Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: InSilico Medicine Hong Kong Limited
Must not be taking: TEAD inhibitors
Disqualifiers: CNS tumors, Severe diseases, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a Phase 1, open-label, multicenter, FIH study to evaluate the safety, tolerability, recommended Phase 2 dose (RP2D), PK/PD, and preliminary anti-tumor activity of ISM6331 in participants with advanced or metastatic malignant mesothelioma or other solid tumors. The study consists of two parts, a dose escalation part (Part 1) and a dose selection optimization part (Part 2).
Will I have to stop taking my current medications?
The trial requires that you stop any anti-tumor therapy at least 28 days before starting the study treatment. The protocol does not specify about other medications, so it's best to discuss with the study team.
How does the drug ISM6331 differ from other cancer treatments?
The drug ISM6331 may offer a unique approach by targeting the CYR61/alpha(v)beta(3) signaling pathway, which is involved in both angiogenesis (formation of new blood vessels) and breast cancer progression, potentially providing dual anti-angiogenic and anti-tumor benefits.
12345Eligibility Criteria
Adults with advanced or metastatic malignant mesothelioma or other solid tumors who have tried at least two treatments, including immune therapy. They must be in relatively good health (ECOG ≤1), expect to live more than 12 weeks, and have proper organ function. Participants need a confirmed diagnosis and measurable disease progression after standard treatment.Inclusion Criteria
I have had at least 2 treatments for mesothelioma, including immunotherapy.
I have at least one tumor that can be measured or evaluated.
My organs are functioning well, as confirmed by a recent medical check.
I am 18 years or older.
I am fully active or have some restrictions but can still care for myself.
Exclusion Criteria
I cannot or will not take pills due to a stomach condition.
I haven't had cancer treatment in the last 28 days or 5 half-lives.
I have an active brain tumor or untreated brain metastases.
I have been treated with a TEAD inhibitor before.
Participant Groups
ISM6331 is being tested for safety, tolerability, optimal dosing levels, how it affects the body (PK/PD), and its ability to shrink tumors. The trial has two parts: first finding the right dose (Part 1) and then optimizing that dose (Part 2).
2Treatment groups
Experimental Treatment
Group I: Part 2 Dose Selection OptimizationExperimental Treatment1 Intervention
Participants will receive ISM6331 once daily at each dose level from the two dose levels recommended by Study Review Committee.
Group II: Part 1 Dose EscalationExperimental Treatment1 Intervention
Patients will receive ISM6331 once daily in sequential cohorts of increasing doses.
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Sarah Cannon Research Institute at HealthONEDenver, CO
University Hospitals Cleveland Medical CenterCleveland, OH
SCRI Oncology PartnersNashville, TN
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Who is running the clinical trial?
InSilico Medicine Hong Kong LimitedLead Sponsor
References
The angiogenic factor CYR61 in breast cancer: molecular pathology and therapeutic perspectives. [2019]CYR61 (CNN1), a member of the cysteine rich 61/connective tissue growth factor/nephroblastoma overexpressed (CYR61/CTFG/NOV) family of growth regulators (CNN), is a pro-angiogenic factor that mediates diverse roles in development, cell proliferation, and tumorigenesis. We have recently shown that CYR61 is overexpressed in invasive and metastatic human breast cancer cells. Accordingly, elevated levels of CYR61 in breast cancer are associated with more advanced disease. Unfortunately, the exact mechanisms by which CYR61 promotes an aggressive breast cancer phenotype are still largely unknown. This review examines the functional role of CYR61 in breast cancer disease, presenting evidence that CYR61 signaling may play a major role in estrogen- as well as growth factor-dependent breast cancer progression. We also emphasize the functional significance of the molecular connection of CYR61 and its integrin receptor alpha(v)beta(3) enhancing breast cancer aggressiveness. Moreover, we describe experimental evidence that establishes a novel role for CYR61 determining the protection of human breast cancer cells against chemotherapy-induced apoptosis through its interactions with the integrin receptor alpha(v)beta(3). All these findings delineate a new noteworthy function of a CYR61/alpha(v)beta(3) autocrine-paracrine signaling pathway within both angiogenesis and breast cancer progression, which would allow a dual anti-angiogenic and anti-tumor benefit with a single drug.
