Cohort Of HR Research Articles

Chemo-Immunotherapy Combination Of Idelalisib With Bendamustine/Rituximab Or Chlorambucil/Rituximab In Patients With Relapsed/Refractory CLL Demonstrates Efficacy and Tolerability

BackgroundPI3K-delta signaling is critical for proliferation, survival, homing and tissue retention of malignant B cells. Idelalisib is a selective, oral inhibitor of PI3Kδ that has been previously shown to be safe and tolerable and has demonstrated considerable activity as monotherapy or in combination with other agents in patients with relapsed/refractory (R/R) CLL. We provide an update on the safety and efficacy of a phase 1 study of idelalisib (IDELA) 150mg po BID administered continuously on a 28-day cycle in combination with two chemo-immunotherapy regimens: bendamustine/rituximab (IDELA+BR) and chlorambucil/rituximab (IDELA+ChR). MethodsTwenty-nine adult subjects (15/14 IDELA+BR; IDELA+ChR) with R/R CLL requiring treatment were enrolled between April and Aug 2011 for the IDELA+BR cohort and Mar and Jul 2012 for the IDELA+ChR cohort. Median age 64 yrs (Min, Max: 41, 82), gender M/F (%) 65/35, WHO PS (%) 0/1/2 59/38/3, current Binet stage (%) A/B/C 21/28/41, and 62% of subjects had bulky adenopathy (presence of ≥1 node with diameter ≥5 cm). Median number of prior therapies was 3 (Min, Max: 1, 9). Thirty-five percent of subjects had refractory disease (not responding to a standard regimen or progressing within 6 month of the last course of a standard regimen) and 55% of subjects were refractory to rituximab. The treatment schedule was as follows: IDELA+BR (IDELA 150 mg BID po d1-28 until progression or withdrawal, rituximab 375 mg/m2 IV on d1 of cycles 1-6, bendamustine 70 or 90 mg/m2 intravenously on d1 and d2 of cycles 1-6). For the IDELA+RCh cohort (IDELA 150 mg BID po on d1-28 until progression or withdrawal, chlorambucil 10 mg/m2 po once a d1-7 of cycles 1-12, rituximab 375 mg/m2 IV d1 of cycles 1-6). Response was assessed by the investigators based on scheduled CT evaluations and clinical criteria following IWCLL 2008. ResultsThe data cut-off date for this analysis was May 2013. Objective response rates for the 2 cohorts were 89.7% (95% CI (%): 72.6-97.8). Median time to response in both cohorts was 1.9 months. For IDELA+BR, the ORR was 86.7% (95% CI (%): 59.5-98.3) (CR 6.7%, PR 80%), neither median DOR nor median PFS have been reached and median exposure was 18.4 months (Min, Max: 1.2, 24.7). For IDELA+ChR, the ORR was 92.9% (95% CI (%): 66.1-99.8) (CR 14.3%, PR 78.6%), neither median DOR nor median PFS has been reached, and median exposure was 7.7 months (Min, Max: 1.9, 11.1).Commonly reported treatment-emergent AEs (≥20% of all subjects) and lab abnormalities of interest for IDELA+BR were (total(%)/≥grade 3 (%)): pyrexia (46.7/0) diarrhea (26.7/13.3), fatigue (20/0), neutropenia (86.7/60), thrombocytopenia (26.7/6.7), transaminase elevations (26.7/0), anemia (33.3/13.3). For IDELA+ChR, common TEAEs were: pyrexia (57.1/7.1), diarrhea (64.3/7.1), fatigue (42.9/21.4), neutropenia (64.3/42.9), thrombocytopenia (42.9/21.4), transaminase elevations (50.0/21.4), and anemia (42.9/14.3). ConclusionThe combination of IDELA+BR or IDELA+ChR is tolerable and demonstrates strong activity with an ORR of 89.7%. Median PFS and DOR have not been reached in the IDELA+BR or the IDELA+ ChR cohorts. The ability to induce responses in this particularly difficult-to-treat patient population with refractory disease, the non-overlapping toxicity with these agents, and the ease of administration makes this an option in this patient population. These results support further studies with these chemo-immunotherapy regimens in patients with CLL. Disclosures:Barrientos:Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Wagner-Johnston:Gilead Sciences: Research Funding. De Vos:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Dansey:Gilead Sciences: Employment. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Adewoye:Gilead Sciences: Employment. Furman:Gilead Sciences: Research Funding.

