Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer: ERIGE trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1095-1095
Author(s):  
Antonino Musolino ◽  
Rosa Porzio ◽  
Daniela Rubino ◽  
Antonio Frassoldati ◽  
Alessia Caldara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Objective Response ◽  
Locally Advanced ◽  
Combination Regimen ◽  
Line Treatment ◽  
Second Line ◽  
Tumor Cell Death ◽  
Study Population

1095 Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Methods: We performed an open-label, national multicenter phase 2 study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC. The Simon's optimal two-stage design was used for estimating objective response rate (ORR) as study primary endpoint. A prospective, molecular correlative study was carried out on germinal DNA of study population to assess the role of germinal DNA polymorphisms and BRCA mutations in predicting efficacy and toxicity of the combination regimen. Results: From July 2013 to September 2016 , 83 (37 in the first stage, 46 in the second one) assessable patients were enrolled. Median age at baseline was 56 years. Sixty-six and 17 patients were in first or second-line treatment, respectively. All patients were previously treated with an anthracycline and/or a taxane. With regard to the first stage of study enrolment, patients received a median number of 6 cycles of treatment. The ORR (CR+PR) was 43.24% (90% CI 29.3-58.0) and the clinical benefit rate (CR+PR+SD) was 64.9% (90% CI: 50.1%-77.8%). The most common grade 3/4 AEs ( > 10% of patients) were neutropenia without febrile neutropenia and liver toxicity. Grade 1/2 AEs were fatigue, anemia, thrombocytopenia, diarrhea, alopecia, peripheral neuropathy, and oral mucositis. Conclusions: The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. More mature toxicity and outcome data of the final study population and correlation with genome analysis will be presented at the meeting. Clinical trial information: 2012-003505-10.

Phase I/II trial of pembrolizumab in combination with binimetinib in unresectable locally advanced or metastatic triple negative breast cancer.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS17-TPS17 ◽  
Author(s):  
Saranya Chumsri ◽  
Mei-Yin Polley ◽  
Sarah L. Anderson ◽  
Ciara Catherine Maria O'Sullivan ◽  
Gerardo Colon-Otero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Genomic Study

TPS17 Background: Emerging studies suggest that breast cancer, particularly triple negative breast cancer (TNBC), may be sensitive to immunotherapy. However, the response rate of single agent immune checkpoint blockade agent in TNBC is rather low. Previous genomic study in residual tumor after neoadjuvant chemotherapy showed inverse correlations between MEK activation signature and the amount of tumor infiltrating lymphocytes (TILs) in residual disease samples as well as poor outcome. Preclinical study also showed that the combination of MEK inhibitor and anti-PD-L1 antibody in mouse model can eradicate TNBC tumors. Methods: This is a single arm, Phase I/II trial of Pembrolizumab (P) in combination with Binimetinib (B) in patients with unresectable locally advanced or metastatic TNBC. This trial is currently opened for accrual at Mayo Clinic in Florida and Minnesota. Patients with TNBC defined as ER ≤ 10% and PR ≤ 10% who received ≤ 3 prior lines with measurable disease will be enrolled. The primary objective of the Phase I part is to determine the maximum tolerated dose of B in combination with P and for the Phase II part is objective response rate (ORR) by RECIST criteria. The secondary endpoints include ORR by irRECIST, progression free survival, and overall survival. The total sample size is 15-38 patients with 6-12 patients in Phase I with 2 dose levels and 9-26 patients in Phase II. Simon’s Two-Stage Optimal Design is used to test the null hypothesis that this two-drug combination has an ORR of at most 15% vs. the alternative hypothesis that it has an ORR of at least 35%. Patients will receive single agent B for 2 weeks prior to starting P. A mandatory biopsy will be performed before starting B and an optional biopsy will be performed after 2 weeks of B. Tumor tissue will be evaluated for the amount and phenotypes of TILs, PD-L1 expression, and gene expression analysis using PanCancer Immune Profiling Panel, and PDJ amplification. Peripheral blood will be evaluated for circulating immunoregulatory cells, cytokine profiling, circulating tumor cells (CTCs), as well as p-ERK and PD-L1 expression on CTCs. Clinical trial information: NCT03106415.

Apatinib plus vinorelbine versus vinorelbine for advanced triple-negative breast cancer with failed first or second-line treatment: The NAN trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1075-1075
Author(s):  
Doudou Li ◽  
Zhonghua Tao ◽  
Biyun Wang ◽  
Leiping Wang ◽  
Jun Cao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Disease Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Line Treatment ◽  
Second Line ◽  
Grade 3 ◽  
To Receive

