198 research outputs found
Truth After cinema: The explosion of facts in the documentary films of Jia Zhangke
No full textThis is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2013 Intellect Books.This article identifies and elaborates on two models of resistance evident in JiaZhangke’s film corpus. The deployment of different cinematic strategies produces an experimental calling into question of the value of truth and of truth as value. In the films here analysed Jia moves from resistance through organic observation to a model of resistance structured around a series of fabulations. If the first regime addresses the truth of ideology, then the target of the second is the ideology of truth. It is in this passage that Jia enters political cinema, collapsing the distinction between factual and fictional and opening up a space that belongs to no collectivity
SOPHIA : A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ metastatic breast cancer
No full textAbstract
Background: Despite significant advances in targeted therapy, HER2+ metastatic breast cancer (MBC) remains incurable. Ideal treatment includes pertuzumab and trastuzumab in combination with a taxane in the first line setting, followed by ado-trastuzumab emtansine on progression. Optimal treatment regimens in the third and greater line of therapy are not defined, but continued anti-HER2 therapy is recommended. Margetuximab is a Fc-modified monoclonal antibody to HER2 that recognizes the same epitope on HER2 as does trastuzumab, with similar affinity. Margetuximab demonstrates increased affinity to the activating CD16A Fc-receptor found on NK cells and macrophages and decreased affinity to the inhibitory CD32B receptor compared to trastuzumab. In vitro studies showed enhanced antibody dependent cell-mediated cytotoxicity compared to trastuzumab. In a Phase 1 dose escalation and expansion trial, margetuximab showed single agent clinical activity against HER2+ tumors in patients previously treated with trastuzumab and other anti-HER2 agents. Methods: SOPHIA is a randomized, prospective study testing the hypothesis that margetuximab plus chemotherapy (CTX) is more effective than trastuzumab plus CTX in patients previously treated for HER2+ MBC. Sequential primary endpoints are centrally assessed progression free survival (PFS) and overall survival (OS). The study size of 530 patients is determined to have 80% power to detect a hazard ratio for OS of 0.75. Secondary endpoints are investigator assessed PFS and centrally assessed overall response rate. Eligibility includes prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine; no more than 3 prior lines of therapy in the metastatic setting; prior demonstration of HER2+ status at a local reference laboratory; and absence of active brain metastases. Eligible patients are randomized 1:1 to receive CTX (physician's choice: capecitabine, eribulin, gemcitabine or vinorelbine) plus either margetuximab or trastuzumab until disease progression or toxicity. Antibody may be continued after stopping CTX in patients with responding or stable disease. Progress to date: The trial was initiated July 2015 and is ongoing in the US and Europe with planned expansion to Korea and Israel. ClinicalTrials.gov Identifier NCT02492711; Eudract 2015-000380-13.
Citation Format: Rugo HS, Pegram MD, Gradishar WJ, Cortes J, Curigliano G, Hong S, Wigginton JM, Lechleider RJ, Cardoso F. SOPHIA: A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-02-07.</jats:p
Abstract P1-09-01: A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC)
No full textAbstract
Background: Abemaciclib is a selective and potent small molecule inhibitor of CDK4 and 6, with evidence of single-agent antitumor activity, and a safety profile that enables dosing on a continuous schedule. Abemaciclib demonstrated anti-tumor activity as a single agent with a 19.7% objective response rate for women with previously treated HR+, HER2- MBC1. In the phase 1b study JPBH, abemaciclib demonstrated a tolerable safety profile when combined with endocrine or HER2 targeted agents for MBC2. Abemaciclib given BID in combination with pembrolizumab also demonstrated a tolerable safety profile in phase 1b study of stage IV NSCLC3.