Abstract A68: Activity of the TORC 1/2 kinase inhibitor, CC-223, in hormone receptor positive (HR+) breast cancer cell lines and patients (pts) with genetically characterized HR+ breast cancer in a Phase I clinical trial.

Abstract Introduction: PIK3CA and PTEN are among the top five most frequently mutated genes in breast cancer. Activating mutation of PIK3CA or loss of function mutation in PTEN leads to constitutive activation of AKT and mTOR driving multiple downstream metabolic and proliferative pathways important to oncogenesis. There is also cross-talk between the PI3K/AKT/mTOR pathway and ER signaling and activation of the PI3K/AKT/mTOR pathway is associated with resistance to endocrine therapy. CC-223 is a potent and selective ATP-competitive mTOR kinase inhibitor, targeting both TORC1 and TORC2 complexes. Results: Pre-clinically, CC-223 potently inhibits the growth of breast cancer cell lines with GI50 values below 1 uM in 38 of 43 lines. Luminal-derived cell lines are more sensitive to CC-223 than basal-derived lines. Within the luminal subset, ER+, HER2+, PIK3CA mutant, or wild-type TP53 cell lines are more sensitive to CC-223; PTEN loss is not associated with increased CC-223 sensitivity. During the dose escalation part of the phase I clinical trial, 3 pts with breast cancer were enrolled. One pt with HR+/Her2- breast cancer had a durable PR (31 weeks). An expansion cohort of HR+/Her2- breast cancer enrolled 17 pts at a CC-223 dose of 45 mg QD in 28-day cycles and 13 pts were evaluable for tumor response. Deep sequencing of tumors for multiple cancer-related genes was performed. The most common (> 20%) related adverse events (all grades) reported in the breast cancer cohort were nausea, stomatitis, fatigue, anorexia, diarrhea, vomiting, hyperglycemia, rash, and thrombocytopenia. Exposure-dependent TORC1 (p4EBP1) and TORC2 (pAKT) inhibition was observed in blood cells; analysis of paired tumor biopsies is ongoing. Reduction in glucose uptake (> 25% decrease in SUV) on PET imaging at day 15 was observed in 4 of 8 patients with PET imaging data currently available. Three pts demonstrated RECIST PR in target lesions (one categorized as PD due to a new bone lesion); PIK3CA mutations were present in all 3 subjects. Of the two additional pts with PIK3CA mutations, one had SD > 6 months. The one PIK3CA mutated subject with PD at first restaging had a concurrent p53 mutation. Additional genetic abnormalities in mTOR and related pathways in subjects with target lesion PR involved PTEN, Rictor, and IGFR1 genes. Six subjects had SD after 2 cycles, with minor target lesion regression (0 to -30%) in 5 of 6, and with SD > 24 weeks in 1 of 6. Conclusion: The safety profile of CC-223 is typical for drugs targeting the mTOR pathway. Preclinical and clinical data support the activity of CC-223 in HR+ positive breast cancer, particularly in tumors with PIK3CA mutations. Breast Cancer Accrual: Cedars-Sinai (Mita): 4; SCRIL (Arkenau): 4; IGR (Varga): 4; SCRI (Bendell): 3 (all Part A); Moffitt (Mahipal): 2; UCSF (Munster): 1; JSOM (Paz-Ares): 1; ICR (DeLord): 1. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A68. Citation Format: Monica M. Mita, Hendrik-Tobias Arkenau, Johanna C. Bendell, Pamela N. Munster, Amit Mahipal, Jean-Pierre Delord, Luis G. Paz-Ares, Jean-Charles Soria, Shuichan Xu, Tam Tran, Tao Shi, Xiaoling Wu, Rajesh Chopra, Kristen Hege, Andrea Varga. Activity of the TORC 1/2 kinase inhibitor, CC-223, in hormone receptor positive (HR+) breast cancer cell lines and patients (pts) with genetically characterized HR+ breast cancer in a Phase I clinical trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A68.

