A phase I dose escalation and expansion study of the next generation oral SERD AZD9833 in women with ER-positive, HER2-negative advanced breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1024-1024
Author(s):  
Erika Paige Hamilton ◽  
Mafalda Oliveira ◽  
Udai Banerji ◽  
Cristina Hernando ◽  
Javier Garcia-Corbacho ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Clinical Benefit ◽  
Sinus Bradycardia ◽  
Phase 1 ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Advanced Breast ◽  
Open Label

1024 Background: AZD9833 is an oral selective estrogen receptor (ER) antagonist and degrader (SERD) that has shown antitumor efficacy in a range of preclinical models of breast cancer. Methods: SERENA-1 (NCT03616587) is an ongoing Phase 1, open-label study in pre- and post-menopausal women, after ≥1 endocrine therapy and ≤2 prior chemotherapies for ER+ HER2- advanced breast cancer (ABC). The primary objective is to determine the safety and tolerability of AZD9833 once daily (QD), with dose-limiting toxicities (DLTs) in 28d defining the maximum tolerated dose. Secondary objectives include pharmacokinetics and anti-tumor response. Pharmacodynamic (PD) analysis includes ER modulation in paired tumor biopsies and ctDNA dynamic changes. Results: At 20 January 2020: 60 patients were treated (median prior therapies 5 (1–9); prior fulvestrant (Fv) 82%; prior CDK4/6i 68%) across five doses; 25 mg QD n=12, 75 mg QD n=12, 150 mg QD n=13, 300 mg QD n=13, 450 mg QD n=10. AZD9833 exposure was dose proportional after multiple doses, with a median terminal t1/2 of 12h. Treatment-related AEs experienced by ≥10% of patients were visual disturbances (53%; 91% G1, 6% G2, 3% G3), bradycardia/sinus bradycardia (45%; 93% G1, 7% G2), nausea (18%; 46% G1, 55% G2), fatigue (13%; 38% G1, 63% G2), dizziness (10%; 83% G1, 17% G3) vomiting (10%; 50% G1, 33% G2, 17% G3), and asthenia (10%; 67% G1, 33% G2). Three patients experienced DLTs: G3 QTcF prolongation (300 mg); G3 vomiting (450 mg); and a combination of G2 visual disturbance, G2 headache and G2 gait disturbance (450 mg). DLTs resolved with dose reduction. No G4 or 5 AEs were reported. Efficacy data are presented in the table below; objective response rate (ORR) and clinical benefit rate (CBR) at 24 weeks. Clinical trial information: NCT03616587 . ER signalling pathway modulation was observed in all dose cohorts. In patients where clinical responses occurred and paired biopsies obtained, 98% reduction in Ki67 was measured. Updated data will be presented. Conclusions: AZD9833 has an encouraging efficacy and dose-dependent safety profile. Evidence of clinical benefit and target engagement was observed at all dose levels in women with ER+ ABC, including patients pre-treated with CDK4/6i and Fv, and those with ESR1 mutations. A Phase 2 study comparing efficacy and safety of three doses AZD9833 vs Fv is planned (NCT04214288). [Table: see text]

scholarly journals Pembrolizumab Plus Gemcitabine in the Subset of Triple-Negative Advanced Breast Cancer Patients in the GEICAM/2015-04 (PANGEA-Breast) Study

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5432
Author(s):  
Luis de la Cruz-Merino ◽  
María Gion ◽  
Josefina Cruz-Jurado ◽  
Vanesa Quiroga ◽  
Raquel Andrés ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Cancer Patients ◽  
Treatment Efficacy ◽  
Triple Negative ◽  
Objective Response ◽  
Suppressor Cells ◽  
Primary Objective ◽  
Advanced Breast ◽  
Breast Cancer Patients

The PANGEA-Breast trial evaluated a new chemo-immunotherapeutic combination that would synergistically induce long-term clinical benefit in HER2-negative advanced breast cancer patients. Treatment consisted of 21-day cycles of 200 mg of pembrolizumab (day 1) plus gemcitabine (days 1 and 8). The primary objective was the objective response rate (ORR). The tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumor, and the myeloid-derived suppressor cells (MDSCs) level in peripheral blood, were analyzed to explore associations with treatment efficacy. Considering a two-stage Simon’s design, the study recruitment was stopped after its first stage as statistical assumptions were not met. A subset of 21 triple-negative breast cancer (TNBC) patients was enrolled. Their median age was 49 years; 15 patients had visceral involvement, and 16 had ≤3 metastatic locations. Treatment discontinuation due to progressive disease (PD) was reported in 16 patients. ORR was 15% (95% CI 3.2–37.9). Four patients were on treatment >6 months before PD. Grade ≥3 treatment-related adverse events were observed in 8 patients, where neutropenia was the most common. No association was found between TILs density, PD-L1 expression or MDSCs levels and treatment efficacy. ORR in TNBC patients also did not meet the assumptions, but 20% were on treatment >6 months.

