Phase II Study to Evaluate Overall Response in Patients With Higher Risk Myelodysplastic Syndromes (MDS) Treated With Azacitidine With or Without Deferasirox.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02159040
• Collaborator: (none)
• Enrollment: 1
• Locations: 6
• Arms: 2
• Actual Duration (Months): 9.5
• Patients Per Site: 0.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The primary objective of the study is to compare the overall response rate (inclusive of complete response, partial response and hematologic improvement) per IWG 2006 criteria in patients with higher risk MDS treated with azacitidine with or without deferasirox achieved over the course of one year. Hematologic improvement must be maintained for at least 8 weeks.

Condition or Disease	Intervention/Treatment	Phase
High Risk MDS	Drug: Azacitidine; Drug: Azacitidine plus Deferasirox	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 2-year, Multi-center, Phase II, Open-label, Fixed-dose, Randomized Comparative Trial of Azacitidine, With or Without Deferasirox in Patients With Higher Risk Myelodysplastic Syndromes
• Actual Study Start Date: Sep 11, 2014
• Actual Primary Completion Date: Jun 26, 2015
• Actual Study Completion Date: Jun 26, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Azacitidine 75mg/m2 7days/28 day cycle	Drug: Azacitidine; SC or IV AZA at 75mg/m2 7 days/28 day cycle
Experimental: Azacitidine and Deferasirox azacitidine 75mg/m2 7 days/28 day cycle deferasirox 10 mg/kg/day	Drug: Azacitidine plus Deferasirox; SC or IV AZA at 75mg/m2 7 days/28 day cycle DFX 10mg/kg/day

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate Per IWG 2006 Criteria [1 year]

   ORR (inclusive of CR, PR and HI) per IWG 2006 criteria including erythroid response, platelet response and neutrophil response over the course of one year. Hematologic improvement must be maintained for at least 8 weeks in order to count as HI.

Secondary Outcome Measures

1. Time to Response [up to 24 months]

   Time to response is defined as time from the date of the first dose of study treatment to the date of the first documented hematologic improvement.

2. Duration of Response [up to 24 months]

   Duration of response is defined as time from the date of the first observed hematologic improvement to the date of the first subsequent documented disease progression or relapse per IWG 2006 criteria.

3. Progression Free Survival [Up to 24 months]

   Progression free survival is defined as time from the date of the first dose of study treatment to the date of the first documented disease progression or relapse per IWG 2006 criteria.

4. Overall Survival [up to 24 months]

   Overall survival is defined as time from the date of the first dose of study treatment to the date of death from any cause.

5. Time to AML Transformation [Up to 24 months]

   Time to AML transformation is defined as time from the date of the first dose of study treatment to the date of the first documented bone marrow blast count ≥ 20% per WHO classification 1999.

6. Change in Serum Ferritin [up to 24 months]

   Change in Serum Ferritin

7. Incidence of Adverse Events [up to 24 months]

   Incidence of adverse events (AEs) overall and by severity, and serious adverse events (SAEs).

8. Rate of Infection [up to 24 months]

   Median number of infections (positive bacterial, viral or fungal culture, or infection requiring IV antimicrobial, or infection resulting in hospitalization or death) in patients treated with azacitidine alone vs. azacitidine + deferasirox

9. Prevalence of MDS/AML Related Gene Mutations [Baseline]

   Prevalence of the following mutations in the study population (TP53, EZH2, ETV6, RUNX1, ASXL1, other mutation that is present in ≥ 5% of patients)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Male or Female, age ≥ 18 years Patients with higher risk MDS with a blast count < 20% at the time of screening IPSS Int-2 or High Risk Serum Ferritin ≥ 300 ng/mL at screening.

Sexually active women must use an effective method of contraception, or must have undergone clinically documented total hysterectomy and/or oophorectomy, or tubal ligation or be postmenopausal (defined as amenorrhea for at least 12 months)

Exclusion Criteria:

Patients currently receiving any therapy other than AZA for MDS (a ≥ 4 week washout period for any agent (excluding AZA) used to treat MDS prior to first dose of study treatment is required).

Patients who have received > 2 cycles of AZA or decitabine at the time of randomization. Patients who have received iron chelation therapy within 1 month of screening.

Patients who have received growth factors within 1 month of screening. Patients who have received Revlimid within 1 month of screening. Patients who have undergone hematopoietic stem cell transplant. ECOG Performance Status > 2 Systemic diseases (cardiovascular, renal, hepatic, etc.) which would prevent study treatment Patients with uncontrolled systemic hypertension Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable cardiac or coronary artery disease not controlled by standard medical therapy Patients with a diagnosis of or history of clinically relevant ocular toxicity related to iron chelation Diagnosis of liver cirrhosis (either established diagnosis or diagnosis by liver biopsy or central ultrasound reading) Clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence of HBsAb OR HCV Ab positive with HCV RNA positive and ALT above the normal range). History of HIV positive test result (ELISA or Western blot) Presence of a surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug Patients with an active malignancy (currently or within the past two years) with the exception of basal cell skin carcinoma or cervical carcinoma in situ or completely resected colonic polyps carcinoma in situ. History of drug or alcohol abuse within the 12 months prior to enrollment. History of non-compliance to medical regimens or patients who are considered potentially unreliable and/or not cooperative.

