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

Myeloproliferative Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01668173
• Other study ID #: 12-076
• Status: Terminated
• Phase: Phase 2
• First received: August 13, 2012
• Last updated: September 18, 2015
• Start date: August 2012
• Est. completion date: May 2015

Study information

• Verified date: September 2015
• Source: Memorial Sloan Kettering Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 7
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Myeloproliferative Disorders
• Myeloproliferative Neoplasms
• Polycythemia
• Polycythemia Vera
• Primary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• AUY922
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.

Locations

Country	Name	City	State
United States	Memorial Sloan Kettering Cancer Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Memorial Sloan Kettering Cancer Center	Novartis

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	efficacy	The primary endpoint is overall response rate defined as the rate of complete response, partial response and clinical improvement by six months.	6 months	No
Secondary	safety	and tolerability of AUY922 in patients with myeloproliferative neoplasms. Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.02.	1 year	Yes
Secondary	pharmacodynamics of AUY922	via measurement of Hsp90, downstream targets of JAK2 (P-STAT3, P-STAT5, P-MAPK), client proteins of Hsp90 (AKT, Raf-1, EGFR, and HER2) by Western blot and flow cytometry. These will be serially compared from the evaluation at baseline. Peripheral blood and bone marrow aspirate samples from pretreatment and post-treatment will be assessed for the above proteins to assess the on-target effect of the AUY922.	1 year	No

External Links

•   Memorial Sloan Kettering Cancer Center