Safety, Pharmacokinetics, and Preliminary Activity of CDK4/6 Inhibitor FCN-437c in Chinese Female Patients with HR+HER2- Advanced Breast Cancer (ABC) From Phase Ia Study

2021 ◽  
Author(s):  
Jian Zhang ◽  
Xiaojia Wang ◽  
Xian Wang ◽  
Aimin Hui ◽  
Zhuli Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Objective Response ◽  
Human Study ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Advanced Breast ◽  
Female Patients ◽  
Best Response ◽  
Dose Levels

Abstract Purpose: This is a phase Ia, first-in-human study aiming to assess the safety, maximum tolerated dose (MTD), pharmacokinetic (PK) and anti-tumor activity of FCN-437c, CDK4/6 inhibitor, as monotherapy in patients with HR+HER2- ABC (advanced breast cancer) who failed standard of care. Methods: Regular 3+3 dose escalation design was utilized with starting dose of 50 mg per day for 3 weeks on -1 week off treatment in a 28-day cycle. Seventeen eligible female patients with HR+HER2- ABC were enrolled at different dose levels: 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 6) and 450 mg (n = 2). Results: Two patients in the 450 mg dose group experienced DLT of grade 4 thrombocytopenia and neutropenia respectively, and no DLT was observed in other dose levels. The most frequently reported TEAEs was hematological, including leukopenia (94.1%), neutropenia (88.2%), anemia (64.7%) and thrombocytopenia (47.1%). Major grade 3-4 TEAEs were neutropenia and leukopenia, occurring in 11 (64.7%) and 8 (47.1%) patients, respectively. The exposure increased almost in proportion to given dose ranging from 50 to 200 mg. At multiple dose levels from 200 to 450 mg, there appeared to be a trend of saturation. MTD was determined to be 300 mg. Of 15 measurable patients, nine (60.0%) had the best response of stable disease and no objective response was observed. Conclusions: FCN-437c has established an acceptable safety profile with no unexpected signals compared to other CDK4/6 inhibitors. (NCT04488107, Jul 13th 2020)

A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2609-2609 ◽  
Author(s):  
Monica Arnedos ◽  
Crystal Shereen Denlinger ◽  
Wael A. Harb ◽  
Olivier Rixe ◽  
John Charles Morris ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Clinical Benefit ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Clinical Benefit Rate

2609 Background: MM-121 is a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3. ErbB3 has been implicated in driving cancer growth and in the development of resistance to conventional chemotherapies across multiple malignancies. Here we present results of an open-label, Phase 1, multicenter, non-randomized, dose-escalation trial which recently completed enrollment evaluating MM-121 in combination with one of the following chemotherapies: Gemcitabine (Arm A, n=11), carboplatin (Arm B, n=11), pemetrexed (Arm C, n=10), or cabazitaxel (Arm D, n=11). Methods: Patients were treated in a dose escalation “3+3” design to assess the safety, tolerability and pharmacokinetics (PK) of MM-121 administered weekly in combination with anticancer therapies in subjects with advanced cancer. Doses were escalated until the maximum tolerated dose (MTD) was identified or the combination was shown to be tolerable at the highest planned doses. Secondary objectives included: Determining the objective response rate, clinical benefit rate, PK and immunogenicity of MM-121. Data summarized are as of 1/17/2013 from a live database. Results: Overall, 43 patients, [22 (51%) female and 21 (49%) male] have been treated with a median treatment duration of 57 days (range 1-302). The median age was 59 years (range 42-84) and patients had received a median of four prior lines of therapy (range 0-13). Common (>20%) adverse events of any grade and causality across all arms included diarrhea (74%), nausea (54%), fatigue (51%), anemia (44%), vomiting (33%), hypokalemia (30%), decreased appetite (26%), thrombocytopenia (26%), peripheral edema (23%), neutropenia (21%), and constipation (21%). Four DLTs were observed: Two in combination with carboplatin (G4 thrombocytopenia and G3 rash), one with gemcitabine (G4 thrombocytopenia), and one with pemetrexed (G4 hyperuricemia). Overall 38 (88%) patients were evaluable for response and the overall clinical benefit rate (PR or SD >18 weeks), is 32% (12/38). Conclusions: MM-121 can be combined at its recommended single agent dose with standard doses of gemcitabine, pemetrexed, and cabazitaxel and adapted doses of carboplatin. Clinical trial information: NCT01447225.

