Sponsor: University of Michigan Rogel Cancer Center (other)
Phase: 2
Start date: April 19, 2024
Planned enrollment: 66
ESK981 (also called CEP-11981 or BOL-303213X) is an investigational oral kinase inhibitor studied in advanced cancers. Human results are available from an early dose-escalation trial and two small, single-arm phase II prostate cancer trials. (pmc.ncbi.nlm.nih.gov)
ESK981 inhibits several kinases involved in blood-vessel formation, including VEGFR-1, VEGFR-2 and Tie-2. Laboratory research also identifies PIKfyve as a direct target: its inhibition disrupts autophagy and altered immune signaling in preclinical prostate cancer models. Those preclinical effects have not translated into demonstrated clinical benefit in the reported prostate cancer trials. (pmc.ncbi.nlm.nih.gov)
In phase I, the maximum tolerated dose was 97.4 mg/m² daily; dose-limiting events at a higher dose included grade 4 neutropenia and grade 3 cardiac symptoms with an electrocardiogram change. In the ESK981-alone phase II trial, reported grade 3 treatment-related events included cardiac disorders, diarrhea, hypertension and elevated liver enzymes; no grade 4–5 events were reported. The combination trial reported grade 3 treatment-related fatigue, anemia and lymphopenia, with no grade 4 events. Its registry states that enrollment closed after two cerebrovascular events. These small trials cannot establish how frequently uncommon harms occur. (openalex.org)
Last updated: Sep 2026
Goal: Assess whether ESK981 controls disease in three advanced cancer subtypes, primarily by measuring the proportion of patients alive and progression-free at 4 months in each cohort.
Patients: Adults with ECOG performance status 0–2 and evaluable advanced disease after progression on, or intolerance of, standard systemic therapy. Cohorts include pancreatic adenocarcinoma or adenosquamous carcinoma; pancreatic or gastrointestinal neuroendocrine neoplasms with Ki-67 >20%; and metastatic prostate cancer with neuroendocrine features or clinical evidence of neuroendocrine differentiation. Adequate organ function is required; key exclusions include uncontrolled hypertension, significant recent cardiovascular or thromboembolic disease, and active infection.
Design: Multicenter, nonrandomized phase II trial with three disease-specific, single-arm cohorts. Each cohort has a separate interim analysis after 10 patients enroll.
Treatments: All participants receive oral ESK981, four capsules once daily for five consecutive days followed by two days off, repeated in 28-day cycles. ESK981 is an investigational kinase inhibitor targeting angiogenesis-related VEGFR-1, VEGFR-2, and Tie-2; preclinical work also identifies PIKfyve inhibition, which disrupts autophagy and alters immune signaling. In a phase I solid-tumor study, no objective responses occurred among 37 evaluable patients, although 51% had stable disease at six weeks or later. Small phase II studies in metastatic castration-resistant prostate cancer showed limited activity, and clinical benefit in the populations enrolled here remains unproven.
Outcomes: The primary endpoint is the proportion alive and progression-free at four months in each cohort. Secondary endpoints include confirmed objective response rate, duration of response, median progression-free survival, overall survival, and adverse events graded by CTCAE v5.0. Response is assessed using RECIST v1.1 for the pancreatic and gastrointestinal cohorts and RECIST v1.1 plus PCWG3 for the prostate cohort.
Burden on patient: Estimated moderate burden. Treatment is taken at home, but patients must follow a five-days-on, two-days-off schedule and maintain a pill diary. Screening requires laboratory testing and contrast CT and/or MRI, with subsequent imaging and safety assessments to evaluate response and toxicity. Archived tissue is requested if available; no mandatory new biopsy or intensive pharmacokinetic sampling is specified. Visit and scan frequency is not stated, so travel burden cannot be quantified.
Last updated: Sep 2026
Eligibility Criteria:
* Patients with histological or cytological confirmation of advanced cancer per specific cohort.
* Cohort 1: Pancreatic adenocarcinoma or adenosquamous carcinoma who have progressed or deemed intolerant of the standard of care chemotherapy regimens.
* Cohort 2: Pancreatic or gastrointestinal neuroendocrine tumor or carcinoma with Ki-67 \> 20% who have progressed or deemed intolerant of at least first-line standard of care systemic therapy.