Prevalence and Risk Factors for Oncogenic Human Papillomavirus Infections in High-Risk Mid-Adult Women

The epidemiology of high-risk (hr) human papillomavirus (HPV) infections in mid-adult women with new sex partners is undefined. We analyzed baseline data from 518 25- to 65-year-old women online daters. Women were mailed questionnaires and kits for self-collecting vaginal specimens for polymerase chain reaction-based hrHPV testing. Risk factors for infection were identified using Poisson regression models to obtain prevalence ratios (PRs). The prevalence of hrHPV infection was 35.9%. In multivariate analysis restricted to sexually active women, the likelihood of hrHPV infection was associated with abnormal Papanicolaou test history (PR = 1.42, 95% confidence interval [CI]: 1.10-1.84), lifetime number of sex partners >14 (compared with 1-4; PR = 2.13, 95% CI: 1.13-4.02 for 15-24 partners; and PR = 1.91, 95% CI: 1.00-3.64 for ≥25 partners), male partners with ≥1 concurrent partnership (PR = 1.34, 95% CI: 1.05-1.71), and male partners whom the subject met online (PR = 1.39, 95% CI: 1.08-1.79). Age was inversely associated with infection only in women who were sexually inactive (PR = 0.67 per 5-year age difference, adjusted for Papanicolaou history and lifetime number of partners). Compared with sexually inactive women, the likelihood of infection increased with increasing risk level (from low-risk to hr partners; P < 0.0001 by trend test). In multivariate analysis, infection with multiple versus single hrHPV types was inversely associated with ever having been pregnant (PR = 0.64, 95% CI: 0.46-0.90) and recent consistent condom use (PR = 0.56, 95% CI: 0.32-0.97), and positively associated with genital wart history (PR = 1.43, 95% CI: 1.03-1.99). Measures of both cumulative and recent sexual history were associated with prevalent hrHPV infection in this hr cohort of mid-adult women.

Conventional Cytogenetics, Molecular Profiling, and Flow Cytometric Response Data Allow the Creation of a Two-Tiered Risk-Group System for Risk-Based Therapy Allocation In Childhood AML- a Report From the Children's Oncology Group

