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  • 1
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    Abstract P6-18-10: A phase 1b/2 study of ribociclib plus trastuzumab for the treatment of advanced, treatment-refractory HER2-positive breast cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P6-18-10-P6-18-10
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P6-18-10-P6-18-10
    Abstract: Introduction: Despite the success of anti-HER2 therapy, acquired resistance usually develops in the metastatic setting. CDK4/6 pathway activity has been identified as a mediator of this resistance, and in preclinical studies the combination of CDK4/6 and HER2 blockade can be more effective than either therapy alone. We conducted a single-arm phase 1b/2 study of the CDK4/6 inhibitor ribociclib given with trastuzumab or T-DM1 to subjects with advanced, treatment-refractory HER2-positive breast cancer. The results of the trastuzumab cohort are presented below. The primary objective was to determine the clinical benefit rate (CBR) at 24 weeks, and secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and adverse events. Methods: Individuals with locally advanced or metastatic, measurable HER2-positive breast cancer were eligible. All subjects must have previously received trastuzumab, pertuzumab, and T-DM1 as (neo)adjuvant or metastatic therapy. There was no limit on the number of prior lines of treatment. Patients with previous CDK4/6 inhibitor exposure, QTcF & gt; 450msec on EKG, or without stable brain metastases were excluded. An initial safety run-in phase (with dose-limiting toxicity (DLT) monitoring) included six subjects who received trastuzumab (8mg/kg loading then 6mg/kg IV three-weekly) and ribociclib 400mg PO daily on a continuous schedule (cycle length 21 days). The study had a two-stage design. The first stage required 20 patients, at least 6 of whom must have demonstrated clinical benefit (CR+PR+ SD & gt;24 weeks) in order to recruit 15 more patients to the second stage. All patients with accessible disease underwent metastatic tumor biopsies at baseline and C2D1. Results: 13 patients were enrolled (6 in the safety run-in and 7 in the expansion cohort). One patient was found to have HER2-negative disease and did not receive treatment. Patient characteristics are shown in Table 1 No DLTs were observed during the safety run-in phase, and ribociclib was thus used at 400mg po daily for the expansion cohort. Grade 3/4 toxicities were observed in 5 patients (41.7%) and included neutropenia (n=2), and fatigue, pain, and muscle weakness (all n=1). No patient demonstrated QTc prolongation & gt;480 msec, or grade 3/4 LFTs. 1/12 patients ((8.3%); 95% CI 0.2%-38.5%) achieved stable disease & gt;24 weeks; no objective responses were observed, and median PFS was 41.5 days. The trastuzumab portion of study was closed early due to limited clinical activity observed (the T-DM1 with ribociclib cohort remains open). Table 1Age (median, range)50.5 (42 - 71)Number of prior lines of systemic therapy for metastatic disease (median, range)5.5 (0-14)Number with Hormone receptor-positive disease (%)8 (67 %)Number of metastatic sites (median, range)2.5 (2 - 5) Conclusions: The combination of trastuzumab and ribociclib (400mg daily continuous schedule) is safe, with no new safety signals observed. The limited activity seen in this heavily pretreated population suggests that future efforts to incorporate CDK4/6 inhibition should be limited to a less extensively treat population. Citation Format: Goel S, Spring L, Rees R, Andrews C, Tahara RK, Mayer EL, Bardia A, Winer EP, Tolaney SM. A phase 1b/2 study of ribociclib plus trastuzumab for the treatment of advanced, treatment-refractory HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P6-18-10
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
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    Abstract GS1-07: Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 4_Supplement ( 2018-02-15), p. GS1-07-GS1-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. GS1-07-GS1-07