Patients with a known hypersensitivity to azacitidine, mannitol, or deferasirox. Calculated creatinine clearance <40mL/min Serum creatinine greater than 1.5x ULN at screening Urine protein/creatinine ratio> 1 AST or ALT greater than 3x ULN at screening Direct Bilirubin greater than 1.5x ULN at screening. Patients who received treatment with systemic investigational drug within the past 4 weeks or topical investigational drug within the past 7 days or are planning to receive other investigational drugs while participating in the study Patients participating in another therapeutic clinical trial Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment. Sexually active males unless they use a condom during intercourse while taking drug and for 3 months after stopping AZA and should not father a child in this period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hematology Oncology Services of Arkansas HOSA 2	Little Rock	Arkansas	United States	72205
2	City of Hope National Medical Center Oncology	Duarte	California	United States	91010
3	University of Maryland Medical Center UM Greenbaum Cancer Ctr (2)	Baltimore	Maryland	United States	21201
4	Rochester General Hospital / Lipson Cancer Center Lipson Cancer Center	Rochester	New York	United States	14621
5	The Jones Clinic	Germantown	Tennessee	United States	38138
6	Utah Cancer Specialists IHO Corp	Salt Lake City	Utah	United States	84106

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02159040
• Other Study ID Numbers: CICL670AUS47
• First Posted: Jun 9, 2014
• Last Update Posted: Apr 4, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Novartis Pharmaceuticals: Int-2 MDS
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Azacitidine; Deferasirox

Study Results

Participant Flow

Recruitment Details	Recruitment ended with patient death.Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Period Title: Overall Study
STARTED	1
COMPLETED	0
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Overall Participants	1
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	0 0%
>=65 years	1 100%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	1 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate Per IWG 2006 Criteria
Description	ORR (inclusive of CR, PR and HI) per IWG 2006 criteria including erythroid response, platelet response and neutrophil response over the course of one year. Hematologic improvement must be maintained for at least 8 weeks in order to count as HI.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

2. Secondary Outcome

Title	Time to Response
Description	Time to response is defined as time from the date of the first dose of study treatment to the date of the first documented hematologic improvement.
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

3. Secondary Outcome

Title	Duration of Response
Description	Duration of response is defined as time from the date of the first observed hematologic improvement to the date of the first subsequent documented disease progression or relapse per IWG 2006 criteria.
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

4. Secondary Outcome

Title	Progression Free Survival
Description	Progression free survival is defined as time from the date of the first dose of study treatment to the date of the first documented disease progression or relapse per IWG 2006 criteria.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as time from the date of the first dose of study treatment to the date of death from any cause.
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

6. Secondary Outcome

Title	Time to AML Transformation
Description	Time to AML transformation is defined as time from the date of the first dose of study treatment to the date of the first documented bone marrow blast count ≥ 20% per WHO classification 1999.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

7. Secondary Outcome

Title	Change in Serum Ferritin
Description	Change in Serum Ferritin
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

8. Secondary Outcome

Title	Incidence of Adverse Events
Description	Incidence of adverse events (AEs) overall and by severity, and serious adverse events (SAEs).
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

9. Secondary Outcome

Title	Rate of Infection
Description	Median number of infections (positive bacterial, viral or fungal culture, or infection requiring IV antimicrobial, or infection resulting in hospitalization or death) in patients treated with azacitidine alone vs. azacitidine + deferasirox
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

10. Secondary Outcome

Title	Prevalence of MDS/AML Related Gene Mutations
Description	Prevalence of the following mutations in the study population (TP53, EZH2, ETV6, RUNX1, ASXL1, other mutation that is present in ≥ 5% of patients)
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Only one patient in trial. No analysis will ever be done.

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
Measure Participants	0

Adverse Events

Arm/Group Title	Azacitidine
Arm/Group Description	75mg/m2 7days/28 day cycle
All Cause Mortality
	Azacitidine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Azacitidine
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Cardiac disorders
Death	1/1 (100%)	1
Other (Not Including Serious) Adverse Events
	Azacitidine
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Gastrointestinal disorders
Infusion site	1/1 (100%)	1
Musculoskeletal and connective tissue disorders
Muscle spasms	1/1 (100%)	1
Musculoskeletal pain	1/1 (100%)	1

Limitations/Caveats

No conclusion pertaining to efficacy and/or safety was drawn, only one patient was randomized to the study and their study participation was terminated prematurely due to fatal outcome of SAE.Only one patient in trial.No analysis will ever be done.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.