AbstractAbstract 761Conventional cytogenetics and morphologic response to induction chemotherapy have historically provided the tools for predicting outcome in patients with acute myeloid leukemia (AML). Several mutations are predictive of clinical outcome and have provided additional tools to help predict outcome in patients with AML without other risk features. Despite these recent advances, our ability to identify specific risk groups has been limited to a subset of patients, and nearly half of the patients with AML are regarded as having standard-risk (SR) disease. We inquired whether adding response by multidimensional flow cytometry (MDF) to data from conventional cytogenetics analysis and presence/absence of genomic alterations of FLT3 (FLT3-ITD), CEBPA, and NPM would provide a more robust risk-stratification system for risk-based therapy allocation. COG AML protocol AAML03P1 collected comprehensive cytogenetics characteristics, mutation profile (FLT3/ITD, CEBPA, and NPM mutation status), and MDF data on most of the 340 eligible patients enrolled on the study. Molecular and cytogenetic data were available for 275 of the 293 (94%) patients with responsive disease at the end of induction I. Disease-free survival (DFS) from the end of induction I was determined based on a combined molecular and cytogenetic risk profile. Risk status was defined based on the presence of t(8;21), inv(16), NPMc, and CEBPA mutations (favorable risk, FR) or the presence of monosomy 7, monosomy 5/del5q, and high allelic ratio FLT3-ITD (high risk, HR). On the basis of this allocation, 88 (32%) patients had FR AML, and 26 (10%) had HR AML. The remaining 161 (59%) patients without specific risk features were considered to have SR AML. DFS at 2 years from the end of induction I was 70%±12% for the FR cohort, 55% ±9% for the SR cohort, and 17%±20% for the HR cohort (p<0.001). The prevalence and prognostic significance of minimal residual disease (MRD) were assessed in the 103 patients with SR disease; 31 (30%) had evidence of MRD by MDF. DFS at 3 years from the end of induction I was significantly worse for those with MRD than for those without it (26%±21% vs. 67%±13%, p=0.01). Corresponding relapse risk in patients with or without MRD was 69%±21% and 30%±13%, respectively (p=0.011). We assessed the clinical impact of MRD in patients with HR or FR disease. Of the 18 patients with HR AML who had MRD data, 8 (44%) had MRD. DFS at 2 years for patients with HR disease with or without MRD was not significantly different (13%±23% vs. 36%±40%; p=0.127). Of the 73 patients with FR AML, MRD was detected in 12 (16%); MRD did not significantly influence DFS at 3 years from the end of induction I in those patients (45%±33% vs. 72%±17%, p=0.138). Thus, although the presence of MRD was significantly associated with worse outcome in patients with SR AML, similar significance could not be demonstrated in the FR or HR cohorts. Clinical outcomes of risk groups were reassessed after combining the MRD data with specific cytogenetic and molecular risk groups, i.e., patients with SR AML and MRD were added to the HR cohort, and those without MRD were added to the FR cohort. In the new risk-stratification system, 57 of 217 (26%) patients were in the HR cohort, and the remaining 160 (74%) patients were in the FR cohort. DFS at 3 years from induction I was 68%±9% for the FR cohort and 20%±16% (p<0.001) for the HR cohort. Cumulative incidence of relapse at 3 years from the end of induction I for those with FR or HR disease was 27%±9% and 71%±17%, respectively (p<0.001). Cytogenetics, molecular genotyping, and post-induction MDF analysis provide a robust means of stratifying all pediatric patients with AML into 2 risk groups with significantly different outcomes. This novel risk-allocation schema will be implemented in the upcoming COG Phase III AML trial. Disclosures:No relevant conflicts of interest to declare.

A phase Ib trial of Bcl-2 inhibitor obatoclax in combination with carboplatin and etoposide for previously untreated patients with extensive-stage small cell lung cancer (ES-SCLC)

3576 Background: Obatoclax (Ob) is a small-molecule antagonist of all the Bcl-2 prosurvival proteins. In vitro it enhances the effects of the drugs cisplatin and etoposide. Bcl-2 family proteins are frequently expressed in SCLC, and SCLC cell lines are sensitive to Ob. Methods: This study was designed to find the maximal tolerated doses (MTD) of oOb when given on a 21 day (D) cycle together with carboplatin (AUC 5 D1) and etoposide (100 mg/m2 D1–3), in separate dose escalations using Ob as a 3-hr infusion D1–3 and as a 24-hr infusion D1–3. Eligible patients had ES-SCLC, measurable disease, ≤1 prior therapy, ECOG PS ≤1, and adequate hematological, renal and hepatic function. 3- 6 patients were enrolled into ascending dose cohorts with standard DLT rules evaluating safety in C1 to determine dose escalation. Results: 24 patients were enrolled into 5 dosing cohorts (14 males; median age 67). A total of 66 cycles (C) have been administered to date. There were no DLTs in the initial cohorts using Ob 15 mg over 3 hr or Ob 30 mg over 24 hr. Two DLTs occurred in the Ob 30 mg over 3 hr cohort - both due to myelosuppression in previously treated patients. As a result, the trial was amended to exclude previously treated patients. 5 previously untreated patients receiving Ob 30 over 3 hr had no DLTs. There were no DLTs in the Ob 45 mg over 24 hr cohort but 2 patients in the Ob 24-hr infusion cohorts had infusion pump malfunctions while at home. There were 2 DLTs in the Ob 45 mg over 3 hr cohort (somnolence, euphoria, &amp; disorientation) establishing MTD of Ob 30 mg over 3 hr daily x 3. After C2 the 6 previously untreated patients on Ob 24-hr infusion cohorts had 3 PRs, 1 SD, 1 PD, and 1 Unk; the 2 previously treated patients had PRs. After C2 all 7 previously-untreated patients at 15 or 30 mg in the 3-hr infusion cohorts have PR; the 3 previously treated patients had SD. Conclusions: Ob can be combined with carboplatin and etoposide using either a 3-hr or a 24-hr infusion, and both regimens are associated with high early response rates in ES-SCLC, perhaps due to inhibition of mcl-1. Due to practical issues with the 24-hr infusion arm, the 3-hr 30 mg MTD dose will be utilized in a randomized phase II versus carboplatin and etoposide alone. [Table: see text]

