Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT3-02-03
C. Santa-Maria, C-L Wang, A. Cimino-Mathews, E. Roussos-Torres, R. Connolly, A. Wolff, E. Jaffee, V. Stearns
Background: While some patients with early stage endocrine receptor positive (ER+) breast cancer experience excellent prognosis, a subset of patients with more aggressive phenotypes still have a high rate of recurrence despite optimal adjuvant endocrine therapy and chemotherapy, thus novel therapies are needed for patients with high risk disease. Although immune checkpoint blockade has shown significant benefit in numerous types of cancer, initial reports demonstrate low response rates to single agent programmed cell death ligand 1 (PD-L1) inhibition in ER+ breast cancer. Inhibitors of cyclin dependent kinases (CDK) 4 and 6 in combination with endocrine therapy are highly active in breast cancer, and recently have been demonstrated to recruit immune cells, and increase PD-L1 on tumor cells in preclinical models. Increased tumor infiltrating lymphocytes (TILs) has been observed with neoadjuvant treatment with CDK4/6 inhibitors in patients with ER+ breast cancer. We thus hypothesize that the addition of palbociclib (CDK4/6 inhibitor) will improve responses to avelumab (PD-L1) inhibitor in patients with high risk ER+ breast cancer. Trial Design: Eligible participants are those stage II or III ER+HER2- breast cancer (T2N0 must have ≥grade 2, T1N+ must have at least a 1.5cm breast primary). Patients will undergo a baseline MRI and biopsy, start tamoxifen +/- palbociclib for 1 cycle (1 cycle =28 days), and then undergo a repeat MRI and biopsy. Avelumab will be added to both arms in cycle 2. Patients will be treated for 3 cycles of avelumab with tamoxifen +/- palbociclib (thus 4 cycles total, including run-in without avelumab). Patients will be treated as long as there is no evidence of progression and therapy is tolerated, and then undergo MRI and surgery. The primary objective is to determine the clinical complete response (cCR) rate by MRI. Secondary objectives include evaluation of TILs (HE 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-03.
{"title":"Abstract OT3-02-03: IMMUNe mOdulation in early stage estrogen receptor positive breast cancer treated with neoADjuvant Avelumab, Palbociclib, and Tamoxifen: The ImmunoADAPT study (NCT03573648)","authors":"C. Santa-Maria, C-L Wang, A. Cimino-Mathews, E. Roussos-Torres, R. Connolly, A. Wolff, E. Jaffee, V. Stearns","doi":"10.1158/1538-7445.SABCS18-OT3-02-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT3-02-03","url":null,"abstract":"Background: While some patients with early stage endocrine receptor positive (ER+) breast cancer experience excellent prognosis, a subset of patients with more aggressive phenotypes still have a high rate of recurrence despite optimal adjuvant endocrine therapy and chemotherapy, thus novel therapies are needed for patients with high risk disease. Although immune checkpoint blockade has shown significant benefit in numerous types of cancer, initial reports demonstrate low response rates to single agent programmed cell death ligand 1 (PD-L1) inhibition in ER+ breast cancer. Inhibitors of cyclin dependent kinases (CDK) 4 and 6 in combination with endocrine therapy are highly active in breast cancer, and recently have been demonstrated to recruit immune cells, and increase PD-L1 on tumor cells in preclinical models. Increased tumor infiltrating lymphocytes (TILs) has been observed with neoadjuvant treatment with CDK4/6 inhibitors in patients with ER+ breast cancer. We thus hypothesize that the addition of palbociclib (CDK4/6 inhibitor) will improve responses to avelumab (PD-L1) inhibitor in patients with high risk ER+ breast cancer. Trial Design: Eligible participants are those stage II or III ER+HER2- breast cancer (T2N0 must have ≥grade 2, T1N+ must have at least a 1.5cm breast primary). Patients will undergo a baseline MRI and biopsy, start tamoxifen +/- palbociclib for 1 cycle (1 cycle =28 days), and then undergo a repeat MRI and biopsy. Avelumab will be added to both arms in cycle 2. Patients will be treated for 3 cycles of avelumab with tamoxifen +/- palbociclib (thus 4 cycles total, including run-in without avelumab). Patients will be treated as long as there is no evidence of progression and therapy is tolerated, and then undergo MRI and surgery. The primary objective is to determine the clinical complete response (cCR) rate by MRI. Secondary objectives include evaluation of TILs (HE 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-03.","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82357122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT2-06-03
M. Telli, I. Wapnir, S. Vinayak, J. Chang, C. Alemany, C. Twitty, S. Gargosky
Triple negative breast cancer (TNBC) accounts for 10-20% of breast cancer diagnoses and is associated with a high risk of recurrence and a more aggressive course in the metastatic setting. Emerging data suggest that some patients with TNBC could benefit from the addition of immune-based therapy due to the important role of tumor infiltrating lymphocytes (TILs) on outcome. Reports show that early-stage TNBC patients with at least 50% TILs demonstrate longer disease-free survival. Additionally, immune-modulating therapies, like the anti-PD-1/PD-L1 monoclonal antibodies, have demonstrated modest activity in the pre-treated metastatic TNBC population with objective response rates (ORR) Citation Format: Telli ML, Wapnir I, Vinayak S, Chang J, Alemany C, Twitty C, Gargosky S. A phase 2 study of intratumoral tavokinogene telseplasmid (tavo) plus electroporation with pembrolizumab in patients with inoperable locally advanced or metastatic triple negative 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 OT2-06-03.
