Relation Of Treatment Research Articles

Phase 1 study of the folic acid (FA) and tubulysin B hydrazide (TubBH) small molecule drug conjugate (SMDC) EC1456 in patients (pts) with advanced cancers (CA).

2551 Background: The folate receptor (FR) is expressed in many cancers, with limited expression in most normal tissues. EC1456, a potent SMDC of FA and the anti-tubulin cytotoxic TubBH, targets delivery of TubBH to FR-expressing cells. EC1456 demonstrated potent activity in paclitaxel- and cisplatin-resistant FR expressing cells. In murine models of FR-expressing xenografts, EC1456 caused complete tumor regression without significant toxicity. Enhanced anti-tumor activity was observed when EC1456 was combined with platinum, taxanes, and topotecan in preclinical models. These data led to this clinical evaluation of EC1456 in advanced CA pts. Methods: The primary objective is to determine the MTD of EC1456 administered on 2 schedules (BIW: days 1, 4, 8, 11 q 21 or 28 days [dosages: 0.5-6.0 mg/m2)], or QW: days 1, 8 q 21 days (dosage: 1.5-6.0 mg/m2). Key inclusion criteria: age ≥ 18 years, ECOG PS 0–1, and adequate organ function. 99mTc-etarfolatide scan to evaluate FR status is to be obtained on enrolled pts. Dose escalation follows the “3+3” protocol for BIW cohort, and continuous reassessment method for QW cohort. Cycle 1 DLT evaluation must be completed for each schedule cohort prior to dosing a new cohort. Results: 16 pts have been treated: median age: 67.5 (48-86), M/F: 7/16. 11 pts have received 50 cycles of EC1456 BIW (median 2; range: 1-16), and 5 pts have received 19 cycles of EC1456 QW (median 4; range: 1-8). The only DLT and treatment related (TR) SAE occurred at 4.5 mg/m2 QW schedule (Grade 3 infusion reaction). There have been no TR-deaths, Grade 4 toxicity, or toxicity causing dose delay, omission or reduction. Most TR-AEs have been Grade 1-2. Stable disease > 14 cycles has been observed in 2 pts with FR expression on 99mTc-etarfolatide SPECT scan (mesothelioma; GEJ CA) on BIW schedule, and SD > 6 cycles in 1 pt (leiomyosarcoma) on QW schedule. Conclusions: Due to the DLT on the QW schedule, cohort expansion is ongoing at 3.5 mg/m2. Dose escalation of EC1456 BIW is ongoing. EC1456 is generally well tolerated. PK data are anticipated in May 2015. Clinical trial information: 001999738.

Total Therapy 4 (TT4) for GEP70-Defined Low Risk Clinical Multiple Myeloma (CMM): Results of Patients Randomized to a Standard v Light Rrm (S-TT4 v L-TT4)