    Abstract: Background: mTNBC has an aggressive course with limited therapeutic options. 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. A phase I/II basket trial (NCT01631552) was conducted in patients (pts) with multiple, advanced epithelial cancers. We previously reported preliminary results in mTNBC (N=69; objective response rate [ORR] = 30%, Bardia et al., JCO 2017;35:2141-2148). In 2016, sacituzumab govitecan was granted Breakthrough Designation based on this encouraging data, and we resumed enrollment in a more defined patient population (≥3rd-line setting in mTNBC). Methods: Pts received sacituzumab govitecan on days 1 & 8 of a 21-day cycle until progression or unacceptable toxicity. Eligibility included & gt; 2 prior lines of therapy for metastatic disease, measurable disease by CT or MRI and prior taxane. Efficacy was assessed locally by RECIST 1.1 and confirmed by independent centralized blinded review. ORR, DOR, progression-free survival (PFS) and overall survival (OS) were determined. Adverse events (CTCAE v4.0), immunogenicity, and Trop-2 expression in archived tumor samples, when available, were evaluated. Results: 110 mTNBC pts (109 female, 1 male; median age 55 yrs, range 31-81), including 53 from the previously reported cohort of 69 pts who had received ≥2 prior regimens for metastatic disease, were accrued between 7/2013 and 2/2017. As of data cutoff on 6/30/2017, 71 are deceased, 23 in long-term follow-up, and 16 still on treatment. All pts were treated at the 10 mg/kg IMMU-132 dose level, receiving 14.5 median doses (range 1-88). Treatment was well tolerated, with no treatment-related deaths, 2 treatment discontinuations for toxicity, and no anti-drug antibodies detected. Grade ≥ 3 toxicity (≥10%) included neutropenia, 39%; leukopenia, 14%; anemia, 10%; the incidence of febrile neutropenia was low (7%). By local radiologist assessment, the ORR is 34% (37/110), including 3 CRs and 34 PRs, the clinical benefit rate (CBR: CR+PR+SD & gt;6 mo.) is 46%, the KM median DOR and PFS are 7.6 mo. (95% CI: 4.8 to 11.3) and 5.5 mo. (95% CI: 4.8 to 6.6), respectively, including 10% (11 pts) with long-term PFS (12 to 30+ mo.), and the KM median OS is 12.7 mo. (95% CI: 10.8 to 13.6). Results of the independent central blinded review along with sensitivity analyses of prior treatment regimens, including checkpoint inhibitor use, and exploratory biomarker analysis of Trop-2 expression will be presented at the meeting. Conclusions: Sacituzumab govitecan demonstrated significant clinical activity as a single agent in the ≥3rd-line setting for patients with relapsed/refractory mTNBC. Given the high unmet medical need, data from this trial is being submitted for consideration of accelerated approval, and a global confirmatory randomized Phase III trial (NCT02574455) is underway. Additional studies including rational combinations are currently being evaluated for mTNBC and other breast cancer subsets. Citation Format: Bardia A, Vahdat LT, Diamond J, Kalinsky K, O'Shaughnessy J, Moroose RL, Isakoff SJ, Tolaney SM, Santin AD, Abramson V, Shah NC, Govindan SV, Maliakal P, Sharkey RM, Wegener WA, Goldenberg DM, Mayer IA. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results [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 GS1-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS17-GS1-07
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    Abstract GS3-07: Genome-wide copy number analysis of chemotherapy-resistant metastatic triple-negative breast cancer from cell-free DNA
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 4_Supplement ( 2018-02-15), p. GS3-07-GS3-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. GS3-07-GS3-07
    Abstract: Introduction: Triple-negative breast cancer (TNBC) is a poor prognosis breast cancer subset characterized by relatively few mutations but extensive copy number alterations (CNAs). Cell-free DNA (cfDNA) offers the potential to overcome infrequent tumor biopsies in metastatic TNBC (mTNBC) and interrogate the genomics of chemotherapy resistance. Methods: 506 archival or fresh plasma samples were identified from 164 patients with mTNBC who had previously received chemotherapy. We performed low coverage whole genome sequencing to determine genome-wide copy number and estimate 'tumor fraction' of cfDNA (TFx) using our recently-developed approach, ichorCNA. In patient samples with TFx & gt;10%, we identified regions that were significantly gained or lost using GISTIC2.0. We compared CNAs of 20 paired primary-metastatic samples and also mTNBCs from cfDNA versus primary TNBCs from TCGA and METABRIC. Results: We successfully obtained high quality, low coverage whole genome sequencing data for 478 (94.5%) plasma samples from 158 patients, with 1 to 14 samples per patient. TFx and copy number profiles were highly concordant with paired metastatic biopsy (n=10, range 0-7 days from biopsy to blood draw) with sensitivity of 0.86 and specificity of 0.90 and reproducible in independently-processed blood draws (TFx intraclass correlation coefficient 0.984). Median overall survival from time of first blood draw was 8 months, and TFx was highly correlated independent of primary stage, primary receptor status, age at primary diagnosis, BRCA status, and metastatic line of therapy: adjusted hazard ratio between 4th and 1st quartiles = 2.14 (95% CI 1.40-3.28; p=0.00049). 