ESK981 for Cancer
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: University of Michigan Rogel Cancer Center
Must not be taking: CYP inhibitors
Disqualifiers: Cerebral metastasis, CNS tumor, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This protocol will enroll patients with pancreatic adenocarcinoma and adenosquamous carcinoma (Cohort 1), gastrointestinal/pancreatic neuroendocrine neoplasms with Ki-67 \> 20% (Cohort 2) and neuroendocrine prostate carcinoma (Cohort 3)). Each cohort will have its own interim analysis after enrollment of 10 patients. Subjects will be given a one-month (28 day) supply of study drug (ESK981). Subjects will be instructed to take 4 capsules, with or without food, once per day for 5 consecutive calendar days, then take a drug holiday for 2 consecutive days before repeating the 5 days on-2 days off cycle in sets of 4 weeks or 28 calendar days. Subjects will be asked to keep a pill diary noting the date they take their study drug.
Do I need to stop my current medications for the ESK981 cancer trial?
The trial requires that you do not use any chronic daily medication known to be a strong or moderate inhibitor of certain enzymes (CYP1A2, CYP2C8, or CYP3A4). If you are taking such medications, you may need to stop them. It's best to discuss your current medications with the trial team to see if any adjustments are needed.
What makes the drug ESK981 unique for cancer treatment?
Eligibility Criteria
This trial is for adults with certain advanced cancers, including pancreatic adenocarcinoma, gastrointestinal/pancreatic neuroendocrine tumors with high Ki-67 levels, and neuroendocrine prostate carcinoma. Participants must have progressed beyond or be intolerant to standard treatments and meet specific criteria like having visceral metastases or a high volume of disease.Inclusion Criteria
Willing to provide archived tissue, if available, from a previous diagnostic biopsy
My advanced cancer type has been confirmed by lab tests.
Ability to understand and willingness to sign IRB-approved informed consent
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Exclusion Criteria
I have not had cancer before, except for certain types.
My blood pressure is controlled and below 150/90.
Patient is living outside the US
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive ESK981 for 5 consecutive days followed by a 2-day drug holiday, repeated in 4-week cycles
4 months
Monthly visits for drug supply and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
up to 18 months
Treatment Details
Interventions
- ESK981 (Other)
Trial OverviewThe study tests ESK981 in patients across three cohorts based on their cancer type. Patients take the drug orally for five days followed by a two-day break, repeating this cycle every four weeks while keeping track of their medication intake in a diary.
Participant Groups
3Treatment groups
Experimental Treatment
Group I: Cohort 3Experimental Treatment1 Intervention
Neuroendocrine prostate carcinoma with Ki-67 \> 20%
Group II: Cohort 2Experimental Treatment1 Intervention
Pancreatic or gastrointestinal neuroendocrine neoplasms with Ki-67 \> 20%
Group III: Cohort 1Experimental Treatment1 Intervention
Pancreatic adenocarcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Rogel Cancer CenterAnn Arbor, MI
Barbara Ann Karmanos Cancer InstituteDetroit, MI
University of Wisconsin Carbone Cancer CenterMadison, WI
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Who Is Running the Clinical Trial?
University of Michigan Rogel Cancer CenterLead Sponsor
References
BCL2 induced by LAMTOR3/MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer. [2021]Mesenchymal-type cancers after epithelial mesenchymal transition (EMT) were recently shown to acquire chemoresistance through expressing EMT specific transcription factors. However, druggable (or actionable) target(s) for chemoresistance in mesenchymal-type lung cancers remain unidentified. Here, we used a public clinical genomic database and mesenchymal lung cancer cells (MLCC) model derived from the A549 lung adenocarcinoma cell line to demonstrate that BCL2 expression, which is highly induced in mesenchymal-type lung cancers, as a predictor of poor prognosis in mesenchymal lung cancer patients and association with acquired chemoradioresistance. Thereby, combination treatment with BH3 mimetics, such as ABT-263 and ABT-737, clearly attenuated chemoresistance in MLCCs. BCL2 expression in MLCCs was induced by ERK1 activity through the upregulation of the MEK1/ERK1 scaffold protein MEK partner-1 (MP1). Interfering with the MEK1/MP1/ERK1 axis using a MEK1 inhibitor or MP1 depletion repressed BCL2 expression and sensitized MLCCs to chemoradiotherapy. Taken together, our results suggest that targeting druggable proteins in the MEK1/MP1/ERK1/BCL2 axis, such as MEK1 or BCL2, with currently available FDA approved drugs is a currently feasible approach to improve clinical outcomes of mesenchymal lung cancer patients.
