Background: CDK4/6 inhibition (CDK4/6i) has a significant role in contemporary management of hormone receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancer (MBC). The addition of a CDK4/6i to endocrine therapy (ET) in HR+/HER2- MBC leads to prolongation of progression-free survival in previously untreated and pre-treated HR+/HER2- MBC. Mechanisms of resistance to CDK4/6i are not well described, and it is not known if continuation of CDK4/6i with subsequent lines of ET improves outcomes over ET alone. Further, preclinical data suggest combination therapy with ET, CDK4/6i, and anti-PDL1 may provide synergistic efficacy. The PACE trial was designed to determine the optimal subsequent line of therapy in patients (pts) with HR+ /HER2- MBC that has progressed despite prior CDK4/6 inhibition and endocrine therapy. Methods: PACE (NCT03147287) is a multicenter phase II trial randomizing pts 1:2:1 to Arm A: fulvestrant alone (with option for Palbociclib (P) monotherapy crossover at time of progression); Arm B: fulvestrant + P; or Arm C: fulvestrant + P + avelumab. The primary objective is to evaluate progression-free survival (PFS) with the combination of fulvestrant + P vs. fulvestrant alone; secondary objectives include overall response (OR), safety and tolerability, and PFS comparisons of avelumab containing arm vs other arms. Exploratory objectives include assessment of outcomes in predefined molecular subgroups (i.e. ESR mutation, PI3K mutation, and loss of Rb); and comparing OR by RECIST vs irRECIST in the avelumab cohort. Extensive molecular profiling of tissue, ctDNA, and CTCs for markers of response and resistance to therapy is also planned. Eligible pts have HR+/HER2- MBC, with prior response to and subsequent progression on any CDK4/6i and ET, defined as at least 6 months of prior treatment, with confirmed subsequent progression, and no more than one prior P dose reduction for toxicity. Pts may have had 1-2 prior ET (aromatase inhibitor or tamoxifen), and 0-1 prior lines of chemotherapy. A sample size of 220 patients is planned. Citation Format: Mayer EL, Wander SA, Regan MM, DeMichele AM, Forero A, Rimawi MF, Ma CX, Cristofanilli M, Anders CK, Huang Bartlett C, Koehler M, Winer EP, Burstein HJ. Palbociclib after CDK inhibitor and endocrine therapy (PACE): A randomized phase II study of fulvestrant versus palbociclib plus fulvestrant, with and without avelumab, for CDK inhibitor pre-treated HR+/HER2- metastatic 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 OT3-05-11.
Background Abemaciclib is a selective CDK4 & 6 inhibitor approved to treat patients (pts) with HR+, HER2- advanced breast cancer (ABC) on a continuous dosing schedule as monotherapy or in combination with endocrine therapy.1,2,3 Clinical data demonstrate that abemaciclib can penetrate the blood brain barrier resulting in comparable abemaciclib concentrations in brain metastases tissues, cerebrospinal fluid, and plasma.4 We report safety and efficacy results of abemaciclib in pts with leptomeningeal metastases (LM) arising from HR+, HER2- ABC. Methods Study I3Y-MC-JPBO (NCT02308020) is a multicenter, open-label, Phase 2 trial evaluating the safety and efficacy of abemaciclib in 6 cohorts of pts with brain metastases secondary to HR+ ABC, non-small cell lung cancer, or melanoma. Here we discuss a subgroup of cohort F: pts with HR+, HER2- LM from ABC, documented by positive CSF cytology or by clinical signs and symptoms associated with abnormal MRI features. Pts with concomitant parenchymal brain metastases were allowed, but must have been stable for ≥4 weeks following wholebrain radiotherapy or stereotactic radiosurgery. Abemaciclib was orally administered 200mg twice daily on a 21-day cycle.The key exploratory objectives were to assess the effect of abemaciclib on pts with LM secondary to HR+, HER2- ABC based on safety and tolerability, and radiological assessment from the Response Assessment in Neuro-Oncology leptomeningeal metastases (RANO-LM) criteria. Results Between December 2015 and July 2016, 17 pts were enrolled in cohort F. This study reports on the 7 pts with HR+, HER2- ABC LM of which 4 pts were diagnosed with concurrent parenchymal brain metastases. Median duration of treatment was 3.9 months (range, 0.9-10.6), with 3 pts remaining on treatment for more than 6 months. Pts discontinued treatment due to progressive disease (PD, n=5) and adverse events (n=2). Median overall survival (OS) was 8.4 months (range, 3.3-14.2). Best investigator-assessed overall response