Oral Posaconazole Three Times Per Day vs Weekly High Dose Amphotericin B Lipid Complex (ABLC)

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00750737
• Collaborator: Enzon Pharmaceuticals, Inc. (Industry)
• Enrollment: 46
• Location: 1
• Arms: 2
• Duration (Months): 48
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The objective of this study is to compare the safety and efficacy of ABLC versus oral Posaconazole in the prevention of invasive fungal infections in high risk patients with hematologic malignancies or hematopoietic stem cell transplant.

Primary objective is to demonstrate the low toxicity rate and low rate of invasive fungal infections associated with ABLC or Posaconazole prophylaxis.

Secondary objective will be to compare the cost effectiveness of these two prophylactic regimens.

Condition or Disease	Intervention/Treatment	Phase
Invasive Fungal Infections; Hematologic Malignancies	Drug: Posaconazole; Drug: ABLC	Phase 3

Detailed Description

The Study Drugs:

ABLC is an antifungal drug that is commonly used to treat and/or prevent a variety of serious invasive fungal infections (IFIs). In this study, ABLC will be used for IFI prevention.

Posaconazole is a newer antifungal drug that is commonly used to prevent serious IFIs.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to receive either posaconazole or ABLC. You will have an equal chance (50/50) of being assigned to either group. You and your study doctor will know which group you are in.

Study Drug Administration:

If you are assigned to the Posaconazole Group, you will take posaconazole 3 times a day by mouth for up to 6 weeks (Days 1-42). The study doctor will advise you about taking it with fatty meals and/or nutritional supplements.

If you are assigned to the ABLC Group, you will receive ABLC once a week by vein over 4-6 hours, for up to 6 weeks (from Day 1 through Day 42). If the creatinine level increases, the dose will be divided into 2 doses per week. The drug may be given in the hospital (if you are admitted to the hospital before or during the study) or at an outpatient treatment center.

Study Visits:

Once a week from Day 1 to Day 42, you will have the following procedures performed:

• Blood (about 1 tablespoon) will be drawn for routine tests.

• You will be asked about any medications and treatments you may be receiving.

• You will be asked about any IFI symptoms that may have developed. You will also be asked about any side effects that may have occurred since your last visit. (You should contact the study doctor and/or study staff right away, if at any time you feel you have had a side effect.)

You may have certain routine diagnostic tests performed at any time in the study, if necessary to confirm you do not have an IFI. These tests may include blood collection (about 1 tablespoon), scans, skin tissue biopsy, and/or bronchoscopy.

Length of Study:

You will receive study treatment for up to 6 weeks (42 days). If you develop an IFI or any intolerable side effects, you will be taken off study early. You may also be taken off study if your neutrophil (a type of white blood cell) counts recover.

End-of-Treatment Visit:

Your End-of-Treatment visit will be on the last day you received the study drug (at most, 42 days after you started). The following procedures will be performed.

• Blood (about 1 tablespoon) will be drawn for routine tests.

• You will have a physical exam, including measurement of vital signs.

• If the study doctor and/or your primary doctor thinks you may have an IFI, routine diagnostic tests may be performed.

Follow-up Visit:

Your follow up visit will be completed 7 - 14 days after your end-of-treatment visit. The following procedures will be performed:

• You will be checked for any signs of IFI.

• If your doctor suspects you have an IFI, a scan (such as an x-ray or CT scan) and/or bronchoscopy may be performed.

• You will be asked about any medications and treatments you may be receiving, and any side effects you may have had.

• Your vital signs will be checked, and a physical exam may be performed.

• Blood (about 1 tablespoon) will be drawn for routine tests.

• An ECG may be performed.

This is an investigational study. ABLC and posaconazole are FDA approved and commercially available for the treatment and prevention of IFIs. Posaconazole is FDA approved for the way it is being used in this study. The study dose and study schedule for ABLC, however, is considered experimental. Currently, this dose and schedule for ABLC is being used in research only.

Up to 100 patients will take part in this study. All will be enrolled at M. D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III Clinical Trial of Oral Posaconazole 3 Times/Day vs Weekly High Dose Amphotericin B Lipid Complex (ABLC) for Prevention of Invasive Fungal Infections In Patients With Hematologic Malignancies & Hematopoietic Stem Cell Transplant
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Posaconazole Posaconazole 200 mg three times daily by mouth up to 6 weeks (Days 1-42)	Drug: Posaconazole; 200 mg three times daily by mouth up to 6 weeks (Days 1-42); Other Names: SCH56592 Noxafil
Experimental: Amphotericin B Lipid Complex (ABLC) 7.5 mg/kg of ABLC intravenously infused over 4-6 hours once per week, for up to 6 weeks (from Day 1 through Day 42)	Drug: ABLC; 7.5 mg/kg of ABLC intravenously infused over 4-6 hours once per week, for up to 6 weeks (from Day 1 through Day 42); Other Names: Amphotericin B Liquid Complex Fungizone

Outcome Measures

Primary Outcome Measures

1. Incidence of Invasive Fungal Infection (IFI) [Within 7 days of antifungal prophylaxis therapy]

   Percentage of participants that developed IFI within 7 days of antifungal prophylaxis therapy (Posaconazole or ABLC).

