Isavuconazole in Preventing Invasive Fungal Infections in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome and Neutropenia

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT03019939
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 65
• Location: 1
• Arm: 1
• Actual Duration (Months): 40.4
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

This phase II trial studies how well isavuconazole works in preventing invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome and neutropenia. Isavuconazole may help to prevent invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia or myelodysplastic syndrome and neutropenia.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia; Myelodysplastic Syndrome; Neutropenia	Drug: Isavuconazole	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess whether prophylaxis with isavuconazole effectively prevents the occurrence of proven or probable invasive fungal infections (IFIs) in patients with newly diagnosed acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) receiving successive cycles of intensive chemotherapy or other therapies for up to 100 days from prophylaxis initiation.

SECONDARY OBJECTIVES:

1. To evaluate the incidence of invasive aspergillosis (IA) within 100 days of beginning isavuconazole prophylaxis in newly diagnosed patients with AML/MDS receiving intensive chemotherapy or other therapies.

2. To evaluate the incidence of other IFIs within 100 days of beginning isavuconazole prophylaxis in newly diagnosed patients with AML/MDS receiving intensive chemotherapy or other therapies.

3. To evaluate the composite outcome of treatment success versus (vs.) failure in this patient population.

4. To measure the overall survival (OS) of study participants. V. To measure the IFI-free survival of study participants. VI. To document the time to death from any cause in the study population. VII. To document the time to death related to IFI in the study population. VIII. To document the time to diagnosis of proven or probable IFI in the study population.

5. To document the time to initiation of empiric anti-fungal therapy in the study population.

6. To characterize the safety, tolerability and adverse event (AE) profile of isavuconazole in the prophylactic setting.

EXPLORATORY OBJECTIVES:

1. To assess the potential role, if any, of therapeutic drug monitoring (TDM) of isavuconazole levels in the prophylactic setting in patients with newly diagnosed AML/MDS receiving cytotoxic chemotherapy or other therapies.

2. To determine the in vitro susceptibility of agents causing "breakthrough" IFIs to antifungal agents.

OUTLINE:

Patients receive isavuconazole orally (PO) every 8 hours for 6 doses and then once daily (QD) or intravenously (IV) over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: A Phase II Study of Isavuconazole Prophylaxis in Adult Patients With AML/MDS and Neutropenia
• Actual Study Start Date: Mar 28, 2017
• Actual Primary Completion Date: Aug 10, 2020
• Actual Study Completion Date: Aug 10, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prevention (isavuconazole) Patients receive isavuconazole PO every 8 hours for 6 doses and then Once a day (QD) or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity.	Drug: Isavuconazole; Given PO or IV; Other Names: BAL8557

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Proven or Probable Invasive Fungal Infections (IFIs) [Up to 100 days from prophylaxis initiation]

   Participants with proven or possible invasive fungal infections.

Secondary Outcome Measures

1. Number of Participants With Invasive Aspergillosis [Up to 100 days from prophylaxis initiation]

   Participants with invasive aspergillosissured.

2. Number of Participants With Other Invasive Fungal Infections (IFIs) [Up to 100 days from prophylaxis initiation]

   Participants with other IFIs will be measured.

3. Number of Participants With Treatment Success [Up to 3 years]

   Will evaluate versus (vs.) failure (defined as Participants with proven or probable IFI, receipt of any other systemic antifungal agent for +/- 4 days for suspected IFI, occurrence of an adverse events possibly or probably related to the study drug resulting in discontinuation of treatment, or withdrawal from the study with no additional follow-up).

4. Number of Participants Who Failed Treatment [Up to 3 years]

   Will evaluate versus success. Success is defined as Participants with proven or probable IFI, receipt of any other systemic antifungal agent for +/- 4 days for suspected IFI, occurrence of an adverse events possibly or probably related to the study drug resulting in discontinuation of treatment, or withdrawal from the study with no additional follow-up).

5. Overall Survival (OS) [Up to 3 years]

   Time from date of treatment start until date of death due to any cause or last Follow-up.

6. Invasive Fungal Infections (IFIs)-Free Survival [Up to 3 years]

   Time measured in days from start of treatment to IFI or off study date

7. Time to Death From Any Cause [Up to 3 years]

   Time to death from any cause will be measured.