In recognition of the lack of progress in GEP70 high-risk CMM, we decided in 2008 to assign low and high risk patients to TT4 and TT5, respectively. In TT4, we elected to examine in a phase 3 trial, to determine whether L-TT4 was associated with lesser toxicity by reducing induction prior to and consolidation cycles after tandem transplants from 2 cycles each in S-TT4 to 1 cycle in L-TT4. To compensate for potentially reduced efficacy by this strategy in L-TT4, the transplant regimen was altered from a single melphalan dose of 200mg/m2 (MEL200) to a fractionated 50mg/m2/d x 4d (MEL50x4) schedule in L-TT4 with the addition of bortezomib and thalidomide (VTD) to exploit synergism between MEL50x4 and VTD. Two-hundred eighty nine patients were randomized (S-TT4, n=145; L-TT4, n=144) and stratified by ISS stage, presence of metaphase cytogenetic abnormalities (CA). With a median follow-up of 38.9m in both arms, 115 and 110 patients remain alive on S-TT4 and L-TT4, respectively. Two-year overall survival (OS) estimates are 90% and 87%; the corresponding PFS estimates are 84% and 80%. At the time of analysis, 91 and 92 achieved CR status, with 2-year CR duration estimates of 87% and 82% (P=0.06). Causes of death (COD) were divided into MM-related mortality (MRM), treatment-related (TRM) and “other/indeterminate” (OIM); at 2y, the relative COD estimates for the 3 groups were 2.1%/6.2%/1.4% for S-TT4 and 5.6%/5.6%/2.1% for L-TT4 (P=0.886/0.735/0.378). Grade 3 or higher non-hematological toxicities were similar between the 2 arms (GI: 39%/32%; Cardiac :22%/20%, infection: 8%/9%). Next we analyzed S-TT4/L-TT4 outcomes in the context of [anm1] metaphase cytogenetic abnormalities (CA). As depicted in Figure 1, a reversal of the CA implications in the 2 arms were observed. With S-TT4, both OS and PFS were inferior in with the chromosome 13 abnormalities or hypodiploidy (with patients having no CA or other CA (virtual all hyperdiploidy) having superior outcome (OS: P=0.01, PFS: P=0.06). With L-TT4, patients with no CA seemed to fare worse in terms of OS and PFS, but the differences did not reach statistical significance. There was a trend towards shorter 2-yr CR duration with L-TT4 visa S-TT4 (82% vs 87%, p=0.06) 2-Year estimate of time to relapse from CR was 8.1% in S-TT4 versus 11.5% in L-TT4 (p=0.07). Overall, the early results of this randomized study suggest that toxicities were similar on both arms. Trends for shorter CR duration and time to relapse from CR were seen in L-TT4. S-TT4 seems to benefit patients with no CA or other CA in terms of OS and PFS. Conversely patients with no CA fared worse with the fractionated MEL-approach although statistical difference was not yet observed. [Display omitted] [Display omitted] Disclosuresvan Rhee:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees.

LIFE YEARS LOST – A NOVEL APPROACH TO COMPARING COMPETING CAUSES OF TREATMENT RELATED MORTALITY

LIFE YEARS LOST – A NOVEL APPROACH TO COMPARING COMPETING CAUSES OF TREATMENT RELATED MORTALITY

Safety and efficacy of ezetimibe monotherapy in 1624 primary hypercholesterolaemic patients for up to 2 years

This report examined the safety and efficacy of treatment for up to 2 years with the cholesterol absorption inhibitor, ezetimibe (EZE). Two identical, randomised, double-blind trials (starting with 827 and 892 patients), evaluated the efficacy and safety of EZE 10 mg/day vs. placebo for 12 weeks in patients with primary hypercholesterolaemia [low-density lipoprotein cholesterol (LDL-C) 3.3-5.1 mmol/l]. Upon completion of these base studies, patients were offered a 2-year, open-label extension study. Adverse event (AE) reports for EZE monotherapy-treated patients were summarised for 3-month intervals to allow for comparison with the placebo group of the 3-month base studies. The primary end-point for this analysis was the evaluation of the long-term safety and tolerability of EZE 10 mg monotherapy dosed daily for up to 24 months. The incidences of new AEs, treatment-related (TR) AEs, serious AEs (SAEs), TRSAEs and discontinuations as a result of AEs during any 3-month interval were comparable with the respective observations in the placebo group of the base studies. The incidences of AEs, TRAEs, SAEs, TRSAEs and discontinuations as a result of AEs decreased in almost every interval compared with earlier intervals throughout the 2-year study. In addition, the incidences of > or = 3-fold consecutive elevations of liver transaminases (0.7%) or > or = 10-fold increases in creatine phosphokinase (0.4%) for the entire 2-year treatment period were comparable with those of the placebo group (0.7% and 0.2% respectively). LDL-C reductions of approximately 18% were maintained throughout the study. Compared with placebo, treatment with EZE for up to 2 years in 1624 patients showed no evidence of increased incidence of AEs with increased treatment duration, while showing sustained effects on LDL-C reduction.

