Study of Hsp90 Inhibitor AUY922 for the Treatment of Patients With Refractory Gastrointestinal Stromal Tumor

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT01404650
• Collaborator: Novartis (Industry)
• Enrollment: 25
• Locations: 8
• Arm: 1
• Duration (Months): 38
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a multicenter, non-randomized, single agent, Phase II study of AUY922 in patients with refractory Gastrointestinal Stromal Tumor (GIST). The primary endpoint of this study is to determine progression-free survival (PFS) for patients with GIST receiving AUY922 intravenously (IV) on Days 1, 8, and 15 of a 21-day treatment cycle with restaging at 6 and 12 weeks and then every 9 weeks thereafter. Patients may continue treatment until evidence of disease progression.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Stromal Tumor	Drug: AUY922	Phase 2

Detailed Description

Gastrointestinal stromal tumors (GIST) are common sarcomas that arise in the gastrointestinal tract. Sunitinib (Pfizer) and imatinib (Novartis) are FDA-approved for treatment of patients with GIST. However, patients with advanced or refractory GIST who are resistant to these agents eventually experience disease progression or death. Heat shock protein-90 (Hsp90) is a substance found in various malignancies that encourages tumor cells to grow and survive. As an inhibitor of Hsp90, AUY922 may decrease growth of tumor cells that were resistant to prior therapies. This study investigates AUY922 monotherapy as treatment for patients who either progressed on, or were resistant to, imatinib and sunitinib.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Hsp90 Inhibitor AUY922 for the Treatment of Patients With Refractory Gastrointestinal Stromal Tumor
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AUY922	Drug: AUY922; AUY922: 70 mg/m2 IV over 60 minutes on Days 1, 8, and 15 of each cycle. Treatment cycles will be repeated every 21 days. Patients will be evaluated for response at 6 and 12 weeks and then every 9 weeks (i.e., every 3 cycles) thereafter. Patients may continue treatment until evidence of disease progression.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [At 6 and 12 weeks then every 9 weeks thereafter until progression or intolerable toxicity, up to 4 years.]

   Measured from time of randomization until objective tumor progression or death; assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Progressive disease (PD) defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest (nadir) sum since the treatment started, or the appearance of one or more new lesions.

Secondary Outcome Measures

1. Response Rate (RR) [At 6 and 12 weeks then every 9 weeks thereafter until progressive disease or intolerable toxicity, for up to 4 years.]

   Defined as the proportion of complete and partial responses, assessed per RECIST v1.1. Complete response (CR) defined as a disappearance of all lesions; partial response (PR) defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

2. Overall Survival (OS) [Every 3 months until patient death or lost to follow-up, for up to 4 years.]

   Evidence of survival was obtained by clinic visit or telephone contact from the time of first dose until death from any cause.

3. Number of Patients With Adverse Events as a Measure of Safety and Tolerability [Days 1, 8 and 15 of each 21-day cycle plus 30 days after treatment discontinuation.]

   Worst toxicity grades per patient were tabulated for select adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.0

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Pts with histologically-confirmed metastatic or unresectable GIST who have progressed on, are intolerant of, or are not a candidate for imatinib and sunitinib therapy. Pts must not have received prior treatment with Hsp90 inhibitors.

2. Must have an ECOG Performance Status of 0-1.

3. Must have a life expectancy of ≥3 mos.

4. Must have at least one unidimensional measurable lesion definable by MRI or CT scan. Disease must be measurable per RECIST v1.1.

5. Must have normal serum phosphorus and magnesium ≥ the lower limit of normal prior to trial entry.

6. Normal bone marrow function defined as: ANC ≥1500/μL Hgb ≥9 g/dL Plt ≥100,000/L

7. Adequate hepatic function defined as: AST or ALT and ALP must be 2.5 x ULN, or ≤5 x ULN in pts with liver mets Total bilirubin ≤1.5 x the institutional ULN

8. Renal function defined as: Serum creatinine ≤1.5 x ULN or 24-hour CrCl 50 mL/min

9. Women of childbearing potential (WOCP) must have a negative serum or urine pregnancy test performed ≤7 days prior to start of treatment.

