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A Phase Ib/IIb, Open-label, Multi-center, Study of Oral Panobinostat Administered With 5-Azacitidine (in Adult Patients With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML).

Primary Purpose

Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Panobinostat (LBH589)

5-Azacytidine

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia, hypomethylating therapy, deacetylase inhibitor, MDS, CMML, AML

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Phase l:

Patients with cytopathologically confirmed diagnosis of AML according to WHO criteria, excluding acute promyelocytic leukemia who are eligible for Vidaza treatment
ECOG performance status greater less than or equal to 2

Phase ll:

Adult patients (age ≥ 18 years) who were candidates for treatment with 5-Aza and present with one of the following:
- intermediate-2 or high-risk myelodysplastic syndromes 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
- chronic myelomonocytic leukemia (CMML)
Patients must have had 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 within normal ranges (WNL) for the institution.

Exclusion Criteria:

Phase l:

Prior treatment with deacetylase inhibitors
Concurrent therapy with any other investigational agent

Phase ll:

Planned hematopoietic stem-cell transplantation (HSCT)
Patients with therapy-related MDS
Patients with therapy-related AML and/or relapsed/refractory AML
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)
- 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).
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
Patient had evidence of clinically significant mucosal or internal bleeding

Sites / Locations

Georgia Health Sciences University Dept. of MCG
Goshen Center for Cancer Care IU Cancer Center
University of Kansas Hospital and Medical Center SC - Univ KS
Dana Farber Cancer Institute Beth Israel Deaconess Med Ctr
Memorial Sloan Kettering Sloan Kettering 2
Cleveland Clinic Foundation Cleve Clinic
Medical University of South Carolina -Hollings Cancer Center MUSC
University of Texas MD Anderson Cancer Center Dept of MD Anderson (16)
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
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Novartis Investigative Site
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Novartis Investigative Site
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Novartis Investigative Site
Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Panobinostat + 5-Azacytidine

5-Azacytidine

Arm Description

In phase I: Panobinostat : Escalating doses starting with 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.

The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.

Outcomes

Primary Outcome Measures

Number of Participants With Dose Limiting Toxicity (DLT) (Phase lb)

Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT

Number of Dose Limiting Toxicity (DLT) (Phase lb)

Composite Complete Response (Phase Llb)

Composite complete response is defined as complete response (CR), Complete response with incomplete blood count recovery (CRi) or bone marrow complete response (BM-CR) as defined by the International Working Group (IWG) response criteria.

Secondary Outcome Measures

Clinical Response Other Than Composite Clinical Response for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb)

This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), bone marrow complete remission (BM-CR), partial remission or hematologic improvement (HI) as defined by the International Working Group (IWG) response criteria.

Clinical Response Other Than Composite Clinical Response for Acute Myelogenous Leukemia (AML) Patients Per Investigator (Phase Llb)

This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), complete remission with incomplete blood count recovery (CRi) or partial remission as defined by the International Working Group (IWG) response criteria.

Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb)

Best overall response as measured by complete remission (CR) or bone marrow CR (BM-CR) or partial remission (PR) or hematologic improvement (HI). Overall response patients achieved other than the composite CR by individual response category: CR, CRi, mCR or PR as defined by the International Working Group (IWG) response criteria.

Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb)

Best overall response as measured by complete remission (CR) or complete response with incomplete blood count recovery (CRi) or partial remission (PR). Overall response patients achieved other than the composite CR by individual response category: CR, CRi or PR.

Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb)

Hematologic response consists of Erythroid response (HI-E), Platelet response (HI-P) and Neutrophil response (HI-N). HI-E: Hgb increase by ≥ 1.5 g/dL over pretreatment & relevant reduction of units of RBC transfusions by an absolute number of at least 4 units of PRBCs/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation. HI-P: Absolute increase of ≥ 30 x 109/L over pretreatment or patients starting with ≥ 20 x 109/L platelets OR increase from <20 x 109/L at pretreatment to > 20 x 109/L and by at least 100%. HI-N: At least 100% increase and an absolute increase > 0.5 x 109/L over pretreatment value.

1-year Survival Rate (Phase Llb)

Overall survival was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact. Patients not known to have died were censored for 'Lost to follow-up' if the time between their last contact date and the analysis cut-off date was longer than 3 months and 2 weeks (104 days) during the first year after study evaluation completion, and longer than 6 months and 2 weeks (194 days), thereafter. The 1-year survival rate was obtained from the Kaplan-Meier analysis of overall survival, and its variance was estimated by Greenwood's formula.

Time to Progression (TTP) (Phase Llb)

Time to progression (TTP) was defined as the time from the date of randomization to the date of the first documented PD per investigator's assessment or death due to study indication. Time to progression was analyzed by the Kaplan Meier method. Based on the Guidelines for Implementation of international working group (IWG) response criteria in AML, MDS and CMML according to Cheson 2003 and 2006.

Full Information

NCT ID

NCT00946647

First Posted

July 7, 2009

Last Updated

July 20, 2020

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT00946647

Brief Title

A Phase Ib/IIb, Open-label, Multi-center, Study of Oral Panobinostat Administered With 5-Azacitidine (in Adult Patients With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML).