{"title":"Abstract OT2-06-03: A phase 2 study of intratumoral tavokinogene telseplasmid (tavo) plus electroporation with pembrolizumab in patients with inoperable locally advanced or metastatic triple negative breast cancer","authors":"M. Telli, I. Wapnir, S. Vinayak, J. Chang, C. Alemany, C. Twitty, S. Gargosky","doi":"10.1158/1538-7445.SABCS18-OT2-06-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-06-03","url":null,"abstract":"Triple negative breast cancer (TNBC) accounts for 10-20% of breast cancer diagnoses and is associated with a high risk of recurrence and a more aggressive course in the metastatic setting. Emerging data suggest that some patients with TNBC could benefit from the addition of immune-based therapy due to the important role of tumor infiltrating lymphocytes (TILs) on outcome. Reports show that early-stage TNBC patients with at least 50% TILs demonstrate longer disease-free survival. Additionally, immune-modulating therapies, like the anti-PD-1/PD-L1 monoclonal antibodies, have demonstrated modest activity in the pre-treated metastatic TNBC population with objective response rates (ORR) Citation Format: Telli ML, Wapnir I, Vinayak S, Chang J, Alemany C, Twitty C, Gargosky S. A phase 2 study of intratumoral tavokinogene telseplasmid (tavo) plus electroporation with pembrolizumab in patients with inoperable locally advanced or metastatic triple negative 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 OT2-06-03.","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"125 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75284610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT1-03-03
Sl Ross, T. Morris, M. Campone, J. Cortés, F. Duhoux, S. Howell
Background: Sulforaphane, a plant secondary metabolite, was first identified as an anti-cancer agent in 1992, although its inherent instability has thus far held back its clinical development. SFX-01 is a proprietary synthetic pharmaceutical development product based upon a stabilised sulforaphane. Preclinical data show sulforaphane and SFX-01 inhibit breast cancer stem cells1,2 and SFX-01 potently suppresses STAT3 in ER+ metastatic breast cancer (mBC) PDX tumours3. It is therefore hypothesised that SFX-01 could become a potential therapy for reducing resistance to hormone therapy in patients with mBC. Trial Design: An open label trial with a maximum target of 60 patients with ER+, HER2-negative, mBC who are on a third generation AI, tamoxifen (Tam) or fulvestrant (Fulv) and have evidence of emerging secondary endocrine resistance. Participants remain on AI, Tam or Fulv and take this in combination with 300mg SFX-01 orally, twice-daily, and are scanned every 6 weeks (wks) until disease progression. Patients come off study at disease progression or at the full term of 24wks. Patients who are progression free as they approach 24wks can be enrolled in a compassionate use phase. Key Eligibility Criteria ·Male or female patients 18yrs or older ·Histological confirmation of ER+ HER2-negative breast cancer ·Clinical or histological confirmation of metastatic or locally advanced disease not amenable to curative surgical resection ·At least 1 site of measurable disease ·Must be on a third generation AI, Tam or Fulv and have evidence of emerging secondary endocrine resistance as evidenced by either: a) Progressive disease while on adjuvant ET but after the first 2 years, or b) Progressive disease within 12 months of completing adjuvant ET, or c) Progressive disease while on ET, ≥6 months after initiating ET for metastatic breast cancer ·No more than 3 lines of endocrine therapy including the treatment at the time of study entry ·No more than 1 prior line of chemotherapy for metastatic/locally advanced breast cancer Specific Aims: The primary objectives are to determine the safety & tolerability of SFX-01 in combination with AI, Tam or Fulv and to determine clinical benefit rate (CBR) at 24wks using RECIST v1.1. Time to response, objective response rate, progression free survival interval and the PK of SFX-01, AI, Tam & Fulv will also be assessed. Statistical Methods: Demographic, baseline characteristics, safety and efficacy data will primarily be summarised descriptively. The sample size of 20 patients in each treatment cohort is such that if the observed CBR on any arm is 15%, it will provide a 90% exact binomial confidence interval (CI) for the true CBR of 4.2% to 34.4%. Duration of response will be compared to duration of response on prior ET. Accrual: To date, 46 of the maximum target of 60 patients have been enrolled across 10 centres in UK, Belgium, France and Spain. Final study results are expected end of 2018. References 1. Li et al, Clin Cancer R