10. Must be accessible for treatment and follow-up.

11. Must be able to understand the investigational nature of this study and give written informed consent prior to study entry

Exclusion Criteria:

1. Currently receiving or have received cancer therapies ≤21 days of initiating study therapy. For pts receiving small molecule targeted therapy, study treatment may begin ≥21 days after last dose or ≥5 half lives of previous treatment, whichever is shorter. The patient must have recovered from or come to a new chronic stable baseline from all treatment-related toxicities.

2. Use of any non-approved or investigational agent ≤30 days of administration of the first dose of study drug. Pts may not receive any other investigational or anti-cancer treatments while participating in this study.

3. Uncontrolled brain mets. Pts with treated brain mets (resection or radiotherapy) are eligible if brain mets have responded to treatment as documented by CT or MRI scan obtained at ≥2 wks after completion of RT, neurologic symptoms are absent, and steroids have been discontinued.

4. Treatment with therapeutic doses of coumadin-type anticoagulants (maximum daily dose of 1 mg allowed for port line patency permitted).

5. Impaired cardiac function with any one of the following: History (or family history) of prolong QT syndrome. Mean QTc ≥450 msec on baseline ECG. History of clinically manifested IHD ≤6 mos prior to study start. History of heart failure or any history of left ventricular (LV) dysfunction (LVEF ≤45%) by MUGA or ECHO. Clinically significant ECG abnormalities including 1 or more of the following: left bundle branch block, right bundle branch block with left anterior hemiblock. ST segment elevation or depression >1 mm, or 2nd (Mobitz II) or 3rd degree AV block. History or presence of A-Fib, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes. Other clinically significant heart disease. Clinically significant resting bradycardia (<50 beats per minute). Currently receiving treatment with any medication which has a relative risk of prolonging the QTcF interval or inducing Torsades de Pointes and cannot be switched to an alternative drug or discontinued prior to commencing AUY922. Obligate use of a cardiac pacemaker.

6. Known diagnosis of HIV, Hep C virus, or acute or chronic Hep B infection.

7. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.

8. Women who are pregnant or lactating.

9. Any condition that would prevent patient comprehension of the nature of, and risk associated with, the study, and the inability to comply with study and/or follow-up procedures.

10. Other malignancies ≤3 years, with the exception of adequately treated basal or squamous cell carcinomas of the skin, carcinoma in situ of the cervix, or localized prostate cancer with a current PSA of <1.0 mg/dL on 2 successive evaluations, at least 3 mos apart, with the most recent evaluation no more than 4 wks prior to entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale School of Medicine	New Haven	Connecticut	United States	06520
2	Florida Cancer Specialists-South	Ft. Myers	Florida	United States	33916
3	Florida Hospital Cancer Institute	Orlando	Florida	United States	32804
4	Woodlands Medical Center	Pensacola	Florida	United States	32503
5	Florida Cancer Specialists-North	St. Petersburg	Florida	United States	33705
6	Research Medical Center	Kansas City	Missouri	United States	64132
7	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
8	Tennessee Oncology	Nashville	Tennessee	United States	37203

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Novartis

Investigators

• Study Chair: Johanna Bendell, MD, SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT01404650
• Other Study ID Numbers: SCRI GI 148
• First Posted: Jul 28, 2011
• Last Update Posted: Oct 4, 2016
• Last Verified: Aug 1, 2016

• Keywords provided by SCRI Development Innovations, LLC: GIST; Refractory; Gastrointestinal; Stromal; Tumor
• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors

Study Results

Participant Flow

Recruitment Details	This multi-center trial evaluated AUY922 monotherapy as treatment for patients with gastrointestinal stromal tumor (GIST) refractory to, or intolerant of, imatinib and sunitinib. Between Dec 2011 and Jan 2015, 25 patients enrolled in the trial. Thirty-four patients (34) were planned to be enrolled but enrollment stopped early due to slow accrual.

