SGNLVA-001: A phase I open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1104-TPS1104
Author(s):  
Heather Christine Beckwith ◽  
Diana Cristina Medgyesy ◽  
Jame Abraham ◽  
Rita Nanda ◽  
Katherine H. R. Tkaczuk ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dose Escalation ◽  
Transmembrane Protein ◽  
Single Agent ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Cytotoxic Chemotherapy ◽  
Definitive Treatment ◽  
Her2 Receptor ◽  
Antibody Drug Conjugate

TPS1104 Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Clinical trial information: NCT01969643 .

Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Locally Advanced or Metastatic Breast Cancer

2014 ◽  
Vol 32 (32) ◽  
pp. 3619-3625 ◽  
Author(s):  
Johanna Bendell ◽  
Mansoor Saleh ◽  
April A.N. Rose ◽  
Peter M. Siegel ◽  
Lowell Hart ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Transmembrane Protein ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Antibody Drug

Purpose Glycoprotein NMB (gpNMB), a novel transmembrane protein overexpressed in 40% to 60% of breast cancers, promotes metastases in animal models and is a prognostic marker of a poor outcome in patients. The antibody-drug conjugate glembatumumab vedotin consists of a fully human anti-gpNMB monoclonal antibody, conjugated via a cleavable linker to monomethyl auristatin E. Glembatumumab vedotin is generally well tolerated, with observed objective responses in advanced melanoma. This is, to our knowledge, the first study of glembatumumab vedotin in breast cancer. Patients and Methods Eligible patients had advanced/metastatic breast cancer with at least two prior chemotherapy regimens, including taxane, anthracycline, and capecitabine. A standard 3+3 dose escalation was followed by a phase II expansion. Immunohistochemistry for gpNMB was performed retrospectively for patients with available tumor tissue. Results Forty-two patients were enrolled. Dose-limiting toxicity (DLT) consisted of worsening neuropathy at 1.34 mg/kg. After excluding patients with baseline neuropathy more than grade 1, no DLT occurred through 1.88 mg/kg (the phase II dose). The phase II primary activity end point was met (12-week progression-free survival [PFS12] = 9 of 27 patients; 33%). Sixteen of 19 (84%) patients tested had gpNMB-positive tumors. At the phase II dose, median PFS was 9.1 weeks for all patients, 17.9 weeks for patients with triple-negative breast cancer (TNBC), and 18.0 weeks for patients with gpNMB-positive tumors. Two patients had confirmed partial responses; both had gpNMB-positive tumors and one had TNBC. Conclusion Glembatumumab vedotin has an acceptable safety profile. Preliminary evidence of activity in treatment-resistant metastatic breast cancer requires confirmation, such as the phase II randomized trial (EMERGE) that also examines the relationship between activity and gpNMB distribution/intensity.

Gemcitabine plus docetaxel versus docetaxel in patients (pts) with HER2-negative locally advanced or metastatic breast cancer (MBC): A randomized phase III study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1015-1015
Author(s):  
D. L. Nielsen ◽  
S. T. Langkjer ◽  
K. Bjerre ◽  
S. Cold ◽  
L. Stenbygaard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Single Agent ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Rank Test ◽  
Hematologic Toxicity ◽  
Phase Iii Study ◽  
Her 2 ◽  
Grade 3

1015 Background: Gemcitabine (G), either as a single agent or in combination with taxanes, has demonstrated efficacy in MBC in phase II and III studies. We conducted a phase III study to compare time to progression (TTP) of G plus docetaxel (T) versus (vs.) T alone. The secondary endpoints included overall survival (OS), overall response rate (ORR), and toxicity. Methods: Females with HER-2-negative locally advanced or MBC and a WHO performance status ≤ 2 were randomized to GT (G 1,000mg/m2 day 1 + 8; T 75mg/m2 day 1) or T (100mg/m2 day 1) every 21 days. Pts were previously untreated, had prior anthracycline-based (neo)adjuvant chemotherapy or had received a single prior anthracycline-bsed chemotherapy regimen for MBC. Time-to-event endpoints were estimated using the Kaplan-Meier method, and the log-rank test was applied for comparisons between regimens. The planned sample size was 254 evaluable pts with α I and β of 0.05 and 0.90, respectively. Results: A total of 336 pts were randomized (170 GT; 166 T), data from one centre are yet missing and the present evaluation is based on data from 306 pts (155 GT; 151 T). The pts had a median age of 58 years in both regimens; range 36–73 years and 30–74 years, respectively. The median TTP was 7.5 months for the GT regimen vs. 6.5 months for the T regimen. The GT arm demonstrated an ORR of 44% vs. 38% in the T arm with 4 and 3 % complete responses, respectively. The OS was 13.4 vs. 13.2 months in the GT and T arm, respectively. Hematologic toxicity was common, especially grade 3–4 neutropenia (GT = 69%; T = 61%); infection was reported in 22 and 20% of the pts, respectively (none of the pts received G-CSF). The most commonly reported non-hematologic toxicities of grade 3–4 included mucositis (GT = 2%; T = 5%), diarrhea (GT = 4%; T = 7 %), fatigue (GT = 6%; T = 11%), oedema (GT = 10%; T = 3%), and peripheral neuropathy (GT = 9%; T = 28%). Conclusions: Preliminary data of GT as first- or second-line chemotherapy demonstrates a TTP advantage among HER-2-negative pts with advanced breast cancer. Updated results and proper statistical analyses will be presented. No significant financial relationships to disclose.

Results from a phase Ib study of trastuzumab emtansine (T-DM1), paclitaxel (T), and pertuzumab (P) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 528-528
Author(s):  
Shanu Modi ◽  
Anthony D. Elias ◽  
Patricia LoRusso ◽  
Meghna Samant ◽  
Ellie Guardino ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Single Agent ◽  
Metastatic Breast ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Phase Ii Studies ◽  
Previously Treated

528 Background: The antibody–drug conjugate T-DM1 has shown single-agent activity in phase II studies in patients (pts) with HER2–positive MBC. Preclinical data suggest synergy for T-DM1 combined with taxanes and with P. Methods: TDM4652g is a phase Ib, open-label, dose-escalation study evaluating the safety and tolerability of T-DM1 (qw and q3w) + T (qw) ± P (q3w) in pts with HER2-positive MBC previously treated with trastuzumab. A 3+3 dose-escalation scheme is used for T-DM1 + T to determine the maximum tolerated dose (MTD); P is added at this MTD. Initial restrictive dose-limiting toxicity (DLT) criteria were modified to establish a more clinically relevant MTD. Results: We report interim results with T-DM1 (qw and q3w) + T (+ P) using modified DLT criteria. 24 pts have been enrolled in these cohorts; median age was 53 yrs (range, 23–69)*; median number of prior systemic therapies in MBC was 7 (range, 2–15)*. See table below. Conclusions: Data support combining T-DM1 + T ± P at the MTD for future clinical trials. The MTD for weekly T-DM1 + T is 2.4 mg/kg + 80 mg/m2 qw; MTD for weekly T-DM1 + T + P is 2.4 mg/kg + 80 mg/m2 qw + 840 mg LD, 420 mg q3w. Updated results will be presented, including the MTD for T-DM1 q3w + T qw ± P q3w, outcomes from pts with prolonged follow-up, and duration of response from an extension trial. [Table: see text]

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