{"title":"Abstract OT1-03-03: STEM: SFX-01 in the treatment and evaluation of metastatic breast cancer","authors":"Sl Ross, T. Morris, M. Campone, J. Cortés, F. Duhoux, S. Howell","doi":"10.1158/1538-7445.SABCS18-OT1-03-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT1-03-03","url":null,"abstract":"Background: Sulforaphane, a plant secondary metabolite, was first identified as an anti-cancer agent in 1992, although its inherent instability has thus far held back its clinical development. SFX-01 is a proprietary synthetic pharmaceutical development product based upon a stabilised sulforaphane. Preclinical data show sulforaphane and SFX-01 inhibit breast cancer stem cells1,2 and SFX-01 potently suppresses STAT3 in ER+ metastatic breast cancer (mBC) PDX tumours3. It is therefore hypothesised that SFX-01 could become a potential therapy for reducing resistance to hormone therapy in patients with mBC. Trial Design: An open label trial with a maximum target of 60 patients with ER+, HER2-negative, mBC who are on a third generation AI, tamoxifen (Tam) or fulvestrant (Fulv) and have evidence of emerging secondary endocrine resistance. Participants remain on AI, Tam or Fulv and take this in combination with 300mg SFX-01 orally, twice-daily, and are scanned every 6 weeks (wks) until disease progression. Patients come off study at disease progression or at the full term of 24wks. Patients who are progression free as they approach 24wks can be enrolled in a compassionate use phase. Key Eligibility Criteria ·Male or female patients 18yrs or older ·Histological confirmation of ER+ HER2-negative breast cancer ·Clinical or histological confirmation of metastatic or locally advanced disease not amenable to curative surgical resection ·At least 1 site of measurable disease ·Must be on a third generation AI, Tam or Fulv and have evidence of emerging secondary endocrine resistance as evidenced by either: a) Progressive disease while on adjuvant ET but after the first 2 years, or b) Progressive disease within 12 months of completing adjuvant ET, or c) Progressive disease while on ET, ≥6 months after initiating ET for metastatic breast cancer ·No more than 3 lines of endocrine therapy including the treatment at the time of study entry ·No more than 1 prior line of chemotherapy for metastatic/locally advanced breast cancer Specific Aims: The primary objectives are to determine the safety & tolerability of SFX-01 in combination with AI, Tam or Fulv and to determine clinical benefit rate (CBR) at 24wks using RECIST v1.1. Time to response, objective response rate, progression free survival interval and the PK of SFX-01, AI, Tam & Fulv will also be assessed. Statistical Methods: Demographic, baseline characteristics, safety and efficacy data will primarily be summarised descriptively. The sample size of 20 patients in each treatment cohort is such that if the observed CBR on any arm is 15%, it will provide a 90% exact binomial confidence interval (CI) for the true CBR of 4.2% to 34.4%. Duration of response will be compared to duration of response on prior ET. Accrual: To date, 46 of the maximum target of 60 patients have been enrolled across 10 centres in UK, Belgium, France and Spain. Final study results are expected end of 2018. References 1. Li et al, Clin Cancer R","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75387035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.sabcs18-ot1-13-02
R. Singh, M. Bayan, S. Kadari, Mn Nganteh, M. Jacksonm, L. Woodson, A. Shamsuddin, Lemus, S. Pratap, J. Murray, S. Adunyah, P. Lammers
{"title":"Abstract OT1-13-02: Molecular testing for minority patients with or at high risk for cancer","authors":"R. Singh, M. Bayan, S. Kadari, Mn Nganteh, M. Jacksonm, L. Woodson, A. Shamsuddin, Lemus, S. Pratap, J. Murray, S. Adunyah, P. Lammers","doi":"10.1158/1538-7445.sabcs18-ot1-13-02","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-ot1-13-02","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75430322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT2-01-02
H. Abe, T. Horiuchi, A. Teramoto, Y. Tanaka, Y. Takei, T. Nagahata
{"title":"Abstract OT2-01-02: Thoracic interfascial nerve blocks versus paravertebral block for improving quality of recovery after breast cancer surgery: A randomized, double-blind, non-inferiority trial","authors":"H. Abe, T. Horiuchi, A. Teramoto, Y. Tanaka, Y. Takei, T. Nagahata","doi":"10.1158/1538-7445.SABCS18-OT2-01-02","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-01-02","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74464435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT1-03-01