Randomized Phase II Trial on Mitomycin-C/Cisplatin ± KLT in Heavily Pretreated Advanced Breast Cancer

2008 ◽  
Vol 36 (04) ◽  
pp. 665-674 ◽  
Author(s):  
H.Y. Guo ◽  
Y. Cai ◽  
X.M. Yang ◽  
Z.H. Wang ◽  
J.L. Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Progressive Disease ◽  
Objective Response ◽  
Advanced Breast ◽  
Randomized Phase Ii ◽  
Heavily Pretreated ◽  
And Control

A randomized phase II study using mitomycin (MMC)/cisplatin (DDP) regimen with or without Kanglaite (KLT, a traditional Chinese medicine) as salvage treatment was conducted to exploit KLT's potential effects on patients with advanced breast cancer (ABC). Triweekly regimen consisted of mitomycin (8 mg/m2) administered intravenously on day 1, and cisplatin (25 mg/m2) intravenously on days 1 to 3. KLT (100 ml) was given intravenously per day on days 1 to 14 every 3 weeks. Between April 2006 and July 2007, 60 patients with a median age of 48 years were randomized into MMC/DDP with or without KLT treatment. In all, the objective response rate (ORR) was 17.5%. There were no significant differences between experimental and control treatments in terms of ORR (14.3% vs. 20.7%, p = 0.730), clinical benefit rates (24.1% vs. 28.6%, p = 0.468), median time to progression (TTP; 3.63 vs. 4.0, p = 0.872), and overall survival (OS; 7.17 vs. not reached, p = 0.120). The median TTP for patients with complete or partial responses was 6.0 months, but only 2.1 months for patients with stable or progressive disease (SD or PD; p = 0.028). While the median OS for patients who obtained clinical benefit from chemotherapy was not reached, that of patients with SD of no more than 6 months or PD was only 7.17 months (p = 0.004). There is no additional benefit when KLT is added to the MMC/DDP doublet in the management of ABC. Patients who obtained clinical benefit from chemotherapy had a longer TTP and OS.

BOLERO-6: Phase II study of everolimus plus exemestane versus everolimus or capecitabine monotherapy in HR+, HER2- advanced breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS660-TPS660 ◽  
Author(s):  
Bent Ejlertsen ◽  
Guy Heinrich Maria Jerusalem ◽  
Sara A. Hurvitz ◽  
Richard H. De Boer ◽  
Tanya Taran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Advanced Breast Cancer ◽  
Clinical Benefit ◽  
Performance Status ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Breast ◽  
Clinical Activity ◽  
Objective Evidence

TPS660 Background: Everolimus (EVE), an orally bioavailable inhibitor of the mammalian target of rapamycin (mTOR), has shown clinical activity as monotherapy and in combination with endocrine therapy (ET) in hormone-receptor–positive (HR+; estrogen and/or progesterone receptors) advanced breast cancer (ABC). In a pivotal phase 3 trial in patients with HR+ ABC progressing on ET, EVE + exemestane (EXE) significantly prolonged median progression-free survival (PFS) vs EXE alone per local (7.8 vs 3.2 months; log-rank P<.0001) or central (11.0 months for EVE+EXE vs 4.1 months for EXE alone; log-rank P<.0001) assessment. Capecitabine, an orally administered fluoropyrimidine carbamate indicated as monotherapy in paclitaxel and/or anthracycline-refractory ABC, has shown clinical benefit in patients with HR+, human epidermal growth factor receptor 2-negative (HER2-) ABC. The BOLERO-6 study in patients with HR+, HER2- ABC progressing on prior anastrozole or letrozole will compare PFS following EVE+EXE combination therapy vs EVE or capecitabine monotherapy. Methods: In this multicenter, open-label, randomized, 3-arm, phase 2 study, 300 patients will be randomized to receive either EVE (10 mg/d) + EXE (25 mg/d) combination therapy, or EVE (10 mg/d) alone, or capecitabine (1,250 mg/m2twice daily for 14 d/3-wk cycle) alone, until disease progression. Patients will be stratified based on the presence of visceral disease. Key eligibility criteria include age ≥18 years, postmenopausal status; histologic or cytologic confirmation of estrogen-receptor–positive, HER2- ABC; radiologic or objective evidence of recurrence or progression on prior aromatase inhibitors; Eastern Cooperative Oncology Group (ECOG) performance status ≤2. The primary endpoint is PFS with EVE+EXE vs EVE, based on local radiologic assessment (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). The key secondary endpoint is PFS with EVE+EXE vs capecitabine. Other secondary endpoints include overall survival, objective response rate, clinical benefit rate, safety, quality of life, and patient satisfaction with treatment. Enrollment will start in Q1 2013. Estimated study completion in Q1 2015. Clinical trial information: NCT01783444.