101/158 patients (63.9%) had at least one sample with TFx & gt;10%, our threshold for high confidence CNA calls. Copy number profiles and percent genome altered were remarkably similar between mTNBCs and primary TNBCs in TCGA and METABRIC (n=433), suggesting that large-scale chromosomal events are infrequent in TNBC metastatic progression. We identified chromosomal gains that demonstrated significant enrichment in mTNBCs relative to paired primary TNBCs (n=20) and also TCGA/METABRIC, including driver genes (NOTCH2, AKT2, AKT3) and putative antibody-drug conjugate targets. Finally, we identify a novel association of gains of 18q11 and/or 19p13 with poor metastatic prognosis, independent of clinicopathologic factors and TFx. Conclusions: Here, we present the first large-scale genomic characterization of metastatic TNBC to our knowledge, derived exclusively from cfDNA. 'Tumor fraction' of cfDNA is an independent prognostic marker in mTNBC. Primary and metastatic TNBC have remarkably similar copy number profiles yet we identify alterations enriched and prognostic in mTNBC. Collectively, these data have potential implications in the understanding of metastasis, therapeutic resistance, and novel therapeutic targets. Citation Format: Stover DG, Parsons HA, Ha G, Freeman S, Barry B, Guo H, Choudhury A, Gydush G, Reed S, Rhoades J, Rotem D, Hughes ME, Dillon DA, Partridge AH, Wagle N, Krop IE, Getz G, Golub TA, Love JC, Winer EP, Tolaney SM, Lin NU, Adalsteinsson VA. Genome-wide copy number analysis of chemotherapy-resistant metastatic triple-negative breast cancer from cell-free DNA [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 GS3-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS17-GS3-07
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
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    Abstract P5-21-10: Phase 2 study and correlative analyses of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic, triple-negative breast cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 4_Supplement ( 2018-02-15), p. P5-21-10-P5-21-10
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. P5-21-10-P5-21-10
    Abstract: Background: Preclinical data supports a role for the IL-6/JAK2/STAT3 signaling pathway in breast cancer (BC). Ruxolitinib is an orally bioavailable receptor tyrosine inhibitor targeting JAK1 and JAK2. We evaluated the safety and efficacy of ruxolitinib in patients with metastatic BC and performed correlative analyses. Methods: This was a non-randomized, phase 2 study of patients with refractory, metastatic, triple-negative BC (TNBC). Patients with inflammatory BC (IBC) of any subtype were also enrolled. The primary endpoint was objective response by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. The study was designed to enroll only patients whose archival tumor tissue was pSTAT3 moderately to strongly positive in the tumor epithelial cells by central immunohistochemistry (IHC). 16 patients underwent pre-treatment biopsy, of whom 4 also had a second biopsy prior to cycle 2. Biopsy samples and paired primary tumor samples (when available) were subjected to multi-color immunofluorescence and/or immune-FISH for leukocyte markers, pSTAT3, and JAK2. RNA sequencing was performed on available on-study frozen biopsy specimens. 