1075 Background: No standard treatment exists for triple negative breast cancer (TNBC) with failure of multi-line therapies. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for TNBC. We aimed to evaluate the safety and efficacy of adding apatinib to chemotherapy in patients with metastatic TNBC with failed first/second-line treatment. Methods: This randomized, open-label, phase 2 trial recruited patients with advanced TNBC who failed to receive first or second-line treatment. A total of 66 patients were randomly assigned, in a 1:1 ratio, to receive vinorelbine 25 mg/m2 (days 1, 8, 15) or vinorelbine 20 mg/m2 (days 7, 14, 21) with apatinib (250 mg once daily, days 1-5, 8-12, 15-19, if tolerable, the second cycle started with 500 mg per day) in 28-day cycles. The efficacy was evaluated every two treatment cycles (8 weeks ± 3 days). According to the RECIST criterion, patients with CR, PR and SD continued treatment until disease progression or unacceptable toxicity or withdrawal of consent. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rate (ORR) and safety. Results: Between Sep 14, 2017 and Dec 08, 2020, 66 patients underwent randomization. Median follow-up was 21.3 months. 33 received apatinib plus vinorelbine and 32 received vinorelbine (1 was withdrawal of consent). Median PFS was significantly longer in the apatinib plus vinorelbine group than in the vinorelbine group (3.8 months vs. 1.9 months; hazard ratio for disease progression or death, 1.76; 95% confidence interval [CI], 1.02 to 3.05; P= 0.039). Median OS was 14.6 months with apatinib plus vinorelbine and 14.1 months with vinorelbine (HR,1.34; 95% CI, 0.60 to 3.00; P= 0.469). The ORR was 48.5% in the apatinib plus vinorelbine group and 31.3% in the vinorelbine group ( P= 0.156). The most common treatment-related hematologic grade 3–4 adverse events in those treated with apatinib plus vinorelbine versus vinorelbine, respectively, were leukopenia (42.4% vs. 34.4%), granulocytopenia (57.6% vs. 28.1%), anemia (9.1% vs. 12.5%) and thrombocytopenia (3.1% vs. 3.0%). The most frequent grade 3 nonhematologic toxicities were hand–foot syndrome (21%), proteinuria (9%), hypertension (9%) and increased ALT (9%) and which only occurred in apatinib plus vinorelbine group. No treatment-related nonhematologic grade 4 adverse events or treatment-related deaths were observed. Conclusions: Collectively, among patients with advanced TNBC with failed first/second-line treatment, apatinib plus vinorelbine show a promising benefit in PFS compared to vinorelbine monotherapy. Apatinib plus vinorelbine regimen shows promising efficacy and manageable toxicity, which might be a previously unappreciated therapeutic option for advanced TNBC. Clinical trial information: NCT03254654 .

Trial in progress: A phase 3, randomized, double-blind trial of trilaciclib versus placebo in patients receiving first- or second-line gemcitabine and carboplatin for locally advanced unresectable or metastatic triple-negative breast cancer (PRESERVE 2).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1107-TPS1107
Author(s):  
Shom Goel ◽  
Joyce O'Shaughnessy ◽  
Antoinette R. Tan ◽  
Boris Milev Krastev ◽  
Hope S. Rugo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Primary Endpoint ◽  
Triple Negative ◽  
Group Performance ◽  
Locally Advanced ◽  
Second Line ◽  
Phase 3 ◽  
Double Blind ◽  
Hematopoietic Stem

TPS1107 Background: Trilaciclib is an intravenous (IV), highly potent and selective, reversible cyclin-dependent kinase (CDK) 4/6 inhibitor that protects hematopoietic stem and progenitor cells during chemotherapy (myeloprotection) and may directly enhance antitumor immunity (anticancer efficacy). In a randomized phase 2 trial of trilaciclib administered prior to gemcitabine and carboplatin (GC) versus GC alone in advanced/metastatic triple-negative breast cancer (mTNBC), although the primary endpoint of myeloprotection was not met, the addition of trilaciclib resulted in a substantial improvement in median overall survival (OS; 19.8 months with trilaciclib vs 12.6 months with placebo, hazard ratio [95% CI] = 0.37 [0.21–0.63]; O’Shaughnessy et al. SABCS 2020 [PD1-06]). Clinically meaningful improvements in OS and progression-free survival (PFS) were also observed in both programmed death ligand-1 (PD-L1)–positive and –negative subsets. Methods: The PRESERVE 2 trial (EudraCT: 2020-004930-39) is a randomized, double-blind, placebo-controlled, international phase 3 trial evaluating the efficacy of trilaciclib administered prior to GC in patients with mTNBC. Two mTNBC patient populations will be studied and analyzed separately: cohort 1 (N = 170) will evaluate first-line, PD-1/PD-L1 inhibitor–naïve patients with ≥6 months between completion of last curative treatment and first recurrence; cohort 2 (N = 80) will evaluate second-line PD-L1–positive patients following ≥4 months of PD-1/PD-L1 inhibitor therapy in the advanced setting. Key eligibility criteria for both cohorts include age ≥18 years, Eastern Cooperative Oncology Group performance status of 0/1, and available tumor tissue. Patients will be randomized (1:1) to trilaciclib 240 mg/m2 or placebo prior to gemcitabine 1000 mg/m2 and carboplatin area under the curve 2 IV on days 1 and 8, every 21 days. Stratification factors (cohort 1 only) include tumor PD-L1 status by Ventana SP-142 IVD assay, disease-free interval, and country. Study treatment will continue until progressive disease per RECIST v1.1, unacceptable toxicity, or investigator/patient decision, after which, patients will be followed every 3 months for survival. Up to 80 patients will be consented for optional paired baseline and on-treatment biopsies. Archival tissue and serial peripheral blood will be collected from all patients. The primary endpoint is OS, and the key secondary endpoint is time to confirmed deterioration in fatigue. Other secondary endpoints include PFS, myeloprotection, and safety/tolerability. Exploratory endpoints will assess pharmacodynamic parameters, including those related to immune-based mechanisms, and efficacy by CDK4/6-dependence signatures. Study enrollment is open. Clinical trial information: 2020-004930-39 .

