CBM588 in Improving Clinical Outcomes in Patients Who Have Undergone Donor Hematopoietic Stem Cell Transplant

Study Overview
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Brief Summary
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This pilot trial studies the side effects and how well CBM588 works in improving clinical outcomes in patients who have undergone donor hematopoietic stem cell transplant. Gut microbiota (formerly called gut flora) is the name given to the microbe (bacteria) population living in the intestine. Gut bacteria help the body to digest certain foods that the stomach and small intestine have not been able to digest. CBM588, may increase gut bacteria biodiversity, prevent recurrent symptoms of gastrointestinal toxicity (ranging from diarrhea to life-threatening inflammation of the colon).

Detailed Description
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PRIMARY OBJECTIVES: I. In patients with hematologic malignancies who are undergoing standard reduced intensity conditioning regimen (RIC) prior to allogeneic stem cell transplantation, to evaluate the safety and feasibility of Clostridium butyricum CBM 588 probiotic strain (CBM588) treatment by assessing: Ia. Type, frequency, severity, attribution, time course and duration of adverse events, including diarrhea, bloodstream/intestinal infections. Ib. Patient compliance, the patients' ability to take CBM588 during the treatment period. SECONDARY OBJECTIVES: I. Compare the incidence and severity of adverse events (AE) among CBM588-treated and untreated patients, including diarrhea, bloodstream infections and intestinal infections. II. Estimate overall survival (OS), cumulative incidence (CI) of chronic graft versus host disease (GVHD), relapse/progression, and non-relapse mortality (NRM) at 100 days, 6 months, 1 year and 2 years. EXPLORATORY OBJECTIVES: I. Compare gut microbiome diversity among CBM588-treated/untreated patients. II. Obtain a preliminary estimate of the possible association between gut microbiome diversity and bloodstream infections. III. Characterize and compare graft versus host disease (GVHD) inflammatory biomarkers (presence, level) among CBM588-treated and untreated patients. IV. Obtain preliminary estimates of gut microbiome diversity, as assessed by the inverse Simpson Index, in CBM588-treated/untreated patients. V. Obtain a preliminary estimate of the possible association between gut microbiome diversity and acute GVHD cumulative incidence, including time to onset. VI. Characterize and compare urinary uindoxyl sulfate, tryptophan and kynurenine levels between CBM588- treated and untreated patients. VII. To obtain a preliminary estimate of gut microbiome diversity and calorie intake. VIII. Characterize and compare impact of CBM588 administration on regulatory T cells (T regs) reconstitution between CBM588-treated and untreated patients. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I (CBM588): Patients receive standard peri-/post-transplant supportive care and CBM588 orally (PO) twice daily (BID) from day of admission to day 28 in the absence of disease progression or unacceptable toxicity. ARM II (STANDARD OF CARE): Patients receive standard peri-/post-transplant supportive care. After completion of study treatment, patients are followed up for 100 days and then up to 2 years.

Official Title
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A Randomized Open Label Pilot Study of Clostridium Butyricum MIYAIRI 588 (CBM588) in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

Conditions
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Hematopoietic and Lymphoid Cell Neoplasm

Intervention / Treatment
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* Other: Best Practice
* Drug: Clostridium butyricum CBM 588 Probiotic Strain


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. Assent, when appropriate, will be obtained per institutional guidelines. Willingness to be followed for the planned duration of the trial (2 years). Karnofsky performance status must be >= 60%. Any hematologic disorders receiving allogeneic hematopoietic stem cell transplant with reduced intensity conditioning. Planned 8/8 or 7/8 (human leukocyte antigens [HLA]-A, B, C, DR) related or unrelated donor hematopoietic cell transplantation (HCT). Clinical Laboratory and Organ Function Criteria: Consistent with City of Hope (COH) standard operating procedure (SOP) for patient evaluation for selection for hematopoietic cell transplantation. Patient is eligible to receive allogeneic hematopoietic cell transplantation with reduced intensity conditioning. 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 at least 3 months 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. Refusing to use contraception up to 90 days post-HCT. Pregnant and/or breast feeding if a female recipient. Patients with history of chronic intestinal disease (e.g., Crohn's disease, ulcerative colitis). In the opinion of the principal investigator (PI), the participant has a condition that will preclude them from complying with study treatment. Research participants receiving any other investigational agents. Known or documented history of hypersensitivity to all the listed antibiotics, used for severe infections related to CBM588: Ampicillin. Chloramphenicol. Clindamycin. Erythromycin. Metronidazole. Tetracycline. Vancomycin. 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 response (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. History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent (i.e., research participants whom are severe lactose intolerance or intolerance to milk products). 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. Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures. Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).

Ages Eligible for Study
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Minimum Age: 18 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: Arm I (CBM588)<br>Patients receive standard peri-/post-transplant supportive care and CBM588 PO BID from day of admission to day 28 in the absence of disease progression or unacceptable toxicity. | Other: Best Practice<br>* Receive standard peri-/post-transplant supportive care<br>* Other names: standard therapy;Drug: Clostridium butyricum CBM 588 Probiotic Strain<br>* Given PO<br>* Other names: MIYAIRI 588 Strain of C. butyricum;|
| Active Comparator: Arm II (standard of care)<br>Patients receive standard peri-/post-transplant supportive care. | Other: Best Practice<br>* Receive standard peri-/post-transplant supportive care<br>* Other names: standard therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Will be scored according to the modified Bearman Scale and National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5 scale. 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. | From initiation of treatment until end of treatment assessed up to 100 days | 
| Feasibility of CBM588 | Will be evaluated by assessment of patients' ability to take half of the specified dose. | During the safety lead-in phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events | Assessed by modified Bearman criteria and NCI CTCAE version 5 scale. Will be compared among CBM588 treated and untreated patients. | Up to 2 years | 
| Overall survival | Will be estimated using the product-limit method of Kaplan and Meier. | Up to 2 years | 
| Cumulative incidence (CI) of chronic graft versus host disease (cGVHD) | Will be estimated using the method described by Gooley et al (1999). | Up to 2 years | 
| CI of acute graft versus host disease (aGVHD) | Will be estimated using the method described by Gooley et al (1999). | Up to 2 years | 
| CI of relapse/progression of disease | Will be estimated using the method described by Gooley et al (1999). | Up to 2 years | 
| Non-relapse mortality | Will be estimated using the method described by Gooley et al (1999). | Up to 2 years |