CX-2009, a CD166-directed probody drug conjugate (PDC): Results from the first-in-human study in patients (Pts) with advanced cancer including breast cancer (BC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 526-526
Author(s):  
Valentina Boni ◽  
Howard A. Burris III ◽  
Joyce F. Liu ◽  
Alexander I. Spira ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Cancer ◽  
Phase Ii ◽  
Dose Escalation ◽  
Human Study ◽  
Population Pharmacokinetic ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Drug Conjugate ◽  
Grade 3

526 Background: CX-2009 is a PROBODY drug conjugate (PDC) directed against CD166 (ALCAM) and conjugated to DM4, a potent microtubule inhibitor (MTI). CD166 is overexpressed in carcinomas but is also ubiquitously expressed in normal epithelium and thus has not been previously considered a viable target for a traditional antibody drug conjugate. PDCs have a peptide mask that blocks normal tissue binding and can be removed by tumor-associated proteases, thereby limiting off-tumor/on-target binding. CX-2009 demonstrated preclinical activity in multiple solid tumor models. Here we report results of the first in human study in patients with advanced cancer. Methods: In this phase I multi-part dose-escalation study, pts with advanced solid tumors received CX-2009 0.25–10 mpk IV every 14 or 21 days (Q2W or Q3W). Tumor types were selected based on expected high CD166 expression and MTI sensitivity. Results: The dose-escalation phase of the trial enrolled 43 pts; 49 additional pts were subsequently enrolled between 4–10 mpk to collect biomarker data and define the recommended phase II dose (RP2D), for a total of 92 pts as of 30 Nov 2019 (39 pts with breast cancer [BC], 22 ovarian [OC], 12 non-small cell lung [NSCLC], 9 head/neck squamous cell [HNSCC], 10 other) with a median of 6 (range 1–19) prior therapies. Median number of CX-2009 doses was 2 (range, 1–15). For Q3W dosing, one dose limiting toxicity (DLT; grade 3 vomiting) was observed at 8 mpk; MTD was not reached up to 10 mpk. The RP2D for Q3W schedule was 7 mpk based on safety, dose-response, and population pharmacokinetic simulations. Q2W dosing continues; DLTs were observed at 6 mpk. Common treatment-related adverse events (TRAEs) at 7 mpk (n=9) were nausea (44%), fatigue, infusion-related reactions (both 33%), vomiting and arthralgias (both 22%). Grade 3 TRAEs occurred in 2 pts (nausea/vomiting; peripheral neuropathy). No pts discontinued at 7 mpk due to TRAEs. Ocular toxicity was dose dependent; mild to moderate reversible keratitis/blurred vision was seen in 3 pts at 7 mpk and mitigated by ocular prophylaxis. Partial responses were seen in 8 pts (2 confirmed, both HR+/HER2- BC) treated between 4–10 mpk, including BC (n=5), OC (n=2), and HNSCC (n=1). SD (≥1 on-study scan) was observed in 21 pts, 5 had SD ≥3 mos. Conclusions: CX-2009 at 7 mpk is the RP2D on Q3W schedule. Phase II expansion has begun in pts with HR+/HER2- BC. The Q2W schedule will continue to enroll pts to define the RP2D. CX-2009 will also be studied in combination with CX-072, a PD-L1 PROBODY therapeutic ( NCT03149549 ) Clinical trial information: NCT03149549 .

Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in breast cancer patients: Phase 1 dose escalation study.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 2512-2512 ◽  
Author(s):  
Takahiro Kogawa ◽  
Kan Yonemori ◽  
Norikazu Masuda ◽  
Shunji Takahashi ◽  
Masato Takahashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Breast Cancer Patients ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Drug Conjugate ◽  
Antibody Drug

A phase I dose escalation study evaluating the safety and tolerability of a novel anti-HER2 antibody-drug conjugate (PF-06804103) in patients with HER2-positive solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1039-1039 ◽  
Author(s):  
Funda Meric-Bernstam ◽  
Emiliano Calvo ◽  
Victor Moreno ◽  
Hyun Cheol Chung ◽  
Yeon Hee Park ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Standard Therapy ◽  
Objective Response ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Dose Escalation Study ◽  
Strong Activity ◽  
Drug Conjugate ◽  
Antibody Drug