A Phase 1 Study of SHR6390, A Cyclin-dependent Kinase 4/6 Inhibitor in Patients with Advanced Breast Cancer

2020 ◽  
Author(s):  
Pin Zhang ◽  
Binghe Xu ◽  
Lin Gui ◽  
Wenna Wang ◽  
Meng Xiu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Human Study ◽  
Advanced Breast ◽  
Clinical Activity ◽  
Cyclin Dependent Kinase ◽  
Open Label ◽  
Phase 1 Study

Abstract Background: SHR6390 is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of SHR6390 in patients with advanced breast cancer (ABC).Methods: In this open-label, phase 1 study, patients who had failed standard therapy were enrolled to receive oral SHR6390 in 3 + 3 dose-escalation pattern at doses of 25−175 mg. Eligible patients were given a single-dose of SHR6390 in week 1, followed by once daily continuous doses for three weeks, and one week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8−10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics. Results: Between Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. SHR6390 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50−175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8−77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4‒97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1‒not reached).Conclusions: SHR6390 showed acceptable safety profile and dose-dependent plasma exposure in patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation.Trial registration: ClinicalTrials.gov identifier: NCT02684266. Registered Feb 17, 2016. https://clinicaltrials.gov/ct2/show/NCT02684266.

Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): Efficacy, safety, and biomarker results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1016-1016 ◽  
Author(s):  
Aditya Bardia ◽  
Sara A. Hurvitz ◽  
Angela DeMichele ◽  
Amy Sanders Clark ◽  
Amelia Bruce Zelnak ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Advanced Breast Cancer ◽  
Clinical Benefit ◽  
Single Agent ◽  
Advanced Breast ◽  
Open Label ◽  
End Point ◽  
Rational Therapy ◽  
Grade 3

1016 Background: The combination of CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) provides consistent improvement in PFS and response rates compared with single-agent ET as first- or subsequent-line therapy in HR+, HER2− advanced breast cancer (ABC), but the optimal regimen postCDK4/6i progression, including the role of continued CDK 4/6 blockade, is unclear. Methods: TRINITI-1 is a Phase I/II, open-label trial (NCT02732119) of triplet therapy: ribociclib (RIB; CDK4/6i) + everolimus (EVE; mTORi) + exemestane (EXE; ET) in men or postmenopausal women with HR+, HER2− ABC that progressed on prior CDK4/6i and up to 3 lines of therapy (≥ 1 ET and ≤ 1 chemotherapy regimen). Phase I determined RP2D; Phase II assessed efficacy/safety of RIB 300 or 200 mg + EVE 2.5 or 5 mg + EXE 25 mg/day. Here we present the first results in the entire patient population who received this triplet regimen and the correlation of biomarkers with outcomes. Results: As of October 24, 2018, 95 patients were evaluable (ET refractory and postCDK4/6i) in Phases I (n = 17) and II (n = 78). Continuous RIB + EVE + EXE demonstrated clinical benefit at week 24 in 39 patients (41.1%), exceeding the predefined primary end point threshold (> 10%). ORR was 8.4% by investigator assessment, median PFS was 5.7 months, and 1-year PFS was 33%. AEs were consistent with known safety profile of RIB, EVE, and EXE. Most common AEs were neutropenia (all grades, 41.7%; grade 3/4, 31.3%), stomatitis (41.7%; 3.1%), and fatigue (35.4%; 1.0%). No grade 3/4 QTc prolongation was noted. ctDNA genotyping revealed patients with certain tumor alterations, eg ESR1, had shorter median PFS vs wild-type: 3.5 vs 6.9 mo (HR 1.76, 95% CI 1.01–3.05). Additional genomic results, including PIK3CA, will be presented. Conclusions: TRINITI-1 met its primary efficacy end point and is the first trial to demonstrate clinical benefit and tolerability of continuous triplet therapy with ET + mTORi + CDK4/6i in patients with ET-refractory HR+, HER2− ABC postCDK4/6i progression. Tumor genomic profile might impact the clinical outcome with triplet therapy and warrants additional research to guide rational therapy selection. Clinical trial information: NCT02732119.

Sign in / Sign up

Export Citation Format

Share Document