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

• Sponsor: Esanex Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01848756
• Collaborator: (none)
• Enrollment: 15
• Locations: 4
• Arm: 1
• Duration (Months): 26
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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

Condition or Disease	Intervention/Treatment	Phase
Cancer	Drug: SNX-5422	Phase 1/Phase 2

Detailed 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm, Phase 1/2 Study of SNX-5422 in Subjects With Selected HER2 Positive Cancers.
• Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SNX-5422 Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety.	Drug: SNX-5422; Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate [Up to 24 months from last patient entry]

   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 at 6 months) will be listed by subject. Tumor measurements made using Response Evaluation Criteria in Solid Tumors (RECIST).

2. Progression Free Survival [Every 3 months until 24 months after the last subject has been enrolled]

   Time on treatment with at worst stable disease.

3. Overall Survival [Every 3 months until 24 months after the last subject has been enrolled]

   Time from start of treatment that patients remain alive.

Secondary Outcome Measures

1. Number of Patients With Adverse Events [Day 28 of each cycle]

   Number of patients experiencing treatment emergent adverse events.

2. Changes in Vital Signs, Physical Examination or Clinical Laboratory From Baseline [Day 28 of each cycle]

   Descriptive summaries of vital signs, physical examination and clinical laboratory changes will be presented by treatment received.

3. Ophthalmologic Changes From Baseline [Screening, end of Cycle 1, final visit]

   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

4. Adverse Events by Severity and Relationship to Treatment [Every 28 day cycle]

   Number of patients experiencing adverse events by highest recorded severity and relationship to study tretament

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Scottsdale Healthcare	Scottsdale	Arizona	United States	85258
2	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
3	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
4	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Esanex Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Esanex Inc.
• ClinicalTrials.gov Identifier: NCT01848756
• Other Study ID Numbers: SNX-5422-CLN1-008
• First Posted: May 7, 2013
• Last Update Posted: Feb 9, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by Esanex Inc.: SNX-5422; HER2 positive cancer

Study Results

Participant Flow

Arm/Group Title	SNX-5422
Arm/Group Description	Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety. SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
Period Title: Overall Study
STARTED	15
COMPLETED	12
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	SNX-5422
Arm/Group Description	Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety. SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
Overall Participants	15
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (12.9)
Gender (Count of Participants)
Female	9 60%
Male	6 40%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 6.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	13 86.7%
More than one race	1 6.7%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate
Description	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 at 6 months) will be listed by subject. Tumor measurements made using Response Evaluation Criteria in Solid Tumors (RECIST).
Time Frame	Up to 24 months from last patient entry

Outcome Measure Data

Analysis Population Description

Per protocol population including all enrolled evaluable subjects.Due to slow recruitment and availability newer targeted treatments the study was terminated for business reasons. No patient completed 6 months on study, the first analysis time point for this endpoint, at the time of study termination

Arm/Group Title	SNX-5422
Arm/Group Description	Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety. SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
Measure Participants	0

2. Primary Outcome

Title	Progression Free Survival
Description	Time on treatment with at worst stable disease.
Time Frame	Every 3 months until 24 months after the last subject has been enrolled

Outcome Measure Data

Analysis Population Description

Due to slow recruitment and availability newer targeted treatments the study was terminated for business reasons. No patient completed 3 months on study, the first analysis time point for this endpoint, at the time of study termination

Arm/Group Title	SNX-5422
Arm/Group Description	SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
Measure Participants	0

3. Primary Outcome

Title	Overall Survival
Description	Time from start of treatment that patients remain alive.
Time Frame	Every 3 months until 24 months after the last subject has been enrolled

Outcome Measure Data

Analysis Population Description

Due to slow recruitment and availability newer targeted treatments the study was terminated for business reasons. No patient completed 3 months on study, the first analysis time point for this endpoint, at the time of study termination

Arm/Group Title	SNX-5422
Arm/Group Description	SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
Measure Participants	0

4. Secondary Outcome

Title	Number of Patients With Adverse Events
Description	Number of patients experiencing treatment emergent adverse events.
Time Frame	Day 28 of each cycle

Outcome Measure Data

Analysis Population Description

All Treated Subjects

Arm/Group Title	SNX-5422
Arm/Group Description	Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety. SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
Measure Participants	15
Number [participants]	15 100%

5. Secondary Outcome

Title	Changes in Vital Signs, Physical Examination or Clinical Laboratory From Baseline
Description	Descriptive summaries of vital signs, physical examination and clinical laboratory changes will be presented by treatment received.
Time Frame	Day 28 of each cycle