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2020

Overall Recruitment Status

Completed

Study Start Date

December 2, 2009 (Actual)

Primary Completion Date

April 29, 2019 (Actual)

Study Completion Date

April 29, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this randomized, two-arm, open-label expansion phase study was to collect preliminary efficacy data of panobinostat at the recommended phase II dose (RPIID) level in combination with azacytidine (5-Aza) versus an active control arm 5-Aza alone. This randomized phase II part also allowed collecting safety data of panobinostat in combination with 5-Aza in comparison to single-agent 5-aza.

Detailed Description

The primary objective of the phase lb portion of this study was to determine the maximum tolerated dose (MTD )and/or recommended phase ll dose (RPIID) of oral panobinostat in combination with a fixed dose of 5-Aza in adult patients with International Prognostic Scoring System intermediate-2 (IPSS INT-2) or high risk myelodysplastic syndrome (MDS), Chronic myelomonocytic leukemia (CMML), or Acute myelogenous leukemia (AML). The primary objective of the phase llb portion of this study was 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 (complete response (CR) or CRi or bone marrow CR). In the phase lb phase of the study, the patients received escalating oral doses of panobinostat commencing in Cycle 1. The starting dose for panobinostat was 20 mg/day administered orally commencing on Day 3. Each treatment cycle consisted of 28 days (4 weeks). In each cycle, panobinostat was administered twice in Week 1 (Day 3, Day 5), thrice in Week 2 (Day 8, Day 10, and Day 12) and once in Week 3 (Day 15), with no dosing in Week 4. Successive cohorts of patients received escalating doses of panobinostat until the MTD/RPIID was determined. The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. After the MTD/RPIID was determined, enrollment in the Phase Ib part was closed and the Phase IIb part of the study commenced. Ongoing patients from the Phase Ib part continued their treatment at the assigned dose level according to the regimen and schedule for the Phase Ib part. Once the RPIID was defined in Phase Ib, additional 80 patients were to be enrolled into the Phase IIb part of the study and randomly assigned in a 1:1 ratio receiving the RPIID of panobinostat plus 5-Aza (investigational arm) or single agent 5-Aza (active control arm). The treatment schedule for the investigational arm was the same as that for the Phase Ib. Single agent 5-Aza (active control arm) was administered according to the locally approved label (75mg/m2 daily for 7 days). Patients continued treatment until disease progression, unacceptable toxicity or consent withdrawal, whichever came first.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia

Keywords

Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia, hypomethylating therapy, deacetylase inhibitor, MDS, CMML, AML

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Masking Description

Treatment was assigned sequentially for the initial dose escalation part (phase Ib): If a dose was safe, the next cohort started with the next dose level. Randomization applies only for the phase IIb part.

Allocation

Randomized

Enrollment

113 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Panobinostat + 5-Azacytidine

Arm Type

Experimental

Arm Description

Arm Title

5-Azacytidine

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Panobinostat (LBH589)

Intervention Description

Panobinostat was supplied by Novartis as immediate-release hard gelatin capsules in strengths of 5 mg, 10 mg, and 20 mg packaged in high density polyethylene bottles.

Intervention Type

Drug

Intervention Name(s)

5-Azacytidine

Primary Outcome Measure Information:

Title

Number of Participants With Dose Limiting Toxicity (DLT) (Phase lb)

Description

Time Frame

within the first 28 days (cycle 1)

Title

Number of Dose Limiting Toxicity (DLT) (Phase lb)

Description

Time Frame

within the first 28 days (cycle 1)

Title

Composite Complete Response (Phase Llb)

Description

Time Frame

48 months

Secondary Outcome Measure Information:

Title

Clinical Response Other Than Composite Clinical Response for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb)

Description

Time Frame

48 months

Title

Clinical Response Other Than Composite Clinical Response for Acute Myelogenous Leukemia (AML) Patients Per Investigator (Phase Llb)

Description

Time Frame

48 months

Title

Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb)

Description

Time Frame

48 months

Title

Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb)

Description

Time Frame

48 months

Title

Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb)

Description

Time Frame

48 months

Title

1-year Survival Rate (Phase Llb)

Description

Time Frame

12 months

Title

Time to Progression (TTP) (Phase Llb)

Description

Time Frame

48 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Phase l: Patients with cytopathologically confirmed diagnosis of AML according to WHO criteria, excluding acute promyelocytic leukemia who are eligible for Vidaza treatment ECOG performance status greater less than or equal to 2 Phase ll: Adult patients (age ≥ 18 years) who were candidates for treatment with 5-Aza and present with one of the following: intermediate-2 or high-risk myelodysplastic syndromes 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 chronic myelomonocytic leukemia (CMML) Patients must have had 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 within normal ranges (WNL) for the institution. Exclusion Criteria: Phase l: Prior treatment with deacetylase inhibitors Concurrent therapy with any other investigational agent Phase ll: Planned hematopoietic stem-cell transplantation (HSCT) Patients with therapy-related MDS Patients with therapy-related AML and/or relapsed/refractory AML 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) 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). 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 Patient had evidence of clinically significant mucosal or internal bleeding