was stable disease (SD) in 5 pts and progressive disease (PD) in 2 pts. Efficacy, as per CNS imaging, revealed SD in 4 pts (no imaging, n=1), 2 of which had stable or improved symptoms per neurological assessment response. Best overall intracranial response of parenchymal metastases was 1 complete response, 1 SD, and 2 PD. All 4 pts with extracranial disease had best overall response of SD. All pts experienced ≥1 TEAE, with the most common grade 3 TEAEs including nausea (28.6%), pain (28.6%), and vomiting (28.6%); 1 pt (14.3%) experienced grade 4 anemia and grade 4 upper gastrointestinal hemorrhage. Conclusion OS for pts with LM arising from HR+, HER2- ABC is typically 4 months or less despite available therapies5. Here we report the median OS within this subgroup as 8.4 months. Concurrent intracranial and extracranial disease control was observed. Safety and tolerability results are similar to those previously reported with abemaciclib. Further study of abemaciclib in a larger pt cohort is warranted. References 1. Dickler et al, Clin Cancer Research 2017 2. Sledge et al, J Clin Oncology 2017 3. Goetz et al, J Clin Oncology 2017 4. Sahebjam et al, 2016 ASCO Annual Meeting, Abstract 14 5. Morikawa et al, Clin Breast Cancer 2017 Citation Format: Tolaney SM, Sahebjam S, Le Rhun E, Lin NU, Markel Bear M, Yang Z, Chen Y, Anders CK. A phase 2 study of abemaciclib in patients with leptomeningeal metastases secondary to HR+, HER2- 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 P1-19-01.
Background: While immunotherapy holds promise in the treatment of mTNBC, response rates (RR) in unselected patients (pts) are approximately 20%. Strategies to augment response to immunotherapy include depletion of regulatory T cells (Tregs). A single dose of cyclophosphamide (Cy) given prior to checkpoint inhibition achieved this goal in preclinical models of TNBC (Taylor et al., JCI, 2017). Thus, we designed a phase II study to evaluate this strategy in the clinical setting of mTNBC. Patients/Methods: In cycle 1 (C1), eligible pts with mTNBC received a single dose of Cy 300mg/m2 IV on day 1 (C1D1) followed by pembrolizumab 200mg IV on day 2 (C1D2), then every 3 weeks thereafter. The co-primary objectives were (1) progression free survival (PFS, null 1.9 mos vs. 2.9 mos, 80% power, alpha 0.05) and (2) reduction in Tregs in peripheral blood measured by flow cytometry. Secondary endpoints were response rate (RR), survival (OS), and RNA-based correlative endpoints. Results: 40 patients were evaluable for efficacy: mean age 54.5 yrs (33 – 82 yrs), 75% white, 22% black, 3% American Indian. All patients had received 1 prior line of chemotherapy in the metastatic setting; 29% received 5 or more prior lines. The most common grade 3 adverse events (AE's), all 5%, were neutropenia, anemia, elevated AST, and fatigue. Immune-related grade 3 AE's, all 3%, included colitis, dry mouth, pneumonitis. Overall RR was 21% (0 CR, 8 PR), 3 pts had stable disease. Median PFS was 1.8 months (mos) (95% CI 1.4–2.5) and OS was 6.3 mos (95% CI 2.8–8.4). There was a non-significant decrease in Tregs from C1D1 to C1D2 (-3.3%, p=0.19); but from C1D2 to C2D1, Tregs increased 21.7% (p=0.005). There was no association between changes in Tregs or number of prior lines of therapy with RR (p>0.09), while immune-related AE's were associated with response (p=0.02). Correlatives studies illustrate B cell immune gene signature expression and B cell receptor repertoire diversity were enriched in responders, while genes/pathways associated with neutrophils, anti-apoptosis, PI3K/AKT and down-regulation of MHC class 1 were associated with non-response. Conclusions: While pembroliuzumab plus Cy was well-tolerated among pts with mTNBC, efficacy was similar to historical control, likely due to minimal effect of Cy on Tregs. Correlative analyses illustrate that study of adaptive immune features, including B cell biology, is a promising strategy for understanding response to PD-1 inhibition in breast cancer. Further strategies to deplete Tregs in a more sustained manner are worthy of future exploration (NCT02768701). Citation Format: Anders CK, Moore D, Sambade M, Cuaboy L, Garrett A, Woodcock M, McKinnon K, Cowens K, Bortone D, Calhoun B, Carey L, Dees C, Jolly T, Muss H, Reeder-Hayes K, Kaltman R, Jankowitz R, Gudena V, Olajide O, Perou C, Vincent B, Serody J. LCCC 1525: A phase II study of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer (mTNBC) [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 P2-09-05.