G. Curigliano, S. Cresta, Y. Yap, D. Juric, F. Duhoux, C. Terret, S. Takahashi, R. Layman, N. Kundamal, D. Baldoni, S. Liao, A. Crystal, K. Jhaveri
Background: Although ET remains the basis of therapy for ER+, HER2– ABC, treatment resistance frequently occurs. Novel strategies to target the receptor and/or alternative pathways to overcome therapeutic resistance are under investigation. LSZ102 is a novel, orally bioavailable, nonsteroidal SERD. Preclinically, LSZ102 inhibits ER gene transcription, induces receptor degradation, blocks ER-dependent cell growth, and has synergistic activity with the phosphoinositide 3-kinase (PI3K)-alpha inhibitor alpelisib (BYL719). The present study is evaluating the safety and tolerability of LSZ102 plus alpelisib in patients with ER+, HER2– ABC with progression on ET. Trial Design: This phase 1/1b, open-label study is enrolling ˜18-30 patients (men and women of any menopausal status) in Arm C of the dose-escalation part of the study, which investigates the combination of LSZ102 and alpelisib; additional study arms will investigate LSZ102 as a single agent or in combination with ribociclib. Enrollment in Arm C started after identification of a safe and tolerable single-agent dose for LSZ102. Alpelisib dosing began at 200 mg/day and will not be escalated beyond the maximum tolerated dose (MTD) determined in the alpelisib single-agent arm of study CBYL719X2101 (400 mg/day). Dose escalation of alpelisib in combination with LSZ102 is guided by BLRM and integrates Cycle 1 DLT rates, lower grade and later cycle AE, PK, PD and preliminary activity to identify a recommended dose for expansion (RDE). Patients will receive treatment until disease progression, unacceptable toxicity, or withdrawal of consent. For inclusion in the study, patients must have histologically confirmed ER+, HER2– ABC and disease progression after ET for ABC or recurrence on/within 12 months of completion of adjuvant ET. In the escalation part of the study, patients are eligible regardless of PIK3CA status. Premenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligible patients must have adequate bone marrow and organ function, Eastern Cooperative Oncology Group performance status of 0 or 1, and have completed and recovered from acute toxicities of radiotherapy and/or prior anticancer therapy. Exclusion criteria include symptomatic central nervous system metastases, clinically significant cardiac disease or impaired cardiac function (including a QT interval corrected for heart rate using Fridericia9s formula [QTcF] >460 ms in women or >450 ms in men), uncontrolled diabetes mellitus type II (or type I), and prior treatment with a PI3K inhibitor. The primary objectives are characterization of safety and tolerability for the combination and identification of a recommended dose. Secondary objectives include characterization of pharmacokinetic properties and pharmacodynamic effects. Recruitment for Arm C is ongoing. NCT02734615 Citation Format: Curigliano G, Cresta S, Yap Y-S, Juric D, Duhoux FP, Terret C, Takahashi S, Layman RM, Kundamal N, Baldoni D,
{"title":"Abstract OT1-03-01: Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 in combination with alpelisib (BYL719) in estrogen receptor-positive (ER+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC) with progression on endocrine thera","authors":"G. Curigliano, S. Cresta, Y. Yap, D. Juric, F. Duhoux, C. Terret, S. Takahashi, R. Layman, N. Kundamal, D. Baldoni, S. Liao, A. Crystal, K. Jhaveri","doi":"10.1158/1538-7445.SABCS18-OT1-03-01","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT1-03-01","url":null,"abstract":"Background: Although ET remains the basis of therapy for ER+, HER2– ABC, treatment resistance frequently occurs. Novel strategies to target the receptor and/or alternative pathways to overcome therapeutic resistance are under investigation. LSZ102 is a novel, orally bioavailable, nonsteroidal SERD. Preclinically, LSZ102 inhibits ER gene transcription, induces receptor degradation, blocks ER-dependent cell growth, and has synergistic activity with the phosphoinositide 3-kinase (PI3K)-alpha inhibitor alpelisib (BYL719). The present study is evaluating the safety and tolerability of LSZ102 plus alpelisib in patients with ER+, HER2– ABC with progression on ET. Trial Design: This phase 1/1b, open-label study is enrolling ˜18-30 patients (men and women of any menopausal status) in Arm C of the dose-escalation part of the study, which investigates the combination of LSZ102 and alpelisib; additional study arms will investigate LSZ102 as a single agent or in combination with ribociclib. Enrollment in Arm C started after