HSP90 Inhibitor, AUY922, in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), and Refractory PV/ET
Primary Purpose
Myeloproliferative Neoplasms
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
AUY922
Sponsored by
About this trial
This is an interventional treatment trial for Myeloproliferative Neoplasms focused on measuring HSP90 Inhibitor, AUY922, 12-076
Eligibility Criteria
Inclusion Criteria:
- Eligible patients must have myeloproliferative neoplasms, specifically, primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), and PV/ET that are refractory to hydroxyurea, phlebotomy and anagrelide or not a candidate for standard therapies.
- ≥ 18 years of age
- ECOG performance status of 0-2
- Acceptable pre-study organ function during screening as defined as:
Hematologic:
- Absolute Neutrophil Count (ANC) ≥1.5x109/L
- Hemoglobin (Hgb) ≥ 8 g/dl (may be supported with transfusion)
- Platelets (plt) ≥50x10^9/L
Biochemistry:
- Potassium within normal limits
- Total calcium (corrected for serum albumin) and phosphorus within normal limits
- Magnesium above LLN or correctable with supplements Liver and Kidney Functions
- AST/SGOT and ALT/SGPT ≤ 1.5 x Upper Limit of Normal (ULN) if AP > 2.5 X ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5
- Serum bilirubin ≤ 1.5 x ULN (Unless attributable to Gilbert's disease)
- Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 ml/min
- Negative serum pregnancy test. The serum pregnancy test must be obtained prior to the first administration of AUY922 (≤ 72 hours prior to dosing) in all pre-menopausal women and women <2 years after the onset of menopause
- Patients who previously received JAK2 inhibitors will be eligible as long as they have been off the drug for more than 4 weeks.
- Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria:
- Requiring ongoing therapy with either G- or GM-CSF, or long-acting versions of these molecules
- Active medical condition such as infection or cancer that is actively requiring treatment.
- Unresolved diarrhea ≥ CTCAE (v4.02) grade 1
- Prior anti-neoplastic treatment with any HSP90 or HDAC inhibitor compound
- Patients who have undergone any major surgery ≤ 2 weeks prior to starting study drug or have not recovered from the side effects of such therapy.
- Patient must be ≥ 4 weeks since last chemotherapy or treatment with another systemic anticancer agent with the exception of hydroxyurea. Hydroxyurea must be discontinued at least 48 hours prior to the initiation of AUY922. Patients must have recovered (CTC ≤ 1) from acute toxicities of any previous therapy (with the exception of alopecia).
- Active anticoagulation with warfarin.
- Pregnant or lactating women
- Fertile women of childbearing potential (WCBP) not using double-barrier methods of contraception (abstinence, oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly, or surgically sterile). Male patients whose partners are WCBP not using double-barrier methods of contraception.
Impaired cardiac function, including any one of the following:
- History (or family history) of long QT syndrome
- Mean QTc ≥ 450 msec on baseline ECG
- History of clinically manifested ischemic heart disease (including myocardial infarction, stable or unstable angina pectoris, coronary arteriography or cardiac stress testing/imaging with findings consistent with infarction or clinically significant coronary occlusion) ≤ 6 months prior to study start
- History of heart failure or 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 (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevation or depression > 1mm, or 2nd (Mobitz II), or 3rd degree AV block.
History or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes
- Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
- Clinically significant resting bradycardia (< 50 beats per minute)
- Patients who are 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 or discontinued to an alternative drug prior to commencing AUY922.
- Obligate use of a cardiac pacemaker
Sites / Locations
- Memorial Sloan Kettering Cancer Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
AUY922
Arm Description
This is an open-label phase II trial to assess the efficacy of the HSP90 inhibitor, AUY922, in patients with PMF, post-PV MF, post-ET MF, and with PV/ET who are refractory to hydroxyurea, phlebotomy or anagrelide.
Outcomes
Primary Outcome Measures
Overall Objective Response
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Secondary Outcome Measures
Full Information
NCT ID
NCT01668173
First Posted
August 13, 2012
Last Updated
April 11, 2016
Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Novartis
1. Study Identification
Unique Protocol Identification Number
NCT01668173
Brief Title
HSP90 Inhibitor, AUY922, in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), and Refractory PV/ET
Official Title
A Phase II Study of the HSP90 Inhibitor, AUY922, in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), and Refractory PV/ET
Study Type
Interventional
2. Study Status
Record Verification Date
April 2016
Overall Recruitment Status
Terminated
Why Stopped
patient safety
Study Start Date
August 2012 (undefined)
Primary Completion Date
May 2015 (Actual)
Study Completion Date
May 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
Novartis
4. Oversight
5. Study Description
Brief Summary
The purpose of this study is to test a new drug called AUY922. AUY922 is not FDA-approved. AUY922 is a new kind of drug that attacks a protein called HSP90. HSP90 is found in both normal and cancer cells, but the investigators think it is more important in cancer cells.