Outcome Measure Data

Analysis Population Description

All Treated Subjects

Arm/Group Title	SNX-5422
Arm/Group Description	Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety. SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
Measure Participants	15
All laboratory abnormalities	8 53.3%
ALT/AST increases	6 40%
Alkaline phosphatase increase	3 20%
Vital signs	0 0%
Systolic/diastolic blood pressure	0 0%
Respiratory rate	0 0%
Temperature	0 0%
ECG	0 0%

6. Secondary Outcome

Title	Ophthalmologic Changes From Baseline
Description	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
Time Frame	Screening, end of Cycle 1, final visit

Outcome Measure Data

Analysis Population Description

ll Treated Subjects

Arm/Group Title	SNX-5422
Arm/Group Description	Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety. SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
Measure Participants	15
Number [participants]	1 6.7%

7. Secondary Outcome

Title	Adverse Events by Severity and Relationship to Treatment
Description	Number of patients experiencing adverse events by highest recorded severity and relationship to study tretament
Time Frame	Every 28 day cycle

Outcome Measure Data

Analysis Population Description

All treated subjects

Arm/Group Title	SNX-5422
Arm/Group Description	Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety. SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
Measure Participants	15
Subjects with adverse events	15 100%
Subjects with Grade 3 or 4 adverse events	8 53.3%
Subjects with Grade 5 adverse events	2 13.3%
Subjects with treatment related adverse events	15 100%
Subjects with Grade 3 or 4 AEs related to treatmen	7 46.7%
Subjects with Grade 5 AEs related to treatment	0 0%

Adverse Events

Time Frame	From patient screening to removal from study, average time on study 49+/-16 days
Adverse Event Reporting Description	Regular Investigator Assessment including patient volunteered reports
Arm/Group Title	SNX-5422
Arm/Group Description	Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety. SNX-5422: Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.
All Cause Mortality
	SNX-5422
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	SNX-5422
	Affected / at Risk (%)	# Events
Total	8/15 (53.3%)
Cardiac disorders
Atrial Fibrillation	1/15 (6.7%)
Cardiac Tamponade	1/15 (6.7%)
Pericardial Effusion	1/15 (6.7%)
Gastrointestinal disorders
Abdominal Pain Upper	1/15 (6.7%)
Diarrhoea	1/15 (6.7%)
Haematemesis	1/15 (6.7%)
Nausea	1/15 (6.7%)
Vomiting	1/15 (6.7%)
General disorders
Asthenia	1/15 (6.7%)
Hepatobiliary disorders
Jaundice	1/15 (6.7%)
Infections and infestations
Pneumonia	1/15 (6.7%)
Wound Infection	1/15 (6.7%)
Metabolism and nutrition disorders
Dehydration	1/15 (6.7%)
Nervous system disorders
Dizziness	1/15 (6.7%)
Renal and urinary disorders
Renal Failure Acute	2/15 (13.3%)
Other (Not Including Serious) Adverse Events
	SNX-5422
	Affected / at Risk (%)	# Events
Total	15/15 (100%)
Blood and lymphatic system disorders
Anaemia	4/15 (26.7%)
Eye disorders
Vision Blurred	1/15 (6.7%)
Gastrointestinal disorders
Diarrhoea	13/15 (86.7%)
Nausea	8/15 (53.3%)
Vomiting	8/15 (53.3%)
Abdominal Pain	3/15 (20%)
Constipation	2/15 (13.3%)
Dry Mouth	2/15 (13.3%)
Abdominal Pain Upper	1/15 (6.7%)
General disorders
Fatigue	6/15 (40%)
Chills	1/15 (6.7%)
Mucosal Inflammation	1/15 (6.7%)
Investigations
Aspartate Aminotransferase increased	5/15 (33.3%)
Alanine Aminotransferase Increased	3/15 (20%)
Blood Alkaline Phosphatase Increased	2/15 (13.3%)
Activated Partial Thromboplastin Time Prolonged	1/15 (6.7%)
Blood Cholesterol Increased	1/15 (6.7%)
Blood Creatinine Increased	1/15 (6.7%)
Lymphocyte Count Decreased	1/15 (6.7%)
White Blood Cell Count Decreased	1/15 (6.7%)
Metabolism and nutrition disorders
Decreased Appetite	3/15 (20%)
Hyperglycaemia	2/15 (13.3%)
Hypoalbuminaemia	2/15 (13.3%)
Dehydration	1/15 (6.7%)
Hyperphosphataemia	1/15 (6.7%)
Hypocalcaemia	1/15 (6.7%)
Hypomagnesaemia	1/15 (6.7%)
hyponatraemia	1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/15 (6.7%)
Back pain	1/15 (6.7%)
Nervous system disorders
Dizziness	1/15 (6.7%)
Headache	1/15 (6.7%)
Renal and urinary disorders
Renal Failure Acute	1/15 (6.7%)
Skin and subcutaneous tissue disorders
Rash Maculo-papular	1/15 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.