Safety and Efficacy of SNX-5422 in Human Epidermal Growth Factor Receptor 2 (HER2) Positive Cancers

Cancer Clinical Trial

Official title:

A Single Arm, Phase 1/2 Study of SNX-5422 in Subjects With Selected HER2 Positive Cancers.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01848756
• Other study ID #: SNX-5422-CLN1-008
• Status: Terminated
• Phase: Phase 1/Phase 2
• First received: May 3, 2013
• Last updated: July 13, 2015
• Start date: April 2013
• Est. completion date: June 2015

Study information

• Verified date: July 2015
• Source: Esanex Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Hsp90 is a chemical in the body that is involved in the promotion of cancer. SNX-5422 is an experimental drug that blocks Hsp90

Description:

Heat shock protein 90 (Hsp90) chaperone proteins stabilize well over 200 different known client proteins helping them to fold correctly as they take up their rightful positions in the cell. Hsp90 has a special fondness for oncoproteins whose structures shift according to functional state. Among Hsp90's clients, a surprising number are well recognized targets in oncology, including human epidermal growth factor receptor 2 (HER2). 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). Treatment of HER2-positive cell lines such as BT-474 with the Hsp90 inhibitor SNX-2112 results in cellular degradation, decreased levels of phospho-AKT/cyclin D1, and increased apoptosis. Furthermore, treatment with SNX-5542 caused tumor regression, including remission in a HER2-overexpressing breast cancer xenograft model. SNX-5422 has demonstrated significant antitumor activity in mouse xenograft models of various human malignancies, including breast (BT474, MX-1), lung (H1975, H1650, EBC-1), colon (HT29), prostate (PC3), and melanoma (A375) with multiple oral dosing regimens.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 15
• Est. completion date: June 2015
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Males or non-pregnant, non-breastfeeding females .

• Confirmed diagnosis of locally advanced or metastatic breast, esophagogastric, urothelial, or non-small cell lung cancer.

• Histological or cytological confirmed carcinoma with HER2 amplification (IHC 3+ or FISH+ (>2 HER2:CEP17)).

• Subjects with advanced or metastatic breast cancer must have received no more than 5 prior lines of anticancer therapy, including trastuzumab (but excluding hormonal treatments).

• Subjects with advanced or metastatic HER2 positive esophagogastric cancer must have received no more than 5 prior lines of anticancer therapy, including trastuzumab.

• Subjects with advanced or metastatic, urothelial carcinoma or non-small cell lung cancer must have received at least one, but no more than 5 prior lines of anticancer therapy.

• Measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

• Life expectancy of at least 3 months.

• Karnofsky performance score =70.

• Adequate baseline laboratory assessments

• Recovered from toxicities of previous anticancer therapy, with the exception of CTCAE grade 1 sensory neuropathy.

Exclusion Criteria:

• Subjects with symptomatic central nervous system (CNS) metastases who are neurologically unstable

• Prior treatment with any Hsp90 inhibitor.

• Surgery, radiotherapy, or lesion ablative procedure to the only area of measurable disease.

• Major surgery within 4 weeks prior to first dose of SNX-5422.

• Treatment with chronic immunosuppressants (e.g., cyclosporine following transplantation).

• 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

• 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.

• Treatment with other anticancer drugs within 28 days or 5 half-lives of anticancer therapy (whichever is shorter), and treatment with any other investigational agent is prohibited from 30 days prior to the first dose of SNX-5422 and throughout 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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cancer

Intervention

Drug:
• SNX-5422
Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.

Locations

Country	Name	City	State
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Scottsdale Healthcare	Scottsdale	Arizona
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Esanex Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate	The effect of SNX-5422 on tumor progression. Objective tumor responses (complete remissions plus partial remissions) and clinical benefit rate (complete remissions plus partial remissions plus stable disease = 6 months) will be listed by subject. Tumor measurements made using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.Progression free survival and overall survival (time frame: every 3 months until 24 months after the last patient has been enrolled) will be listed by subject.	24 months	No
Secondary	Number of patients with adverse events	Number and percentage of patients experiencing treatment emergent adverse events described by relationship to treatment and severity.	Day 28 of each cycle	Yes
Secondary	Changes in vital signs, physical examination or clinical laboratory from baseline	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.	Day 28 of each cycle	Yes
Secondary	Ophthalmologic changes from baseline	Ophthalmologic assessments 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	Day 28 of every 3 cycles	Yes