17 patients had plasma collected with cell-free DNA (cfDNA) extracted and subjected to low coverage whole-genome sequencing. Results: Of 217 patients who consented to archival tumor testing, T-score for pSTAT3 was 'high' ( & gt;5) in 69 patients (31.8%), demonstrating frequent activation of the JAK/STAT pathway in metastatic TNBC or IBC. 23 pSTAT3 high patients were enrolled. Ruxolitinib was generally well-tolerated. The most commonly observed adverse events (any grade) were anemia, neutropenia, thrombocytopenia, constipation, nausea, and increased AST/ALT. Grade 3 or higher toxicities were uncommon. No objective responses were seen among 21 evaluable patients, therefore the study was closed to accrual based on study design. Intensive correlative analyses revealed important insights regarding ruxolitinib effects. Pharmacodynamic analyses of baseline versus cycle 2 biopsies demonstrate downregulation of JAK2 target genes, STAT3 signatures, and JAK/STAT gene ontology gene sets, suggesting on-target activity. There was evidence of immune microenvironment modulation: gene set enrichment analysis implicated reduced macrophage/myeloid phenotypes after treatment and CIBERSORT analysis of inferred immune cell subsets demonstrated reduced monocyte/macrophage proportion after treatment (t-test p=0.013). Multi-color immunofluorescence analyses of immune microenvironment are ongoing and will be reported. 17 patients underwent cfDNA analysis with 8 patients (47%) demonstrating gain or amplification of JAK2. Conclusions: Ruxolitinib, as a single agent, did not meet the primary efficacy endpoint in this refractory patient population. Correlative studies demonstrate evidence of on-target activity and immune microenvironment modulation. Frequent JAK/STAT pathway activation and JAK2 locus chromosomal gains in this cohort suggest that the JAK/STAT pathway remains a potential therapeutic target in BC. Citation Format: Stover DG, Gil Del Alcazar CR, Tolaney SM, Bardia A, Guo H, Balko JM, Overmoyer BA, Gelman RS, Lloyd M, Wang V, Brock JE, Winer EP, Polyak K, Lin NU. Phase 2 study and correlative analyses of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic, triple-negative breast cancer [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 P5-21-10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS17-P5-21-10
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 5
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    Abstract PD6-13: Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 4_Supplement ( 2018-02-15), p. PD6-13-PD6-13
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. PD6-13-PD6-13
    Abstract: Background: Eribulin mesylate (ERI), a nontaxane microtubule inhibitor with effects on tumor biology (increased vascular perfusion, reversal of epithelial to mesenchymal transition), is approved as a monotherapy for the treatment of patients (pts) with metastatic breast cancer who received ≥2 prior chemotherapeutic regimens for metastatic disease. In a pooled analysis, ERI significantly prolonged OS compared with capecitabine or treatment of physician's choice in pts with metastatic triple-negative breast cancer (mTNBC; 12.9 vs 8.2 mo, n=428). Pembrolizumab (PEM) is a human programmed death (PD) receptor-1–blocking antibody approved for the treatment of several advanced cancers. In a phase (Ph) 2 study in mTNBC, PEM monotherapy as first-line therapy demonstrated ORR, 23%; median PFS, 2.1 mo [95% CI 2.0-3.9], and in pts pretreated with ≥1 prior chemotherapy demonstrated ORR, 5%; median OS, 8.9 mo [95% CI 7.2-11.2] ). Methods:This open-label Ph 1b/2 trial enrolled pts (aged ≥18 yrs; ECOG PS ≤1) with mTNBC treated with ≤2 prior lines of chemotherapy for metastatic disease. Ph 1b included a safety cohort of ≥6 pts who received intravenous (IV) ERI 1.4 mg/m2 on day (d) 1 and d8 and IV PEM 200 mg on d1 of a 21-d cycle. In Ph 2, pts were enrolled based on prior chemotherapy in the metastatic setting [0 vs 1–2 lines]. Primary endpoints: safety, tolerability (Ph 1b), and ORR (Ph 2); secondary endpoints: PFS, OS, and efficacy in PD-L1+ pts. Results: We report data from 82 of 104 enrolled pts (data cut-off Nov 1, 2016).The RP2D was ERI 1.4 mg/m2 on d1 and d8 and PEM 200 mg on d1 of a 21-d cycle. Most common treatment-emergent adverse events (TEAEs) were fatigue (73.2%), nausea (51.2%), peripheral sensory neuropathy (46.3%), alopecia (43.9%), and pyrexia (36.6%). Most common Grade (G) 3 or 4 TEAEs related to ERI: neutropenia (29.3%), peripheral neuropathy (8.5%), and asthenia/fatigue (7.3%). G3/4 immune-related TEAEs related to PEM: 19.5% of pts. TEAEs that led to drug withdrawal/dose reduction: 18.3%/28.0% of pts. G5 events: 3 pts (respiratory failure, pleural effusion, and multiple organ failure; none related to study drug). Response was irrespective of PD-L1 status (Table1). Results of the final analysis will be available for presentation.  