Safety and Pharmacology of SNX-5422 Plus Everolimus in Subjects With Neuroendocrine Tumors
Study Details
Study Description
Brief Summary
Study is designed to determine the maximum tolerated dose (MTD) of SNX-5422 when given in combination with everolimus.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: SNX-5422 Open-label administration of SNX-5422 capsules dosed in the morning once every other day (qod) for 21 days (11 doses), followed by a 7 day drug free period. Dose escalation will be based on safety defined as 1 or less dose limiting toxicities during the first 28 day cycle at any dose level. Dose escalation will not exceed a dose of 100 mg/m2 SNX-5422 qod even if the MTD has not been identified. Subjects will receive daily oral everolimus in the PM about the same time every day for 28 days. |
Drug: SNX-5422
Capsule dosed every other day for 21 days out of a 28 day cycle. Dose escalation based on safety not to exceed a dose of 100 mg/m2. Maintenance therapy of SNX-5422 at the MTD will be allowed for all patients not experiencing significant toxicity.
|
Outcome Measures
Primary Outcome Measures
- Number of patients with dose limiting toxicities [First 28 day cycle]
Number of patients with dose limiting toxicities defined as adverse events or laboratory abnormalities of Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 ≥ Grade 3 that are not clearly related to disease progression or delay by more than 4 weeks in receiving the next scheduled cycle due to persisting toxicities and attributable to the combination of SNX-5422 and everolimus despite optimal medical supportive management.
Secondary Outcome Measures
- Number of patients with adverse events as a measure of tolerability [Every 4 weeks]
Frequency and severity of adverse events
- Changes in ECG, vital signs, laboratory or physical examination [Every 4 weeks]
Changes in ECG, vital signs, laboratory or physical examination from baseline
- Tumor response [Every 8 weeks]
Measurements from tumor imaging within 1 month prior to the screening visit will be used as the baseline assessment. This assessment will be performed using Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Follow-up imaging of known sites of the disease, preferably by CT scan, will be performed at intervals appropriate to the subject's disease and clinical findings.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Males or non-pregnant, non-breastfeeding females 18 years-of-age or older.
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Archived neuroendocrine tumor sample or biopsy sample (will also be used for genetic testing).
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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.
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Measurable (RECIST) indicator lesion not previously irradiated.
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Life expectancy of at least 3 months.
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No more than 4 prior lines of systemic anti-cancer therapy.
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Karnofsky performance score ≥70.
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Adequate baseline laboratory assessments, including
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Absolute neutrophil count (ANC) ≥1.5 x 109/L.
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WBC >3000/microliter
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Platelet count of ≥100 x 109/L.
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Total bilirubin level ≤1.5 times institutional upper limit of normal (ULN), alanine aminotransferase or aspartate aminotransferase ≤2 x ULN
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Hemoglobin ≥9 mg/dL.
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Creatinine <1.5 X upper limit of normal or estimated plasma creatinine clearance of ≥40 mL/min
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Signed informed consent form
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Recovered from toxicities of previous anticancer therapy
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Subjects with reproductive capability must agree to practice adequate contraception methods.
Exclusion Criteria:
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Subjects in whom everolimus is contraindicated.
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Subjects with clinically significant interstitial lung disease, or obstructive disease without sufficient reserve
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Carcinoid with hormone related symptoms
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Neuroendocrine cancer of the thyroid or thymus.
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Rare pancreatic neuroendocrine cancers such as, insulinomas, glucagonomas, gastrinomas.
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Prior treatment with any Hsp90 inhibitor.
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Prior failed treatment with mTOR inhibitors
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CNS metastases that are symptomatic and /or requiring escalating doses of steroids.
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Major surgery or significant traumatic injury within 4 weeks of starting study treatment.
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Conventional chemotherapy or radiation within 4 weeks.
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Palliative radiation within 2 weeks.
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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
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Screening ECG QTc interval ≥470 msec for females, ≥450 msec for males.
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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.
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Patients with chronic diarrhea or with Grade 2 or greater diarrhea despite appropriate medical management.
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Gastrointestinal diseases or conditions that could affect drug absorption, including gastric bypass.
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Gastrointestinal diseases that could alter the assessment of safety, including irritable bowel syndrome, ulcerative colitis, Crohn's disease, or hemorrhagic coloproctitis.
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History of documented adrenal dysfunction not due to malignancy.
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Known seropositive for human immunodeficiency virus (HIV) or hepatitis C virus (HCV).
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History of chronic liver disease.
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Active hepatitis A or B.
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Current alcohol dependence or drug abuse.
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Use of an investigational treatment from 30 days prior to the first dose of SNX-5422 and during the study.
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Glaucoma, retinitis pigmentosa, macular degeneration, or any retinal changes detected by ophthalmological examination.
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Other serious concurrent illness or medical condition.
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Psychological, social, familial, or geographical reasons that would hinder or prevent compliance with the requirements of the protocol or compromise the informed consent process.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mayo Clinic | Scottsdale | Arizona | United States | 85259-5499 |
| 2 | Stanford Medicine | Stanford | California | United States | 94305 |
| 3 | Georgetown University Medical Center | Washington | District of Columbia | United States | 20007 |
| 4 | Center for Cancer Research, National Cancer Institute | Bethesda | Maryland | United States | 20892 |
| 5 | hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
Sponsors and Collaborators
- Esanex Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SNX5422-CLN-009