Methods: JPCE is a multicenter, nonrandomized, open-label, phase 1b study of abemaciclib plus pembrolizumab for patients with HR+, HER2- MBC or NSCLC (ClinicalTrials.gov NCT02779751). The study has 3 disease-specific cohorts, each with approximately 25 patients (N=75); the HR+, HER2- MBC cohort (part C) will be presented here. The primary objective was to characterize safety of the abemaciclib and pembrolizumab combination. Secondary objectives included efficacy endpoints (objective response rate, disease control rate, duration of response, progression-free survival, and overall survival), pharmacokinetics of abemaciclib plus pembrolizumab, and changes in patient-reported pain and disease-related symptoms. Patients received 150 mg of abemaciclib orally Q12H plus pembrolizumab 200 mg as a 30-minute IV infusion on Day 1 every 21 days. Eligible patients included women with confirmed HR+, HER2- MBC who have previously received at least 1 but no more than 2 prior chemotherapy regimens for MBC; are able to provide tumor tissue at baseline and at cycle 3, day 1; have measurable disease (RECIST v.1.1), adequate organ function, ECOG PS ≤1, are able to swallow oral medications; and have not received treatment with CDK4 & 6 or PD-1/ PD-L1 inhibitors.
Results: At the time of abstract submission, study JPCE part C cohort (HR+, HER2- MBC) was fully enrolled at 25 patients. Data to be presented include patient demographics, baseline disease characteristics, adverse events by frequency and by grade, and preliminary efficacy of the abemaciclib plus pembrolizumab combination in HR+, HER2- MBC.
References:
1. Dickler et al, Clin Cancer Res. 2017
2. Goetz et al. poster presented at SABCS, 2015
3. Goldman et al. poster presented at IASLC 2016
Citation Format: Rugo HS, Kabos P, Dickler MN, John WJ, Smith I, Lu Y, Young S, Tolaney SM. A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-01.</jats:p
Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer: how the latest results are improving therapeutic options
No full textHuman epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) remains an incurable disease, and approximately 25% of patients with HER2+ early breast cancer still relapse after adjuvant trastuzumab-based treatment. HER2 is a validated therapeutic target that remains relevant throughout the disease process. Recently, a number of novel HER2 targeted agents have become available, including lapatinib (a small molecule tyrosine kinase inhibitor of both HER2 and the epidermal growth factor receptor), pertuzumab (a new anti-HER2 monoclonal antibody) and ado-trastuzumab emtansine (T-DM1, a novel antibody-drug conjugate), which provide additional treatment options for patients with HER2+ MBC. The latest clinical trials have demonstrated improved outcome with treatment including pertuzumab or T-DM1 compared with standard HER2 targeted therapy. Here we review the clinical development of approved and investigational targeted agents for the treatment of HER2+ MBC, summarize the latest results of important clinical trials supporting use of these agents in the treatment of HER2+ MBC, and discuss how these results impact therapeutic options in clinical practice.SCI(E)[email protected]
Abstract OT2-3-04: A PILOT PHASE II STUDY TO EVALUATE THE IMPACT OF DENOSUMAB ON DISSEMINATED TUMOR CELLS (DTC) IN PATIENTS WITH EARLY STAGE BREAST CANCER (ESBC)
No full textAbstract OT2-07-06: Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009)
No full textAbstract
Background:Hormone receptor positive (HR+) disease is the most common subset of advanced breast cancer (BC). The majority of women with HR+ metastatic BC (MBC) develop resistance to endocrine therapy (ET), with a median survival of 2-3 years. A new strategy to treat HR+ MBC involves the combination of ET and a cyclin-dependent kinase 4/6 inhibitor (CDKi 4/6), which has demonstrated improved progression-free survival (PFS) in both first-and later-line MBC. Preclinical evidence in PI3K-mutant cell-line xenografts demonstrated that combinations of PI3K and CDK4/6i reduced intrinsic and adaptive resistance to ET, leading to tumor regression (Vara, 2004; Pfizer data). Inhibition of the PI3K/mTOR pathway by gedatolisib (G) may provide a new therapy to overcome ET resistance. These findings support developing the triplet combination of G with the CDKi 4/6 palbociclib (P)+letrozole (L) or fulvestrant (F) for the treatment of patients (pts) with ER+/HER2- BC.
