Tumor ablation is a minimally invasive technique commonly used to treat solid tumors in the liver, kidney, bone and lung and is based on thermal and nonthermal approaches. Local and in-situ tumor ablation methods demonstrated enhance anti-tumor immune responses resulting in the destruction of residual malignant cells in primary tumors and distant metastases. Nitric oxide (NO) is a colorless gas and is short-lived free radical. It is ubiquitous, endogenously generated gas implicated in the homeostatic regulation of physiological processes, as well as in numerous pathological conditions. Preclinical studies evaluating the effect of high concentration exogenously administered NO demonstrated its anti-cancer properties and suggested that it may serve as a potent tumoricidal agent. We have previously shown that treating mouse colon carcinoma (CT26) tumor bearing mice with ultra-high concentrations of nitric oxide (UNO) upregulates innate and adaptive immune cells both locally and systemically. Beyond Air and Beyond Cancer is currently conducting a first-in-human, first-in-class Phase 1 safety and preliminary efficacy clinical study of UNO at multiple institutions in Israel.
Methods
The study is a 2-part Phase 1 trial with a Dose Escalation and a Dose Expansion portion (NCT05351502). A conventional 3+3 dose escalation will evaluate three single escalating doses of UNO: 25,000, 50,000, and 100,000 ppm delivered intratumorally over 5 minutes at a flow rate of 0.2 liters-per-minute in subjects with relapsed or refractory unresectable primary or metastatic cutaneous and subcutaneous solid tumors. Upon determination of the maximum tolerated dose or biological effective dose, the recommended Phase 2 dose will be further evaluated in the Dose Expansion potion of the study. RECIST version 1.1 will be utilized to assess the rate of malignant tumor response after UNO administration and toxicity will be graded per NCI CTCAE version 5.0. Up to thirty-eight enrolled subjects are anticipated. This study was approved by the Israel Ministry of Health (Form 8; 202124820) as well as the participating institution's Ethics Board. Written informed consent was obtained for all enrolled subjects and a copy of the written consent is available for review.
Trial Registration
NCT05351502
Consent
Written informed consent was obtained from the patient for publication of this abstract and any accompany images. A copy of the written consent is available for review by the Editor of this journal.
Abstract SGI-110 is a novel second generation HMA, formulated as a low volume SQ injection. It is designed as a dinucleotide incorporating decitabine and guanosine, to prolong in vivo exposure and potentially improve efficacy of its active component, decitabine by protecting decitabine from rapid deamination by cytidine deaminase. Preclinically, SGI-110 demonstrated potent activity in-vivo using different routes of administration. A randomized Phase 1-2 FIH PK/PD-guided, dose-escalation study is being conducted in subjects with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage of the study is to determine the safety and tolerability of SGI-110 and to establish the MTD and the biologically effective dose (BED). Subjects are randomized to one of two SQ regimens (daily x5 or once weekly x3, both given in 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage of the study will be a randomized Phase 2 dose expansion, once the BED and MTD have been determined. Currently, 5 dose-cohorts have been fully enrolled, (n= 55) at doses ranging from 3mg/m2 to 60 mg/m2 daily x5, and 6mg/m2 to 90 mg/m2 weekly x3 but are not yet fully evaluable. PK guidance has allowed rapid dose escalation, and PD assessment of global hypomethylation has been correlated with increased dose and exposure levels. Apart from manageable local injection site pain, SGI-110 has been well tolerated. Other AE's were neutropenia, thrombocytopenia, or anemia. There have been 3 remissions in relapsed AML subjects: 1 CR with weekly (60mg/m2) and 1 PR and 1 CR with daily (36 and 60 mg/m2 respectively). The PK profile showed efficient conversion of SGI-110 to decitabine achieving exposures in the therapeutic range as predicted from the SGI-110 rational design, characterized by