Akt / ERK Inhibitor ONC201 in Treating Patients with Neuroendocrine Tumors That Are Locally Advanced, Metastatic, Recurrent, Refractory, or Cannot Be Removed by Surgery

This phase II trial studies how well akt / ERK inhibitor ONC201 works in treating patients with neuroendocrine tumors that have spread to other places in the body, have come back, do not respond to treatment, or cannot be removed by surgery. Akt / ERK inhibitor ONC201 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

• Subjects must have unresectable, recurrent, locally advanced, or metastatic neuroendocrine tumor including * Cohort A; unresectable, recurrent, locally advanced, or metastatic pheochromocytoma-paraganglioma (PC-PG) who have failed or are refractory to available therapies; sample size (N)=12 * Cohort B will include only patients with unresectable, locally advanced or metastatic tumors who have failed or are refractory to available therapy; other neuroendocrine cancer varieties as characterized by expression of neuroendocrine markers on tumor tissue including CD56, synaptophysin, chromogranin and/or presence of a detectable serum or urine biomarker (3-methoxytyramine, normetanepherine, metanepherines, homovanillic acid [HVA], vanillylmandelic acid [VMA], and dopamine), varieties will include neuroblastoma, Ewing sarcoma, neuroectodermal tumor, clear call sarcoma, myoepithelial tumor, primitive neuroectodermal tumor [PNET], desmoplastic small round cell tumor, round cell sarcoma, and unresectable, metastatic or locally advanced , well-differentiated neuroendocrine tumors who have relapsed or are refractory to at least 2 systemic therapies (e.g. lanreotide, sunitinib, or everlimus); patients with small cell carcinomas will not be included in this clinical trial; N=12
• There is no limit on number of prior therapies
• Hemoglobin >= 10.0 g/dl
• Leukocytes >= 1500/mcL
• Absolute neutrophil count >= 1,000/mcL
• Platelet count >= 75000/mcL
• Total bilirubin within 1.5 x normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 5 X institutional upper limit of normal
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X institutional upper limit of normal
• Serum creatinine < 3.0 mg/dL
• >= 1 lesion detectable on CT, MRI, fludeoxyglucose F-18 (18FDG) PET-CT, or PET-MRI
• Subjects must have the ability to understand and the willingness to sign a written informed consent document
• Karnofsky performance status >= 60%

Exclusion Criteria

• Subjects not able to take oral drugs
• Subjects receiving any other investigational agents
• Subjects receiving cytotoxic chemotherapy
• Patients who occasionally or regularly use medications that impact dopamine receptor signaling and can cause side effects in people with neuroendocrine tumors including PC-PG such as metoclopromide, chloropromazine, prochlorperazine, droperidol, ephedrine, pseudoephedrine, fenfluramine, methylphenidate, phentermine, amitryptaline, imipramine, tranciproamine, moclobemide, phenelzine, paroexetine, and fluoxetine
• Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, severe, uncontrolled hypertension (systolic >150/diastolic > 100 mmHg) or other symptoms of catecholamine excess after efforts to achieve adequate alpha blockade then beta blockade
• Psychiatric illness/social situations that would limit compliance with study requirements including returning for scans, taking oral medication, home monitoring of blood pressure and heart rate, recording side effects in a self-report diary, or becoming pregnant while on study drug
• Pregnant and breast-feeding subjects
• Patients with prolactinomas

PRIMARY OBJECTIVES:

I. To demonstrate objective responses using magnetic resonance imaging (MRI) or computed tomography (CT), positron emission tomography (PET)-CT and/or PET-MRI imaging.

SECONDARY OBJECTIVES:

I. Progression – free survival.

II. Overall survival.

III. To determine efficacy of akt/ERK inhibitor ONC201 (ONC201) by reduction in dose of anti-hypertensive medications (pheochromocytoma-paraganglioma [PC-PG] only).

TERTIARY OBJECTIVES:

I. To determine time course of ONC201 efficacy - by measurement of pharmacodynamics (PD) and relevant blood biomarkers such as prolactin, normetanepherine, metanepherines, chromogranin A, and/or bombesin.

OUTLINE:

Patients receive akt/ERK inhibitor ONC201 orally (PO) weekly. Courses repeat every week for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 2 years, and then yearly for 2 years.

Lead Organization
Case Comprehensive Cancer Center

Principal Investigator
Peter Meade Anderson

Primary ID CASE2716
Secondary IDs NCI-2017-01645
Clinicaltrials.gov ID NCT03034200