Comparison of the cost per distant disease-free year gained for upfront letrozole or anastrozole, or switched exemestane compared to tamoxifen for early breast cancer in hormone receptor-positive postmenopausal women: The UK perspective

557 Background: Due to subsequent poor prognosis, prevention of distant recurrence (DR) is a primary aim of adjuvant hormonal therapy for early breast cancer. Compared to 5 years TAM in hormone receptor positive (HR+) postmenopausal women, DR relative risks are 0.73 (95% CI 0.6 - 0.88) for 5 years letrozole (LET), 0.84 (95% CI 0.7 - 1.0) for 5 years anastrozole (ANA), 0.73 (95% CI 0.59 - 0.9) for 2–3yrs exemestane after 2–3 years (EXE/TAM). This analysis evaluates the incremental cost per distant disease free year gained from a UK NHS perspective of LET, ANA, EXE/TAM versus 5 years TAM using the same health economic model. Methods: A Markov model described pathways through relevant health states over the remaining lifetime of a cohort of HR+ women aged 61 yrs. Probabilities of breast cancer events (contralateral; locoregional; soft tissue, bone, and visceral metastases) adverse events (endometrial cancer, hip and other fractures, cardiovascular disease, thromboembolic events, and arthralgia) were based on the latest early breast cancer overview, published results of the BIG 1–98, ATAC, and IES trials, and UK population-based studies as appropriate. Conservatively, no carry-over effect was assumed for the AIs after therapy discontinuation. Costs (2005 UK£) of breast-cancer care were obtained from a primary costing study in Scotland, and treatment costs for AEs were obtained from published studies. Costs and DR-free years were discounted at 3.5% annually. Results: The mean durations of DDFS were estimated to be 12.81, 12.66, 12.57, and 12.35 years for LET, ANA, TAM/EXE, and TAM, respectively. The incremental cost per distant disease free year gained of LET vs TAM is £10,379 (95% CI £5,286-£17,818), of ANA vs TAM is £11,428 (95% CI £5,071- £48,856), and of TAM/EXE vs TAM alone is £11,020 (95% CI £4,820-£36,947). Conclusion: Compared to 5 years TAM, adjuvant treatment of postmenopausal HR+ women with an AI is a cost-effective use of UK NHS resources. Based on the mean results, LET appears to be the most cost-effective of the three AIs, despite its higher acquisition cost compared to ANA in the UK, though the confidence intervals are wide. [Table: see text]

International comparison of the cost-effectiveness of 5 years letrozole or anastrozole compared to 5 years tamoxifen for early breast cancer in hormone receptor-positive postmenopausal women: Belgium, Canada, UK, and US analyses

