/m2/d). The current MTD (+GCSF) is ≥8 mg/m2 and dose escalation is continuing. This dose density (0.57 mg/m2/d) is nearly 3-fold higher than observed in the FIH trial with a q21d schedule (0.2 mg/m2/d). SB-921 is well tolerated with few Grade 3/4 AEs other than hematologic. Activity has been observed in HL, with 2 PRs at doses ≥ the (−GCSF) MTD.

Somatostatin receptors subtypes 2 and 5, dopamine receptor type 2 expression and gsp status as predictors of octreotide LAR® responsiveness in acromegaly

We present two acromegalic patients in which clinical and molecular data are discussed in regard to their ability to predict long term octreotide LAR therapy response. Patient 1: female, 36 years old at diagnosis. Basal GH and IGF-I at diagnosis were 133 ng/mL and 181% above the upper limit of reference values (ULRV), respectively. Growth hormone during acute test with subcutaneous octreotide decreased from 133 to 13 ng/mL. Patient started on primary octreotide LAR therapy (20mg q28 days) and achieved biochemical parameters of disease control after 6 months. Molecular analysis of tumor fragments: gsp +; quantitative analysis of SSTR (somatostatin receptor) and DR (dopamine receptor) mRNA - SSTR2 23954; SSTR5 2407; DR2 total 17016 copies. Patient 2: male, 38 years old at diagnosis. Basal GH and IGF-I at diagnosis were 120 ng/mL and 114% ULRV, respectively. Patient underwent non-curative trans-sphenoidal surgery. Post-operative GH and IGF-I were 112 ng/mL and 137% ULRV, respectively. Growth hormone during acute test with subcutaneous octreotide decreased from 112 to 7 ng/mL. Octreotide LAR therapy (20 mg q28 days) was then initiated. After 6 months of treatment, patient did not attain biochemical control of disease and displayed increased tumor volume. Molecular analysis of tumor fragments: gsp not done; quantitative analysis of SSTR and DR mRNA - SSTR2 416; SSTR5 3767; DR2 total 3439 copies. In conclusion, these two cases illustrate how laboratory data can be conflicting as predictors of octreotide LAR responsiveness and how molecular analysis of tumor fragments can help explain different behaviors in clinically similar patients.

Safety, pharmacokinetics and preliminary activity of the anti-IGF-IR antibody CP-751,871 in patients with sarcoma

10501 Background: CP-751,871 is a fully human IgG2 monoclonal antibody against the insulin-like growth factor-I receptor (IGF-IR). Inhibition of the IGF-IR is a promising novel therapy for sarcoma. IGF-IR is implicated in autocrine and paracrine control of sarcoma, and IGF-IR blockade increases apoptosis and decreases migration, invasion, metastatic spread, and angiogenesis in sarcoma models. Methods: A cohort of patients (pts) ≥9 years of age with relapsed or refractory sarcoma, ECOG PS 0/1, and adequate hematological and biochemical function was opened with the primary objective of investigating the safety and tolerability of CP-751,871 in this pt population. Secondary objectives included evaluating pharmacokinetics and preliminary efficacy (RECIST). CP-751,871 was given by intravenous infusion at a dose of 20 mg/kg either q28 or q21 days. Results: Twenty-two pts were enrolled. Sarcoma subtypes treated were Ewing’s (n=9), synovial (n=5), desmoplastic small round cell tumors (DSRCT; n=3), rhabdomyosarcoma (n=2), fibrosarcoma (n=2), and chondrosarcoma (n=1). Median pt age was 35 years (range 12–63); 64% had ECOG PS 1. Median number of previous regimens was 3 (range 1–5). Pts received a median of 2 treatment cycles (range 1–16). Grade ≥3 treatment-related adverse events (CTCAE v3.0) reported included grade 4 uric acid increase (1 pt) and grade 3 bilateral deep-vein thrombosis (1 pt). Pharmacokinetics of CP-751,871 in sarcoma pts were comparable to those in other pt populations, with a half-life supporting the q21 or q28 day dosing regimen. Among 19 pts evaluable for response, one partial response was observed in a 12-year-old pt with Ewing’s sarcoma. Disease stabilization >3 months was observed in 6 pts (1 fibrosarcoma, 1 chondrosarcoma, 1 DSRCT, 1 synovial and 2 Ewing’s sarcoma pts). Six pts remain on study. Conclusions: CP-751,871 was well tolerated in pts with relapsed and/or refractory sarcoma. Preliminary activity in Ewing’s sarcoma warrants further investigation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology ImClone Systems Incorporated, Pfizer Oncology, sanofi-aventis Pfizer Oncology ImClone Systems Incorporated, sanofi-aventis Novartis, Pfizer Oncology, sanofi-aventis

