ESK981 for Cancer

Recruiting at 2 trial locations

Overseen By Cancer AnswerLine

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Michigan Rogel Cancer Center

Must not be taking: CYP inhibitors

Disqualifiers: Cerebral metastasis, CNS tumor, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 4 months

66 Participants Needed

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?

The drug ESK981 is unique because it targets specific pathways involved in cancer cell survival and resistance, potentially offering a novel approach to overcoming chemoresistance in certain types of cancer, such as mesenchymal lung cancer, by interfering with the MEK1/MP1/ERK1/BCL2 axis. ^{1 2 3 4 5}

Research Team

Vaibhav Sahai, MBBS, MS

Principal Investigator

University of Michigan

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

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

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

Trial Overview The 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

Group I: Cohort 3 Experimental Treatment 1 Intervention

Neuroendocrine prostate carcinoma with Ki-67 \> 20%

Group II: Cohort 2 Experimental Treatment 1 Intervention

Pancreatic or gastrointestinal neuroendocrine neoplasms with Ki-67 \> 20%

Group III: Cohort 1 Experimental Treatment 1 Intervention

Pancreatic adenocarcinoma

Who Is Running the Clinical Trial?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Findings from Research

BCL2 expression is linked to poor prognosis and chemoresistance in mesenchymal-type lung cancers, indicating it as a potential target for treatment.

Combination therapies using BH3 mimetics like ABT-263 and ABT-737 can effectively reduce chemoresistance in mesenchymal lung cancer cells, suggesting that targeting the MEK1/MP1/ERK1/BCL2 pathway could improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL2 induced by LAMTOR3/MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer. Kwon, OS., Hong, SK., Kwon, SJ., et al.[2021]

ZD1839 (Iressa) effectively inhibits the growth of renal cell carcinomas (RCC) by reducing cell proliferation and inducing cell cycle arrest, with a significant decrease in tumor growth observed in xenograft models after 3 weeks of treatment.

The drug also reduces angiogenesis, as evidenced by decreased levels of vascular endothelial growth factor and interleukin-8, and a significant reduction in new blood vessel formation in treated tumors, highlighting its dual mechanism of action against RCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of tumor growth and tumor induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 in renal cell carcinoma. Asakuma, J., Sumitomo, M., Asano, T., et al.[2018]

V158411, a selective Chk1 inhibitor, significantly upregulates the BCL2A1 gene in U2OS cells, increasing its mRNA levels over 400-fold, which is not observed in other cell lines like HT29.

The increase in BFL1 protein in U2OS cells, which is linked to the PI3K/AKT/mTOR/MEK signaling pathway, does not prevent apoptosis in response to V158411, indicating that high BFL1 levels do not confer resistance to cell death from Chk1 inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chk1 inhibitor-induced DNA damage increases BFL1 and decreases BIM but does not protect human cancer cell lines from Chk1 inhibitor-induced apoptosis. Massey, AJ.[2023]

CHK1 inhibitors, when combined with MEK1/2 inhibitors, effectively kill breast cancer cells and transformed fibroblasts, indicating a potential therapeutic strategy for targeting these cancer types.

The lethality of CHK1 inhibitors is linked to the activation of SRC family kinases, and the effectiveness of these treatments can be enhanced by using BCL-2/BCL-XL antagonists, suggesting a complex interplay between these pathways in cancer cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous exposure of transformed cells to SRC family inhibitors and CHK1 inhibitors causes cell death. Mitchell, C., Hamed, HA., Cruickshanks, N., et al.[2021]

ZD1839 ('Iressa') is a selective inhibitor of the epidermal growth factor receptor that effectively blocks cancer cell growth and survival, showing promising results in preclinical studies with various tumor cell lines and human tumor xenografts.

Preliminary phase I trials indicate that ZD1839 is well-tolerated and shows clinical efficacy, especially in non-small cell lung cancer (NSCLC), leading to its ongoing phase III development for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZD1839 ('Iressa') as an anticancer agent. Baselga, J., Averbuch, SD.[2018]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

BCL2 induced by LAMTOR3/MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Modulation of tumor growth and tumor induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 in renal cell carcinoma. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Chk1 inhibitor-induced DNA damage increases BFL1 and decreases BIM but does not protect human cancer cell lines from Chk1 inhibitor-induced apoptosis. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Simultaneous exposure of transformed cells to SRC family inhibitors and CHK1 inhibitors causes cell death. [2021]

5. New Zealand pubmed.ncbi.nlm.nih.gov

ZD1839 ('Iressa') as an anticancer agent. [2018]