Background: Nal-IRI (MM-398, nanoliposomal irinotecan) is designed for extended circulation relative to free irinotecan and to exploit leaky tumor vasculature for enhanced drug delivery to tumors. Tumor deposition of nal-IRI and subsequent conversion to SN-38 in both neoplastic cells and tumor associated macrophages (TAM) may positively correlate with response to therapy. In phase I studies of nal-IRI, activity has been shown in metastatic breast cancer (MBC), pancreatic and colorectal cancer. Ferumoxytol (FMX) is an iron-oxide superparamagnetic nanoparticle that has been used off-label for its MRI contrast properties. FMX has long-circulating pharmacokinetics and is taken up by TAMs with similar distribution patterns to nal-IRI in preclinical models. A single site pilot study established the feasibility of performing quantitative FMX MRI. Thirteen patients with advanced cancer (3 with ER/PR+ MBC) were imaged with FMX MRI and treated with nal-IRI. Median tumor lesion FMX uptake in the pilot study was 32.6 and 34.5 μg/mL at 1 h and 24 h, respectively. Lesions with FMX uptake above the median were associated with greater reductions in tumor size following treatment with nal-IRI as determined by CT lesion measurements. The relationship between FMX levels in tumor lesions and nal-IRI activity may serve as a potential biomarker for nal-IRI deposition and response in solid tumors. This study has been expanded to include additional MBC patients to further evaluate the technical feasibility of FMX MRI at multiple study sites, and to evaluate activity of nal-IRI in patients with MBC. Trial Design: Three cohorts of 10 patients with MBC in the following categories will be enrolled: ER and/or PR positive/HER2-negative, triple negative (TNBC) and MBC with brain metastases. An imaging phase will be followed by a treatment phase. The imaging phase consists of a baseline MRI scan, FMX infusion, and follow-up MRI scans at 1-4 and 24 h after infusion. The treatment phase begins 1-6 days after imaging and consists of nal-IRI 80 mg/m2 q2w. A pretreatment biopsy is required for correlative studies. Study Objectives: The primary objective of this multisite expansion is to investigate the feasibility of FMX quantitation in tumor lesions at multiple lesion sites in breast cancer. The secondary objective is to characterize the efficacy of nal-IRI in patients with metastatic breast cancer. Eligibility Criteria: The key inclusion criteria include patients with MBC, ECOG 0 or 1 with adequate bone marrow reserve and no prior topoisomerase 1 inhibitor or anti-VEGF treatment. ER and/or PR positive/HER2-negative and TNBC patients must have had 1-3 prior lines of chemotherapy in the metastatic setting and have at least 2 measurable lesions. Patients with brain metastasis must be neurologically stable and have new or progressive brain metastases after prior radiation therapy with at least one lesion measuring ≥ 1 cm in longest diameter on gadolinium-enhanced MRI. Status: This trial is currently recruiting patients. Citation Format: Sachdev JC, Ramanathan RK, Raghunand N, Anders C, Munster P, Minton S, Northfelt D, Blanchette S, Campbell K, Lee H, Klinz SG, Hendriks BS, Moyo V, Fitzgerald JB, Korn RL. A phase 1 study in patients with metastatic breast cancer to evaluate the feasibility of magnetic resonance imaging with ferrumoxytol as a potential biomarker for response to treatment with nanoliposomal irinotecan (nal-IRI, MM-398). [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 OT3-02-14.