Phase II study of neoadjuvant bevacizumab and trastuzumab administered with albumin-bound paclitaxel (nab paclitaxel) and carboplatin in HER2+ locally advanced breast cancer

627 Background: HER2 signaling up-regulates vascular endothelial growth factor (VEGF) resulting in subsequent tumor angiogenesis and tumor progression. SPARC is a known prognostic factor for poor survival and its expression increases with tumor aggressiveness. SPARC may mediate enhanced intratumoral accumulation of nab paclitaxel (nab-pac) via a SPARC-albumin specific binding activity. This multicenter phase II pilot study was designed to evaluate feasibility, toxicity, and preliminary efficacy of dual VEGF and HER2 receptor blockade with bevacizumab (B) and trastuzumab (T) in combination with neoadjuvant nab-pac and carboplatin. SPARC tumor assessments were performed at baseline. Methods: Eligibility: cT1–4, N0–3, M0 adenocarcinoma, FISH HER2+, normal LVEF, ECOG PS ≤2, adequate organ function, controlled hypertension (HTN), neuropathy ≤ G1, tumor tissue availability for SPARC testing. Treatment: Nab-pac 100mg/m2 weekly days 1, 8, 15 q28 days with carboplatin AUC of 6 day 1 q28 days x 6 cycles, B 5mg/kg qwk x 23 wks with T 4mg/kg loading dose followed by 2mg/kg qwk x 22 wks. Surgery ≥ 4 wks following last B. T at 6mg/kg and B 15mg/kg q3wk post op for a total of 1 year (B began ≥ 4 weeks post op). LVEF at baseline, 3, 6, 12, and 18 months. SPARC IHC was scored on a 0–3 level (0=absent, 1= weak, 2=moderate, 3=strong). Results: 25 pts are evaluable for toxicity. Histology: ductal 80%, lobular 12%. 48% ER-PR-. ECOG PS 0 - 90%. G3/4 toxicity in >5% of patients included: neutropenia 12 pts (48%) and hypertension 3 pts (13%). No LVEF dysfunction was noted. 4 pts went off study: 2 - pt wishes, 2 - toxicity (fatigue, reflux). 2 pts did not complete post op therapy (unrelated to treatment). Complete pathologic responses were noted in 5 pts and PRs in 3 pts. SPARC data were available for 19 pts (1 pt-level 0, 4 pts level 1, 10 pts level 2, 6 pts level 3). Conclusions: Neoadjuvant T plus B with nab paclitaxel and carboplatin is feasible with promising activity. No unexpected toxicities have been reported and there has been no early evidence of LVEF dysfunction. Correlation of SPARC tumor staining with pathologic responses as well as hormone receptor status will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech Abraxis, Genentech

Phase II study of neoadjuvant gemcitabine, epirubicin, and albumin-bound nab paclitaxel (GEA) in locally advanced breast cancer with SPARC tumor assessments

