Results of a completed phase I trial of CBL0137 administered intravenously (IV) to patients (Pts) with advanced solid tumors.

Abstract

3583 Background: The novel curaxin CBL0137 intercalates into DNA, interfering with histone/DNA binding. Consequent trapping of histone chaperone FACT leads to MYC, NF-kB, and HSF1 inhibition, p53 activation, and an IFN response. CBL0137 shows broad nonclinical antitumor activity (Gasparian et al. Sci Transl Med. 2011; 3(95):95ra74). Methods: This dose-ranging study assessed the CBL0137 maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and CBL0137 safety, pharmacokinetics (PK), and efficacy in adults with advanced treatment-refractory solid tumors. CBL0137 was administered IV on Days 1, 8, and 15 of repeated 28-day cycles until progressive disease (PD) or unacceptable toxicity. Doses were escalated using a 3+3 design based on Cycle 1 dose-limiting toxicities (DLTs). PK was assessed through 168 hours after Day 1. Efficacy was evaluated every 8 weeks. Results: The study enrolled 83 pts (M/F [n] = 49/34; median [range] age = 64 [33-85] years; ECOG status [n] = 1/2 [32/51]), with cancer types (n) of colorectal (23), prostate (7), glioblastoma (6), liver (6), non-small-cell (5), and others (36) across 17 dose levels from 10 to 700 mg/m2/infusion. Durations of therapy ranged to 24 months. Cycle 1 DLTs (n type) were observed at 240 mg/m2 (1 Gr 3 photosensitivity), 400 mg/m2 (1 Gr 3 anemia), 700 mg/m2 (1 Gr 4 thrombocytopenia, 1 Gr 4 neutropenia/Gr 4 thrombocytopenia), and 650 mg/m2 (1 Gr 3 thrombocytopenia, 1 Gr 4 neutropenia/Gr 3 thrombocytopenia). Nausea and vomiting were successfully prevented with dexamethasone/serotonin antagonists. Photosensitization was effectively managed with sun protection. Peripheral venous thrombosis required central vein infusion in subjects with glioblastoma. PK showed dose-proportional increases in plasma CBL0137 area under the concentration-time curve (AUC), a high mean (range) volume of distribution (Vd) of 1,030 (655-1460) L/m2 consistent with extensive tissue distribution and DNA intercalation, and an average mean (range) half-life (t1/2) of 24.7 (10.3-40.7) hours without dose dependence. The best response was stable disease: 2 pts with liver cancer had tumor control for 9 and 24 months and a maximum tumor regression of 10%; 2 pts with prostate cancer had tumor regressions by 11% and 22%; 1 pt with uterine cancer had a 20% tumor regression. Conclusions: CBL0137 administered IV was generally well tolerated with manageable toxicities The MTD and RP2D were estimated at 540 mg/m2 due to myelosuppressive DLTs. PK were predictable. Preliminary evidence of antitumor activity supports Phase 2 testing. Clinical trial information: NCT01905228 .

MYC overexpression leads to increased chromatin interactions at super-enhancers and MYC binding sites

“…Crucially, both chromatin looping disruption and FACT complex trapping led to reduced expression of MYC family genes (Carter et al 2015;Kantidze et al 2019;Wang et al 2020). Although complete degradation of CTCF is lethal in normal cells (Moore et al 2012;Kemp et al 2014), curaxins were well tolerated in xenograft models across multiple cancer cell types (Dermawan et al 2016;Kim et al 2016;Barone et al 2017) and recently completed phase I clinical trials (Sarantopoulos et al 2020), making it a promising drug against MYC-addicted cancers.…”

Z-DNA enhances immunotherapy by triggering death of inflammatory cancer-associated fibroblasts

“…CBL0137 has been trialed in humans as a monotherapy where the primary concern was a manageable combined thrombocytopenia/neutropenia occurring in 2 of the 83 patients treated. 39 These findings may represent an off-target effect as we noted that CBL0137 can induce both ZBP1-dependent and non-ZBP1-dependent cell death in bone marrow derived myeloid cells. Further study will reveal if these effects impact outcomes when CBL0137 is combined with ICB in the clinic.…”

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

“…This includes human pancreatic cancer [ 145 ]; neuroblastoma [ 146 ]; glioblastoma [ 147 – 149 ]; extremity melanomas [ 150 ]; small cell lung cancer [ 151 , 152 ]; hepatocellular carcinoma [ 153 ]; leukemia [ 154 ]; and medulloblastoma [ 155 ]. Importantly, a phase 1 clinical trial result of CBL0137 from cancer patients with solid tumors was communicated at the ASCO 2020 Annual meeting [ 156 ]. This phase 1 is a dose-ranging study that assessed the CBL0137 maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), safety, pharmacokinetics (PK), and preliminary efficacy in adults with advanced treatment-refractory solid tumors.…”

“…These authors concluded that CBL0137 administered via IV was generally well tolerated with manageable toxicities and predictable PK, and the MTD and RP2D were estimated at 540 mg/m2 due to myelosuppressive DLTs. Preliminary evidence of antitumor activity supports Phase 2 testing [ 156 ].…”