identification of a safe and tolerable single-agent dose for LSZ102. Alpelisib dosing began at 200 mg/day and will not be escalated beyond the maximum tolerated dose (MTD) determined in the alpelisib single-agent arm of study CBYL719X2101 (400 mg/day). Dose escalation of alpelisib in combination with LSZ102 is guided by BLRM and integrates Cycle 1 DLT rates, lower grade and later cycle AE, PK, PD and preliminary activity to identify a recommended dose for expansion (RDE). Patients will receive treatment until disease progression, unacceptable toxicity, or withdrawal of consent. For inclusion in the study, patients must have histologically confirmed ER+, HER2– ABC and disease progression after ET for ABC or recurrence on/within 12 months of completion of adjuvant ET. In the escalation part of the study, patients are eligible regardless of PIK3CA status. Premenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligible patients must have adequate bone marrow and organ function, Eastern Cooperative Oncology Group performance status of 0 or 1, and have completed and recovered from acute toxicities of radiotherapy and/or prior anticancer therapy. Exclusion criteria include symptomatic central nervous system metastases, clinically significant cardiac disease or impaired cardiac function (including a QT interval corrected for heart rate using Fridericia9s formula [QTcF] >460 ms in women or >450 ms in men), uncontrolled diabetes mellitus type II (or type I), and prior treatment with a PI3K inhibitor. The primary objectives are characterization of safety and tolerability for the combination and identification of a recommended dose. Secondary objectives include characterization of pharmacokinetic properties and pharmacodynamic effects. Recruitment for Arm C is ongoing. NCT02734615 Citation Format: Curigliano G, Cresta S, Yap Y-S, Juric D, Duhoux FP, Terret C, Takahashi S, Layman RM, Kundamal N, Baldoni D,","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72617279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT3-05-04
Angela Alexander, An Marx, S. Reddy, J. Reuben, Hc Le-Petross, D. Lane, Monica L. Huang, S. Krishnamurthy, Yilei Gong, D. Gombos, Nalini Patel, C. Tung, Rc Allen, Tj Kandl, J. Wu, S. Liu, A. Patel, A. Futreal, I. Wistuba, R. Layman, V. Valero, D. Tripathy, N. Ueno, B. Lim
Background: IBCs that do not completely respond to chemotherapy often have dysregulated immune pathways, and novel therapies are needed to improve outcomes in recurrent/metastatic disease. One-third of IBCs express the atezolizumab target PD-L1, and cobimetinib increases PD-L1 expression; thus, we hypothesize that atezolizumab and cobimetinib may act synergistically in IBC. The FDA-approved agent eribulin is active in IBC and has anti-stem cell activity and can reverse the IBC phenotype of epithelial-to-mesenchymal transition. Hence the use of eribulin as a chemotherapy backbone in combination with other novel agents is well justified. Trial Design: This single-arm, open-label trial is enrolling patients with recurrent IBC or de novo metastatic IBC that has progressed on at least 1 line of standard chemotherapy. During a 4-week pharmacodynamic window, patients have an upfront biopsy, receive atezolizumab and cobimetinib treatment for 4 weeks, and have a second biopsy. Triple-combination treatment then commences, with standard eribulin dosing. After 4 cycles of eribulin, patients receive maintenance targeted therapy until disease progression or intolerable toxicity. Eligibility Criteria: Patients with metastatic IBC of any molecular subtype must have measurable disease (per RECIST 1.1) amenable to biopsy. Patients with HER2+ disease must have received both pertuzumab and T-DM1. Patients with treated stable brain metastases are allowed. Patients must have recovered from the acute effects of any prior therapies and have adequate hematologic, organ, and cardiac function. Patients with autoimmune diseases or a history of pneumonitis are ineligible. Specific Aims: The primary objective is to determine the overall response rate (ORR) of the combination therapy. Secondary objectives include determining the safety and tolerability, clinical benefit rate, response duration, progression-free survival, 2-year overall survival rate and predictive biomarker analyses. Statistical Methods: The trial will enroll up to 9 patients in its phase I/safety lead-in portion and up to 33 patients total. A Bayesian optimal interval design is used to efficiently determine the maximum tolerated cobimetinib dose in phase I. Patients start cobimetinib at the FDA-approved dose of 60 mg/day with a target toxicity rate is 0.3. Phase II will enroll 24 patients to determine the efficacy of the triple-combination therapy. The historical ORR in metastatic IBC is 10%; our sample size provides 80% power to detect an ORR improvement to 25%. Accrual: The trial has enrolled 7 patients since its start in August 2017. Citation Format: Alexander A, Marx AN, Reddy SM, Reuben JM, Le-Petross HC, Lane D, Huang ML, Krishnamurthy S, Gong Y, Gombos DS, Patel N, Tung CI, Allen RC, Kandl TJ, Wu J, Liu S, Patel AB, Futreal A, Wistuba I, Layman RM, Valero V, Tripathy D, Ueno NT, Lim B. Phase II study of atezolizumab, cobimetinib, and eribulin in patients with recurrent or metastatic inflammatory breast