Contributions of the alpha6 integrins to breast carcinoma survival and progression. [2021]This review summarizes recent findings that support a key role for the alpha6 integrins (alpha6beta1 and alpha6beta4) in the progression of breast carcinoma. The hypothesis that emerges from the existing data is that both of these integrins have the ability to sustain the survival of breast carcinoma cells, especially in stress conditions such as those that exist in the tumor microenvironment. The mechanisms by which these integrins promote survival appear to involve their ability to regulate the expression of vascular endothelial growth factor (VEGF), either at the level of transcription or translation. VEGF produced by breast carcinoma cells in response to alpha6 integrin regulation can function in an autocrine manner to promote survival signaling.
High expression level of alpha 6 integrin in human breast carcinoma is correlated with reduced survival. [2004]We recently reported that alpha 6 integrin mediates experimental metastasis in mice by functioning in the adhesion of tumor cells to the vascular endothelium. In the current study, we investigated the expression of human alpha 6 integrin in invasive breast carcinomas of 119 women. In 50% of the tumors alpha 6 integrin was expressed in the majority of the cells, and this expression was correlated with reduced survival time. By contrast, the 24% of patients with breast tumors devoid of alpha 6 integrin expression all survived. The tumors were also evaluated for clinical risk factors including histological grading and steroid receptor level. The combination of these factors with alpha 6 integrin expression was superior in predicting overall survival than considering the other factors alone. The correlation with decreased survival time was consistent, regardless of whether the tumors expressed the alpha 6 integrin A or B forms, which differ in their cytoplasmic domain. On the basis of this pilot study we consider alpha 6 integrin expression to be a novel prognostic marker for human breast cancer.
Involvement of alpha6beta4 integrin in the mechanisms that regulate breast cancer progression. [2018]Integrin alpha6beta4 is mostly expressed in epithelial tissues and endothelial and Schwann cells. Expression of alpha6beta4 is increased in many epithelial tumours, implicating its involvement in tumour malignancy. Moreover, this integrin activates several key signalling molecules in carcinoma cells, but its ability to activate the phosphatidylinositol 3-kinase/Akt pathway is among the mechanisms by which alpha6beta4 integrin regulates tumour behaviour. In this review we discuss the biological and clinical features of alpha6beta4 integrin that allow it to promote tumour survival and progression of mammary tumours.
Expression of the beta 4 integrin subunit induces monocytic differentiation of 32D/v-Abl cells. [2021]The alpha 6 beta 4 integrin is the receptor for various laminin isoforms and is a component of the hemidesmosome. Increased expression levels of this integrin correlate with the aggressive phenotype of many epithelial tumors compared with surrounding normal tissue. Furthermore, the long cytoplasmic tail of the beta 4 integrin subunit has been implicated in several signal transduction pathways that are involved not only in invasion, but also in proliferation and apoptosis. Here we report that the exogenous expression of beta 4 integrin in 32D/v-abl-transformed cells reduces tumor aggressiveness in vivo and strongly inhibits cell proliferation in vitro by inducing monocytic differentiation. These effects are accompanied by growth arrest and p73 protein accumulation. The hypothesis that the inhibition of v-Abl oncogenic capacity could allow the activation of the endogenous c-Abl was tested in RKO cells. The results clearly demonstrated a strong increase of c-Abl phosphorylation that is accompanied by its association with p73 protein. Overall, the reported findings indicate that alpha 6 beta 4 integrin promotes growth arrest and differentiation by modulating Abl kinases and p73 protein pathway(s).