1039 Background: PF-06804103 is an anti-HER2 immunoglobulin G1 antibody-drug conjugate (ADC), comprising an anti-HER2 monoclonal antibody conjugated with a cleavable linker to the cytotoxic agent Aur0101. PF-06804103 demonstrated strong activity in low to high HER2-expressing preclinical tumor models. In this study, the safety and tolerability of PF-06804103 was assessed in patients with advanced breast cancer (BC) or gastric cancer (GC). Methods: This multi-center, open-label, first-in-patient, phase I study (NCT03284723) has two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, groups of adult patients (pts) with HER2+ BC or HER2+ GC, who are resistant or intolerant to standard therapy or for which no standard therapy is available, received PF-06804103 intravenously once every 21 days (Q3W); dosage was escalated per cohort. Primary objectives were to evaluate the safety and tolerability of PF-06804103, characterize its dose-limiting toxicities (DLTs), and determine the recommended phase 2 dose. Response was assessed using RECIST v1.1. Objective response rate (ORR) was calculated for response-evaluable pts with target lesions at baseline and ≥1 post-baseline assessment (including unconfirmed responses). Results: A total of 35 pts (BC: n = 20; GC: n = 15) received PF-06804103 at escalating dose levels (0.15 mg/kg: n = 2; 0.5 mg/kg: n = 2; 1.2 mg/kg: n = 2; 2 mg/kg: n = 4; 3 mg/kg: n = 10; 4 mg/kg: n = 9; 5 mg/kg: n = 6). The median (range) number of prior therapies was 6 (3–18) and 3 (1–6) for BC and GC groups, respectively (all pts had prior HER2-targeted therapy). The 3 most common, drug-related adverse events (any grade) were alopecia (n = 17, 48.6%), fatigue (n = 15, 42.9%), and neuropathy (n = 9, 25.7%). DLTs (mostly grade 3) occurred in 3 pts and included arthralgia, neuropathy, myalgia, fatigue, and osteomuscular pain. Preliminary ORR in the patients treated with doses ≥3mg/kg was 52.4% (11/21). Conclusions: The PF-06804103 ADC demonstrated manageable toxicity and promising anti-tumor activity in this small, heavily pretreated study population. Clinical trial information: NCT03284723 .

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.

scholarly journals Phase 1 dose-escalation study of mirvetuximab soravtansine (IMGN853), a folate receptor α-targeting antibody-drug conjugate, in patients with solid tumors

Cancer ◽  
2017 ◽  
Vol 123 (16) ◽  
pp. 3080-3087 ◽  
Author(s):  
Kathleen N. Moore ◽  
Hossein Borghaei ◽  
David M. O'Malley ◽  
Woondong Jeong ◽  
Shelly M. Seward ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Folate Receptor ◽  
Phase 1 ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Drug Conjugate ◽  
Antibody Drug

Complete remissions with weekly dosing of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in a phase I dose-escalation study in patients with relapsed or refractory Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8500-8500 ◽  
Author(s):  
N. Bartlett ◽  
A. Forero-Torres ◽  
J. Rosenblatt ◽  
M. Fanale ◽  
S. J. Horning ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Large Cell ◽  
Antibody Drug Conjugate ◽  
Dose Escalation Study ◽  
Drug Conjugate ◽  
Cycle Arrest ◽  
Heavily Pretreated ◽  
Antibody Drug

8500 Background: A defining feature of HL and sALCL is CD30 expression on malignant cells. The ADC SGN-35 comprises an anti-CD30 antibody conjugated to the antitubulin agent monomethyl auristatin E (MMAE). SGN-35 causes cell cycle arrest and apoptosis by binding to CD30 on the tumor cell surface, internalizing, and releasing MMAE into the cell. In a previous phase 1 study with q3 wk dosing, 54% of pts achieved an objective response (CR/PR) at SGN-35 doses ≥1.2 mg/kg [ASH 2008 abstract 1006]. Methods: To assess if more frequent dosing might maximize anti-tumor activity with acceptable tolerability, a multicenter, phase 1, weekly dosing, dose-escalation study (3+3 design) was conducted in pts with refractory or recurrent HL or sALCL. SGN-35 was administered weekly at doses of 0.4–1 mg/kg (2-hr IV infusions). Pts with stable disease or better (Cheson 2007) after two 28-day cycles (6 doses) were eligible to continue SGN-35 treatment. Results: In 17 pts, median age was 38 yrs (range 25–67). Pts received a median of 4 prior therapies; 65% received an autologous SCT. MTD has not been defined. One related G3 event (diarrhea) and no related G4 events occurred. The most common related adverse events were G1/G2 rash, nausea, and peripheral neuropathy. Exposure to SGN-35 (AUC) increased relative to dose level. Multiple CRs were observed at higher doses ( table ); observed time to response in the 1 mg/kg dose group was approximately 8 wks. The 7 pts with CRs all remain on treatment. Enrollment to SGN-35 monotherapy continues at 1.2 mg/kg; combination therapy will be subsequently explored. Conclusions: SGN-35 was generally well tolerated and induced CRs in 7 of 8 evaluable pts at the two highest doses in heavily pretreated patients. Pivotal trials of this antibody-drug conjugate will initiate in early 2009. [Table: see text] [Table: see text]

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