603 Background: Gemcitabine (G), anthracyclines and taxanes have significant activity as neoadjuvant therapy. SPARC, a known prognostic factor for poor survival, is an albumin binding protein that may mediate intratumoral accumulation of nab-paclitaxel (nab-pac) via a SPARC-albumin specific binding activity. This study investigated SPARC tumor status with pathologic correlatives and responses to neoadjuvant chemotherapy. Methods: Eligibility: Clinical T1c-T4-d and/or N0–3, M0 breast cancer (T1N0M0 excluded). ER/PR/HER2 status were obtained for all pts. ECOG PS 0–2, normal LVEF, Treatment: 6 cycles neoadjuvant G 2,000 mg/m2, epirubicin 50 mg/m2, and nab-pac 175 mg/m2 q14 days followed by surgery. Postoperative therapy: 4 cycles G 2,000 mg/m2 and nab-pac 220 mg/m2 q14 days. Myeloid growth factors were mandated with all cycles. Tumor SPARC immunohistochemistry was scored on a 0–3 scale (0=absent, 1= weak, 2=moderate, 3=strong). Fisher's exact test was used for statistical analyses. Results: 123 pts have enrolled with pathologic responses available for 95. 49 pts consented to SPARC testing, 32 pts declined, and 42 are in progress. Median age 51 (29–72). Median tumor size 4.5 cm. Histology: 78% ductal, 9% lobular, 13% others. 42% ER and PR negative. 55% clinical T3/T4 and 66% lymph node positive at presentation. G3/4 toxicity present in >5% of patients: neutropenia 10% (febrile neutropenia 1 pt), thrombocytopenia 5% with arthralgias, fatigue, and infection each in 7%. 20 pts did not complete study treatment for the following reasons: disease progression 7, toxicity 3, patient/MD request 5, and other 5. Total of 1,049 cycles were administered. pCR was noted in 21 pts (22%) with PRs in 69 pts (67%), and 5 SD. SPARC data were available for 44 pts (6 pts- level 0, 5 pts level 1, 14 patients level 2, 19 pts level 3). Pts who were ER+ were more likely to be SPARC+ (p=0.01). Pts who were triple negative were more likely to be SPARC- (p=0.04). Conclusions: Neoadjuvant dose dense GEA demonstrated favorable activity with pathologic response rates comparable to other neoadjuvant regimens albeit with minimal toxicity. Additional data on SPARC analyses are in progress and will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly and Company, Pfizer Abraxis Oncology, Eli Lilly and Company, Pfizer

A phase I study of concurrent pemetrexed (P)/cisplatin (C)/radiation (RT) for unresectable stage IIIA/B non-small cell lung cancer (NSCLC)

7550 Background: Concurrent chemoradiation is standard of care for most patients with unresectable stage III A/B NSCLC but no standard chemotherapy regimen/schedule has been established. A 3rd generation agent plus C provides maximal activity in stage IV NSCLC but to date, no 3rd generation agent is tolerable at full dose combined with RT and C. Pemetrexed/Cisplatin (PC) has shown activity in the stage IV setting and full dose P plus RT or RT/carboplatin appears tolerable. Methods: Starting Jan 30/06 (completed June 18/07), 13 patients with unresectable stage IIIA/B NSCLC were entered on four dose levels of a phase I trial evaluating PCRT (last follow-up Nov 8, 2007). Eligibility: < 5% weight loss; ECOG PS 0/1; no malignant effusions; FEV1 >1.3 l; adequate organ function. Pts received PC (Dose levels 1–3: P 300, 400 or 500 mg/m2 day 1, C 25 mg/m2 days 1–3; Dose level 4: P 500 mg/m2 day 1, C 20 mg/m2 days 1–5) q21 days x 2 concurrent with RT (61 - 66 Gy in 6 - 6.5 weeks) followed by PC alone x 2 q21 days (P 500 mg/m2 day 1, C 75 mg/m2 day 1). Dose escalation was governed by acute dose limiting grade 3/4 toxicities (DLT) delaying RT or PC (RT > 1 week, cycle 2 or 3 PC > 2 weeks). Results: 13 patients were accrued (Dose levels 1/2/3/4: 3/3/4/3). Demographics: median age - 64 years [range 47–74]; stage IIIA/B - 6/7; PS 0/1 - 4/9; median radiation dose - 64 Gy [range 60.5–66]. One patient had dose reduction of C for cycles 3 and 4 (elevated creatinine), cycles 3 and 4 were omitted for 2 (1 refusal; 1 cisplatin allergy). No DLT were observed. Neutropenia grade 3/4/febrile: 2/2/0 pts. Grade 3 esophagitis: 1 pt. Other grade 3 treatment-related toxicities were uncommon: pneumonitis (1); hypertension (2); diarrhea (1); anemia (1); hyperglycemia (1); hypophosphatemia (1); thrombocytopenia (1). Two pts required dilation for late (grade 3) esophageal stricture.12/13 pts achieved partial response (RECIST) after independent review. Disease progression has occurred in 5 pts (local - 1/13, distant - 5/13). Dose level 4 was recommended for phase 2 study. Conclusions: Full dose PC and full dose concurrent RT is well tolerated and active in stage III/B NSCLC. P is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent C/RT. A phase II study evaluating dose level 4 is accruing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly