Safety and Pharmacology Study of SNX-5422 in Subjects With Resistant Lung Adenocarcinoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01851096
Recruitment Status : Completed
First Posted : May 10, 2013
Last Update Posted : August 16, 2016
Information provided by (Responsible Party):
Esanex Inc.

Brief Summary:
Heat shock protein 90 (Hsp90) is a chemical in the body that is involved in the promotion of cancer. SNX-5422 is an experimental drug that blocks Hsp90.

Condition or disease Intervention/treatment Phase
Cancer Drug: SNX-5422 Phase 1

Detailed Description:

Heat shock protein 90 (Hsp90) chaperone proteins stabilize many client proteins including mutant EGFR, and are also hypothesized to help maintain the malignant phenotype of mutant EGFR in lung adenocarcinoma. Treatment of EGFR mutant cell lines with the Hsp90 inhibitor geldanamycin results in cellular degradation, decreased levels of pAKT/cyclin D1, and increased apoptosis. Furthermore, Hsp90 inhibitors hamper growth of tumors in nude mice with gefitinib-resistant H1975-xenografts in vivo.

Clinical data showed that mono-therapy with some Hsp90 inhibitors provides stable disease and some patients have partial remissions as best responses in heavily pre-treated non small cell lung cancer patients.

SNX-5422 is a pro-drug of SNX-2112, a potent, highly selective, small-molecule inhibitor of the molecular chaperone Hsp90. Inhibitors of the chaperone protein Hsp90 are of current interest because of the central role that Hsp90 plays in the maturation and maintenance of numerous proteins, for example HER2 and mutated EGFR, that are critical for tumor cell viability and growth.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-label, Dose-escalation Study of SNX 5422 and Erlotinib in Subjects With Lung Adenocarcinoma With "Acquired Resistance" to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.
Study Start Date : March 2013
Actual Primary Completion Date : October 2015
Actual Study Completion Date : August 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Erlotinib

Arm Intervention/treatment
Experimental: SNX-5422
Open label administration of SNX-5422 tablets every other day for 21 days on a 28 day cycle. Dose escalation of SNX-5422 based on safety outcomes
Drug: SNX-5422
Capsules dosed every other day in the morning starting at a dose of 50 mg/m2. Dose escalation based on safety. Subjects will also receive 150 mg erlotinib daily (in the afternoon).

Primary Outcome Measures :
  1. Number of patients with dose limiting toxicities [ Time Frame: Day 28 of first dose cycle ]
    Number of patients with dose limiting toxicities defined as adverse events (AE) or laboratory abnormalities of Common Terminology Criteria for Adverse Events(CTCAE) version 4.03 ≥ Grade 3 that are not clearly related to disease progression

Secondary Outcome Measures :
  1. Tumor response [ Time Frame: Weeks 4, 12, 20 and 28 ]
    Tumor progression relative to baseline; assessment of tumor response will be performed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

  2. Changes in vital signs, physical examination or clinical laboratory from baseline [ Time Frame: Weeks 4, 8, 12, 16, 20, 24 and 28 ]
    Descriptive summaries of vital signs, physical examination and quantitative clinical laboratory changes will be presented by treatment received and study visit. Laboratory toxicities will be graded by severity using common terminology criteria for adverse events (CTCAE) Version 4.03. Frequency and percentage of subjects experiencing clinically relevant toxicities will be summarized by treatment received. Summaries may be repeated by treatment cycle.

  3. Number of patients with ophthalmological changes from baseline [ Time Frame: Weeks 4, 16 and 28 ]
    Ophthalmologic assessments (visual acuity, visual field, ophthalmoscopy, dark adaptation, optical coherence tomography) will be presented by cohort, study visit and dose. Number of subjects experiencing clinically relevant changes from baseline in any of these examinations will be presented using descriptive summary

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Males or non-pregnant, non-breastfeeding females 18 years-of-age or older.
  • Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time.
  • Must have undergone a biopsy after the development of acquired resistance.
  • Pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically
  • Radiographic progression by RECIST during treatment with erlotinib/gefitinib.
  • Measurable (RECIST) indicator lesion not previously irradiated.
  • No more than 4 prior lines of cytotoxic chemotherapy, including erlotinib/gefitinib
  • 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 (ALT) or aspartate aminotransferase (AST) ≤1.5 x ULN.
    • Hemoglobin ≥9 mg/dL.
    • Creatinine <1.5 X upper limit of normal or estimated plasma creatinine clearance of ≥40 mL/min (using the Cockroft-Gault equation)
  • Signed informed consent form (ICF).
  • Subjects with reproductive capability must agree to practice adequate contraception methods.
  • Adequate venous access.

Exclusion Criteria:

  • CNS metastases which are symptomatic and /or requiring escalating doses of steroids.
  • Prior treatment with any Hsp90 inhibitor.
  • Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed).
  • 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 maximal 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01851096

United States, District of Columbia
Georgetown University Medical Center
Washington, District of Columbia, United States, 20007
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Esanex Inc.

Responsible Party: Esanex Inc. Identifier: NCT01851096     History of Changes
Other Study ID Numbers: SNX-5422-CLN1-007
First Posted: May 10, 2013    Key Record Dates
Last Update Posted: August 16, 2016
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Phase 1 pharmacology study

Keywords provided by Esanex Inc.:
Lung adenocarcinoma

Additional relevant MeSH terms:
Lung Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Erlotinib Hydrochloride
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action