Human Lysozyme Goat Milk for the Prevention of Graft Versus Host Disease in Patients With Blood Cancer Undergoing a Donor Stem Cell Transplant

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized Pilot Study of Human Lysozyme Goat Milk in Recipients of Standard Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Allogeneic Hematopoietic Stem Cell Transplant Recipient, Hematopoietic and Lymphoid Cell Neoplasm

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Cyclophosphamide
* Drug: Etoposide
* Radiation: Fractionated Stereotactic Radiation Therapy
* Drug: Goat Milk
* Biological: Palifermin
* Drug: Sirolimus
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented informed consent of the participant and/or legally authorized representative Willingness to be followed for the planned duration of the trial (2 years) All subjects must have the ability to understand and the willingness to sign a written informed consent Karnofsky performance status >= 60 per COH SOP Patients must be undergoing allogeneic hematopoietic stem cell transplantation (alloHCT) for hematologic malignancies from matched related or matched unrelated donors with 8/8 (A, B, C, DRB 1) high resolution human leukocyte antigen (HLA) donor allele matching Patients must be receiving a fractionated total body radiation (FTBI) based- myeloablative conditioning regimen; (acceptable conditioning regimens include total body irradiation [TBI] + cyclophosphamide or TBI + etoposide) Ejection fraction measured by echocardiogram or multi gated acquisition scan (MUGA) > 50% Diffusing capacity for carbon monoxide (DLCO) adjusted for hemoglobin or forced vital capacity (FVC) > 50% predicted Total serum bilirubin < 2 times upper limit of normal Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 2.5 x the upper normal limit Alkaline phosphatase =< 2.5 x the upper normal limit Measured creatinine clearance more than 60 mL/min Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through 90 days after the last dose of protocol therapy Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) Exclusion Criteria: Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this pilot study. A legal guardian may substitute for the research participant Research participants receiving any other investigational agents Research participants with presence of other active malignancy within 2 years of study entry. Participants with history of prior malignancy treated with curative intent who achieved complete remission (CR) more than 2 years before study entry are eligible. This exclusion rule does not apply to non-melanoma skin tumors and in-situ cervical cancer Research participants having any uncontrolled illness including ongoing or active infection. Research participants with known active hepatitis B or C infection; research participants who are human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of enrollment; research participants with any signs or symptoms of active infection, positive blood cultures, or radiological evidence of infections Refusing to use contraception up to 90 days post-HCT Pregnant and/or breast feeding if a female recipient Lactose intolerance or intolerance to milk products In the opinion of the principal investigator (PI), the participant has a condition that will preclude them from complying with study treatment

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (conditioning, goat milk, transplant, prophylaxis)<br>CONDITIONING: Patients receive palifermin on days -10 to -8 and days 0 to 2, 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. HLZ: Patients receive human lysozyme goat milk PO 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. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allo-HCT<br>* Other names: HSCT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Radiation: Fractionated Stereotactic Radiation Therapy<br>* Undergo FTBI<br>* Other names: Fractionated Stereotactic Radiotherapy;Drug: Goat Milk<br>* Given human lysozyme goat milk PO<br>Biological: Palifermin<br>* Given IV<br>* Other names: rhu Keratinocyte Growth Factor;Drug: Sirolimus<br>* Given PO<br>* Other names: WY-090217;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;|
| Active Comparator: Group B (conditioning, transplant, prophylaxis)<br>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. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo allo-HCT<br>* Other names: HSCT;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Etoposide<br>* Given IV<br>* Other names: VP16;Radiation: Fractionated Stereotactic Radiation Therapy<br>* Undergo FTBI<br>* Other names: Fractionated Stereotactic Radiotherapy;Biological: Palifermin<br>* Given IV<br>* Other names: rhu Keratinocyte Growth Factor;Drug: Sirolimus<br>* Given PO<br>* Other names: WY-090217;Drug: Tacrolimus<br>* Given IV and PO<br>* Other names: Protopic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients' 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. | 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. | 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. | 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. | Up to 28 days post-transplant or date of discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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). | 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. | 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. | 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. | 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. | 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. | 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. | At 2 years |