decitabine AUC in therapeutic range (cohorts 4-5), lower Cmax, and longer effective half life, as compared to historical data based on molar equivalent doses of IV decitabine. Dose-dependent hypomethylation induction in the first 5 cohorts was observed. The subject who achieved a CR had the highest degree of hypomethylation induction of all subjects tested to date, and also the highest decitabine AUC in the cohort. Updated efficacy, safety, PK, and PD data of both regimens will be presented. SGI-110 is safe and well tolerated to date; biologically effective and therapeutic dose levels have been achieved with little toxicity so far with both regimens. Preliminary efficacy (PR+CR) has been observed in relapsed AML subjects. The PK profile showed efficient conversion of SGI-110 to decitabine with achievable therapeutic exposures, longer apparent half life, and lower Cmax than predicted equivalent decitabine doses given IV. Global Hypomethylating effects were observed at all dose levels, evaluated to date with both regimens. The results justify the progress of the study to the second dose-expansion Phase 2 stage after establishing the BED and MTD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-214. doi:1538-7445.AM2012-LB-214
<p>Supplementary methods Supplementary Tables S1-S6 Supplementary Figure legends for SF1-SF11 Supplementary Table S1. Primers used for qRT-PCR Supplementary Table S2. Primers used for pyrosequencing Supplementary Table S3. IC50 values for CDDP resensitization by SGI-110 and 5-aza-dC in vitro Supplementary Table S4. Relative induction of MLH1 mRNA levels in response to SGI-110 Supplementary Table S5. Candidate drivers of OC CDDP Resistance Supplementary Table S6. Relative induction of ZIC1 mRNA levels in response to SGI-110</p>
Abstract Background: The role of the tumor microenvironment (TME) in fostering the development of malignancies is prompting the pursuit of anticancer therapies that target its components as to opposed to the tumor itself. As part of their immune surveillance duties, immune cells form part of this microenvironment, and yet, cancer cells have devised means to downplay their tumoricidal capabilities. Colony stimulating factor 1 receptor (CSF-1R) may offer such a means of controlling tumor associated macrophages in the tumor microenvironment. Methods: The IC50 of CBT-102 against CSF1R was evaluated in both cell free system and cell based assays, where enzyme activity was evaluated with radiometric assay format, and cell growth inhibition was evaluated in the Ba/F3 hCSF1R cell line by the CellTiter-Glo (CTG) method. Further evaluation of CBT-102 IC50 was undertaken in M-NFS-60 syngeneic cell lines and human monocytes. In vivo studies of CBT-102 in combination with anti-PD1 antibody were performed in H22 and MC38 syngeneic models. Results: CBT-102 demonstrated a reproducible activity against CSF1R in a radiometric enzyme activity assay. Using engineered BaF3 hCSF1R cell lines, we demonstrated the IC50 value of CBT-102 was 0.588 µM compared to 1.333 µM of sulfatinib, a similar multi-kinase inhibitor, and 0.279 µM of GW2580, a more specific CSF1R kinase inhibitor. Similar studies conducted in M-NFS-60 cell lines and human monocyte also showed sub-micromolar activities of CBT-102. In vivo study combining CBT-102 with anti-PD1 antibody in syngeneic models demonstrated a favorable combination effect compared to each of the single agents. Conclusions: We demonstrated previously that CBT-102 effectively inhibits VEGFR and angiogenesis. The newly revealed mechanism of CBT-102, inhibiting CSF1R and macrophages, offers a promising dual mechanism of action in addition to targeting VEGFR and angiogenesis. Rational combination with check-point inhibitors (CPIs) may improve the efficacy of CBT-102 and broaden the impact of CPIs. Further studies may be needed to delineate the interplay among CBT-102’s different mechanisms and its impact in combination with CPIs. Citation Format: Elaine Liu, Lan Yang, Gavin Choy, Xiaoling Zhang, Tillman Pearce, Mamatha Reddy, Sanjeev Redkar, Qian Shi. CBT-102, an oral small molecule multi-kinase inhibitor, demonstrates favorable CSF-1R activity, offering means of controlling tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2205.