* Cohort 3: The subject has histologically proven prostate cancer who have progressed or deemed intolerant of at least first-line standard of care systemic therapy with radiologic evidence of metastases and at least one of the following:
* Small cell or neuroendocrine morphology on the basis of tissue sample.
* Prostate adenocarcinoma with IHC staining for neuroendocrine markers (e.g., chromogranin and synaptophysin).
* Presence of visceral metastases or high-volume disease (\> 4 sites of metastases) with a PSA ≤ 5.
* Serum chromogranin A level ≥ 5x upper limit of normal (ULN) and/or serum neuron specific enolase (NSE) ≥ 2x ULN.
* Trans-differentiated carcinoma or poorly-differentiated carcinoma
* Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
* Must be ≥ 18 years of age.
* Evaluable disease determined using guidelines of Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)
* Ability to understand and willingness to sign IRB-approved informed consent.
* Willing to provide archived tissue, if available, from a previous diagnostic biopsy.
* Must be able to tolerate CT and/or MRI with contrast.
* At least 4 weeks from major surgery with resolution of any sequela to date of enrollment
* Laboratory values ≤2 weeks during screening must be:
* Platelet count ≥ 75,000 cells/mm3
* Absolute neutrophil count ≥ 1500 cells/mm3
* Hemoglobin ≥ 9 g/dL
* AST/ALT ≤ 3x upper limit of normal \[ULN\], or (≤ 5x ULN if liver metastasis present)
* Bilirubin ≤ 1.5x ULN, or (≤ 2.5 x ULN for subjects with Gilbert's syndrome)
* Albumin ≥ 3 g/dL
* Serum creatinine clearance CrCl ≥ 50 mL/min per Cockcroft-Gault Formula
* INR ≤ 1.5 (or \<2.0 if on anticoagulants)
* Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must agree to use acceptable highly effective contraceptive methods (abstinence, intrauterine device \[IUD\], oral contraceptive(s), intrauterine hormone releasing system (IUS), bilateral tubal occlusion or vasectomized partner) during and for 9 months after last study dose and must have a negative serum or urine pregnancy test during screening.
* Males with female partners (of childbearing potential) and female partners (of childbearing potential) with male partners must agree to use double barrier contraceptive measure (a combination of male condom with either cap, diaphragm or sponge with spermicide) in addition to oral contraception, or avoidance of intercourse during the study and for 6 months after last study dose is received.
* Female patients must not be pregnant, have a positive pregnancy test, breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 9 months after the last dose of study treatment.
* Male patients must be willing to abstain from donating sperm during treatment and for 6 months after completion of study treatment.
* No evidence of active infection and no serious infection within the past 30 days. Patient must have completed antibiotic course.
* No known cerebral metastasis, central nervous system (CNS), or epidural tumor (unless previously treated, asymptomatic and stable for at least 3 months).
* No active heart disease including but not limited to myocardial infarction that is \<3 months prior to registration, symptomatic congestive heart failure (NYHA class 3 or 4), symptomatic coronary artery disease, symptomatic angina pectoris.
* No history of acute cerebrovascular disease, arterial or venous thromboembolism, percutaneous angioplasty, or coronary artery bypass surgery within 6 months prior to registration
* No pre-existing coagulopathy, or serious bleeding within 3 months prior to registration.
* No prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, in situ cancer, localized prostate cancer (Gleason score \<8), or adequately treated cancer from which the patient has been disease-free for at least 3 years prior to registration.
* Must not have uncontrolled diarrhea at the time of enrollment.
* Patients must not use a chronic daily medication known to be a strong or moderate inhibitor of CYP1A2, CYP2C8 or CYP3A4 at registration (as per Appendix II).
* Patients must have recovered to baseline or ≤ grade 1 CTCAE v5.0 from toxicities related to any prior treatments, unless adverse event(s) is deemed clinically non-significant and/or stable on supportive therapy.
* Patients must not have uncontrolled hypertension defined as blood pressure \>150/90 despite optimal medical management.
* No known hypersensitivity to gelatin or lactose monohydrate.
Detroit, Michigan, 48201, United States
No email / No phone
Status: Recruiting
Ann Arbor, Michigan, 48109, United States
No email / 734-936-4991
Status: Recruiting
Madison, Wisconsin, 53792, United States
[email protected] / 800-622-8922
Status: Recruiting