Safety and Pharmacology of SNX-5422 Plus Everolimus in Subjects With Neuroendocrine Tumors
This trial is active, not recruiting.
|Targets||Hsp90, mTOR, FKBP-12|
|Start date||February 2014|
|End date||February 2017|
|Trial size||19 participants|
|Trial identifier||NCT02063958, SNX5422-CLN-009|
Study is designed to determine the maximum tolerated dose (MTD) of SNX-5422 when given in combination with everolimus.
|United States||No locations recruiting|
|Other countries||No locations recruiting|
|Endpoint classification||safety study|
|Intervention model||single group assignment|
Number of patients with dose limiting toxicities
time frame: First 28 day cycle
Number of patients with adverse events as a measure of tolerability
time frame: Every 4 weeks
Changes in ECG, vital signs, laboratory or physical examination
time frame: Every 4 weeks
time frame: Every 8 weeks
Male or female participants at least 18 years old.
Inclusion Criteria: - Males or non-pregnant, non-breastfeeding females 18 years-of-age or older. - Archived neuroendocrine tumor sample or biopsy sample (will also be used for genetic testing). - Pathologic evidence of chemo-resistant Small Cell Lung cancer (relapse <90 days after 1st line), chemo-sensitive Small Cell Lung Cancer (relapse >90 days after first line), locally advanced metastatic neuroendocrine tumor of gastro-entero, pancreatic, pulmonary (other than Small Cell Lung) or thymic origin, or advanced renal cell carcinoma for which everolimus is indicated. - Measurable (RECIST) indicator lesion not previously irradiated. - Life expectancy of at least 3 months. - No more than 4 prior lines of systemic anti-cancer therapy. - Karnofsky performance score ≥70. - Adequate baseline laboratory assessments, including - Absolute neutrophil count (ANC) ≥1.5 x 109/L. - WBC >3000/microliter - Platelet count of ≥100 x 109/L. - Total bilirubin level ≤1.5 times institutional upper limit of normal (ULN), alanine aminotransferase or aspartate aminotransferase ≤2 x ULN - Hemoglobin ≥9 mg/dL. - Creatinine <1.5 X upper limit of normal or estimated plasma creatinine clearance of ≥40 mL/min - Signed informed consent form - Recovered from toxicities of previous anticancer therapy - Subjects with reproductive capability must agree to practice adequate contraception methods. Exclusion Criteria: - Subjects in whom everolimus is contraindicated. - Subjects with clinically significant interstitial lung disease, or obstructive disease without sufficient reserve - Carcinoid with hormone related symptoms - Neuroendocrine cancer of the thyroid or thymus. - Rare pancreatic neuroendocrine cancers such as, insulinomas, glucagonomas, gastrinomas. - Prior treatment with any Hsp90 inhibitor. - Prior failed treatment with mTOR inhibitors - CNS metastases that are symptomatic and /or requiring escalating doses of steroids. - Major surgery or significant traumatic injury within 4 weeks of starting study treatment. - Conventional chemotherapy or radiation within 4 weeks. - Palliative radiation within 2 weeks. - The need for treatment with medications with clinically-relevant metabolism by the cytochrome P450 (CYP) 3A4 isoenzyme within 3 hours before or after administration of SNX-5422 - Screening ECG QTc interval ≥470 msec for females, ≥450 msec for males. - At increased risk for developing prolonged QT interval, including hypokalemia or hypomagnesemia, unless corrected to within normal limits prior to first dose of SNX-5422; congenital long QT syndrome or a history of torsade de pointes; currently receiving anti-arrhythmics or other medications that may be associated with QT prolongation. - Patients with chronic diarrhea or with Grade 2 or greater diarrhea despite appropriate medical management. - Gastrointestinal diseases or conditions that could affect drug absorption, including gastric bypass. - Gastrointestinal diseases that could alter the assessment of safety, including irritable bowel syndrome, ulcerative colitis, Crohn's disease, or hemorrhagic coloproctitis. - History of documented adrenal dysfunction not due to malignancy. - Known seropositive for human immunodeficiency virus (HIV) or hepatitis C virus (HCV). - History of chronic liver disease. - Active hepatitis A or B. - Current alcohol dependence or drug abuse. - Use of an investigational treatment from 30 days prior to the first dose of SNX-5422 and during the study. - Glaucoma, retinitis pigmentosa, macular degeneration, or any retinal changes detected by ophthalmological examination. - Other serious concurrent illness or medical condition. - Psychological, social, familial, or geographical reasons that would hinder or prevent compliance with the requirements of the protocol or compromise the informed consent process.
|Official title||A Phase 1, Open-label, Dose-escalation Study of SNX 5422 and Everolimus in Subjects With Neuroendocrine Tumors.|
|Description||Heat shock protein 90 (Hsp90) plays a central role in the maturation and maintenance of numerous proteins, for example HER2 and mutated EGFR, that are critical for tumor cell viability and growth; SNX-5422 is a pro-drug of SNX-2112, a potent, highly selective, small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 has been found to be expressed in 95% of subjects with pancreatic neuroendocrine tumors. This study will determine the MTD of SNX-5422 when given in combination with everolimus in patients with neuroendocrine tumors.The clinical starting dose of 50 mg/m2 qod for SNX-5422 in combination with daily everolimus is 50% of the SNX-5422 qod mono-therapy MTD. The choice to continue once every other day SNX-5422 dosing is based on the safety and efficacy profiles from prior studies, so that drug holidays are interspersed into weekly dosing. The planned subsequent dose levels are 75% and 100% of the SNX-5422 qod mono-therapy MTD.|
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