背景:对化疗没有完全反应的IBCs通常有失调的免疫通路，需要新的治疗方法来改善复发/转移性疾病的预后。三分之一的IBCs表达atezolizumab靶点PD-L1，而cobimetinib增加PD-L1表达;因此，我们假设atezolizumab和cobimetinib可能协同作用于IBC。fda批准的药物eribulin在IBC中具有活性，具有抗干细胞活性，可以逆转IBC从上皮到间质转化的表型。因此，使用伊瑞布林作为化疗骨干与其他新药联合是很有道理的。试验设计:这项单臂、开放标签试验招募了复发性IBC或新发转移性IBC患者，这些患者至少接受了1条标准化疗。在4周的药效学窗口期，患者进行前期活检，接受atezolizumab和cobimetinib治疗4周，并进行第二次活检。然后开始使用标准剂量的三联治疗。4个疗程后，患者接受维持性靶向治疗，直至疾病进展或出现无法忍受的毒性。资格标准:任何分子亚型的转移性IBC患者必须有可测量的疾病(根据RECIST 1.1)，适合活检。HER2+疾病患者必须同时接受帕妥珠单抗和T-DM1治疗。接受治疗的稳定脑转移患者是允许的。患者必须从任何先前治疗的急性影响中恢复，并具有足够的血液学，器官和心脏功能。有自身免疫性疾病或肺炎病史的患者不适用。具体目的:主要目的是确定联合治疗的总有效率(ORR)。次要目标包括确定安全性和耐受性、临床获益率、反应持续时间、无进展生存期、2年总生存率和预测性生物标志物分析。统计方法:该试验将在I期/安全性导入部分招募最多9名患者，总计最多33名患者。采用贝叶斯最优间隔设计有效确定i期患者的最大耐受cobimetinib剂量。患者以fda批准的剂量60mg /天开始服用cobimetinib，目标毒性率为0.3。二期试验将招募24名患者，以确定三联疗法的疗效。转移性IBC的历史ORR为10%;我们的样本量提供80%的功率来检测ORR提高到25%。自2017年8月开始以来，该试验已招募了7名患者。引用本文:Alexander A, Marx AN, Reddy SM, Reuben JM, Le-Petross HC, Lane D, Huang ML, Krishnamurthy S, Gong Y, Gombos DS, Patel N, Tung CI, Allen RC, Kandl TJ, Wu J, Liu S, Patel AB, Futreal A, Wistuba I, Layman RM, Valero V, Tripathy D, Ueno NT, Lim B. atezolizumab、cobimetinib和eribulin治疗复发或转移性炎性乳腺癌(IBC)的II期研究[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志，2019;79(4增刊):OT3-05-04。
{"title":"Abstract OT3-05-04: Phase II study of atezolizumab, cobimetinib, and eribulin in patients with recurrent or metastatic inflammatory breast cancer (IBC)","authors":"Angela Alexander, An Marx, S. Reddy, J. Reuben, Hc Le-Petross, D. Lane, Monica L. Huang, S. Krishnamurthy, Yilei Gong, D. Gombos, Nalini Patel, C. Tung, Rc Allen, Tj Kandl, J. Wu, S. Liu, A. Patel, A. Futreal, I. Wistuba, R. Layman, V. Valero, D. Tripathy, N. Ueno, B. Lim","doi":"10.1158/1538-7445.SABCS18-OT3-05-04","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT3-05-04","url":null,"abstract":"Background: IBCs that do not completely respond to chemotherapy often have dysregulated immune pathways, and novel therapies are needed to improve outcomes in recurrent/metastatic disease. One-third of IBCs express the atezolizumab target PD-L1, and cobimetinib increases PD-L1 expression; thus, we hypothesize that atezolizumab and cobimetinib may act synergistically in IBC. The FDA-approved agent eribulin is active in IBC and has anti-stem cell activity and can reverse the IBC phenotype of epithelial-to-mesenchymal transition. Hence the use of eribulin as a chemotherapy backbone in combination with other novel agents is well justified. Trial Design: This single-arm, open-label trial is enrolling patients with recurrent IBC or de novo metastatic IBC that has progressed on at least 1 line of standard chemotherapy. During a 4-week pharmacodynamic window, patients have an upfront biopsy, receive atezolizumab and cobimetinib treatment for 4 weeks, and have a second biopsy. Triple-combination treatment then commences, with standard eribulin dosing. After 4 cycles of eribulin, patients receive maintenance targeted therapy until disease progression or intolerable toxicity. Eligibility Criteria: Patients with metastatic IBC of any molecular subtype must have measurable disease (per RECIST 1.1) amenable to biopsy. Patients with HER2+ disease must have received both pertuzumab and T-DM1. Patients with treated stable brain metastases are allowed. Patients must have recovered from the acute effects of any prior therapies and have adequate hematologic, organ, and cardiac function. Patients with autoimmune diseases or a history of pneumonitis are ineligible. Specific Aims: The primary objective is to determine the overall response rate (ORR) of the combination therapy. Secondary objectives include determining the safety and tolerability, clinical benefit rate, response duration, progression-free survival, 2-year overall survival rate and predictive biomarker analyses. Statistical Methods: The trial will enroll up to 9 patients in its phase I/safety lead-in portion and up to 33 patients total. A Bayesian optimal interval design is used to efficiently determine the maximum tolerated cobimetinib dose in