Modulation of tumor growth and tumor induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 in renal cell carcinoma. [2018]ZD1839 or Iressa (AstraZeneca, Macclesfield, United Kingdom) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor. We evaluated the antitumor activity of ZD1839 in human renal cell carcinomas (RCC).
Chk1 inhibitor-induced DNA damage increases BFL1 and decreases BIM but does not protect human cancer cell lines from Chk1 inhibitor-induced apoptosis. [2023]V158411 is a potent, selective Chk1 inhibitor currently in pre-clinical development. We utilised RNA-sequencing to evaluate the gene responses to V158411 treatment. BCL2A1 was highly upregulated in U2OS cells in response to V158411 treatment with BCL2A1 mRNA increased > 400-fold in U2OS but not HT29 cells. Inhibitors of Chk1, Wee1 and topoisomerases but not other DNA damaging agents or inhibitors of ATR, ATM or DNA-PKcs increased BFL1 and decreased BIM protein. Increased BFL1 appeared limited to a subset of approximately 35% of U2OS cells. Out of 24 cell lines studied, U2OS cells were unique in being the only cell line with low basal BFL1 levels to be increased in response to DNA damage. Induction of BFL1 in U2OS cells appeared dependent on PI3K/AKT/mTOR/MEK pathway signalling but independent of NF-κB transcription factors. Inhibitors of MEK, mTOR and PI3K effectively blocked the increase in BFL1 following V15841 treatment. Increased BFL1 expression did not block apoptosis in U2OS cells in response to V158411 treatment and cells with high basal expression of BFL1 readily underwent caspase-dependent apoptosis following Chk1 inhibitor therapy. BFL1 induction in response to Chk1 inhibition appeared to be a rare event that was dependent on MEK/PI3K/AKT/mTOR signalling.
Simultaneous exposure of transformed cells to SRC family inhibitors and CHK1 inhibitors causes cell death. [2021]The present studies were initiated to determine in greater molecular detail the regulation of CHK1 inhibitor lethality in transfected and infected breast cancer cells and using genetic models of transformed fibrobalsts. Multiple MEK1/2 inhibitors (PD184352, AZD6244 (ARRY-142886)) interacted with multiple CHK1 inhibitors (UCN-01 (7-hydroxystaurosporine), AZD7762) to kill mammary carcinoma cells and transformed fibroblasts. In transformed cells, CHK1 inhibitor -induced activation of ERK1/2 was dependent upon activation of SRC family non-receptor tyrosine kinases as judged by use of multiple SRC kinase inhibitors (PP2, Dasatinib; AZD0530), use of SRC/FYN/YES deleted transformed fibroblasts or by expression of dominant negative SRC. Cell killing by SRC family kinase inhibitors and CHK1 inhibitors was abolished in BAX/BAK -/- transformed fibroblasts and suppressed by over expression of BCL-XL. Treatment of cells with BCL-2/BCL-XL antagonists promoted SRC inhibitor + CHK1 inhibitor -induced lethality in a BAX/BAK-dependent fashion. Treatment of cells with [SRC + CHK1] inhibitors radio-sensitized tumor cells. These findings argue that multiple inhibitors of the SRC-RAS-MEK pathway interact with multiple CHK1 inhibitors to kill transformed cells.
ZD1839 ('Iressa') as an anticancer agent. [2018]ZD1839 ('Iressa') is an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor which blocks signal transduction pathways implicated in the proliferation and survival of cancer cells and other host-dependent processes promoting cancer growth. In preclinical studies, ZD1839 produced reversible growth inhibition and growth delay in a wide range of tumour cell lines and human tumour xenografts. Moreover, this activity was enhanced when ZD1839 was coadministered with cytotoxic agents. Preliminary results from phase I trials in patients with advanced disease and a wide variety of tumour types suggest that ZD1839 has an acceptable tolerability profile and promising clinical efficacy, particularly in non-small cell lung cancer (NSCLC). ZD1839 is currently in phase III clinical development for the treatment of advanced NSCLC. In addition, further trials are ongoing or planned in a number of other tumour types.