A phase I study of HM781-36B, a novel pan-HER inhibitor, in patients (pts) with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3076-3076 ◽  
Author(s):  
Tae Min Kim ◽  
Keun-Wook Lee ◽  
Do-Youn Oh ◽  
Jong-Seok Lee ◽  
Seock-Ah Im ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Advanced Solid Tumors ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Expansion Cohort ◽  
Positive Breast Cancer

3076 Background: HM781-36B is a pan-HER tyrosine kinase inhibitor, which showed a potent activity against the gefitinib- or erlotinib-resistant, EGFR L858R/T790M double mutant cells. A phase I study was conducted to determine the MTD, pharmacokinetics, and antitumor activity. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation part, and additional 12 pts were enrolled in the expansion cohort of molecular enrichment. Results: In dose-escalation part, 43 pts (median age: 55 yrs (range 25-82), M:F=25:18, ECOG PS 0/1/2/3: 23/17/2/1, median prior chemotherapy: 4) were treated. DLTs were G3 diarrheas in 5 pts, one at 12 mg, 16 mg, 24 mg, and two at 32 mg. The MTD was determined as 24mg. The most common drug-related adverse events were diarrhea, stomatitis, rash, pruritus, and anorexia. Among 41 evaluable pts, 4 pts achieved PR (1 unconfirmed, duration of response: 11.9 mo, 7.07 mo+, 4.5 mo+), and 19 pts had SD. Two of 4 PR pts were Her2-positive breast cancer pts. The median duration of treatment in pts with PR or SD was 3.87 (2.47- 15.17) months. In the dose range of 0.5 to 24 mg, it showed linear pharmacokinetics proportional to dose-escalation, relatively short half-life, and little accumulation. Additional 12 pts in the expansion cohort are under treatment at 24 mg (6 pts: EGFR-mutant NSCLC, 3 pts: Her2-positive gastric cancer, 2 pts: Her2-positive breast cancer, 1 pt: rectal cancer). Conclusions: HM781-36B was safe and well tolerable in advanced solid tumors. Preliminary evidence of anticancer activity has been observed. Updated data will be presented at the meeting.

A phase I dose-escalation study evaluating weekly paclitaxel with neratinib and trastuzumab in women with metastatic HER2-positive breast cancer, NSABP FB-8.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 611-611 ◽  
Author(s):  
Rachel Catherine Jankowitz ◽  
Jame Abraham ◽  
Antoinette R. Tan ◽  
Steven A. Limentani ◽  
Laura M Adamson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Weekly Paclitaxel ◽  
Erbb Receptors ◽  
Her2 Positive ◽  
Dose Escalation Study ◽  
Cancer Trial ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

611 Background: Dual blockade of ErbB receptors combined with chemotherapy compared with single-agent blockade improves efficacy in HER2-positive disease. FB-8 is single arm, Phase I dose-escalation study to determine safety and tolerability of weekly paclitaxel (P), the irreversible tyrosine kinase inhibitor, neratinib (N) and trastuzumab (T) in women with metastatic, HER2-positive breast cancer (MBC). Methods: Women with measurable or non-measurable MBC (ECOG PS 0 - 2) received P (80 mg/m2 IV days 1, 8, 15 of 28-day cycle), T (4 mg/kg IV, then 2 mg/kg IV weekly), and N (oral, daily). N was dose-escalated using 3+3 design at 120 mg, 160 mg, and 240 mg, dose-limiting toxicity (DLT) determined in cycle 1. All patients (pts) received prophylactic anti-diarrheals. Results: All pts were taxane and trastuzumab pre-treated, with mean of 4 prior regimens. At N=120 mg, there was 1 DLT, grade (gr) 3 diarrhea with dehydration. Three more pts were enrolled; none experienced DLT. At N=160 mg, there were no DLTs. At N=240 mg, 2 of 3 pts had DLTs: one gr 3 diarrhea and dehydration, one gr 3 diarrhea, dehydration, and gr 3 mucositis. After de-escalation to N=160 mg, 3 more pts were added. If N=160 mg is well tolerated, a 200 mg cohort is planned. 12 pts completed cycle 1. Efficacy data are available on 10: CR 1, PR 3, SD 1 (8+months). One pt* had resolution of non-target disease (skin and breast mass). 4 pts were off-study before the first scan (DLT 3 and progressive disease 1) and are considered non-responders (NR). The most frequent grade 3-4 adverse event was diarrhea, 3 pts. Conclusions: Dual anti-HER blockade with N, T combined with P is tolerable and highly active in pts pre-treated with anti-HER2 agents and chemotherapy. This combination will be studied in a phase II neoadjuvant breast cancer trial (NSABP FB-7). We thank Pfizer, Inc and Puma Biotechnology, Inc for their support. [Table: see text]