SGNLVA-002: Single-arm, open label phase Ib/II study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS1110-TPS1110 ◽  
Author(s):  
Hyo S. Han ◽  
Carlos A. Alemany ◽  
Ursa Abigail Brown-Glaberman ◽  
Timothy J. Pluard ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Objective Response ◽  
Locally Advanced ◽  
Synergistic Activity ◽  
First Line ◽  
Open Label ◽  
Open Label Phase

TPS1110 Background: There are currently no curative treatments for patients with metastatic triple-negative breast cancer (mTNBC), and prognosis for this disease is very poor. Emerging treatment combinations of anti-programmed death ligand 1 (PD-L1) agents with chemotherapy have shown promise in mTNBC. SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1, which is highly expressed in breast cancer cells. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death (ICD). Preliminary results from an ongoing phase 1 study of LV monotherapy has shown LV to be well tolerated and to have encouraging antitumor activity in patients with mTNBC. Combining LV and pembrolizumab may result in complementary, as well as synergistic, activity through LV-induced ICD that creates a microenvironment favorable for enhanced anti-PD-L1 activity. Methods: This single-arm, open-label, phase 1b/2 study evaluates the safety and antitumor activity of LV in combination with pembrolizumab as first-line therapy for patients with unresectable locally advanced or mTNBC (NCT03310957, 2017-002289-35). Patients must have measureable disease per RECIST v1.1, an ECOG score of 0 or 1, and no prior cytotoxic or anti-PD-L1 treatment for advanced disease. This study has 2 parts that are enrolling sequentially: a dose-finding phase that starts at LV 2.5 mg/kg + pembrolizumab 200 mg intravenously every three weeks, and a dose expansion phase. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab, and identify the recommended phase 2 dose of LV. The secondary objectives are to assess duration of response, disease control rate, progression-free survival, and overall survival. Additional objectives include assessing PD-L1 and LIV-1 expression-response relationship. Study enrollment is ongoing in the US and EU. Clinical trial information: NCT03310957.

Safety and efficacy of eribulin in combination with gemcitabine in patients with advanced triple negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12578-e12578
Author(s):  
Vasiliki Michalaki ◽  
Georgios Fragulidis ◽  
Ioannis Kondis ◽  
Eleni Karvouni ◽  
Nikolaos Dafnios ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Clinical Benefit ◽  
Overall Response Rate ◽  
Triple Negative ◽  
Response Rate ◽  
Locally Advanced ◽  
Tumor Cell Death ◽  
Overall Response ◽  
Grade 3

e12578 Background: Triple negative breast cancer (TNBC) characterized by aggressive tumor behavior with very poor prognosis following progression after standard chemotherapeutic regimens.The combination of Gemcitabine, a nucleoside analogue, and eribulin a microtubule-targeting agent exhibited synergistic cytotoxic effects in pre-clinicall and clinical setting . Thus, eribulin combined with gemcitabine may synergistically induce tumor cell death, especially in tumors like TNBC. Based on this rationale, we conducted a phase II study evaluating this combination either in first- or in second-line treatment for advanced TNBC.Methods: Females with locally advanced or metastatic TNBC who had received previous chemotherapy , with an ECOG (PS) ≤ 1, and adequate hematological, renal and hepatic function. Patients received eribulin (1mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 until disease progression. CT scans were performed every 12 weeks. The main objective of this trial was to evaluate the overall response rate (ORR) and secondary were Feasibiliy, safety and clinical benefit rate (CBR ). Results: Thirty –two females (median age: 62 years, median ECOG performance status (PS) 1) were enrolled the study. The majority had visceral disease (78.5%). A median of 9 (range:4–18) treatment cycles was administered (69% of patients received ≥ 6 cycles), .All patients were evaluable for response. We did observe 12 partial responses for an overall response rate of 37.5% (95%CI,26.1-57.0). A stable disease was observed in 15 patients (46.8%). Clinical benefit, was observed in 21 patients (65.6%; 95%CI,48.1-76.6). The most common grade 3 or 4 toxicities were haematologic . The main grade 3 or 4 non-hematolgic toxicities were fatigue, diarrhoea, nausea and vomiting. Of the 32 patients in total 7 patients had dose reductions and 14 patients had dose delays. Conclusions: Resistance to current standard therapieslimits the available options for previously treated patients with metastatic TNBC and there is currently no preferred standard chemotherapy. This study demonstrated that the combination of eribulin and gemcitabine was efficacious, feasible and toxicity was generally manageable

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