Cancer
Conditions
Keywords
Neuroendocrine tumor, Hsp90
Brief summary
Study is designed to determine the maximum tolerated dose (MTD) of SNX-5422 when given in combination with everolimus.
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.
Interventions
DRUGSNX-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.
Sponsors
Esanex Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Outcome results
None listed