phase I. Patients start cobimetinib at the FDA-approved dose of 60 mg/day with a target toxicity rate is 0.3. Phase II will enroll 24 patients to determine the efficacy of the triple-combination therapy. The historical ORR in metastatic IBC is 10%; our sample size provides 80% power to detect an ORR improvement to 25%. Accrual: The trial has enrolled 7 patients since its start in August 2017. Citation Format: Alexander A, Marx AN, Reddy SM, Reuben JM, Le-Petross HC, Lane D, Huang ML, Krishnamurthy S, Gong Y, Gombos DS, Patel N, Tung CI, Allen RC, Kandl TJ, Wu J, Liu S, Patel AB, Futreal A, Wistuba I, Layman RM, Valero V, Tripathy D, Ueno NT, Lim B. Phase II study of atezolizumab, cobimetinib, and eribulin in patients with recurrent or metastatic inflammatory breast","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"85 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77000278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT1-07-01
Jessica D. Lang, S. Chawla, J. Chang, G. diZerega, Rm Cavanna-Mast, C. Savoie, M. Lacouture
{"title":"Abstract OT1-07-01: Phase 1/2 study of topical SOR007 (nanoparticle paclitaxel ointment) for cutaneous metastasis","authors":"Jessica D. Lang, S. Chawla, J. Chang, G. diZerega, Rm Cavanna-Mast, C. Savoie, M. Lacouture","doi":"10.1158/1538-7445.SABCS18-OT1-07-01","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT1-07-01","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77007145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT3-02-04
A. Nijhof, A. Voort, I. Konings, A. Jager, G. Sonke
BACKGROUND Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) is an effective strategy to improve progression-free survival (PFS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). There is a lack of comparative data to help clinicians decide whether CDK4/6 inhibitors can best be added to first- or second-line ET. The former strategy may provide longer PFS benefit, but is associated with longer use of the drug, which results in more toxicity and costs, whereas no clear benefit on overall survival (OS) or quality of life (QoL) has been proven thus far. No predictive biomarker exists to select patients who are most likely to benefit from the addition of CDK4/6 inhibition. TRIAL DESIGN AND AIMS The SONIA study is an investigator-initiated, multicenter, randomized phase III study, funded by 9ZonMw9 and 9Zorgverzekeraars Nederland9. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor (NSAI) + CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with NSAI, followed on progression by fulvestrant + CDK4/6 inhibition). Each CDK4/6 inhibitor can be used according to its approved EMA label. The primary objective is to test whether strategy A is superior to strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include OS, safety, QoL, and cost-effectiveness. Additional biomarker analyses will be performed to optimize patient selection. ELIGIBILITY CRITERIA Patients with a proven diagnosis of HR+/HER2-negative advanced breast cancer without prior systemic therapy for advanced disease who are candidates to receive NSAIs as first-line treatment, are eligible for the study. Exclusion criteria include advanced visceral spread with the risk of life-threatening complications in the short term. Other conditions excluding a patient from participating are other malignancies, prolonged QTc time (>480ms) or any other medical condition that interferes with study procedures or compliance. STATISTICAL METHODS The difference in PFS2 will be estimated using the intention-to-treat population in a Cox proportional hazards model accounting for all stratification factors (visceral versus non-visceral disease, yes versus no prior ET in (neo)adjuvant setting, hospital, and type of CDK4/6 inhibitor). Five-hundred seventy-four primary outcome events yield 89% power to show that strategy A has statistically significant, clinically meaningful (according to European Society for Medical Oncology - Magnitude of Clinical Benefit Scale) superior PFS2 in a log-rank test at the two-sided 95% confidence level. ACCRUAL TARGET: with an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required. A total of 76 Dutch hospitals will participate. PRESENT: th