Phase II trial of sequential bevacizumab (B), erlotinib (E) and chemotherapy for first line treatment of clinical stage IIIB or IV non-small cell lung cancer (NSCLC)

19130 Background: B improves survival in first-line treatment of selected patients (pts) with NSCLC. The addition of an EGFR inhibitor to B appears promising. Methods: Eligible pts with untreated stage IIIB (pleural effusion) or IV NSCLC and good PS were enrolled. Pts with brain metastasis, squamous histology, or hemoptysis were excluded. Treatment consisted of 3 modules. Module A: up to 4 cycles of B (15 mg/kg) every 21 days and E (150 mg qd). Module B: up to 4 cycles of carboplatin (AUC=6), paclitaxel (200 mg/m2) and B (15 mg/kg) every 21 days. Pts who had SD or any response in module A then continued treatment in module C: B every 21 days and E until PD. This study follows a three- stage design, with a maximum sample of 48 pts. The primary objective was to determine the rate of non-PD after module A. Results: 48 pts have been enrolled. Demographics: 30 males (62%), with a median age of 65 years (35–80). 79.2% (n=38) were Caucasian. ECOG PS was 1 in 60% (n=29). 45 (94%) pts had stage IV disease. 66% (n=32) of pts’ tumors were adenocarcinomas, followed by NSCLC not otherwise specified in 25% (n=12). 70% of pts were heavy smokers. In module A, 63% of pts had 4 cycles (n=30). Lack of progression was seen in 64% (n=31), and 12% had a PR. Treatment-related (TR) grade 3/4 AEs: 12% of pts had rash, 6% neuropathy, 4% diarrhea, 4% bowel perforation. 37 pts were treated on module B, with 36 evaluable for response (1 was taken off study due to thrombosis), resulting in PR in 21% (n=8), SD in 45% (n=17) and PD in 29% (n=11). TR grade 3/4 AEs: 10% of pts had neutropenia, 10% neuropathy, 8% infection. 23 pts were treated on module C (median 7 cycles per pt). 19 pts were evaluated for response: 17% (n=4) had PR, 39% (n=9) had SD and 26% (n=6) had PD. TR grade 3/4 AEs: 10% had thrombosis, 10% diarrhea, 10% neuropathy, one patient each with vomiting, anorexia, weight loss and one required an aneurysmal repair. 10 pts remain on study. Median survival for all pts was 12.9 months (95% CI= 7.1 to 18.6 mo). 1-year survival rate was 49%. Pts who had SD or PR in module A had a median survival of 23.2 mo (versus 6.6 mo, p<0.001). Conclusions: The combination of B and E followed by chemotherapy is feasible in pts with advanced NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech

Short and Long Term Efficacy of Autologous Bone Marrow Cells To Support Intensive Chemotherapy in Patients Failing Peripheral Blood Stem Cell Mobilization.