Background: The incidence of CNS metastatic disease in breast cancer patients (pts) seems to have increased in recent years with the improvement of systemic therapy. However, treatment options for CNS metastases have remained limited due to the inability of most agents to cross the BBB. ANG1005 is a novel peptide drug-conjugate, consisting of 3 paclitaxel molecules covalently linked to Angiopep-2, a peptide designed to utilize the LRP-1 transport system to cross the BBB/BCB and to penetrate malignant cells. Methods: We conducted an open label phase II clinical study to test its activity in metastatic breast cancer (BC) pts with recurrent brain metastasis (BM), including BCBM pts with newly diagnosed leptomeningeal carcinomatosis (LC). Adult pts with measurable, recurrent BM from breast cancer, with or without LC (n=72 safety population; n=58 efficacy population) were enrolled in the study. ANG1005 was administered IV at 600 mg/m2 q3w. HER2+ patients were allowed to continue trastuzumab +/- pertuzumab. Intracranial (IC) response was assessed by Gd-MRI using CNS RECIST 1.1 and extracranial response (EC) was evaluated per RECIST 1.1. Results: Median age was 47.5 (26-76) years. Safety was similar to that of paclitaxel with myelosuppression as the predominant toxicity (WBC: 83%, RBC: 71%, PLT: 69%). Pts received a median of 6 (1-29) prior therapies for BC, including 84% with taxanes. As prior therapy for BM, 87% pts had cranial surgery and/or radiation and 19% pts received systemic therapies. Intracranial tumor response is presented for all pts as well as the various patient subsets as shown below: Table 1: Intracranial Response by Breast Cancer SubsetOutcome by CNS RECISTAllHER2+HER2-TNBCLCSample size, n5828301223PR (best response), n (%)8 (14%)4 (14%)4 (13%)2 (17%)5 (22%)Confirmed PR, n (%)3 (5%)2 (7%)1 (3%)02 (9%)SD, n (%)33 (57%)19 (68%)14 (47%)5 (42%)12 (52%))PD, n (%)17 (29%)5 (18%)12 (40%)5 (42%)6 (26%)Clinical benefit (SD+PR), %71%82%60%59%74%Abbreviations: TNBC, triple-negative breast cancer, a sub-group of HER2-; LC, leptomeningeal carcinomatosis Table 1 definitions: data based on evaluable pts with clinical or radiological evaluation ≥ 4 weeks from C1D1; LC pts included 15 HER2+ and 8 HER2-; best response is the best response recorded from the start of the study treatment until the disease progression; confirmed PR requires a ≥28-day confirmation of response. Extracranial tumor responses of 1 (3%) CR, 2 (7%) PRs and 24 (80%) SDs were seen in 30 evaluable pts, including after prior taxanes (93%). The 6 month OS in all pts was 50.2% (95% CI: 37.4, 61.6). In general, CNS clinical symptoms post-ANG1005 were improved, including in LC pts. Conclusions: ANG1005 is active against previously treated BC metastasis both within and outside the CNS. A randomized study is planned. Updated efficacy and safety data will be presented at the meeting. Citation Format: Ibrahim NK, Tang S-C, Brenner AJ, Kesari S, Piccioni DE, Anders CK, Carillo JA, Chalasani P, Kabos P, Puhalla S, Garcia AA, Tkaczuk KH, Ahluwalia MS, Lakhani NJ, Kumthekar P. A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant peptide-drug conjugate, in breast cancer patients with recurrent CNS 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 P1-12-01.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.