Arm/Group Title	AUY922
Arm/Group Description	AUY922: 70 mg/m2 IV over 60 minutes on Days 1, 8, and 15 of each cycle. Treatment cycles repeated every 21 days. Patients are evaluated for response at 6 and 12 weeks and then every 9 weeks (i.e., every 3 cycles) thereafter until evidence of disease progression or intolerable toxicity.
Period Title: Overall Study
STARTED	25
COMPLETED	25
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	AUY922
Arm/Group Description	AUY922: 70 mg/m2 IV over 60 minutes on Days 1, 8, and 15 of each cycle. Treatment cycles repeated every 21 days. Patients are evaluated for response at 6 and 12 weeks and then every 9 weeks (i.e., every 3 cycles) thereafter until evidence of disease progression or intolerable toxicity.
Overall Participants	25
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 64%
>=65 years	9 36%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63
Sex: Female, Male (Count of Participants)
Female	11 44%
Male	14 56%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 20%
White	20 80%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	Measured from time of randomization until objective tumor progression or death; assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Progressive disease (PD) defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest (nadir) sum since the treatment started, or the appearance of one or more new lesions.
Time Frame	At 6 and 12 weeks then every 9 weeks thereafter until progression or intolerable toxicity, up to 4 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AUY922
Arm/Group Description	AUY922: 70 mg/m2 IV over 60 minutes on Days 1, 8, and 15 of each cycle. Treatment cycles repeated every 21 days. Patients are evaluated for response at 6 and 12 weeks and then every 9 weeks (i.e., every 3 cycles) thereafter until evidence of disease progression or intolerable toxicity.
Measure Participants	25
Median (95% Confidence Interval) [months]	3.9

2. Secondary Outcome

Title	Response Rate (RR)
Description	Defined as the proportion of complete and partial responses, assessed per RECIST v1.1. Complete response (CR) defined as a disappearance of all lesions; partial response (PR) defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.
Time Frame	At 6 and 12 weeks then every 9 weeks thereafter until progressive disease or intolerable toxicity, for up to 4 years.

Outcome Measure Data

Analysis Population Description

Of 25 patients enrolled, 4 patients were not evaluable for response due to treatment discontinuation prior to first disease evaluation.

Arm/Group Title	AUY922
Arm/Group Description	AUY922: 70 mg/m2 IV over 60 minutes on Days 1, 8, and 15 of each cycle. Treatment cycles repeated every 21 days. Patients are evaluated for response at 6 and 12 weeks and then every 9 weeks (i.e., every 3 cycles) thereafter until evidence of disease progression or intolerable toxicity.
Measure Participants	21
Stable Disease	60 240%
Objective Response	4 16%
Progressive Disease	20 80%

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Evidence of survival was obtained by clinic visit or telephone contact from the time of first dose until death from any cause.
Time Frame	Every 3 months until patient death or lost to follow-up, for up to 4 years.

Outcome Measure Data

Analysis Population Description

All 25 patients who received treatment were included in the analysis of overall survival.

Arm/Group Title	AUY922
Arm/Group Description	AUY922: 70 mg/m2 IV over 60 minutes on Days 1, 8, and 15 of each cycle. Treatment cycles repeated every 21 days. Patients are evaluated for response at 6 and 12 weeks and then every 9 weeks (i.e., every 3 cycles) thereafter until evidence of disease progression or intolerable toxicity.
Measure Participants	25
Median (95% Confidence Interval) [months]	8.5

4. Secondary Outcome

Title	Number of Patients With Adverse Events as a Measure of Safety and Tolerability
Description	Worst toxicity grades per patient were tabulated for select adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.0
Time Frame	Days 1, 8 and 15 of each 21-day cycle plus 30 days after treatment discontinuation.