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Georgia Health Sciences University Dept. of MCG

City

Augusta

State/Province

Georgia

ZIP/Postal Code

30912

Country

United States

Facility Name

Goshen Center for Cancer Care IU Cancer Center

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46202

Country

United States

Facility Name

University of Kansas Hospital and Medical Center SC - Univ KS

City

Kansas City

State/Province

Kansas

ZIP/Postal Code

66160

Country

United States

Facility Name

Dana Farber Cancer Institute Beth Israel Deaconess Med Ctr

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Memorial Sloan Kettering Sloan Kettering 2

City

New York

State/Province

New York

ZIP/Postal Code

10017

Country

United States

Facility Name

Cleveland Clinic Foundation Cleve Clinic

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

Medical University of South Carolina -Hollings Cancer Center MUSC

City

Charleston

State/Province

South Carolina

ZIP/Postal Code

29425

Country

United States

Facility Name

University of Texas MD Anderson Cancer Center Dept of MD Anderson (16)

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Novartis Investigative Site

City

Innsbruck

ZIP/Postal Code

A-6020

Country

Austria

Facility Name

Novartis Investigative Site

City

Vienna

ZIP/Postal Code

A-1100

Country

Austria

Facility Name

Novartis Investigative Site

City

Brugge

ZIP/Postal Code

8000

Country

Belgium

Facility Name

Novartis Investigative Site

City

Yvoir

ZIP/Postal Code

5530

Country

Belgium

Facility Name

Novartis Investigative Site

City

Edmonton

State/Province

Alberta

ZIP/Postal Code

T6G 2B7

Country

Canada

Facility Name

Novartis Investigative Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2M9

Country

Canada

Facility Name

Novartis Investigative Site

City

Bobigny Cedex

ZIP/Postal Code

93009

Country

France

Facility Name

Novartis Investigative Site

City

Frankfurt

ZIP/Postal Code

60590

Country

Germany

Facility Name

Novartis Investigative Site

City

Freiburg

ZIP/Postal Code

79106

Country

Germany

Facility Name

Novartis Investigative Site

City

Budapest

ZIP/Postal Code

1097

Country

Hungary

Facility Name

Novartis Investigative Site

City

Debrecen

ZIP/Postal Code

4032

Country

Hungary

Facility Name

Novartis Investigative Site

City

Kaposvar

ZIP/Postal Code

7400

Country

Hungary

Facility Name

Novartis Investigative Site

City

Szeged

ZIP/Postal Code

H 6725

Country

Hungary

Facility Name

Novartis Investigative Site

City

Firenze

State/Province

ZIP/Postal Code

50134

Country

Italy

Facility Name

Novartis Investigative Site

City

Reggio Calabria

State/Province

ZIP/Postal Code

89124

Country

Italy

Facility Name

Novartis Investigative Site

City

Roma

State/Province

ZIP/Postal Code

00161

Country

Italy

Facility Name

Novartis Investigative Site

City

Seoul

State/Province

Korea

ZIP/Postal Code

05505

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Seoul

ZIP/Postal Code

06351

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Malaga

State/Province

Andalucia

ZIP/Postal Code

29010

Country

Spain

Facility Name

Novartis Investigative Site

City

Barcelona

State/Province

Catalunya

ZIP/Postal Code

08035

Country

Spain

Facility Name

Novartis Investigative Site

City

Madrid

ZIP/Postal Code

28006

Country

Spain

Facility Name

Novartis Investigative Site

City

Gothenburg

ZIP/Postal Code

413 45

Country

Sweden

Facility Name

Novartis Investigative Site

City

Stockholm

ZIP/Postal Code

SE-118 83

Country

Sweden

Facility Name

Novartis Investigative Site

City

Basel

ZIP/Postal Code

4031

Country

Switzerland

Facility Name

Novartis Investigative Site

City

Geneve

ZIP/Postal Code

1205

Country

Switzerland

Facility Name

Novartis Investigative Site

City

St. Gallen

ZIP/Postal Code

9007

Country

Switzerland

Facility Name

Novartis Investigative Site

City

Bangkok

ZIP/Postal Code

10330

Country

Thailand

Facility Name

Novartis Investigative Site

City

Bangkok

ZIP/Postal Code

10700

Country

Thailand

Facility Name

Novartis Investigative Site

City

London

ZIP/Postal Code

EC1A 7BE

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

Wolverhampton

ZIP/Postal Code

WV10 0QP

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

IPD Sharing URL

https://www.clinicalstudydatarequest.com

Citations:

PubMed Identifier

28546581

Citation

Garcia-Manero G, Sekeres MA, Egyed M, Breccia M, Graux C, Cavenagh JD, Salman H, Illes A, Fenaux P, DeAngelo DJ, Stauder R, Yee K, Zhu N, Lee JH, Valcarcel D, MacWhannell A, Borbenyi Z, Gazi L, Acharyya S, Ide S, Marker M, Ottmann OG. A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts. Leukemia. 2017 Dec;31(12):2799-2806. doi: 10.1038/leu.2017.159. Epub 2017 May 26.

Results Reference

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