Introduction: Most autologous hematopoietic cell transplants (AHCT) are performed using peripheral blood mobilized progenitor cells (PBSC). However a small but significant proportion of patients (pts) are unable to mobilize adequate numbers of PBSC. The use of G-CSF-stimulated bone marrow (BM) derived progenitor cells is one method to circumvent this problem and enable AHCT to be performed. However, the long and short-term ability to engraft and the impact of this method on overall and progression free survival (OS and PFS) have not been established.Methods: We reviewed 52 pts (17 AML, 24 NHL, 11 HL) who failed PBSC collection between Jan 1999-Dec 2006 (<2×5106 CD34+cells/kg) and underwent G-CSF stimulated BM harvest to permit high dose therapy (etoposide 60 mg/kg + melphalan 160–180 mg/m2, + TBI 500 or 1200 cGy for pts with AML). 23 pts were supported by harvested BM (44%) and 29 (56%) with a mixture (Mx) of BM and PBSC. Overall and PFS was compared to pts undergoing AHCT using chemotherapy-mobilized PBSCs (n=440) in the same time period (AML n=32, NHL n=273, HL=135) who had a similar median age, pre-transplant induction, salvage therapy and intensive therapy regimens. Kaplan-Meier curves and the Log-rank test were used to compare the OS and PFS between cases and controls. Due to skewed data, the non-parametric Wilcoxon Rank Test was used for simple comparisons of clinical factors.Results: Median age of the cohort at AHCT was 43 years (range 24–68, 67% females). Status prior to AHCT was CR 44%, PR 54%, and SD 2%. Number of chemotherapy regimens (median):AML: 3; NHL: 3; HL: 2. Median BM CFU-GM infused was 4.4×104/kg and median PBSC infused was 0.1×106/kg (n=29). Median follow up times for AML/NHL/HL was 20, 18 and 50 months respectively. Twenty-three pts died:18 from disease progression, 4 treatment-related (TRM) and one of second cancer. Median engraftment time for neutrophils (>0.5×109/L) was 14 days and platelets (>20×109/L) was 27 days and was significantly longer compared to pts who received PBSC alone (10 and 11 days, respectively, p<0.0001). Pts receiving Mx grafts had significantly faster engraftment vs those receiving BM alone (p<0.001). Transfusion requirements (median) during the ASCT admission were 4 units for RBC and 25 units for platelets. Median 12 month Hb, platelet and neutrophil counts were 116 g/L (70–149), 113×109/L (21–238) and 2.4×109/L (0.3–6.2). Two year OS of patients who received harvested BM versus PBSC alone was: 63%/71% (AML, p=0.51), 57%/70% (NHL, p=0.04) and 71%/94% (HL, p=0.04). There was no significant difference in PFS between BM recipients and controls. Non relapse mortality was 5/52 (9.6%) for pts receiving BM compared to 18/440 (4%) supported by PBSCs.Conclusion: Performing an AHCT with BM in patients failing PBSC collection is feasible. Although engraftment is significantly delayed it appears sustained at 12 months post AHCT. Overall survival is inferior compared with patients receiving PBSC alone. Reasons for inferior disease-specific outcomes for pts with lymphoma receiving BM need to be determined.

Open-label, multicenter, phase II trial of ABI-007 in previously treated and previously untreated patients with metastatic malignant melanoma

7558 Background: ABI-007 (Abraxane TM), is an albumin-bound, nanoparticle form of paclitaxel with an improved therapeutic index that may be related to biological interactions with endogenous albumin receptors (eg, gp60) and binding proteins (eg, SPARC). The albumin-binding protein SPARC (osteonectin) was overexpressed in primary and metastatic malignant melanomas but not in normal melanocytes (Ledda et al, J Invest Derm 108:210, 1997) and was a predictor of clinical outcome in thin melanomas (Massi et al, Human Path 30:339, 1999). Methods: We conducted a Phase II study of ABX administered weekly for 3 weeks q4w without premedication in chemotherapy-naive (CN) (150 mg/m2) and previously treated (PT) (100 mg/m2) patients (pts) with measurable metastatic malignant melanoma (MMM). Results: 13 CN and 36 PT pts have been enrolled; 11 CN and 13 PT pts are currently evaluable for toxicity and response. Median age was 59 (range, 32–79); median number of metastatic sites was 2 (range, 1–8); median ECOG PS was 0 (range, 0–1). 8 CN and 12 PT pts had visceral involvement. The median number of monthly cycles received was 4 (range, 2–6) for CN pts and 4 (range, 1–6) for PT pts. 9 CN and 25 PT pts are continuing treatment. 84% (CN) and 92% (PT) of cycles were given without dose modification. No treatment-related (TR) deaths or TR grade (G) 4 toxicities occurred; no cases of febrile neutropenia were reported. TR G3 toxicities included fatigue (13%); neutropenia (13%); leukopenia (8%); rash (8%); alopecia, anemia, infection, lymphedema, motor neuropathy, and tumor pain (4% each). 3 CN and 9 PT pts have progressive disease. 2 CN pts have achieved a partial response; 1 additional CN and 4 PT pts with stable disease have continued on ABX without progression for >/= 24 weeks. Conclusions: ABX was well tolerated and resulted in long-term disease control in patients with MMM, some of whom had rapidly progressive disease while on previous therapy. Final study results will be presented. However, based on these encouraging early results in pts with aggressive visceral disease, further studies with ABX in MMM are being considered. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration American BioScience American BioScience

Long term disease control in taxane-refractory metastatic breast cancer treated with nab paclitaxel

