Gastrointestinal Stromal Tumor
Conditions
Keywords
GIST, Refractory, Gastrointestinal, Stromal, Tumor
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.
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.
Interventions
DRUGAUY922
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.
Sponsors
Novartis
SCRI Development Innovations, LLC
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
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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. |
| 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. |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| AUY922 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. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | AUY922 |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 63 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 8 / 25 |
Outcome results
Primary
Progression-free Survival (PFS)
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AUY922 | Progression-free Survival (PFS) | 3.9 months |
Secondary
Number of Patients With Adverse Events as a Measure of Safety and Tolerability
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.
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Diarrhea | 16 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Fatigue | 13 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Nausea | 11 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Vomiting | 7 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Asthenia | 5 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Abdominal Pain | 3 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Pain | 3 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Alkaline phosphatase increased | 2 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Anorexia | 2 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Dehydration | 2 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Floaters | 2 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Decreased color perception | 2 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Light sensitivity | 4 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Vision darkening | 2 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Vision change NOS | 3 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Anemia | 10 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Leukopenia | 1 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Thrombocytopenia | 1 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Headache | 3 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Dysgeusia | 2 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Blurred vision | 9 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Flashing lights | 7 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Delayed light/darl adaptation | 4 participants |
| AUY922 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Night Blindness | 3 participants |
Secondary
Overall Survival (OS)
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.
Population: All 25 patients who received treatment were included in the analysis of overall survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AUY922 | Overall Survival (OS) | 8.5 months |
Secondary
Response Rate (RR)
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.
Population: Of 25 patients enrolled, 4 patients were not evaluable for response due to treatment discontinuation prior to first disease evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AUY922 | Response Rate (RR) | Stable Disease | 60 percentage of participants |
| AUY922 | Response Rate (RR) | Objective Response | 4 percentage of participants |
| AUY922 | Response Rate (RR) | Progressive Disease | 20 percentage of participants |