This phase I trial studies the side effects of human lysozyme goat milk in preventing graft versus host disease in patients with blood cancer undergoing a donor stem cell transplant. Sometimes the transplanted cells from a donor can cause an immune response against the body's own normal cells (call graft versus host disease). The goat milk in the study is from goats that have been genetically engineered to produce human lysozyme in the milk. Human lysozyme is a natural enzyme found in human milk and acts as an antimicrobial. Lysozyme is key to the digestive health of breast-fed human infants, since it helps the growth of beneficial gut bacteria and reduces the growth of bacteria that causes diarrhea and intestinal disease. Giving human lysozyme goat milk may reduce the rate of graft versus host disease in blood cancer patients undergoing a donor stem cell transplant.
PRIMARY OBJECTIVES: I. To evaluate the safety and feasibility of human lysozyme goat milk (hLZ) treatment by assessing: Ia: Type, frequency, severity, attribution, time course and duration of adverse events, including diarrhea, bloodstream/intestinal infections. Ib. Patients' ability to drink the specified volume (250 ml 3 x/day) of hLZ during the treatment period. SECONDARY OBJECTIVES: I. To compare the incidence and severity of adverse events (AE) among hLZ-treated and untreated patients, including diarrhea, bloodstream infections and intestinal infections. II. To obtain preliminary estimates of gut microbiome diversity, as assessed by the Simpson Index, in hLZ-treated/untreated patients. III. To compare gut microbiome diversity among hLZ-treated/untreated patients. IV. To obtain a preliminary estimate of the possible association between gut microbiome diversity and bloodstream infections. V. To obtain a preliminary estimate of the possible association between gut microbiome diversity and acute graft versus host disease (GVHD) cumulative incidence, including time to onset. VI. To characterize and compare GVHD inflammatory biomarkers (presence, level) among hLZ-treated and untreated patients. VII. To characterize and compare urinary uindoxyl sulfate, tryptophan and kynurenine levels between hLZ-treated and untreated patients. IX. To obtain a preliminary estimate of gut microbiome diversity and calorie intake. X. To estimate overall survival (OS) cumulative incidence (CI) chronic GVHD of relapse/progression, and non-relapse mortality (NRM) at 100 days (excluding chronic GVHD), 6 months, 1 year and 2 years. OUTLINE: Patients are randomized to 1 of 2 groups. GROUP A: CONDITIONING: Patients receive palifermin on days -10 to -8 and days 0 to 2, undergo fractionated total body irradiation (FTBI) on days -7 to -4, and receive cyclophosphamide on days -3 to -2 or etoposide on day -3 per City of Hope (COH) standard operating procedure (SOP) in the absence of disease progression or unacceptable toxicity. HLZ: Patients receive human lysozyme goat milk orally (PO) three times daily (TID) on days -8 to 28 in the absence of disease progression or unacceptable toxicity. TRANSPLANT: Patients undergo stem cell transplant on day 0. GVHD PROPHYLAXIS: Beginning on day -2, patients receive tacrolimus and sirolimus daily per COH SOP in the absence of disease progression or unacceptable toxicity. GROUP B: CONDITIONING: Patients receive palifermin on days -10 to -8 and days 0 to 2 per COH SOP, undergo FTBI on days -7 to -4, and receive cyclophosphamide on days -3 to -2 or etoposide on day -3 per COH SOP in the absence of disease progression or unacceptable toxicity. TRANSPLANT: Patients undergo stem cell transplant on day 0. GVHD PROPHYLAXIS: Beginning on day -2, patients receive tacrolimus and sirolimus daily per COH SOP in the absence of disease progression or unacceptable toxicity. After the completion of study treatment, patients are followed up for up to 30-100 days and then up to 2 years after transplant.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
53
Undergo allo-HCT
Given IV
Given IV
Undergo FTBI
Given human lysozyme goat milk PO
Given IV
Given PO
Given IV and PO
City of Hope Medical Center
Duarte, California, United States
RECRUITINGPatients' ability to drink the specified daily amount of 750 ml human lysozyme goat milk (hLZ)
In the safety lead-in phase, we are going to investigate if a patient can drink the daily amount of 750 ml of hLZ.. The actual volume of milk consumed per day will be measured using graduated cups and recorded on daily basis. To calculate the average daily consumption, total volume of hLZ consumed by each patient for the whole inpatient stay will be divided by the total number of inpatient stay for that patient. Tolerable dose established based on the average daily hLZ consumption in the first 6 patients (safety lead-in) will be brought forward for additional study randomization.
Time frame: from study initiation until up to 28 days post-transplant or until discharge, whoever comes first
Unacceptable toxicity
The modified Bearman Scale will be used to define unacceptable toxicity events. Unacceptable toxicity in a given patient is defined as either of the following that are considered at least possibly related to drinking hLZ milk: GI toxicity grade III or IV per Bearman scale or inability to consume hLZ milk for \> 7 days.
Time frame: Up to 28 days post-transplant or date of discharge
Adverse events
Incidence and severity of adverse events will be reported according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Time frame: Up to 100 days post-transplant
Volume of hLZ consumed
Tolerability is defined as the ability to consume \>= 150 ml/day over the treatment period.