Secondary Outcome Measures

1. Efficacy Outcome Measured as Success or Failure [Day 1 through Day 42]

   Success: Defined as the absence of proven or probable invasive fungal infection through the end of prophylaxis and absence of Grade 1-4 toxicity related to prophylaxis requiring the discontinuation of the drug. Failure: Presence of proven or probable fungal infection or development of Grade 1-4 toxicity related to prophylaxis while on study drug and requiring discontinuation of study drug or inability to tolerate intravenous ABLC (due to infusion related toxicities) or oral Posaconazole (due to mucositis or vomiting).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Subjects: 18 years of age or above.

2. Any allogeneic hematopoietic stem cell transplant (HSCT) patient who is at risk of invasive fungal infection (IFI) within 6 months of the transplant will be eligible for the study according to HSCT institutional anti-fungal prophylaxis guidelines.

3. Subjects must be willing to give written informed consent and able to adhere to dosing and study visit schedule.

4. Female subjects of childbearing potential must have a negative serum pregnancy test (beta-human chorionic gonadotropin [hCG]) at Baseline or within 96 hours before the start of study drug.

5. Female subjects of childbearing potential must agree to use a medically accepted method of contraception prior to screening, while receiving protocol-specified medication, and for 30 days after stopping the medication. Acceptable methods of contraception include condoms with/without a spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed IUD (intrauterine device), oral/injectable hormonal contraceptive, surgical sterilization (e.g. hysterectomy/tubal ligation).

Exclusion Criteria:

1. Subjects previously treated with antifungal therapy (voriconazole, fluconazole, or itraconazole) for proven or probable IFI within 30 days of enrollment.

2. Subjects who have taken the following drugs: terfenadine, cisapride, primazide, and ebastine; that are known to interact with azoles and that may lead to life-threatening side effects, within 24 hours before study drug administration. And astemizole within 7 days before study drug administration.

3. Subjects who have taken the following drugs: cimetidine, rifampin, carbamezapine, phenytoin, rifabutin, barbiturates, isoniazid, and vinca alkaloids (vincristine, vinblastine); that are known to lower the serum concentration/efficacy of azole antifungal agents, within 24 hours before study drug administration.

4. Subjects with a history of hypersensitivity or idiosyncratic reactions to azole agents or Amphotericin B.

5. Subjects on other nephrotoxic agents (e.g. foscarnet).

6. Patients who are unable to take pills.

7. Subjects with proven or probable invasive fungal infection.

8. Subjects with renal insufficiency (estimated creatine clearance less than 50mL/minute at Baseline or likely to require dialysis during the study).

9. Subjects having ECG with a prolonged QTc interval by manual reading: QTc greater than 500 msec. at Baseline.

10. Subjects with moderate or severe liver dysfunction at baseline, defined as aspartate amniotransferase (AST), alanine amniotransferase (ALT) and / or a total bilirubin level greater than 3 times the upper limit of normal (ULN).

11. Women who are breast feeding, pregnant, or intend to become pregnant during the course of the study.

12. Prior enrollment in this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Enzon Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Issam Raad, MD/Professor, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The University of Texas MD Anderson Cancer Center Official Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00750737
• Other Study ID Numbers: 2007-0020
• First Posted: Sep 11, 2008
• Last Update Posted: Sep 29, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by M.D. Anderson Cancer Center: Hematologic Malignancies; Blood Cancer; Lymphatic Cancer; Amphotericin B Lipid Complex; Amphotericin B; ABLC; Fungizone; Noxafil; SCH56592; Posaconazole; Invasive fungal infections; IFI; Hematopoietic Stem Cell Transplant; HSCT; Bone Marrow Transplant; Allogeneic hematopoietic stem cell transplant
• Additional relevant MeSH terms: Infections; Mycoses; Invasive Fungal Infections; Neoplasms; Hematologic Neoplasms; Amphotericin B; Posaconazole

Study Results

Participant Flow

Recruitment Details	Recruitment Period: July 2008 to May 2009. All recruitment done at UT MD Anderson Cancer Center.
Pre-assignment Detail	A total of 46 participants were randomized, out of which 40 participants were included in the analysis and 6 participants withdrew consent.

