Dataset Information

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

ABSTRACT:

Purpose

RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer.

Patients and methods

This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48.

Results

Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20).

Conclusion

RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status.

Clinical trial information

NCT02881190.

SUBMITTER: Xu Y

PROVIDER: S-EPMC8205919 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

Xu Yingying Y Wang Yakun Y Gong Jifang J Zhang Xiaotian X Peng Zhi Z Sheng Xinan X Mao Chenyu C Fan Qingxia Q Bai Yuxian Y Ba Yi Y Jiang Da D Yang Fen F Qi Changsong C Li Jian J Wang Xicheng X Zhou Jun J Lu Ming M Cao Yanshuo Y Yuan Jiajia J Liu Dan D Wang Zhenghang Z Fang Jianmin J Shen Lin L

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 20210504 4

<h4>Purpose</h4>RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer.<h4>Patients and methods</h4>This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg ...[more]

PMID: 33945049

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Project description:DP303c is a HER2-targeted ADC with a cleavable linker-MMAE payload. Previous in vitro studies demonstrated that DP303c showed similar or better antitumor activity than T-DM1 in xenograft models. This was a multicenter, dose escalation and dose expansion phase 1 study in China. Eligible patients were 18-75 years old with HER2-positive advanced solid tumors who were unable to benefit from standard therapy. DP303c was administered intravenously every 3 weeks, with accelerated titration at lower dose of 0.5 mg/kg and 3 + 3 design with dose levels of 1.0, 2.0, 3.0 or 4.0 mg/kg at dose escalation part, followed by the selected dose level at dose expansion part. The primary endpoints were safety and tolerability, as well as identification of recommended phase 2 dose. As of Feb 28, 2023, 94 patients were enrolled and received DP303c (dose escalation: n = 22; dose expansion: n = 72), of whom 68 patients had breast cancer. One dose limiting toxicity (Grade 3 eye pain) was observed at 4.0 mg/kg dose, and the maximum tolerated dose was not reached. The most common treatment-related adverse events at grade 3 or higher were blurred vison (16.0%), dry eye (6.4%), and peripheral neuropathy (5.3%). No treatment-related death occurred. Overall, among 91 efficacy evaluable patients, 39 patients (42.9%) achieved an objective response. Disease control was observed in 62 patients (68.1%). In 66 efficacy evaluable patients with breast cancer, 34 patients achieved an objective response (51.5%). Disease control was achieved in 51 patients (77.3%). Median PFS was 6.4 months. On a molar basis, DP303c Cmax at 3.0 mg/kg doses was 132-folder higher than that for free MMAE. DP303c demonstrated promising anti-tumor activity with acceptable safety in patients with pre-treated advanced HER2 positive solid tumors, especially in breast cancer. Based on safety and efficacy results, 3.0 mg/kg Q3W was determined as recommended phase 2 dose for DP303c. (Trial registration: ClinicalTrials.gov Identifier: NCT04146610).

Dataset Information

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

Purpose

Patients and methods

Results

Conclusion

Clinical trial information

Publications

Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors.

Similar Datasets

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