8575 Background: In nonclinical and clinical studies, liposomal encapsulation of vincristine sulfate (VCR) increased the circulation time and accumulation of VCR at the tumor site, and thus improved antitumor efficacy in comparison to VCR. Marqibo (vincristine sulfate liposomes injection) may be administered safely at doses exceeding that typically employed by VCR, with a manageable pattern of clinical toxicities consistent with VCR. Methods: We conducted a phase I, single-center, open-label, randomized, 2-arm crossover study designed to compare the pharmacokinetics (PK) of Marqibo utilizing the 3- and 5-vial kits administered 2 mg/m 2 IV infusion once every 2 weeks in histologically confirmed, surgically nonresectable Stage III or IV metastatic cutaneous, mucosal, or choroidal melanoma patients. Patients randomized to receive the 3-vial kit at Cycle 1 were crossed over to receive the 5-vial kit at Cycle 2 or vice versa. The 3-vial kit was used for all patients at all cycles from Cycle 3 to end of treatment. Antitumor activity was assessed by CT scan every 4 cycles. Blood samples for PK analysis was collected at pretreatment, during infusion, end of infusion, and at various time points within 96 hours post end of infusion at Cycles 1 and 2. Total VCR concentration and released vincristine concentration was measured using HPLC-MS/MS method. Results: Fifteen patients were enrolled and treated; 11 were evaluable for the PK analysis. Median number of cycles received was 4 (1- 24). Objective response was observed in 13% (1 CR, 1 PR) or stable disease (20%, 3 SD) as their best response. The 90% CI (0.83–1.12) on the ratio of the means of the AUC 0-inf of the 3- and 5-vial kits was within the interval of 0.80–1.25 confirming the bioequivalence of the two kits. Seventy-three percent discontinued treatment due to disease progression and 13% discontinued due to adverse events. Adverse events included hypoesthesia or paresthesia, constipation, numbness, weakness, fatigue, nausea, vomiting. Conclusions: Single agent Marqibo demonstrated moderate activity in advanced Stage IV melanoma patients and was generally well tolerated with similar adverse event profile to VCR. The 3- and 5-vial kits produced similar bioequivalent PK profiles. No significant financial relationships to disclose.
Abstract Background: Cancer is a complex disease involving disruption of more than one receptor or signaling pathway. Inhibiting multiple oncogenic targets have been shown to be an important strategy in managing relapse and resistance. CBT-102 is an oral mTKI inhibiting several key oncogenic drivers including angiogenesis via VEGFR and PDGFR, MAPK pathway via B-RAF and C-RAF, in addition to inhibiting RET, CSF1R, c-KIT, and FLT3. Antitumor activity of CBT-102 was compared to sorafenib in two human primary HCC carcinoma xenografts in nude mice (LIMsh050 and PLCPRF5) and cardiac safety was evaluated in rabbit heart Purkinje fibers and in conscious telemeterized beagle dogs. Methods: Female BALB/c nude mice were inoculated with LIMsh050 and PLCPRF5 tumors to establish the tumor models. In the LIMsh050 model, CBT-102 was administered orally QD x 21 days at 4, 10, and 25 mg/kg and sorafenib at 10 mg/kg (n=8/group). In the PLCPRF5 model, CBT-102 was administered orally QD x 14 days at 3, 8, and 20 mg/kg vs. 8 and 20 mg/kg sorafenib group (n=7/group). In both experiments, in addition to tumor volume, body weight and mortality were monitored. For the cardiac safety studies, rabbit Purkinje fibers were isolated from adult rabbit right heart perfused for 10 minutes with vehicle control, CBT-102 groups (1, 3, and 10 µM) or sorafenib and changes in action potentials were measured. In the second study, ECG parameters were measured after single oral administration of CBT-102 at 15, 45, and 67.5 mg/kg to beagle dogs (n=6/group) via telemetry for 24 h. Results: In both the LIMsh050 and PLCPRF5 models, CBT-102 and sorafenib doses were well tolerated with no suspension of dosing due to weight loss or deaths. CBT-102 demonstrated inhibition of tumor growth in both models, to a significantly greater extent than sorafenib at comparable doses. In the PLCPRF5 model, CBT-102 demonstrated an ED50 of 2.5 mg/kg vs. 16.8 mg/kg of sorafenib. Importantly, unlike sorafenib, CBT-102 did not show a cardiac liability: there were no changes in action potential duration in rabbit Purkinje fibers nor any changes in cardiac conduction parameters (HR, QTc, RR, PR, and QRS intervals) in beagle dogs. Conclusions: CBT-102 demonstrated improved efficacy in HCC xenografts models compared to sorafenib and does not appear to have the cardiac liability observed with sorafenib. CBT-102 will advance into GLP toxicology studies with a potential IND filing in 2H 2018. Citation Format: Sarath Kanekal, Xiquan Zhang, Yanrui Song, Tan Wenmiao, Juan Zhang, Deyi Zhang, Henry Li, Mamatha Reddy, Gavin Choy, Sanjeev Redkar. CBT-102, an oral multi-kinase small molecule, demonstrates favorable activity in human hepatocellular carcinoma animal models and cardiac safety in rabbit Purkinje and beagle dogs compared to sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3945.
