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Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.

ABSTRACT: Background IMGN901 is a CD56-targeting antibody-drug conjugate designed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1 study investigated the safety, tolerability, pharmacokinetics, and preliminary activity of IMGN901 in patients with CD56-expressing solid tumors. Methods Patients were enrolled in cohorts of escalating IMGN901 doses, administered intravenously, on 3 consecutive days every 21 days. A dose-expansion phase accrued patients with small cell lung cancer (SCLC), Merkel cell carcinoma (MCC), or ovarian cancer. Results Fifty-two patients were treated at doses escalating from 4 to 94 mg/m(2)/day. The maximum tolerated dose (MTD) was determined to be 75 mg/m(2). Dose-limiting toxicities included fatigue, neuropathy, headache or meningitis-like symptoms, chest pain, dyspnea, and myalgias. In the dose-expansion phase (n = 45), seven patients received 75 mg/m(2) and 38 received 60 mg/m(2) for up to 21 cycles. The recommended phase 2 dose (RP2D) was established at 60 mg/m(2) during dose expansion. Overall, treatment-emergent adverse events (TEAEs) were experienced by 96.9 % of all patients, the majority of which were Grade 1 or 2. The most commonly reported Grade 3 or 4 TEAEs were hyponatremia and dyspnea (each 8.2 %). Responses included 1 complete response (CR), 1 clinical CR, and 1 unconfirmed partial response (PR) in MCC; and 1 unconfirmed PR in SCLC. Stable disease was seen for 25 % of all evaluable patients who received doses ?60 mg/m(2). Conclusions The RP2D for IMGN901 of 60 mg/m(2) administered for 3 consecutive days every 3 weeks was associated with an acceptable tolerability profile. Objective responses were observed in patients with advanced CD56+ cancers.

SUBMITTER: Shah MH

PROVIDER: S-EPMC4859861 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.

Shah Manisha H MH Lorigan Paul P O'Brien Mary E R ME Fossella Frank V FV Moore Kathleen N KN Bhatia Shailender S Kirby Maurice M Woll Penella J PJ

Investigational new drugs 20160309 3

Background IMGN901 is a CD56-targeting antibody-drug conjugate designed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1 study investigated the safety, tolerability, pharmacokinetics, and preliminary activity of IMGN901 in patients with CD56-expressing solid tumors. Methods Patients were enrolled in cohorts of escalating IMGN901 doses, administered intravenously, on 3 consecutive days every 21 days. A dose-expansion phase accrued patients with small cell lung cancer ( ...[more]

PMID: 26961907

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Project description:Purpose and Methods Trop-2 is a glycoprotein over-expressed in many solid tumors but at low levels in normal human tissue, providing a potential therapeutic target. We conducted a phase 1 dose-finding study of PF-06664178, an antibody-drug conjugate that targets Trop-2 for the selective delivery of the cytotoxic payload Aur0101. The primary objective was to determine the maximum tolerated dose and recommended phase 2 dose. Secondary objectives included further characterization of the safety profile, pharmacokinetics and antitumor activity. Eligible patients were enrolled and received multiple escalating doses of PF-06664178 in an open-label and unblinded manner based on a modified continual reassessment method. Results Thirty-one patients with advanced or metastatic solid tumors were treated with escalating doses of PF-06664178 given intravenously every 21 days. Doses explored ranged from 0.15 mg/kg to 4.8 mg/kg. Seven patients experienced at least one dose limiting toxicity (DLT), either neutropenia or rash. Doses of 3.60 mg/kg, 4.2 mg/kg and 4.8 mg/kg were considered intolerable due to DLTs in skin rash, mucosa and neutropenia. Best overall response was stable disease in 11 patients (37.9%). None of the patients had a partial or complete response. Systemic exposure of PF-06664178 increased in a dose-related manner. Serum concentrations of free Aur0101 were substantially lower than those of PF-06664178 and total antibody. No correlation of Trop-2 expression and objective response was observed, although Trop-2 overexpression was not required for study entry. The intermediate dose of 2.4 mg/kg appeared to be the highest tolerated dose, but this was not fully explored as the study was terminated early due to excess toxicity. Conclusion PF-06664178 showed toxicity at high dose levels with modest antitumor activity. Neutropenia, skin rash and mucosal inflammation were dose limiting toxicities. Findings from this study may potentially aid in future antibody drug conjugate design and trials.

Dataset Information

Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.

Publications

Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.

Similar Datasets

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