A Phase Ib Study of Panobinostat (LBH589) in Combination With 5-Azacitidine for Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML) Patients

A Phase Ib, Open-label, Multi-center, Dose-escalation Study of Oral Panobinostat (LBH589) Administered With 5-Azacitidine (Vidaza®) in Adult Japanese Patients With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML)

The purpose of this study is to confirm the safety and tolerability of oral panobinostat (PAN) in combination with a fixed dose of 5-Azacitidine (5-Aza) in adult Japanese patients with Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML) or Acute Myeloid Leukemia (AML).

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes (MDS); Acute Myeloid Leukemia (AML); Chronic Myelomonocytic Leukemia (CMML)
• Intervention / Treatment: Drug: Panobinostat

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Kyoto, Japan, 602-8566
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan, 460-0001
      • Novartis Investigative Site
    • Nagoya-city, Aichi, Japan, 466-8650
      • Novartis Investigative Site
  • Hyogo
    • Kobe-city, Hyogo, Japan, 650-0017
      • Novartis Investigative Site
  • Miyagi
    • Sendai-city, Miyagi, Japan, 980-8574
      • Novartis Investigative Site
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Japanese patients 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% blasts (former RAEB-T according to FAB) OR CMML
2. Patient has an ECOG performance status of ≤ 2
3. Patients must have the following laboratory values unless elevations are considered due to MDS or leukemia: AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN; serum creatinine ≤ 1.5 x ULN; serum bilirubin (total and direct) ≤ 2 x ULN; electrolyte panel without clinically relevant abnormalities

Exclusion Criteria:

1. Patient who is planned for or has history of hematopoietic stem-cell transplantation (HSCT)
2. Patients with relapsed/refractory AML
3. Patient is receiving concurrent anti-cancer therapy
4. Patient has received prior treatment with deacetylase inhibitors (DACi)
5. Patient has received prior treatment with 5-Aza or 6-aza-2'-deoxycytidine (decitabine)

7. Patient has shown suspected hypersensitivity to 5-Aza or Mannitol 8. Patients with impaired cardiac function 9. Patient taking medications with relative risk of prolonging the QT interval or inducing Torsade de pontes if such treatment cannot be discontinued or switched to a different medication prior to starting study treatment 10. Patients with clinical evidence of relevant mucosal or internal bleeding 11. Patient has any other concurrent severe and/or uncontrolled medical conditions

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panobinostat and Azacitidine; combination regimen	Drug: Panobinostat; Other Names: LBH589

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Dose Limiting Toxicitiy(DLT)	DLT will be assessed during PK run-in period (up to 7 days) and 1st cycle (28 days)	first 5 weeks of treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK parameter - Cmax		Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours
PK parameter - Tmax		Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours
PK parameter - AUC (AUC0-48, AUC0-tlast)		Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours
PK parameter - T1/2 (apparent oral clearance, volume distribution)		Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours
PK parameter - AUC0-inf		Day 1 to 3 of PK run-in period; pre-dose (0 hour), 0.5, 1, 2, 3, 4, 6, 8, 24 and 48 hours
Trough level of PAN in combination with 5-Aza		Day 4, 5, 8 of the 1st cycle; pre-dose (0 hour)
Frequency and severity of Adverse Events (AEs)	Safety will be measured in terms of type, frequency and severity of adverse events according to CTCAE v4.03.	Participants will be followed for the duration of treatment, an expected average of 6 months
Laboratory abnormalities		duration of treatment, an expected average of 6 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Kobayashi Y, Munakata W, Ogura M, Uchida T, Taniwaki M, Kobayashi T, Shimada F, Yonemura M, Matsuoka F, Tajima T, Yakushijin K, Minami H. Phase I study of panobinostat and 5-azacitidine in Japanese patients with myelodysplastic syndrome or chronic myelomonocytic leukemia. Int J Hematol. 2018 Jan;107(1):83-91. doi: 10.1007/s12185-017-2327-9. Epub 2017 Sep 13.

Helpful Links

• Novartis results database

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: May 24, 2012
• First Submitted That Met QC Criteria: June 6, 2012
• First Posted (Estimate): June 7, 2012

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; AML; MDS; Myelodysplastic Syndromes; Azacitidine; Panobinostat; LBH589; CMML; Chronic Myelomonocytic Leukemia; 5-Aza
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Panobinostat
• Other Study ID Numbers: CLBH589H1101