Time frame: Up to 28 days post-transplant or date of discharge
Cumulative incidence (CI) of chronic graft versus host disease (GVHD)
Chronic graft versus host disease is scored according to NIH Consensus Staging. The first day of chronic GvHD onset will be used to calculate confidence interval (CI) incidence curves, with relapse/death prior to onset considered competing events. CI of chronic GVHD will be estimated using the method described by Gooley et al (1999).
Time frame: At 6 months
Cumulative incidence (CI) of chronic GVHD
Chronic graft versus host disease is scored according to NIH Consensus Staging. The first day of chronic GvHD onset will be used to calculate CI incidence curves, with relapse/death prior to onset considered competing events. CI of chronic GVHD will be estimated using the method described by Gooley et al (1999).
Time frame: At 1 year
Cumulative incidence (CI) of chronic GVHD
Chronic graft versus host disease is scored according to NIH Consensus Staging. The first day of chronic GvHD onset will be used to calculate CI incidence curves, with relapse/death prior to onset considered competing events. CI of chronic GVHD will be estimated using the method described by Gooley et al (1999).
Time frame: At 2 years
CI of non-relapse mortality (NRM)
Non-relapse mortality (NRM) is defined as death occurring in a patient from causes other than relapse. NRM is measured from start of treatment until non-disease related death, or last follow-up, whichever comes first. The cumulative incidence of NRM will be calculated reflecting relapse as a competing risk. CI of NRM will be estimated using the method described by Gooley et al (1999).
Time frame: At 100 days
CI of NRM
Non-relapse mortality (NRM) is defined as death occurring in a patient from causes other than relapse. NRM is measured from start of treatment until non-disease related death, or last follow-up, whichever comes first. The cumulative incidence of NRM will be calculated reflecting relapse as a competing risk. CI of NRM will be estimated using the method described by Gooley et al (1999).
Time frame: At 1 year
CI of NRM
Non-relapse mortality (NRM) is defined as death occurring in a patient from causes other than relapse. NRM is measured from start of treatment until non-disease related death, or last follow-up, whichever comes first. The cumulative incidence of NRM will be calculated reflecting relapse as a competing risk. CI of NRM will be estimated using the method described by Gooley et al (1999).
Time frame: At 2 years
CI of relapse/progression
The event is relapse/progression. Time to this event is measured from start of treatment. Death without relapse/progression is considered a competing risk. Surviving patients with no history of relapse are censored at time of last follow-up. CI of relapse/progression will be estimated using the method described by Gooley et al (1999).
Time frame: At 100 days
CI of relapse/progression
The event is relapse/progression. Time to this event is measured from start of treatment. Death without relapse/progression is considered a competing risk. Surviving patients with no history of relapse are censored at time of last follow-up. CI of relapse/progression will be estimated using the method described by Gooley et al (1999).
Time frame: At 1 year
CI of relapse/progression
The event is relapse/progression. Time to this event is measured from start of treatment. Death without relapse/progression is considered a competing risk. Surviving patients with no history of relapse are censored at time of last follow-up. CI of relapse/progression will be estimated using the method described by Gooley et al (1999).
Time frame: At 2 years
Gut microbiome diversity
Gut microbiome diversity will be assessed by the Simpson Index and compared between hLZ-treated/untreated patients. Association between treatment and gut microbial diversity will be assessed by Fisher's Exact test.
Time frame: Day - 8 +/- 3, day 0, day +7, day +14, day +21, day +28
CI of acute graft versus host disease (aGVHD)
Acute graft versus host disease will be graded according to the Consensus Grading. The first day of acute GvHD onset at a certain grade will be used to calculate cumulative incidence curves for that GvHD grade; relapse/death prior to onset will be considered competing events. CI of aGVHD will be estimated using the method described by Gooley et al (1999). Association between gut microbial diversity (inverse Simpson index: high \[\> 4\], intermediate \[2-4\], and low \[\< 2\]) or treatment and CI of aGVHD will be assessed by Gray's test.
Time frame: At 100 days
Incidence of bloodstream infections
Incidence of bloodstream infections and infectious enterocolitis will be evaluated and a preliminary estimate of the association between gut microbiome diversity and bloodstream infections will be obtained. Association between gut microbial diversity (inverse Simpson index: high \[\> 4\], intermediate \[2-4\], and low \[\< 2\]) or treatment and CI of bloodstream infections will be assessed by Gray's test.
Time frame: Up to 100 days
Overall survival (OS)
Patients are considered a failure for this endpoint if they die, regardless of cause. The time to this event is the time from start of treatment until death, or last follow-up, whichever comes first. OS will be estimated using the product-limit method of Kaplan and Meier.
Time frame: At 100 days
Overall survival (OS)
Patients are considered a failure for this endpoint if they die, regardless of cause. The time to this event is the time from start of treatment until death, or last follow-up, whichever comes first. OS will be estimated using the product-limit method of Kaplan and Meier.
Time frame: At 1 year
Overall survival (OS)
Patients are considered a failure for this endpoint if they die, regardless of cause. The time to this event is the time from start of treatment until death, or last follow-up, whichever comes first. OS will be estimated using the product-limit method of Kaplan and Meier.
Time frame: At 2 years
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