Methods: This ongoing study in women with ER+/HER2- MBC, in first- and later-line settings, includes a dose-escalation (DE) to evaluate dose-limiting toxicities (DLTs, primary endpoint [pEP]) and determine the maximum tolerated dose and recommended phase 2 dose (RP2D) for a triplet regimen of G+P+L or G+P+F. The escalation rules follow the modified toxicity probability interval method (G doses: 180 and 215 mg IV weekly). Treatment assignment to the triplet is based on investigator decision and bone-only disease is permitted. After RP2D determination for each triplet, a 3-arm expansion for early signs of efficacy (ESOE) will investigate objective response rate (ORR) compared to historical controls [pEP] of Arm A) G+P+L in first-line, B) G+P+F in pts with no prior CDKi 4/6 in second-line and C) G+P+F in pts who have received prior CDKi 4/6. Pts receive G+P (125 mg oral daily for 21 days [D] on and 7 D off) + L (2.5 mg oral daily) or F (500 mg IM on D1, 15 of cycle [C] 1; D1 of C2 and then 500 mg IM on D1 of all 28-D cycles). Secondary endpoints include safety, tumor response (DE), PFS (ESOE), pharmacokinetics (PK), and biomarker correlations associated with the PI3K/mTOR pathway.
Results: 27 pts received G (180 mg/week) in combination with P+L (L cohort, n=12) or P+F (F cohort, n=15). Median prior therapies were: L cohort: 1 (range: 0-4); F cohort: 2 (range 1-5). The 3 most common, drug-related adverse events (%) were in L cohort: nausea (75), neutropenia (67), and stomatitis (67); F cohort: stomatitis (67), nausea (60), and neutropenia (53). C1 DLTs were: L cohort: grade (gr) 3 neutropenia (n=1); F cohort: gr 3 stomatitis (n=1). Preliminary rates of stable disease/partial response were: L cohort: 33%/16%; F cohort: 40%/13%. PK parameters and next-generation sequencing of PI3K-related mutations are pending.
Conclusions: G can be combined with P+L or P+F with manageable toxicity and promising preliminary antitumor activity, even in heavily pretreated pts. Dose escalation, followed by expansion for ESOE, is ongoing.
This study is sponsored by Pfizer. Editorial support was provided by Engage Scientific Solutions and was funded by Pfizer.
Citation Format: Forero A, Han HS, Dees EC, Wesolowski R, Bardia A, Kabos P, Kern KA, Perea R, Pierce KJ, Houk B, Rugo HS. Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-06.</jats:p
Abstract OT2-07-05: A phase III, randomized trial of sacituzumab govitecan (IMMU-132) vs treatment of physician choice (TPC) for metastatic triple-negative breast cancer (mTNBC)
No full textAbstract
Background: Metastatic TNBC has an aggressive course with limited therapy options and poor survival. Sacituzumab govitecan (IMMU-132) is a novel antibody drug conjugate consisting of SN-38, the active metabolite of the topoisomerase I inhibitor, irinotecan, conjugated to a humanized mAb targeting Trop-2, which is highly expressed in most epithelial cancers, including TNBC. We previously reported that patients (pts) with mTNBC treated with IMMU-132 after a median of 5 prior therapies from initial diagnosis achieved a 30% objective response rate (ORR), 8.9 mo median duration of response (DOR), and an acceptable safety profile with nausea, neutropenia, and diarrhea the most common toxicities (Bardia et al., JCO, 2017). IMMU-132 was awarded Breakthrough Designation by the FDA based on this data. Accordingly, we are enrolling additional patients with relapsed/refractory mTNBC with intention of seeking regulatory approval as a ≥3rd-line therapeutic option.
Trial design: An international, open-label, Phase III study in pts with refractory/relapsed mTNBC after ≥2 prior chemotherapies for advanced disease or &gt;1 therapy for pts who progress within 12 months of adjuvant therapy (NCT02574455). Pts are randomized 1:1 to receive either IMMU-132 (10 mg/kg IV, days 1 and 8 every 21 days) or TPC from one of 4 prespecified single-agent regimens (capecitabine, eribulin, vinorelbine or gemcitabine). Pts continue treatment until progression requiring discontinuation or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) and additional endpoints include overall survival (OS), ORR, DOR, safety and quality of life. Independent, blinded reads of scans will be performed.
Eligibility criteria: Adults &gt;18 yrs old, with metastatic breast cancer, triple-negative by most recent biopsy, measurable disease by CT or MRI as per RECIST1.1, ECOG performance score 0 or 1, adequate safety laboratories. Refractory/relapsed after ≥2 prior standard chemotherapy regimens for advanced disease, or &gt;1 therapy for pts who progress within 12 months of adjuvant therapy. Pts must have received taxane and be eligible by investigator to receive at least one of the TPC agents. Pts with treated, non-progressive brain metastases are eligible.