周期蛋白依赖性激酶4和6 (CDK4/6)抑制剂联合内分泌治疗(ET)是改善激素受体阳性(HR+)、人表皮生长因子受体2 (HER2)阴性晚期乳腺癌(ABC)无进展生存期(PFS)的有效策略。目前缺乏比较数据来帮助临床医生决定CDK4/6抑制剂是否可以最好地添加到一线或二线ET中。前一种策略可能提供更长的PFS益处，但与更长的药物使用相关，这导致更多的毒性和成本，而迄今为止尚未证明对总生存期(OS)或生活质量(QoL)有明显的益处。目前还没有预测性的生物标志物来选择最有可能从CDK4/6抑制中获益的患者。索尼亚研究是一项由研究者发起的多中心随机III期研究，由9ZonMw9和9Zorgverzekeraars nederland资助。患者被随机分配接受策略A(一线使用非甾体芳香化酶抑制剂(NSAI) + CDK4/6抑制，随后使用氟维司汀进展)或策略B(一线使用NSAI，随后使用氟维司汀+ CDK4/6抑制进展)。每种CDK4/6抑制剂都可以根据其批准的EMA标签使用。主要目的是检验策略A是否优于策略b。主要终点是从随机化到第二目标进展(PFS2)的时间。次要终点包括OS、安全性、生活质量和成本效益。将进行额外的生物标志物分析以优化患者选择。经证实诊断为HR+/ her2阴性的晚期乳腺癌患者，既往未接受过晚期疾病的全身治疗，作为接受非甾体抗炎药作为一线治疗的候选者，符合本研究的资格。排除标准包括有短期危及生命的并发症风险的晚期内脏扩散。其他排除患者参与的条件包括其他恶性肿瘤、QTc时间延长(>480ms)或任何其他影响研究程序或依从性的医疗条件。统计学方法:在考虑所有分层因素的Cox比例风险模型中，使用意向治疗人群估计PFS2的差异(内脏与非内脏疾病，(新)辅助设置中有ET与无ET，医院和CDK4/6抑制剂类型)。574个主要结局事件产生89%的功率，表明策略A在双侧95%置信水平的对数秩检验中具有统计学意义，临床意义(根据欧洲肿瘤医学学会-临床获益量表大小)优于PFS2。目标:累积期为42个月，另外随访18个月，需要纳入1050例可评估患者。共有76家荷兰医院将参加。目前:该研究在51家医院开放，包括106名患者。引用格式:van Ommen - Nijhof A, van der Voort A, Konings IR, Jager A, Sonke GS，代表SONIA调查员(SONIA指导委员会)和荷兰乳腺癌研究小组(BOOG)。选择CDK4/6抑制剂在激素受体阳性晚期乳腺癌中的最佳位置:BOOG 2017-03 SONIA研究[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志，2019;79(4增刊):OT3-02-04。
{"title":"Abstract OT3-02-04: Selecting the optimal position of CDK4/6 inhibitors in hormone-receptor-positive advanced breast cancer: The BOOG 2017-03 SONIA study","authors":"A. Nijhof, A. Voort, I. Konings, A. Jager, G. Sonke","doi":"10.1158/1538-7445.SABCS18-OT3-02-04","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT3-02-04","url":null,"abstract":"BACKGROUND Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) is an effective strategy to improve progression-free survival (PFS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). There is a lack of comparative data to help clinicians decide whether CDK4/6 inhibitors can best be added to first- or second-line ET. The former strategy may provide longer PFS benefit, but is associated with longer use of the drug, which results in more toxicity and costs, whereas no clear benefit on overall survival (OS) or quality of life (QoL) has been proven thus far. No predictive biomarker exists to select patients who are most likely to benefit from the addition of CDK4/6 inhibition. TRIAL DESIGN AND AIMS The SONIA study is an investigator-initiated, multicenter, randomized phase III study, funded by 9ZonMw9 and 9Zorgverzekeraars Nederland9. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor (NSAI) + CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with NSAI, followed on progression by fulvestrant + CDK4/6 inhibition). Each CDK4/6 inhibitor can be used according to its approved EMA label. The primary objective is to test whether strategy A is superior to strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include OS, safety, QoL, and cost-effectiveness. Additional biomarker analyses will be performed to optimize patient selection. ELIGIBILITY CRITERIA Patients with a proven diagnosis of HR+/HER2-negative advanced breast cancer without prior systemic therapy for advanced disease who are candidates to receive NSAIs as first-line treatment, are eligible for the study. Exclusion criteria include advanced visceral spread with the risk of life-threatening complications in the short term. Other conditions excluding a patient from participating are other malignancies, prolonged QTc time (>480ms) or any other medical condition that interferes with study procedures or compliance. STATISTICAL METHODS The difference in PFS2 will be estimated using the intention-to-treat population in a Cox proportional hazards model accounting for all stratification factors (visceral versus non-visceral disease, yes versus no prior ET in (neo)adjuvant setting, hospital, and type of CDK4/6 inhibitor). Five-hundred seventy-four primary outcome events yield 89% power to show that strategy A has statistically significant, clinically meaningful (according to European Society for Medical Oncology - Magnitude of Clinical Benefit Scale) superior PFS2 in a log-rank test at the two-sided 95% confidence level. ACCRUAL TARGET: with an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required. A total of 76 Dutch hospitals will participate. PRESENT: th","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84319568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-02-15DOI: 10.1158/1538-7445.SABCS18-OT1-03-04
S. Damodaran, F. Meric-Bernstam, K. Hess, J. Litton, V. Raymond, R. Lanman, N. Ueno, S. Hamilton, I. Wistuba, V. Valero, S. Moulder, D. Tripathy
{"title":"Abstract OT1-03-04: INTERACT- INTegrated Evaluation of Resistance and Actionability using Circulating Tumor DNA in hormone receptor (HR) positive metastatic breast cancers (MBC)","authors":"S. Damodaran, F. Meric-Bernstam, K. Hess, J. Litton, V. Raymond, R. Lanman, N. Ueno, S. Hamilton, I. Wistuba, V. Valero, S. Moulder, D. Tripathy","doi":"10.1158/1538-7445.SABCS18-OT1-03-04","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT1-03-04","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88764674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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