Filip Janku, MD at MD Anderson discusses an ASCO 2020 abstract entitled Phase I study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors.
Bottom line:
IM156, a novel oral potent biguanide OXPHOS inhibitor of the mitochondrial electron transport chain’s Protein Complex 1 (PC1), induces phosphorylation of AMPK, the downstream effects of which are harmful to energy stress-prone OXPHOS-dependent cancer cells. In solid tumor and hematologic malignancy models, preclinical studies with IM156 showed activity as a single agent and in combinations.
Approaches:
This was an open label, first-in-human, multi-center, dose-escalation study using a 3 + 3 configuration (NCT03272256). The primary endpoint was to evaluate the maximum tolerated dose and/or the recommended phase 2 dose (RP2D) based on safety, tolerability and dose limiting toxicity (DLT). Pharmacokinetics (PK), pharmacodynamics (PD) and tentative signs of efficacy were among the secondary endpoints. Adults with advanced solid tumors refractory to normal ECOG Output Status < 2, sufficient organ function, and detectable disease (RECIST 1.1 or RANO [gliomas]) is eligible for treatment. IM156 was administered orally on a 28-day period every other day (QOD) or regularly (QD).
Reviews:
Seven cohorts (100 , 200, 400, 800, and 1,200 mg QOD; 800 and 1,200 mg QD) were enrolled in 22 patients (gastric cancer: N = 8; ovarian cancer: N = 3; colorectal cancer: N = 3; endometrial cancer: N = 2; sarcoma: N = 2; others: N = 4). The most common adverse effects associated with treatment (TRAEs) were gastrointestinal (nausea [N = 16, 73 percent], diarrhea [N = 12, 55 percent], and vomiting N = 11, 50 percent]). The only Grade 3 TRAE was nausea, recorded in 3 (14 percent) patients. There were no DLTs estimated; the estimated RP2D was 800 mg as 1,200 mg QD was associated with Grade 2/3 nausea requiring dose adjustments. Dose-proportional increases in Cmax and AUC0-last exceeding the predicted effective range were shown by PK. In 3 patients, PD showed a decrease in tumor growth rate (1,200 mg QOD: N = 2; 800 mg QD: N = 1) and a decrease in VEGF and tumor markers in 800 mg QD treated gastric cancer patients with neuroendocrine differentiation who are still under research in cycle 11. In 7 (32 per cent) patients, the best response was stable disease.
Conclusions:
IM156 is the first PC1 OXPHOS inhibitor to be successfully investigated for the detection of RP2D in cancer patients. It was well tolerated in preclinical models at dose levels active, and showed moderate clinical activity in an unselected patient population. Subsequent development would focus on tumors based on OXPHOS and combinations with agents in which the metabolism of OXPHOS is a resistance mechanism. Details on clinical trials: NCT03272256.