Phase I study of A166 in patients with HER2-expressing locally advanced or metastatic solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1024-1024
Author(s):  
Xichun Hu ◽  
Jian Zhang ◽  
Rujiao Liu ◽  
Shuiping Gao ◽  
Yan Qing ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dry Eye ◽  
Phase I Study ◽  
Locally Advanced ◽  
Her2 Positive ◽  
Grade 3 ◽  
Positive Breast Cancer

1024 Background: A166 is an antibody-drug conjugate composed of a novel cytotoxic drug (Duo-5, anti-microtubule agent) site-specifically conjugated to an anti-HER2 antibody (transtuzumab) via a stable protease-cleavable valine citrulline linker. In a phase I trial in US patients (pts) with relapsed or refractory advanced solid tumor, A166 had an acceptable toxicity profile and best objective response rate (ORR) of 36% at efficacious dose levels (Yongheng Liu et al. ASCO 2020). Here we report a phase I study of A166 in Chinese pts with locally advanced or metastatic solid tumors (CTR20181301). Methods: KL166-I-01-CTP is a single arm, open-label, dose-escalation and dose-expansion phase I study evaluating A166 in pts with HER2-expressing locally advanced or metastatic solid tumors. Pts received A166 at doses of 0.1, 0.3, 0.6, 1.2, 2.4, 3.6, 4.8, 6.0 mg/kg IV Q3W. Dose cohorts were expanded at 4.8 and 6.0 mg/kg Q3W. The objectives were to determine the safety and tolerability, pharmacokinetics and antitumor activity of A166. Results: 57 pts (median age 53 [range 26-74], 50 female, 7 male) enrolled from Aug 1, 2018 to Nov 30, 2020. HER2 expression was available for all 57 pts: 51 HER2-positive (3+ or 2+/ISH+), 6 HER2-low (1+ or 2+/ISH-). 61.4% (35/57) had received ≥5 prior lines of therapy. No DLTs were observed in all dose groups. Any grade treatment-related AEs (TRAEs) were documented in 96.5% (55/57) of pts, with 31.6% (18/57) being grade 3 or higher. Common TRAEs were corneal epitheliopathy (73.7%), vision blurred (59.6%), peripheral sensory neuropathy (26.3%), dry eye (21.1%), anemia (19.3%), hyponatremia (19.3%). Most common grade ≥3 TRAEs were corneal epitheliopathy (17.5%), hypophosphatemia (5.3%), and dry eye (5.3%). Four pts had serious AEs, two of which were possibly related to the study drug, including thrombosis and fatigue. TRAEs led to 5.3% (3/57) dose reduction and 5.3% (3/57) treatment discontinuation. One death occurred during the treatment due to progressive disease. At the doses of 0.3-6.0 mg/kg, the exposure of ADC in serum were dose dependent and the mean half-life was found to be 1.17-11.04 days. Serum free toxins was about 0.1% and 0.2% of total A166 (ADC) on a molar basis with the Cycle 1 Cmax and AUC, respectively. At efficacious dose, 36 HER2-positive breast cancer pts with measurable disease were assessed for efficacy, best ORR were 59.1% (13/22) and 71.4% (10/14) in 4.8 and 6.0 mg/kg cohort, respectively. Median progression-free survival (PFS) was not reached, and one patient in 4.8 mg/kg cohort has undergone the treatment for more than 19 months. Conclusions: A166 had a manageable safety profile and high stability in the circulation with much lower acute hematological and gastrointestinal toxicities in terms of incidence rate and grade. It demonstrated promising antitumor activity with clinically meaningful responses in heavily pretreated subjects with HER2-positive breast cancer. Clinical trial information: CTR20181301 .

Phase I Study of Nonpegylated Liposomal Doxorubicin plus Trastuzumab in Patients with HER2-Positive Breast Cancer

2009 ◽  
Vol 9 (2) ◽  
pp. 101-107 ◽  
Author(s):  
Maria Theodoulou ◽  
Gerald Batist ◽  
Susana Campos ◽  
Eric Winer ◽  
Lauri Welles ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Liposomal Doxorubicin ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

scholarly journals Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC)

2017 ◽  
Vol 23 (14) ◽  
pp. 3529-3536 ◽  
Author(s):  
Stacy L. Moulder ◽  
Virginia F. Borges ◽  
Tara Baetz ◽  
Tessa Mcspadden ◽  
Gina Fernetich ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Advanced Solid Tumors ◽  
Expansion Cohort
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