Overall (n=82)No prior chemotherapy in metastatic setting (n=48)1-2 Prior lines of chemotherapy in metastatic setting (n=34)PD-L1+ (n=35)PD-L1- (n=36)ORR, n (%) [95% CIa]21 (25.6) [16.8, 35.4] 12 (25.0) [14.0, 37.8]9 (26.5) [13.3, 41.8] 9 (25.7) [12.9, 40.8]9 (25.0) [12.5, 39.8] CBRb, n (%)25 (30.5)13 (27.1)12 (35.3)10 (28.6)12 (33.3)DCRc, n (%)46 (56.1)28 (58.3)18 (52.9)19 (54.3)21 (58.3)Median PFS, mo [95% CI]4.1 [2.3-4.8] 4.1 [2.2-4.9]3.9 [2.1-6.3] 4.1 [2.1-4.8]4.1 [2.3-6.3] Median OS, mo [95% CI]NE [17.7-NE] 17.7 [13.7-NE]NE [13.1-NE] ----a Credible interval from Bayesian analysis; b clinical benefit rate = CR+PR+SD; c disease control rate = CR+PR+SD ≥24 weeks. NE, not estimable. Conclusions: ERI+PEM was well tolerated and demonstrated activity in pts with mTNBC. The combination resulted in improved ORR, with longer PFS, OS, and comparable TEAEs to those observed with either treatment as monotherapy. Further exploration of this combination is warranted. Citation Format: Tolaney SM, Kalinsky K, Kaklamani V, Savulsky C, Olivo M, Aktan G, Kaufman PA, Xing D, Almonte A, Misir S, Karantza V, Diab S. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer [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 PD6-13.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS17-PD6-13
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    Abstract P4-13-25: Abemaciclib, an inhibitor of CDK4 and CDK6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 4_Supplement ( 2016-02-15), p. P4-13-25-P4-13-25
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. P4-13-25-P4-13-25
    Abstract: Background: Abemaciclib, a small molecule inhibitor of CDK4 and CDK6, induces G1 cell cycle arrest in Rb-proficient human cancers.1 The clinical safety profile of abemaciclib enables continuous oral dosing to achieve sustained target inhibition, resulting in single-agent antitumor activity against multiple human cancers. The drug also reaches relevant concentrations in the central nervous system and, in patients taking the drug orally, can be detected in the cerebrospinal fluid.2 For women with previously treated hormone receptor positive (HR+) metastatic breast cancer (MBC), abemaciclib as a single agent achieved a six-month clinical benefit rate of 61.1% and an objective response rate of 33.3%.3 Clinical trials investigating abemaciclib combined with fulvestrant4 or aromatase inhibitors5 have led to randomized Phase 3 studies for women with HR+ breast cancer.6,7 Methods: This Phase 1b study (NCT02057133) with multiple cohorts evaluates safety and tolerability of abemaciclib combined with endocrine or HER2-targeted therapies for MBC. Secondary objectives include pharmacokinetics (PK) and antitumor activity of abemaciclib when given in combination with other therapies. Cohorts were opened to enrollment sequentially. Patients with HR+ HER2 negative MBC received abemaciclib orally every 12 hours (Q12H) in combination with the following standard therapies daily until progression: letrozole (Part A), anastrozole (Part B), tamoxifen (Part C), exemestane (Part D), or exemestane plus everolimus (Part E). Patients with HER2 positive MBC received abemaciclib orally Q12H in combination with trastuzumab every 21 days until progression (Part F). Adverse events (AEs) were graded by NCI CTCAE v4.0 and tumor response was assessed radiographically using RECIST v1.1. Results: Abemaciclib has been combined with multiple targeted therapies for the treatment of women with MBC. We previously reported safety and early efficacy results for the combinations of abemaciclib with letrozole, anastrozole, tamoxifen, exemestane, and exemestane plus everolimus.5 Due to limited follow-up at that time, the efficacy results were not mature. Safety, PK, and efficacy results with approximately 6 months of additional follow-up will be reported across all parts of the study. The most common treatment-emergent AEs include effects on the gastrointestinal and hematopoietic systems. Consistent with previously reported results for both single-agent abemaciclib and the combination of abemaciclib with fulvestrant, tumor responses have been observed among women receiving abemaciclib in combination with targeted therapies for MBC. Conclusions: This study for women with MBC demonstrates the potential for abemaciclib to be combined with therapies targeting specific signaling pathways. References: 1Gelbert et al. Invest New Drugs. 2014;32(5):825-37. 2Shapiro et al. J Clin Oncol 31, 2013 (suppl; abstr 2500). 3Tolaney et al. SABCS 2014: Abstract 763. 4Patnaik et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 534). 5Tolaney et al. J Clin Oncol 33, 2015 (suppl; abstr 522). 6Llombart et al. SABCS 2014: OT1-1-07 (MONARCH 2, NCT02107703). 7Goetz et al. J Clin Oncol 33, 2015 (suppl; abstr TPS624) (MONARCH 3, NCT02246621). Citation Format: Goetz MP, Beeram M, Beck T, Conlin AK, Dees EC, Dickler MN, Helsten TL, Conkling PR, Edenfield WJ, Richards DA, Turner PK, Cai N, Chan EM, Pant S, Becerra CH, Kalinsky K, Puhalla SL, Rexer BN, Burris HA, Tolaney SM. Abemaciclib, an inhibitor of CDK4 and CDK6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-25.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS15-P4-13-25
