Clinical trial NCT01613976: 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
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myelodysplastic Syndromes (MDS)
Chronic Myelomonocytic Leukemia (CMML)
Acute Myeloid Leukemia (AML)
Keywords: Myelodysplastic Syndromes
MDS
Chronic Myelomonocytic Leukemia
CMML
Acute Myeloid Leukemia
AML
Panobinostat
LBH589
5-Aza
Azacitidine
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-06-07
Enrollment: 10
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Dose Limiting Toxicitiy(DLT)
timeFrame: first 5 weeks of treatment period
Secondary outcomes:
measure: PK parameter - Cmax
timeFrame: 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
measure: PK parameter - Tmax
timeFrame: 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
measure: PK parameter - AUC (AUC0-48, AUC0-tlast)
timeFrame: 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
measure: PK parameter - T1/2 (apparent oral clearance, volume distribution)
timeFrame: 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
measure: PK parameter - AUC0-inf
timeFrame: 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
measure: Trough level of PAN in combination with 5-Aza
timeFrame: Day 4, 5, 8 of the 1st cycle; pre-dose (0 hour)
measure: Frequency and severity of Adverse Events (AEs)
timeFrame: Participants will be followed for the duration of treatment, an expected average of 6 months
measure: Laboratory abnormalities
timeFrame: duration of treatment, an expected average of 6 months
Other outcomes:
Locations:
city: Nagoya-city
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kobe-city
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Sendai-city
country: Japan
facility: Novartis Investigative Site
state: Miyagi
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Kyoto
country: Japan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.