Arm/Group Title	Posaconazole 200 mg Oral	Amphotericin B Lipid Complex (ABLC) 7.5 mg/kg IV
Arm/Group Description	Posaconazole 200 mg three times daily by mouth up to 6 weeks (Days 1-42)	7.5 mg/kg of ABLC intravenously infused over 4-6 hours once per week, for up to 6 weeks (from Day 1 through Day 42)
Period Title: Overall Study
STARTED	24	22
COMPLETED	21	19
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	Posaconazole 200 mg Oral	Amphotericin B Lipid Complex (ABLC) 7.5 mg/kg IV	Total
Arm/Group Description	Posaconazole 200 mg three times daily by mouth up to 6 weeks (Days 1-42)	7.5 mg/kg of ABLC intravenously infused over 4-6 hours once per week, for up to 6 weeks (from Day 1 through Day 42)	Total of all reporting groups
Overall Participants	24	22	46
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55.5	56	55.5
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	23 95.8%	20 90.9%	43 93.5%
>=65 years	1 4.2%	2 9.1%	3 6.5%
Sex: Female, Male (Count of Participants)
Female	5 20.8%	13 59.1%	18 39.1%
Male	19 79.2%	9 40.9%	28 60.9%
Region of Enrollment (participants) [Number]
United States	24 100%	22 100%	46 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Invasive Fungal Infection (IFI)
Description	Percentage of participants that developed IFI within 7 days of antifungal prophylaxis therapy (Posaconazole or ABLC).
Time Frame	Within 7 days of antifungal prophylaxis therapy

Outcome Measure Data

Analysis Population Description

Out of 46 participants, 40 were included in the analysis and 6 withdrew consent.

Arm/Group Title	Posaconazole 200 mg Oral	Amphotericin B Lipid Complex (ABLC) 7.5 mg/kg IV
Arm/Group Description	Posaconazole 200 mg three times daily by mouth up to 6 weeks (Days 1-42)	7.5 mg/kg of ABLC intravenously infused over 4-6 hours once per week, for up to 6 weeks (from Day 1 through Day 42)
Measure Participants	21	19
Number [percentage of participants]	0 0%	5 22.7%

2. Secondary Outcome

Title	Efficacy Outcome Measured as Success or Failure
Description	Success: Defined as the absence of proven or probable invasive fungal infection through the end of prophylaxis and absence of Grade 1-4 toxicity related to prophylaxis requiring the discontinuation of the drug. Failure: Presence of proven or probable fungal infection or development of Grade 1-4 toxicity related to prophylaxis while on study drug and requiring discontinuation of study drug or inability to tolerate intravenous ABLC (due to infusion related toxicities) or oral Posaconazole (due to mucositis or vomiting).
Time Frame	Day 1 through Day 42

Outcome Measure Data

Analysis Population Description

Out of 46 participants, 40 were included in the analysis and 6 withdrew consent.

Arm/Group Title	Posaconazole 200 mg Oral	Amphotericin B Lipid Complex (ABLC) 7.5 mg/kg IV
Arm/Group Description	Posaconazole 200 mg three times daily by mouth up to 6 weeks (Days 1-42)	7.5 mg/kg of ABLC intravenously infused over 4-6 hours once per week, for up to 6 weeks (from Day 1 through Day 42)
Measure Participants	21	19
Success	62 258.3%	21 95.5%
Failure	38 158.3%	79 359.1%

Adverse Events

Time Frame	Adverse Events (AEs) were evaluated from the time of the first infusion of study drug through the end of the post-treatment visit. Collection period: July 10, 2008 to July 31, 2009.
Arm/Group Title	Posaconazole 200 mg Oral		Amphotericin B Lipid Complex (ABLC) 7.5 mg/kg IV
Arm/Group Description	Posaconazole 200 mg three times daily by mouth up to 6 weeks (Days 1-42)		7.5 mg/kg of ABLC intravenously infused over 4-6 hours once per week, for up to 6 weeks (from Day 1 through Day 42)
All Cause Mortality
	Posaconazole 200 mg Oral		Amphotericin B Lipid Complex (ABLC) 7.5 mg/kg IV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Posaconazole 200 mg Oral		Amphotericin B Lipid Complex (ABLC) 7.5 mg/kg IV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Posaconazole 200 mg Oral		Amphotericin B Lipid Complex (ABLC) 7.5 mg/kg IV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/21 (100%)		19/19 (100%)
Gastrointestinal disorders
Nausea	14/21 (66.7%)	14	10/19 (52.6%)	10
Vomiting	6/21 (28.6%)	6	5/19 (26.3%)	5
Diarrhea	14/21 (66.7%)	14	8/19 (42.1%)	8
General disorders
Chills	1/21 (4.8%)	1	6/19 (31.6%)	6
Infections and infestations
Invasive Fungal Infection	0/21 (0%)	0	1/19 (5.3%)	1
Metabolism and nutrition disorders
Hypomagnesemia	6/21 (28.6%)	6	8/19 (42.1%)	8
Increase in ALT	10/21 (47.6%)	10	5/19 (26.3%)	5
Increase in Bilirubin	7/21 (33.3%)	7	4/19 (21.1%)	4
Increase in Creatinine	5/21 (23.8%)	5	16/19 (84.2%)	16

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.