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
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    Abstract P4-04-02: Identifying ERBB-2 activating mutations (mts) in HER2 negative tumors for clinical trials – Impact of institute-wide genomic testing and trial matching on trial enrollment in clinical practice
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P4-04-02-P4-04-02
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P4-04-02-P4-04-02
    Abstract: Introduction Tailored treatment trials with biomarker-driven hypotheses are becoming an important strategy in drug development. Umbrella, basket and enrichment trials with eligibility predicated upon results of tumor sequencing are increasingly common. Several institutional and commercial genomic assays have been developed. However, the value of broad-based testing in recruiting patients (pts) to molecular-based clinical trials designed for small subgroups has not been fully evaluated and has been challenging to assess in a real-world setting. We evaluated the likelihood of trial enrollment based upon an institute-wide genomic test. Methods Since 2013, all pts with metastatic breast cancer (MBC) seen at least once at Dana-Farber Cancer Institute have been offered the option of tumor sequencing using multiplexed copy number variation (CNV) and mts detection across the full coding regions of a total of 447 cancer genes and 191 regions across 60 genes for rearrangement detection (Oncopanel; OP). For our primary analysis, we selected the ongoing multi-center phase II trial (NCT01670877) activated at our site on Sep 30, 2013, evaluating neratinib in ERBB-2 mutated pts, as the study provided a clear delineation of eligible mts, and timing of slot availability was retrievable retrospectively over an extended time frame. Our primary aim was to describe the proportion of pts with a qualifying ERBB-2 mt detected by OP who enrolled on the selected trial. Secondary objectives included median time from OP result to trial registration and description of ERBB-2 mts spectrum within each subtype. Associations were calculated by Fisher's test. Results We identified a total of 1,046 pts with HER-2 negative MBC and who had OP results between Sep 1, 2013 and Jun 1, 2017. A total of 43 pts (4.1%) were found to have ERBB-2 mts. Of these, 20 (1.9%) had activating eligible mts. The proportion of these pts who enrolled in the trial was 30% (6/20). Of the remaining 14 pts, 5 screen-failed and 2 were enrolled with known ERBB-2 mt through other testing modalities. Seven of 20 (35%) molecularly eligible pts were not approached (3 pts lost to follow-up, 3 enrolled in other clinical trials and 1 pt chose standard treatment). The median time from OP result to trial enrollment was 85 days (34-554). A significantly higher frequency of ERBB2 activating mts was found in ER+ compared to ER- primary tumors (2.5% vs. 0.3%, p =0.036), and in lobular tumors compared with ductal (5.5% vs. 1.25%, p=0.003). Frequency of eligible mts in primary tumors were similar to metastatic site (1.9% and 1.8%, respectively p=1.0) Discussion In this cohort, activating ERBB-2 mts were present in 20 of 1046 (1.9%) pts tested. Although over half of pts with eligible mts on OP testing were approached for NCT01670877, only 0.5% of the total tested population were enrolled (6/1046). Our data illustrate the substantial challenges in screening and enrolling to trials of rare subsets, even within a large academic institution, and point to the need for creative and novel approaches to leverage pts and community- and academic-based providers to more effectively support the success of such studies. Citation Format: Exman P, Garrido-Castro A, Hughes ME, Freedman RA, Ma C, Bose R, Cerami E, Wagle N, Barroso-Sousa R, Fitz CD, Lindeman NI, MacConaill L, Bychkovsky BL, Lloyd MR, Mackichan CR, Kumari P, Tolaney SM, Krop IE, Winer EP, Dillon DA, Lin NU. Identifying ERBB-2 activating mutations (mts) in HER2 negative tumors for clinical trials – Impact of institute-wide genomic testing and trial matching on trial enrollment in clinical practice [abstract] . In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-04-02.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P4-04-02