Specific aims: To compare IMMU-132 to TPC as measured by PFS, OS, ORR, DOR,QOL, adverse events, safety laboratories, incidence of dose delays and reductions, and treatment discontinuations due to toxicity.
Statistical methods: Assuming a median PFS of 3 mo. and OS of 10 mo. with TPC vs. 5 and 15 mo. with IMMU-132, respectively, a study size of 328 patients has &gt;95% and &gt;80% power to detect a statistically significant difference in PFS and OS, respectively, between the two treatment arms.
Present accrual and target accrual: Trial enrollment will begin prior to SABCS 2017 with approximately 328 patients expected to be enrolled over 18 months at approximately 100 institutions in North America, Europe and potentially elsewhere.
Contact: [email protected]
Citation Format: Bardia A, Rugo HS, Horne H, Wegener WA, Goldenberg DM, O'Shaughnessy J. A phase III, randomized trial of sacituzumab govitecan (IMMU-132) vs treatment of physician choice (TPC) for metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-05.</jats:p
Abstract OT1-04-04: A phase 2 randomized, double-blind, placebo-controlled trial of endocrine therapy ± radium-223 dichloride in HER2-negative, hormone receptor–positive breast cancer patients with bone metastases
No full textAbstract
Background: Bone-metastatic breast cancer (MBC) treatment is limited. In a phase 2a study of bone-dominant MBC patients, radium-223, a first-in-class α emitter with targeted cytotoxic effect on bone metastases (mets), reduced bone biomarker levels with favorable safety (Coleman et al. Breast Cancer Res Treat. 2014).
Trial design: This study evaluates efficacy and safety of radium-223 versus placebo (pbo), each + endocrine treatment (ET), in patients with HER2- estrogen receptor+ (ER+)bone-dominant MBC (NCT02258464). Patients receive (1:1) radium-223 50 kBq/kg IV or pbo q 4 wk (6 cycles) + ET + denosumab or bisphosphonates + best supportive care. Stratification is by geographic region (EU/N America vs Asia), number of prior ET lines (1 vs ≥ 2) for MBC, and number of prior skeletal-related events (SREs) (1 vs 2).
Eligibility criteria: Eligible patients are pre- or postmenopausal with HER2- ER+ bone-dominant MBC and ≥ 2 bone mets or with soft tissue and/or visceral mets, and 1-2 prior SREs (external beam radiotherapy, pathologic bone fracture, spinal cord compression, orthopedic surgery); they have received ≥ 1 line of ET for MBC and are considered appropriate for further ET. Patients must have evaluable disease (RECIST 1.1), be taking bisphosphonates or denosumab for ≥ 1 month before study treatment, have an ECOG score 0-1, and have adequate hematologic, renal, and liver function. Patients must not have had visceral or brain mets or leptomeningeal disease, or need chemotherapy for MBC, and must not be suitable for everolimus for MBC. Patients are not eligible if they had prior radium-223 treatment or have untreated spinal cord compression.
Specific aims: The primary end point is SSE-free survival (SSE-FS). Secondary end points are radiologic progression-free survival; overall survival; times to opioid use, pain progression, and cytotoxic chemotherapy; pain improvement rate; and safety. Patients are assessed for efficacy and safety and are followed to SSE, radiologic progression, death, or withdrawal.
Statistical methods: Assuming 1-sided α 0.1, power 90%, ∼ 119 SSE-FS events are needed for analysis. Time-to-event analysis will use a log-rank test, accounting for stratification. Kaplan-Meier estimates and survival curves will be given for each treatment group. Safety analyses will be descriptive.
Present and target accrual: Target accrual is ∼ 227. Currently, 40 patients are randomized.
Contact Oana Petrenciuc, Bayer HealthCare Pharmaceuticals, [email protected], for more information.
