Safety and Pharmacology of SNX-5422 Plus Everolimus in Subjects With Neuroendocrine Tumors

Study Overview
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Brief Summary
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Study is designed to determine the maximum tolerated dose (MTD) of SNX-5422 when given in combination with everolimus.

Detailed Description
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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.

Official Title
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A Phase 1, Open-label, Dose-escalation Study of SNX 5422 and Everolimus in Subjects With Neuroendocrine Tumors.

Conditions
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Cancer

Intervention / Treatment
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* Drug: SNX-5422


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SNX-5422<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with dose limiting toxicities | 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. | First 28 day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events as a measure of tolerability | Frequency and severity of adverse events | Every 4 weeks | 
| Changes in ECG, vital signs, laboratory or physical examination | Changes in ECG, vital signs, laboratory or physical examination from baseline | Every 4 weeks | 
| Tumor response | 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. | Every 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroendocrine tumor, Hsp90