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    Abstract P1-13-12: Quality of life and patient-reported outcomes in US patients enrolled in the MONALEESA-2 study
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 4_Supplement ( 2018-02-15), p. P1-13-12-P1-13-12
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. P1-13-12-P1-13-12
    Abstract: Background: Improvement to and maintenance of the highest possible health-related quality of life (QoL), in addition to disease control, are key goals of treatment in patients with advanced breast cancer (ABC). Endocrine therapy is preferred as first-line therapy in ABC because of its preferable safety profile compared with chemotherapy. In the MONALEESA-2 study, the cyclin-dependent kinases 4 and 6 inhibitor ribociclib, in combination with letrozole, significantly extended progression-free survival (PFS) compared with placebo + letrozole in patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) ABC. Patient-reported outcomes demonstrated similar QoL among patients in both treatment groups. Here, we present data from US patients enrolled in the MONALEESA-2 study on overall QoL as well as individual domains. Methods: Postmenopausal women (N=668) with HR+, HER2− ABC who did not receive prior systemic treatment for ABC and had an Eastern Cooperative Oncology Group performance status score of ≤1, adequate bone marrow and organ function, and no history of active cardiac dysfunction were randomized 1:1 to receive either ribociclib (600 mg/d, 3 weeks on/1 week off) + letrozole (2.5 mg/d, continuous) or placebo + letrozole. The primary end point was locally assessed PFS. Quality of life was reported using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the EuroQol 5-domain 5 level (EQ-5D-5L) visual analog scale (VAS) of overall health, and the breast symptom score of the EORTC QLQ-Breast Cancer 23 (EORTC QLQ-BR23) module. Data cutoff in this analysis was January 29, 2016. Results: Patient characteristics and QoL survey reports were well balanced across treatment groups in US patients (n=213). The global health status/QoL scores of the EORTC QLQ-C30 were maintained between groups, and improved over time in the ribociclib group (mean ± standard deviation [SD] score at baseline, 69.1 ± 19.0; at 8 months, 71.3 ± 18.2; and at 16 months, 73.0 ± 16.0) and the placebo group (mean ± SD score at baseline, 69.9 ± 20.0; at 8 months, 75.9 ± 19.2; and at 16 months, 77.0 ± 15.0), which was consistent with scores in the overall population. At 16 months, the proportion of patients who did not experience ≥10% deterioration of all QoL scores was similar among treatment groups. Quality of Life Outcomes of US Patients in the MONALEESA-2 Study at 16 MonthsOutcomeTreatment, nPatients without ≥10% deterioration in score, % (95% CI, %)EORTC QLQ-C30  Global health status/QoLRIB + LET, 2664.0 (49.4–75.4) PBO + LET, 3550.5 (36.2–63.2)Physical functioningRIB + LET, 2175.7 (62.6–84.7) PBO + LET, 1773.1 (57.2–83.9)Emotional functioningRIB + LET, 2271.6 (58.6–81.2) PBO + LET, 3159.7 (45.7–71.2)Social functioningRIB + LET, 1780.1 (68.5–87.8) PBO + LET, 2660.2 (44.1–73.0)EORTC QLQ-BR23 breast symptom scoreRIB + LET, 888.0 (76.6–94.0) PBO + LET, 886.2 (70.6–93.9)EQ-5D-5L VAS of overall healthRIB + LET, 1386.6 (76.9–92.4) PBO + LET, 1873.4 (56.8–84.4)LET, letrozole; PBO, placebo; RIB, ribociclib. Conclusions: Addition of ribociclib to letrozole in US patients enrolled in MONALEESA-2 led to significant prolongation of PFS while maintaining QoL. Citation Format: Tolaney SM, Tan-Chiu E, Truica C, Volas-Redd G, Shtivelband M, Dalal AA, Chandiwana D, Hortobagyi G. Quality of life and patient-reported outcomes in US patients enrolled in the MONALEESA-2 study [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 P1-13-12.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS17-P1-13-12
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 9
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    Abstract P4-22-12: Ribociclib + fulvestrant in postmenopausal women with HR+, HER2– advanced breast cancer (ABC)