8. Number of Participants With Death Related to Invasive Fungal Infections (IFIs) [Up to 3 years]

   Death's from invasive fungal infections

9. Time to Diagnosis of Proven or Probable Invasive Fungal Infections (IFIs) [Up to 3 years]

   Time measured in days from start of treatment to invasive fungal infections

10. Time to Initiation of Empiric Anti-fungal Therapy [Up to 3 years]

    Time days from start of empiric anti-fungal therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with either newly diagnosed AML or MDS who have either begun (within 4 days of starting study drug) or are planned to begin specific treatment for their AML/MDS; hydroxyurea and cytarabine used for cytoreduction while awaiting initiation of definitive therapy are not considered "specific" treatment; patients who are participating in other therapeutic clinical trials for their AML/MDS may participate in this trial

• Patients must have or be anticipated to have neutropenia (absolute neutrophil count [ANC] < 0.5 x 10^9/L) (75) for >= 7 days as a result of treatment of their AML/MDS

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2

• Total bilirubin =< 3 x upper limit of normal (ULN)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5 x ULN

• Patients must be able to take oral medications, although a brief period of IV therapy (< 4 days) is permitted at trial entry

• Patients must be willing and able to provide written informed consent for the trial

• Women of childbearing potential (WOCBP) must practice 2 effective methods of birth control during the course of the study; male patients who are partners of WOCBP should also practice an effective method of contraception; effective methods of birth control include diaphragm or condoms with spermicidal foam or jelly, birth control pills (BCPs), injections or patches, intra-uterine devices (IUDs) and surgical sterilization

• Postmenopausal women must be amenorrheic for >= 12 months to be considered of non-childbearing potential

• Women and men must continue birth control for the duration of the trial and >= 3 months after the last dose of study drug

• All WOCBP MUST have a negative pregnancy test prior to first receiving study medication

Exclusion Criteria:

• Proven, probable or possible IFI within the previous 30 days

• Use of any systemic antifungal therapy for > 72 hours during the week prior to study drug initiation

• History of hypersensitivity or idiosyncratic reactions to azoles

• Patients with familial short QT syndrome or with corrected QT (QTc) interval =< 300 ms

• Patients on strong CYP3A4 inducers or inhibitors that cannot be discontinued

• Women who are pregnant or nursing, or intend to be/do so during the course of the study

• Patients with severe hepatic impairment (Child-Pugh class C)

• Patients with known or suspected Gilbert's syndrome at the time of study enrollment

• Patients with known gastrointestinal conditions that could potentially interfere with absorption of orally administered medications

• Any condition that, in the opinion of the investigator, may interfere with the objectives of the study, e.g., any condition requiring the use of prohibited drugs or unstable medical conditions other than AML/MDS, such as a cardiac or neurologic disorder expected to be unstable or progressive during the course of the study (e.g., seizures or demyelinating syndromes, acute myocardial infarction within 3 months of study entry, myocardial ischemia or unstable congestive heart failure, unstable arrhythmias)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Prithviraj Bose, M.D. Anderson Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 15, 2018

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT03019939
• Other Study ID Numbers: 2016-0373; NCI-2017-00323; 2016-0373
• First Posted: Jan 13, 2017
• Last Update Posted: Oct 26, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Neutropenia; Syndrome; Isavuconazole

Study Results

Participant Flow

Recruitment Details	Recruitment Period: April 28, 2017 to July 26, 2019

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Period Title: Overall Study
STARTED	65
COMPLETED	65
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Overall Participants	65
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	31 47.7%
>=65 years	34 52.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	67
Sex: Female, Male (Count of Participants)
Female	29 44.6%
Male	36 55.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 4.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 4.6%
White	57 87.7%
More than one race	0 0%
Unknown or Not Reported	2 3.1%
Region of Enrollment (participants) [Number]
United States	65 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Proven or Probable Invasive Fungal Infections (IFIs)
Description	Participants with proven or possible invasive fungal infections.
Time Frame	Up to 100 days from prophylaxis initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Count of Participants [Participants]	4 6.2%

2. Secondary Outcome

Title	Number of Participants With Invasive Aspergillosis
Description	Participants with invasive aspergillosissured.
Time Frame	Up to 100 days from prophylaxis initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Count of Participants [Participants]	2 3.1%

3. Secondary Outcome

Title	Number of Participants With Other Invasive Fungal Infections (IFIs)
Description	Participants with other IFIs will be measured.
Time Frame	Up to 100 days from prophylaxis initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Count of Participants [Participants]	2 3.1%