556 Background: The BIG1–98 and ATAC trials have proven the effectiveness of 5 years letrozole (LET) and anastrozole (ANA), respectively, compared to 5 years tamoxifen (TAM) for the treatment of postmenopausal women with hormone receptor positive (HR+) early stage breast cancer. This analysis uses similar assumptions to those used in the NICE appraisal in the UK, and country specific input data to estimate the cost-effectiveness of LET vs TAM and ANA vs. TAM from the Belgian, Canadian, UK, and US health care perspective (8 analyses). Methods: The same Markov model was used to estimate the incremental cost per quality-adjusted life year (QALY) gained (ICQ) across the 8 analyses in postmenopausal women with HR+ early stage breast cancer. Model events and assumptions were based on the analysis undertaken by the NICE appraisal team in the UK. Probabilities of breast cancer events (contralateral; locoregional; and metastases) were based on the latest early breast cancer (Lancet) overview. Country-specific cost, utility, and adverse event parameter values were informed by relevant population-based studies. LET and ANA effects were informed by published results of the BIG 1–98 and ATAC trials, which were assumed to cease after therapy discontinuation (other than fracture risk that continued for 5 further years). Costs and QALYs were estimated over the remaining lifetime of a cohort of HR+ women aged 60 yrs, discounted at 3.5% annually. Conclusion: Compared to TAM, adjuvant treatment of postmenopausal HR+ women with LET or ANA for 5 years is a cost-effective use of resources in all of the countries included in this analysis. Based on the model assumptions used by the NICE appraisal team in the UK, the mean results indicate that LET is more cost-effective than ANA, though the confidence intervals are wide. [Table: see text] No significant financial relationships to disclose.

Cost-effectiveness of letrozole and anastrozole as adjuvant therapy for hormone receptor positive early breast cancer in postmenopausal women

10577 Background: The BIG 1–98 and ATAC studies demonstrated that, in postmenopausal women with hormone receptor positive (HR+) early breast cancer, 5 years of initial adjuvant therapy with the aromatase inhibitors (AIs) letrozole (LET) or anastrozole (ANA) is superior to tamoxifen (TAM). The cost-effectiveness TAM, LET, and ANA have not been previously evaluated using a consistent methodology. Methods: A Markov model was used to estimate the incremental cost per quality-adjusted life year (QALY) gained with initial adjuvant therapy with LET vs TAM, ANA vs TAM, and LET vs ANA in postmenopausal women with HR+ early stage breast cancer from the US healthcare system perspective. Probabilities of recurrence (including contralateral tumor) and adverse events (endometrial cancer, thromboembolism, fractures, hypercholesterolemia, MI, and stroke) for TAM were based primarily on published US population-based studies and trials of prophylactic TAM vs placebo. Corresponding probabilities for LET and ANA were calculated by multiplying probabilities for TAM by estimated relative risks of LET vs TAM and ANA vs TAM from the BIG 1–98 and ATAC trials respectively. Other probabilities, costs, and health-state utilities were obtained from published studies. Expected lifetime costs and QALYs were estimated for a cohort of HR+ postmenopausal women with early breast cancer, aged 61 years at therapy initiation and discounted at 3% annually. Probabilistic sensitivity analyses were conducted to assess precision of results. Results: Incremental cost per QALY gained for LET vs TAM is $33,536 (95% CI $20,409 to $70,566) and for ANA vs TAM is $38,967 (95% CI $23,826 to $81,904). Compared with ANA, LET is less costly ($9,647 vs $10,190) and gains more QALYs (0.29 vs 0.26), although differences in costs (95% CI -$1,669 to $671) and QALYs (95% CI -0.16 to 0.22) are not statistically significant. Conclusions: In postmenopausal women with HR+ early breast cancer, adjuvant therapy with either LET or ANA is cost-effective from a US healthcare system perspective. Although LET dominates ANA in our base-case analysis, definitive conclusions regarding the cost-effectiveness of LET vs ANA must await results of comparative clinical studies. [Table: see text]