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. P4-22-12-P4-22-12
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. P4-22-12-P4-22-12
    Abstract: Background: Endocrine therapy (ET) is the treatment backbone for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC, but efficacy is limited by ET resistance. The cyclin-dependent kinase (CDK) 4/6–cyclin D (CCND1)–retinoblastoma (Rb) and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways have been implicated in ET resistance. CDK4/6 and PI3K/mTOR inhibitors act synergistically with ET in preclinical and clinical studies of HR+ breast cancer. Ribociclib (LEE011; CDK4/6 inhibitor) + fulvestrant ± alpelisib (BYL719) or buparlisib (BKM120) in HR+, HER2– ABC is being investigated in a Phase Ib/II study (NCT02088684). Here, we present results from the ribociclib + fulvestrant combination, with intermittent and continuous ribociclib dosing. Methods: Postmenopausal patients (pts) with HR+, HER2– ABC refractory to aromatase inhibitors received ribociclib intermittently (600 mg/day, 3-weeks-on/1-week-off; Arm A) or continuously (400 mg/day; Arm B; following Arm A safety evaluation) + fulvestrant (500 mg; Cycle 1 Day 1 and 15; subsequent cycles Day 1). Primary objective: dose-limiting toxicities (DLTs) to confirm the recommended Phase II dose of ribociclib + fulvestrant. Secondary objectives: safety, pharmacokinetics, and preliminary antitumor activity (RECIST v1.1); biomarkers that may correlate with response were also assessed. Results: As of March 10, 2016, 24 pts received ribociclib + fulvestrant (Arm A, n=13; Arm B, n=11); 4 pts in Arm B were ongoing; median duration of exposure was 7.4 (Arm A) and 4.5 (Arm B) months. Median number of prior regimens: 4 (Arm A) and 3 (Arm B). Treatment discontinuation (n; Arm A, Arm B) was due to disease progression (11, 4), physician decision (1, 2), and adverse events (AEs; 1, 1). DLTs in Cycle 1 (n; Arm A, Arm B) were Grade [G] 3 pulmonary embolism (1, 0) and G3 aspartate aminotransferase elevation (0, 1). The most common G3/4 drug-related AE (Arm A, Arm B) was neutropenia (62%, 36%); 5 pts had QTcF prolongation & gt;60 ms (n; 4, 1). Common all-Grade drug-related AEs ( & gt;35% pts) n (%)Arm A (n=13)Arm B (n=11)Neutropenia10 (77)7 (64)Fatigue9 (69)3 (27)Nausea6 (46)5 (46)Anemia6 (46)0 (0)Reduced appetite5 (39)1 (9) Best overall responses (BORs; n; Arm A, Arm B): partial response (PR; 3, 1), stable disease (SD; 9, 6), and neither complete response nor progressive disease (NCRNPD; non-measurable disease; 1, 4). Overall response rate: 23% (Arm A) and 9% (Arm B); disease control rate (BOR of complete response, PR, SD, or NCRNPD): 100% in both arms. Next-generation sequencing data (n; Arm A, Arm B) were available for 16 pts (7, 9): 5 pts had CCND1 alterations (PR [1, 0], SD [2, 1] , and NCRNPD [0, 1]); 11 pts had PIK3CA alterations (PR [1, 0] , SD [3, 4], and NCRNPD [1, 2] ); 2 of these pts had both CCND1 and PIK3CA alterations (SD [1, 0] and NCRNPD [0, 1] ). Conclusions: Ribociclib + fulvestrant has a manageable safety profile and shows preliminary clinical activity in pretreated pts with HR+, HER2– ABC. Both ribociclib intermittent and continuous dosing schedules were well tolerated. Clinical responses were observed in tumors with and without CDK4/6–cyclin D–Rb and PI3K/mTOR pathway alterations. Citation Format: Tolaney SM, Forero-Torres A, Boni V, Bachelot T, Lu Y-S, Maur M, Fasolo A, Motta M, Pan C, Dobson J, Hewes B, Chin Lee S. Ribociclib + fulvestrant in postmenopausal women with HR+, HER2– advanced breast cancer (ABC) [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 P4-22-12.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-P4-22-12
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 10
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    Abstract P6-17-01: Withdrawn
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P6-17-01-P6-17-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P6-17-01-P6-17-01
    Abstract: This abstract was withdrawn by the authors. Citation Format: Tolaney SM, Wardley AM, Zambelli S, Hilton JF, Troso-Sandoval TA, Ricci F, Im S-A, Kim S-B, Johnston SR, Chan A, Goel S, Catron K, Yang Z, Gainford C, André F. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P6-17-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 410466-3
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