This study will see if AUY922 helps people with myelofibrosis, essential thrombocythemia and polycythemia vera. This study will also see if AUY922 is safe in people with myelofibrosis, essential thrombocythemia and polycythemia vera. It will find out what effects, good and/or bad, AUY922 has on the patient and the disease. The researchers hope that this study will help them to find better treatments for primary myelofibrosis, essential thrombocythemia and polycythemia vera.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myeloproliferative Neoplasms
Keywords
HSP90 Inhibitor, AUY922, 12-076
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)
8. Arms, Groups, and Interventions
Arm Title
AUY922
Arm Type
Experimental
Arm Description
This is an open-label phase II trial to assess the efficacy of the HSP90 inhibitor, AUY922, in patients with PMF, post-PV MF, post-ET MF, and with PV/ET who are refractory to hydroxyurea, phlebotomy or anagrelide.
Intervention Type
Drug
Intervention Name(s)
AUY922
Intervention Description
AUY922 will be administered as an intravenous infusion over 60 minutes, on a once weekly schedule. A cycle on study will be defined as 28 days. The dose to be studied are 70 mg/m2 and 55 mg/m2 if DLTs are identified in the first 3-6 patients. The same schedule of administration will be used for all patients in this trial.
Primary Outcome Measure Information:
Title
Overall Objective Response
Description
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame
6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Eligible patients must have myeloproliferative neoplasms, specifically, primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), and PV/ET that are refractory to hydroxyurea, phlebotomy and anagrelide or not a candidate for standard therapies.
≥ 18 years of age
ECOG performance status of 0-2
Acceptable pre-study organ function during screening as defined as:
Hematologic:
Absolute Neutrophil Count (ANC) ≥1.5x109/L
Hemoglobin (Hgb) ≥ 8 g/dl (may be supported with transfusion)
Platelets (plt) ≥50x10^9/L
Biochemistry:
Potassium within normal limits
Total calcium (corrected for serum albumin) and phosphorus within normal limits
Magnesium above LLN or correctable with supplements Liver and Kidney Functions
AST/SGOT and ALT/SGPT ≤ 1.5 x Upper Limit of Normal (ULN) if AP > 2.5 X ULN
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5
Serum bilirubin ≤ 1.5 x ULN (Unless attributable to Gilbert's disease)
Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 ml/min
Negative serum pregnancy test. The serum pregnancy test must be obtained prior to the first administration of AUY922 (≤ 72 hours prior to dosing) in all pre-menopausal women and women <2 years after the onset of menopause
Patients who previously received JAK2 inhibitors will be eligible as long as they have been off the drug for more than 4 weeks.
Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria:
Requiring ongoing therapy with either G- or GM-CSF, or long-acting versions of these molecules
Active medical condition such as infection or cancer that is actively requiring treatment.
Unresolved diarrhea ≥ CTCAE (v4.02) grade 1
Prior anti-neoplastic treatment with any HSP90 or HDAC inhibitor compound
Patients who have undergone any major surgery ≤ 2 weeks prior to starting study drug or have not recovered from the side effects of such therapy.
Patient must be ≥ 4 weeks since last chemotherapy or treatment with another systemic anticancer agent with the exception of hydroxyurea. Hydroxyurea must be discontinued at least 48 hours prior to the initiation of AUY922. Patients must have recovered (CTC ≤ 1) from acute toxicities of any previous therapy (with the exception of alopecia).
Active anticoagulation with warfarin.
Pregnant or lactating women
Fertile women of childbearing potential (WCBP) not using double-barrier methods of contraception (abstinence, oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly, or surgically sterile). Male patients whose partners are WCBP not using double-barrier methods of contraception.
Impaired cardiac function, including any one of the following:
History (or family history) of long QT syndrome
Mean QTc ≥ 450 msec on baseline ECG
History of clinically manifested ischemic heart disease (including myocardial infarction, stable or unstable angina pectoris, coronary arteriography or cardiac stress testing/imaging with findings consistent with infarction or clinically significant coronary occlusion) ≤ 6 months prior to study start
History of heart failure or 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 (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevation or depression > 1mm, or 2nd (Mobitz II), or 3rd degree AV block.
History or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes
Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
Clinically significant resting bradycardia (< 50 beats per minute)
Patients who are 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 or discontinued to an alternative drug prior to commencing AUY922.
Obligate use of a cardiac pacemaker
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Raajit Rampal, MD, PhD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
12. IPD Sharing Statement
Links:
URL
http://www.mskcc.org/
Description
Memorial Sloan Kettering Cancer Center
Learn more about this trial
HSP90 Inhibitor, AUY922, in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), and Refractory PV/ET
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