4. Secondary Outcome

Title	Number of Participants With Treatment Success
Description	Will evaluate versus (vs.) failure (defined as Participants with proven or probable IFI, receipt of any other systemic antifungal agent for +/- 4 days for suspected IFI, occurrence of an adverse events possibly or probably related to the study drug resulting in discontinuation of treatment, or withdrawal from the study with no additional follow-up).
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Count of Participants [Participants]	46 70.8%

5. Secondary Outcome

Title	Number of Participants Who Failed Treatment
Description	Will evaluate versus success. Success is defined as Participants with proven or probable IFI, receipt of any other systemic antifungal agent for +/- 4 days for suspected IFI, occurrence of an adverse events possibly or probably related to the study drug resulting in discontinuation of treatment, or withdrawal from the study with no additional follow-up).
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Count of Participants [Participants]	19 29.2%

6. Secondary Outcome

Title	Overall Survival (OS)
Description	Time from date of treatment start until date of death due to any cause or last Follow-up.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Median (Full Range) [Months]	19.9

7. Secondary Outcome

Title	Invasive Fungal Infections (IFIs)-Free Survival
Description	Time measured in days from start of treatment to IFI or off study date
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Median (Full Range) [Days]	86

8. Secondary Outcome

Title	Time to Death From Any Cause
Description	Time to death from any cause will be measured.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Median (Full Range) [Months]	4

9. Secondary Outcome

Title	Number of Participants With Death Related to Invasive Fungal Infections (IFIs)
Description	Death's from invasive fungal infections
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Count of Participants [Participants]	0 0%

10. Secondary Outcome

Title	Time to Diagnosis of Proven or Probable Invasive Fungal Infections (IFIs)
Description	Time measured in days from start of treatment to invasive fungal infections
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Median (Full Range) [Days]	24

11. Secondary Outcome

Title	Time to Initiation of Empiric Anti-fungal Therapy
Description	Time days from start of empiric anti-fungal therapy.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
Measure Participants	65
Median (Full Range) [Days]	22

Adverse Events

Time Frame	Up to 3 years
Arm/Group Title	Prevention (Isavuconazole)
Arm/Group Description	Patients receive isavuconazole PO every 8 hours for 6 doses and then QD or IV over 1 hour every 8 hours for 6 doses and then QD for up to 4 days for 12 weeks in the absence of disease progression or unacceptable toxicity. Isavuconazole: Given PO or IV
All Cause Mortality
	Prevention (Isavuconazole)
	Affected / at Risk (%)	# Events
Total	4/65 (6.2%)
Serious Adverse Events
	Prevention (Isavuconazole)
	Affected / at Risk (%)	# Events
Total	30/65 (46.2%)
Blood and lymphatic system disorders
Neutropenic Fever	17/65 (26.2%)	19
Cardiac disorders
Supraventricular Tachycardia	1/65 (1.5%)	1
Gastrointestinal disorders
Nausea	1/65 (1.5%)	1
General disorders
Abdominal Pain	1/65 (1.5%)	1
Death	1/65 (1.5%)	1
Fever	4/65 (6.2%)	5
Pain Extremity	1/65 (1.5%)	1
Infections and infestations
Infection	2/65 (3.1%)	2
Lung Infection	1/65 (1.5%)	1
Sepsis	4/65 (6.2%)	4
Skin Infection	1/65 (1.5%)	1
Upper Respiratory Infection	1/65 (1.5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/65 (1.5%)	2
Renal and urinary disorders
Acute Kidney Injury	1/65 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/65 (1.5%)	1
Other (Not Including Serious) Adverse Events
	Prevention (Isavuconazole)
	Affected / at Risk (%)	# Events
Total	14/65 (21.5%)
Blood and lymphatic system disorders
Neutropenic Fever	7/65 (10.8%)	8
Gastrointestinal disorders
Colitis	1/65 (1.5%)	1
Gastrointestinal Other	1/65 (1.5%)	1
Oral Pain	2/65 (3.1%)	2
General disorders
Fever	2/65 (3.1%)	2
Infections and infestations
Infection	1/65 (1.5%)	1
Sinusitis	1/65 (1.5%)	1
Investigations
Alanine Aminotransferase Increased	3/65 (4.6%)	3
Aspartate Aminotransferase Increased	2/65 (3.1%)	2
Metabolism and nutrition disorders
Tumor Lysis Syndrome	1/65 (1.5%)	1
Nervous system disorders
Headache	1/65 (1.5%)	1
Reproductive system and breast disorders
Enlarged Prostate	1/65 (1.5%)	1
Vascular disorders
Flushing	1/65 (1.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.