543 Background: nanoparticle albumin bound (nab) paclitaxel (ABI-007, Abraxane, ABX) is a novel, cremophor-free paclitaxel preparation with a high therapeutic index that does not require pre-medication. Methods: We have conducted a Phase II study of weekly ABX in patients with taxane-refractory, measurable metastatic breast cancer (MBC). Patients received ABX 100mg/m2 weekly over 30 minutes on day 1, 8, and 15 on a 28-day cycle without pre-medication. Results: 106 patients have been enrolled and 66 patients are currently evaluable for toxicity and response. Patients were considered taxane-refractory if they had progressive MBC while receiving paclitaxel, docetaxel or both (59 patients); or if they had relapsed within 12 months of adjuvant taxane (7 patients). Median age was 53 (range, 34–75); median number of metastatic sites was 3 (range, 1–6); 31 (47%) patients have hormone receptor positive MBC; median number of prior chemotherapy regimens (metastatic setting) was 3 (range, 1–10). Thirty-five (53%) patients were treated with docetaxel and 40 (61%) patients received paclitaxel for MBC; 21 (32%) patients received an adjuvant taxane. Based upon AE reporting the only treatment related (TR) Grade (GR) 4 toxicity was neutropenia, occurring in 5 (8%) patients; there was 1 case of febrile neutropenia. Other TR toxicities included: GR 3 nausea, infection (3 patients); GR 2: fatigue, vomiting (2 patients each); GR 1 constipation, dehydration, diarrhea, edema, mucositis and sensory neuropathy (1 patient each). Among the 66 evaluable patients, 13 (20%, 95% CI: 10–29%) had PR. Seven responding patients and 3 additional patients with stable disease (total of 10 patients, 15%, 95% CI: 7–24%) have continued on ABX without progression for ≥ 24 weeks; 5 of these patients are still on treatment with ABX for > 1 year. Conclusion: ABX has an excellent safety profile and resulted in long term disease control in heavily pretreated patients with taxane-refractory MBC. Based upon these results, this study has been amended to treat additional patients using this schedule at an increased dose of 125 mg/m2. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration American Bioscience, Inc.

Thoracic radiation therapy before autologous bone marrow transplantation in relapsed or refractory Hodgkin’s disease

The aim of this study was to assess the relationship between radiation therapy (RT) and treatment-related mortality in patients receiving high-dose chemotherapy (HDCT) and autologous bone marrow transplantation (ABMT) for recurrent/refractory Hodgkin’s disease (HD). Between December 1986 and December 1992, 59 patients previously treated at the Princess Margaret Hospital underwent HDCT (etoposide 60 mg/kg, melphalan 160 mg/m 2) and ABMT, performed for refractory (13 patients) or relapsed (46 patients) HD. RT was incorporated in the salvage treatment with the intent to achieve complete control of disease prior to ABMT. RT was given before ABMT in 33 patients, and after ABMT in 4 patients. Treatment-related (TR) mortality was defined as any death occurring within 100 days of ABMT. Autopsies were performed for all patients with TR deaths. With a median follow-up of 4.6 years (range 1.2–7.4 years), the actuarial overall survival was 41%±14% at 5 years. We observed 37 deaths, and 10 of these were TR deaths. Among the 24 patients who received thoracic RT before ABMT, there were 8 TR deaths, 3 of these solely attributable to radiation pneumonitis. The remaining 5 TR deaths all had respiratory failure with complicating sepsis as a major medical problem. The interval from RT to ABMT was shorter for 8 patients dying of TR death (mean 37 days; range 0–103 days), than for the 16 survivors (mean 105 days; range 0–263 days) ( P=0.026). Among 9 patients with ABMT within 50 days of thoracic RT, 6 had TR death. In contrast, among the 35 patients without thoracic RT (26 no RT, 9 non-thoracic RT), there were only 2 TR deaths. The 4 patients treated with mantle RT post-ABMT had no serious pulmonary complications. The use of thoracic RT before HDCT and ABMT was associated with a high post-transplant mortality rate. It was most evident in patients who received thoracic RT within 50 days prior to ABMT, or when the target volume included large volume of lung. We recommend that the use of post-transplant RT be investigated to decrease TR mortality.