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug.

Arm/Group Title	AUY922
Arm/Group Description	AUY922: 70 mg/m2 IV over 60 minutes on Days 1, 8, and 15 of each cycle. Treatment cycles repeated every 21 days. Patients are evaluated for response at 6 and 12 weeks and then every 9 weeks (i.e., every 3 cycles) thereafter until evidence of disease progression or intolerable toxicity.
Measure Participants	25
Anemia	10 40%
Leukopenia	1 4%
Thrombocytopenia	1 4%
Diarrhea	16 64%
Fatigue	13 52%
Nausea	11 44%
Vomiting	7 28%
Asthenia	5 20%
Abdominal Pain	3 12%
Headache	3 12%
Pain	3 12%
Alkaline phosphatase increased	2 8%
Anorexia	2 8%
Dehydration	2 8%
Dysgeusia	2 8%
Blurred vision	9 36%
Flashing lights	7 28%
Delayed light/darl adaptation	4 16%
Night Blindness	3 12%
Floaters	2 8%
Decreased color perception	2 8%
Light sensitivity	4 16%
Vision darkening	2 8%
Vision change NOS	3 12%

Adverse Events

Time Frame	Adverse events collected on Days 1, 8 and 15 of each 21-day cycle and up to 30 days post-treatment.
Adverse Event Reporting Description	Patients were permitted to continue treatment in the absence of disease progression or intolerable toxicity. 25 patients received a median of 2 cycles (6 weeks) of treatment
Arm/Group Title	AUY922
Arm/Group Description	AUY922: 70 mg/m2 IV over 60 minutes on Days 1, 8, and 15 of each cycle. Treatment cycles repeated every 21 days. Patients are evaluated for response at 6 and 12 weeks and then every 9 weeks (i.e., every 3 cycles) thereafter until evidence of disease progression or intolerable toxicity.
All Cause Mortality
	AUY922
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	AUY922
	Affected / at Risk (%)	# Events
Total	8/25 (32%)
Cardiac disorders
Chest pain	1/25 (4%)	1
Gastrointestinal disorders
Gastrointestinal hemmorhage	3/25 (12%)	4
Intestinal obstruction	2/25 (8%)	2
Abdominal pain	1/25 (4%)	1
Infections and infestations
Bacteraemia	1/25 (4%)	1
Septic shock	1/25 (4%)	1
Injury, poisoning and procedural complications
Feeding tube complication	1/25 (4%)	1
Psychiatric disorders
Confusional state	1/25 (4%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/25 (4%)	1
Vascular disorders
Haemorrhage	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	AUY922
	Affected / at Risk (%)	# Events
Total	25/25 (100%)
Blood and lymphatic system disorders
Anemia	10/25 (40%)
Eye disorders
Blurred vision	9/25 (36%)
Flashing lights	7/25 (28%)
Delayed light/dark adaptation	4/25 (16%)
Decreased color perception	2/25 (8%)
Night blindness	3/25 (12%)
Floaters	2/25 (8%)
Light sensitivity	4/25 (16%)
vision change NOS	3/25 (12%)
Vision darkening	2/25 (8%)
Gastrointestinal disorders
Abdominal pain	3/25 (12%)
Constipation	3/25 (12%)
Nausea	11/25 (44%)
Diarrhea	16/25 (64%)
Vomiting	7/25 (28%)
Anorexia	2/25 (8%)
General disorders
Fatigue	13/25 (52%)
Investigations
Alkaline phosphatase increased	2/25 (8%)
Metabolism and nutrition disorders
Dehydration	2/25 (8%)
Musculoskeletal and connective tissue disorders
Asthenia	5/25 (20%)
Nervous system disorders
Headache	3/25 (12%)
Pain	3/25 (12%)
Dysgeusia	2/25 (8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.