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A Human Peripheral Blood Mononuclear Cell PBMC Engrafted Humanized Xenograft Model for Translational Immuno-oncology I-O Research
Published on: August 15, 2019
First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients
Filip Janku1, Seung-Hoon Beom2,3, Yong Wha Moon4
1The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Preclinical models suggest anticancer activity of IM156, a novel biguanide mitochondrial protein complex 1 inhibitor of oxidative phosphorylation (OXPHOS). This first-in-human dose-escalation study enrolled patients with refractory advanced solid tumors to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Eligible patients received oral IM156 every other day (QOD) or daily (QD) and were assessed for safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary signals of efficacy. 22 patients with advanced cancers (gastric, n = 8; colorectal, n = 3; ovarian, n = 3; other, n = 8) received IM156 100 to 1,200 mg either QOD or QD. There were no DLTs. However, 1,200 mg QD was not well tolerated due to nausea; 800 mg QD was determined as the RP2D. The most frequent treatment-related AEs (TRAEs) were nausea (n = 15; 68%), diarrhea (n = 10; 46%), emesis (n = 9; 41%), fatigue (n = 4; 18%) and abdominal pain, constipation, and blood lactate increased (n = 2 each; 9%). Grade 3 nausea (n = 3; 14%) was the only grade ≥ 3 TRAE. Plasma exposures increased dose proportionally; mean Day 27 area under the curve (AUC0-24) values were higher following QD administration compared to the respective QOD regimen. Stable disease (SD), observed in 7 (32%) patients (confirmed in 2 [9%]), was the best response. To our knowledge, this is the first phase 1 study of an OXPHOS inhibitor that established a RP2D for further clinical development in cancer. Observed AEs of IM156 were manageable and SD was the best response.
Insights
The first human trial of IM156, an oxidative phosphorylation inhibitor, established 800 mg daily as the recommended dose for advanced cancers. This novel biguanide showed manageable side effects and preliminary stable disease in patients.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Preclinical studies indicated anticancer potential for IM156, a novel biguanide targeting mitochondrial complex I.
- IM156 inhibits oxidative phosphorylation (OXPHOS), a key metabolic pathway in cancer cells.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of IM156 in patients with advanced solid tumors.
- To evaluate the safety, pharmacokinetics, and preliminary efficacy of IM156 in a first-in-human study.
Main Methods:
- A dose-escalation study involving 22 patients with refractory advanced solid tumors.
- Patients received oral IM156 at doses ranging from 100 to 1,200 mg, either daily (QD) or every other day (QOD).
- Safety assessments included dose-limiting toxicities (DLTs), adverse events (AEs), and pharmacokinetic profiling.
Main Results:
- No DLTs were observed. The RP2D was determined to be 800 mg QD.
- The most frequent treatment-related AEs were nausea (68%), diarrhea (46%), and emesis (41%). Grade 3 nausea occurred in 14% of patients.
- Plasma exposure increased dose-proportionally, with higher exposure observed with QD administration.
- Stable disease (SD) was the best overall response, observed in 32% of patients.
Conclusions:
- IM156 is the first OXPHOS inhibitor to establish an RP2D for further clinical development in cancer.
- The observed AEs of IM156 were manageable, and preliminary efficacy in the form of stable disease was noted.
- This study supports further investigation of IM156 as a novel anticancer therapeutic agent.