Citation Format: Coleman RE, Fried G, Petrenciuc O, Sawhney A, Li R, Rugo HS. A phase 2 randomized, double-blind, placebo-controlled trial of endocrine therapy ± radium-223 dichloride in HER2-negative, hormone receptor–positive breast cancer patients with bone metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-04.</jats:p
Abstract OT1-04-05: A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases
No full textAbstract
Background: Treatment options for bone-dominant metastatic breast cancer (MBC) are limited. Radium-223, a first-in-class α emitter with a targeted antitumor effect on bone metastases (mets), was well tolerated and reduced bone biomarker levels in a phase 2 study in patients with bone-dominant MBC (Coleman et al. Breast Cancer Res Treat. 2014). In patients with HER2- estrogen receptor+ (ER+) bone-dominant MBC, everolimus + exemestane (EVE+EXE) improved progression-free survival (PFS) versus EXE alone. Radium-223 combined with EVE+EXE may improve outcomes in patients with HER2- ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of radium-223 versus placebo in these patients (NCT02258451).
Trial design: Patients are randomized to receive (1:1) radium-223 (50 kBq/kg [55 kBq/kg after National Institute of Standards and Technology update] IV) or placebo × 6 cycles q 4 wk + EXE (25 mg PO q d) + EVE (10 mg PO q d) plus best supportive care. EXE+EVE continues until disease progression or unacceptable toxicity. Stratification is by geographic region (EU/N America vs Asia), prior hormone therapy (1 vs ≥ 2), and presence of visceral disease (yes vs no).
Eligibility criteria: Eligible patients are pre- or postmenopausal with HER2- ER+ MBC and have ≥ 2 bone mets or have soft tissue and/or visceral mets. Patients must have measurable disease per RECIST v1.1, ≥ 1 prior line of hormone therapy for MBC, and 1-2 prior skeletal-related events; be on bisphosphonates or denosumab; and have an ECOG score of 0-1. Patients must have had no past or current need for chemotherapy for MBC, no unresolved spinal cord compression, and no prior EVE treatment.
Specific aims: The primary end point is symptomatic skeletal event–free survival (SSE-FS). Secondary end points are overall survival; times to opiate use, pain progression, and cytotoxic chemotherapy; radiologic PFS; and safety. Safety and efficacy are assessed every 4 weeks. Long-term safety is assessed until study termination.
Statistical methods: Assuming a 1-sided α of 0.1, 90% power, ∼ 160 SSE-FS events will be required for the analysis. Efficacy will be analyzed by a stratified log-rank test. Safety analysis will be descriptive.
Present and target accrual: Estimated enrollment is ∼ 311 patients. Currently, 74 patients are randomized.
Contact Oana Petrenciuc, Bayer HealthCare Pharmaceuticals, [email protected], for more information.
Citation Format: Rugo HS, Drumea KC, Campone M, Barnadas A, Petrenciuc O, Zhang A, Li R, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-05.</jats:p
Dosing and Safety Implications for Oncologists When Administering Everolimus to Patients With Hormone Receptor-Positive Breast Cancer
No full textAbstractAberrations in the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway are common abnormalities in breast cancer and are associated with the development of resistance to endocrine- and human epidermal growth factor receptor (HER)2-targeted therapies. Because of the significant improvement in progression-free survival for everolimus plus exemestane compared with exemestane plus placebo, everolimus, an mTOR inhibitor, was approved in the United States for the treatment of patients with hormone receptor-positive (HR+), HER-negative, advanced breast cancer whose disease had progressed while receiving letrozole or anastrozole. To provide optimal prevention and management strategies, it is crucial that clinicians are aware of the adverse events (AEs) associated with mTOR inhibition. Understanding the appropriate dose modifications will help reduce toxicity and improve drug tolerance, thus achieving the optimal benefit from everolimus. Analyses of data from the Breast Cancer Trials of Oral Everolimus 2 trial have shown that, despite a greater frequency of AEs in the everolimus plus exemestane treatment arm, the AEs were effectively managed with temporary dose reductions or interruptions. In some cases, the full dose of everolimus could be resumed. Despite a lower mean dose and duration of exposure in patients aged ≥ 70 versus < 70 years, everolimus plus exemestane was similarly efficacious, suggesting that appropriate dose reductions for toxicity will not adversely impact efficacy. Appropriate modification of the everolimus dose and dose delay according to the severity of AEs, with resumption of the optimal dose of everolimus when toxicity has improved, will positively affect patient outcomes in HR+ advanced breast cancer
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