MDACC Study Summary 2009-0619

Study Summary
No. 2009-0619:.......Leukemia......Guillermo Garcia-Manero......Leukemia

Study Summary Title



Study Summary Number:	2009-0619

Study Title:	A phase Ib/IIb, open-label, multi-center study of oral Panobinostat (LBH589) administered with 5-Azacitidine (Vidaza®) in adult patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML)

Physician

New Patient Referral



Name:	Guillermo Garcia-Manero	Patients Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Dept:	Leukemia	Referring MD Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Phone:	713-745-3428 Contact us about clinical trials

General Information



Disease Group:	Leukemia	Supported By:	Novartis Pharmaceuticals

Phase of Study:	Phase I	Return Visit:	Cycle 1: Days 1-10, then every 2-4 days (Days 12, 15, 17, 19, 22, 24, and 28, possibly Days 35 and 42 as well) Cycle 2 and beyond: weekly

Treatment Agents:	Azacitidine Panobinostat	Home Care:	NA

Treatment Loc:	Both at MDACC & outside MDACC at one or more Collaborating Sites or Institutions

Estimated Length of Stay in Houston:	NA


Description/ Intervention:	The goal of this clinical research study is to find the highest tolerable dose of panobinostat that can be given in combination with Vidaza® (azacitidine) to patients with MDS, CMML, or AML. The safety of this drug combination will also be studied.

Study Objectives / Outcomes

Phase Ib part
Primary objectives

To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RPIID) of oral panobinostat in combination with a fixed dose of 5-Azacitidine (5-Aza) in adult patients with International Prognostic Scoring System (IPSS) intermediate-2 (INT-2) or high risk MDS, CMML, or AML.

End-points for primary objectives

Incidence of dose limiting toxicity (DLT)
To determine the pharmacokinetic characteristics of the combination of oral panobinostat in combination with 5-azacitidine.

Secondary objectives

To characterize the safety and tolerability of panobinostat in combination with 5-Aza in the target patients population.

End-points for secondary objectives

Type, duration, frequency and relatedness of Adverse Events (AE). AE severity will also be assessed according to NCI Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
Laboratory (such as biochemistry, hematology)
ECG monitoring (central review by eRT)

Exploratory objectives

To evaluate preliminary anti-leukemic activity of panobinostat in combination with 5-Aza in terms of response, according to International Working Group (IWG) response criteria in AML and MDS
To assess the effect of combined study treatment on gene expression and methylation status of specific genes known or suspected to be relevant to MDS/CMML/AML.

Endpoints for exploratory objectives

Clinical response for AML: CR, CRi, PR; for MDS/CMML: CR, bone marrow CR, PR, HI
Changes in DNA methylation and changes in gene expression in peripheral blood cells before and during therapy

Phase IIb part
Primary objective

To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at the RPIID relative to treatment with single agent 5-Aza through the assessment of composite CR (CR or CRi or bone marrow CR).

End-points

Composite CR (CR or CRi or bone marrow CR)

Secondary objectives

To assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at the RPIID relative to treatment with single agent 5-Aza through the assessment of clinical responses other than the composite CR specified in the primary objective, 1 yr survival, and time to progression (TTP).
To characterize the safety and tolerability of panobinostat at the MTD and/or RPIID in combination with 5-Aza, as well as, 5-Aza alone in the target patient population.

End-points

Clinical response for AML: PR; for MDS/CMML: PR, HI
Overall response (CR or CRi or bone marrow CR or PR)
1-yr survival rate
TTP based on the Guidelines for Implementation of IWG response criteria in AML, MDS and CMML.
Type, duration, frequency and relatedness of AEs. AE severity will be assessed according to CTCAE, version 3.0
Laboratory (biochemistry, hematology)
ECG monitoring (central review by eRT)

Exploratory objectives

To assess gene mutation status of specific target genes known to be relevant to MDS/CMML/AML disease.

End-points

Mutation status of genes known to be related to MDS/CMML/AML disease.

Study Status Information



Study Activation / Registration Date:	05/27/2010

IRB Review and Approval Date:	05/27/2010

Study Type:	Phase I

Recruitment Status:	Open

Projected Accrual:	80

Enrollment Eligibility

If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:

1) Adult patients (age >/= 18 years) who are candidates for treatment with 5-Aza and present with one of the following: • intermediate-2 or high-risk MDS according to the International Prognostic Scoring System (IPSS) OR • AML with multilineage dysplasia and maximum of 30% bone marrow blasts (former RAEB-T according to FAB, currently AML according to WHO definition) OR • Chronic Myelomonocytic Leukemia (CMML)

2) ECOG performance status </= 2

3) Patients must have the following laboratory values unless elevations are considered due to underlying disease: AST/SGOT and/or ALT/SGPT </= 2.5 x ULN; Serum creatinine </= 1.5 x ULN; Serum bilirubin (total and direct) </= 2 x ULN; Serum electrolytes (i.e., Calcium, Magnesium and Potassium) within normal ranges for the institution

4) - Not applicable -

5) Negative pregnancy test

6) Patients who are not clinically euthyroid.

7) Written informed consent obtained prior to any screening procedures

Exclusion Criteria:

1) Planned hematopoietic stem-cell transplantation (HSCT)

2) Patients with therapy-related MDS

3) Patients with therapy-related AML and/or relapsed/refractory AML

4) Clinical symptoms suggesting CNS leukemia

5) Concurrent therapy with any other investigational agent

6) Prior treatment with deacetylase inhibitor(s)

7) Prior treatment with 5-Aza or 5-aza-2'-deoxycytidine (decitabine)

8) Time windows for prior therapies: Last dose of therapy, including cytokines and/or retinoids, immunotherapy, low-dose ara-C, investigational agent less than 28 days with the exception of hydroxyurea (24 hours) prior to receipt of study medication or AEs that have not recovered at least to NCI CTCAE Grade 1.

9) Patients with impaired cardiac function including any of the following: Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmia, clinically significant resting bradycardia (<50 beats per minute), QTcF > 460 ms on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block)

10) Continue from #9: • Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients with stable atrial fibrillation are eligible provided they do not meet the other cardiac exclusion criteria • Previous history of angina pectoris or acute MI within 6 months • Screening LVEF <45% by echocardiography or MUGA • Other clinically significant heart disease (e.g. uncontrolled hypertension or history of poor compliance with an antihypertensive regimen).

11) Drugs which may cause QT prolongation and the treatment cannot be discontinued or switched to a different medication prior to starting study drug

12) Any of concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study. For example: • Uncontrolled diabetes • Active or uncontrolled infection • Uncontrolled hypothyroidism • Acute or chronic liver or renal disease. By uncontrolled we mean that either the diabetes mellitus or hypothyroidism are resulting in acute clinical deterioration of the patient.

13) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat (e.g., ulcerative diseases, diarrhea, malabsorption syndrome, or small bowel resection)

14) HIV, Hepatitis B/C infection according to the medical history (testing will not be performed).

15) Female patients who are pregnant or breast feeding or patients of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and for 3 months following the last dose of study drug.

16) Male patients whose sexual partner(s) are WOCBP who are not willing to use a double barrier method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment.

17) Suspected hypersensitivity to 5-Aza or Mannitol

18) Inability to swallow capsules

19) Unwilling or unable to comply with the protocol

20) Patient has evidence of clinically significant mucosal or internal bleeding.

Links

Registration Number: NCT00946647
Study Information on Clinical Trials Registry (clinicaltrials.gov)