Uproleselan (GMI-1271) for GI Toxicity Prophylaxis During Melphalan-Conditioned Autologous Hematopoietic Cell Transplantation (Auto-HCT) for Multiple Myeloma (MM)

Study Overview
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Brief Summary
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The investigators hypothesize that prophylactic E-selectin inhibition via administration of uproleselan during melphalan conditioning will reduce the gastrointestinal (GI) toxicity in multiple myeloma (MM) patients undergoing auto-transplant, as assessed via diarrhea severity scoring per CTCAE v5.0, while potentially increasing chemosensitivity of malignant MM cells to high-dose melphalan.

Official Title
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A Phase II Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Uproleselan (GMI-1271) for GI Toxicity Prophylaxis During Melphalan-Conditioned Autologous Hematopoietic Cell Transplantation (Auto-HCT) for Multiple Myeloma (MM)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Uproleselan
* Drug: Placebo
* Drug: Melphalan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy-confirmed multiple myeloma (MM) (per IMWG criteria). Undergoing first auto-HCT for MM in first partial response (PR) or better Conditioning regimen to be single agent melphalan (200 mg/m^2) Adults 18 to 75 years of age, inclusive ECOG performance status ≤ 2 Mobilized ≥ 5.0 x 10^6 CD34+ cells/kg (i.e. sufficient CD34+ HSCs for one auto-HCT, with at least one back-up graft in reserve) Adequate bone marrow and organ function prior to stem cell mobilization as defined below: Leukocytes, absolute neutrophil count, and platelets within institutional standard limits for high-dose melphalan autologous stem cell transplant Total bilirubin ≤ 1.5 x ULN (unless the patient has a history of Gilbert's Syndrome, in which case, total bilirubin must be ≤ 2.5 times the ULN) AST(SGOT)/ALT(SGPT) ≤ 3.0 x ULN Creatinine clearance ≥ 30 mL/min by Cockcroft-Gault Baseline pulmonary function test (PFT) with carbon monoxide diffusion capacity in the lung (DLCO) ≥ 50% and forced expiratory volume in 1 second (FEV1) both within institutional standard limits for high-dose melphalan autologous stem cell transplant The effects of uproleselan (GMI-1271) on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, prior sterilization procedure, abstinence, etc.) prior to study entry, for the duration of study participation and for 12 weeks after the completion of the study. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Should a man who is participating in the study become aware that he has impregnated a partner, he must inform his treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: A history of other malignancy with the exception of malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease. Active signs or symptoms of CNS involvement by malignancy (lumbar puncture not required). Prior history of CNS involvement is acceptable, if patient has completed treatment for CNS involvement with documented treatment response. Prior exposure to uproleselan (GMI-1271) Currently receiving any other investigational agents A history of allergic reactions attributed to compounds of similar chemical or biologic composition to uproleselan or melphalan Known active infection with hepatitis A, B (e.g., HBsAg positive), or C (e.g., anti-HCV positive), or human immunodeficiency virus Uncontrolled acute life-threatening bacterial, viral, or fungal infection-Myocardial infarction within 6 months of uproleselan/placebo dosing, or subject has current significant cardiovascular disease, such as uncontrolled or symptomatic arrhythmias, congestive heart failure, hemodynamic instability, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification Any medical, psychiatric, or other condition which, in the opinion of the investigator, unfavorably alters the risk-benefit of subject participation, is likely to interfere with trial completion, assessments, or interpretation of trial results, or otherwise would make the subject an inappropriate subject for this trial. Pregnant and/or breastfeeding. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during the trial and for 12 weeks following the last dose of uproleselan/placebo. Women who are postmenopausal with amenorrhea for at least 1 year prior to trial entry and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status (>28U/L) will be considered NOT of childbearing potential. Highly effective contraception includes: Total abstinence with a male partner. Female sterilization (has had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before uproleselan/placebo. In case of oophorectomy alone, the subject would be eligible only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. Male sterilization (at least 6 months prior to Screening). For female subjects on the trial, the vasectomized male partner should be the sole partner for that subject. BOTH of the following forms of contraception consistently used together: Injected, transdermal, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%) with the exception of intrauterine devices, which are excluded due to the risk of infection and bleeding. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with or without spermicidal foam/gel/film/cream/vaginal suppository. Men who are sexually active and not willing to use condoms during the trial and for 12 weeks following the last dose of uproleselan/placebo, unless they have undergone vasectomy for sterilization (at least 6 months prior to Screening), are excluded from trial participation. Men who are sexually active and not willing to use condoms during the trial and for 12 weeks following the last dose of uproleselan/placebo, unless they have undergone vasectomy for sterilization (at least 6 months prior to Screening), are excluded from trial participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Uproleselan + Standard of Care Melphalan<br>On the evening of Day -3, patients will receive dose #1 of uproleselan On the following morning of Day -2 (12 +/- 2 hours from prior dose), patients will receive dose #2 of uproleselan On the evening of Day -2 (12 +/- 2 hours from prior dose), patients will receive dose #3 of uproleselan On Day -2 following completion of dose #3 of uproleselan, the patient will be administered the conditioning dose of melphalan (200mg/m^2) as per institutional practice. On the following morning of Day -1 (12 +/- 2 hours from prior dose), patients will receive dose #4 of uproleselan On the evening of Day -1 (12 +/- 2 hours from prior dose), patients will receive dose #5 of uproleselan On the following morning of Day 0 (12 +/- 2 hours from prior dose) patients will receive dose #6 (final dose) of uproleselan On Day 0, 4 hours (+/- 2 hours) after the final dose of uproleselan, the patient will be infused with the HSC product. The patient will remain inpatient until engraftment | Drug: Uproleselan<br>* Provided by study<br>* Other names: GM-1271;Drug: Melphalan<br>* -Standard of care<br>|
| Placebo Comparator: Placebo + Standard of Care Melphalan<br>On the evening of Day -3, patients will receive dose #1 of placebo On the following morning of Day -2 (12 +/- 2 hours from prior dose), patients will receive dose #2 of placebo On the evening of Day -2 (12 +/- 2 hours from prior dose), patients will receive dose #3 of placebo. On Day -2 following completion of dose #3 of placebo, the patient will be administered the conditioning dose of melphalan (200mg/m^2) as per institutional practice. On the following morning of Day -1 (12 +/- 2 hours from prior dose), patients will receive dose #4 of placebo. On the evening of Day -1 (12 +/- 2 hours from prior dose), patients will receive dose #5 of placebo. On the following morning of Day 0 (12 +/- 2 hours from prior dose) patients will receive dose #6 (final dose) of placebo. On Day 0, 4 hours (+/- 2 hours) after the final dose of placebo, the patient will be infused with the HSC product. The patient will remain inpatient until engraftment | Drug: Placebo<br>* Provided by study<br>Drug: Melphalan<br>* -Standard of care<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Diarrhea as Assessed Per CTCAE v5.0 | Grade 0 is defined as no diarrhea, or no change from baseline. Grade 1 is defined as an increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline. Grade 2 is defined as an increase of 4-6 stools per day over baseline; moderate increase in ostomy output compared to baseline; limiting instrumental ADL. Grade 3 is defined as an increase of >=7 stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limited self care ADL. Grade 4 is defined as life-threatening consequences; urgent intervention indicated. Grade 5 is defined as death. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Oral Mucositis as Assessed Per CTCAE v5.0 | Grade 0 oral mucositis is defined as no presence of mucositis. Grade 1 oral mucositis is defined as asymptomatic or mild symptoms; intervention not indicated. Grade 2 oral mucositis is defined as moderate pain or ulcer that does not interfere with oral intake; modified diet indicated. Grade 3 oral mucositis is defined as severe pain; interfering with oral intake. Grade 4 oral mucositis is defined as life-threatening consequences; urgent intervention indicated. Grade 5 oral mucositis is defined as death. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Esophagitis as Assessed Per CTCAE v5.0 | Grade 0 esophagitis is defined as no presence of esophagitis. Grade 1 esophagitis is defined as asymptomatic; clinical or diagnostic observations only; intervention not indicated. Grade 2 esophagitis is defined as symptomatic; altered GI function; limiting instrumental ADL. Grade 3 esophagitis is defined as severely altered GI function; TPN indicated; elective invasive intervention indicated; limiting self care ADL. Grade 4 esophagitis is defined as life-threatening consequences; urgent operative intervention indicated. Grade 5 esophagitis is defined as death. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Gastritis as Assessed Per CTCAE v5.0 | Grade 0 gastritis is defined as no presence of esophagitis. Grade 1 gastritis is defined as asymptomatic; clinical or diagnostic observations only; intervention not indicated. Grade 2 gastritis is defined as symptomatic; altered GI function; medical intervention indicated. Grade 3 gastritis is defined as severely altered eating or gastric function; TPN or hospitalization indicated. Grade 4 gastritis is defined as life-threatening consequences; urgent operative intervention indicated. Grade 5 gastritis is defined as death. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Esophageal Pain as Assessed Per CTCAE v5.0 | Grade 0 esophageal pain is defined as no esophageal pain. Grade 1 esophageal pain is defined as mild pain. Grade 2 esophageal pain is defined as moderate pain; limiting instrumental ADL. Grade 3 esophageal pain is defined as severe pain; limiting self care ADL. There is no grade 4 or 5 esophageal pain defined in the CTCAE v5.0. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Abdominal Pain as Assessed Per CTCAE v5.0 | Grade 0 abdominal pain is defined as no abdominal pain. Grade 1 abdominal pain is defined as mild pain. Grade 2 abdominal pain is defined as moderate pain; limiting instrumental ADL. Grade 3 abdominal pain is defined as severe pain; limiting self care ADL. There is no grade 4 or 5 abdominal pain defined in the CTCAE v5.0. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Nausea as Assessed Per CTCAE v5.0 | Grade 0 nausea is defined as no nausea. Grade 1 nausea is defined as loss of appetite without alteration in eating habits. Grade 2 nausea is defined as oral intake decreased without significant weight loss, dehydration or malnutrition. Grade 3 nausea is defined as inadequate oral caloric or fluid intake; tube feeding, TPN, or hospitalization indicated. There is no grade 4 or 5 nausea defined in the CTCAE v5.0. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Vomiting as Assessed Per CTCAE v5.0 | Grade 0 vomiting is defined as no vomiting. Grade 1 vomiting is defined as intervention not indicated. Grade 2 vomiting is defined as outpatient IV hydration; medical intervention indicated. Grade 3 vomiting is defined as tube feeding, TPN, or hospitalization indicated. Grade 4 vomiting is defined as life-threatening consequences. Grade 5 vomiting is defined as death. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Enterocolitis as Assessed Per CTCAE v5.0 | Grade 0 enterocolitis is defined as no enterocolitis. Grade 1 enterocolitis is defined as asymptomatic; clinical or diagnostic observations only; intervention not indicated. Grade 2 enterocolitis is defined as abdominal pain; mucus or blood in stool. Grade 3 enterocolitis is defined as severe or persistent abdominal pain; fever; ileus; peritoneal signs. Grade 4 enterocolitis is defined as life-threatening consequences; urgent intervention indicated. Grade 5 enterocolitis is defined as death. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Proctitis as Assessed Per CTCAE v5.0 | Grade 0 proctitis is defined as no proctitis. Grade 1 proctitis is defined as rectal discomfort, intervention not indicated. Grade 2 proctitis is defined as symptomatic (e.g., rectal discomfort, passing blood or mucus); medical intervention indicated; limiting instrumental ADL. Grade 3 proctitis is defined as severe symptoms; fecal urgency or stool incontinence; limiting self-care ADL. Grade 4 proctitis is defined as life-threatening consequences; urgent intervention indicated. Grade 5 proctitis is defined as death. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Hemorrhoids as Assessed Per CTCAE v5.0 | Grade 0 hemorrhoids is defined as no hemorrhoids. Grade 1 hemorrhoids is defined as asymptomatic; clinical or diagnostic observations only; intervention not indicated. Grade 2 hemorrhoids is defined as symptomatic; banding or medical intervention indicated. Grade 3 hemorrhoids is defined as severe symptoms; invasive intervention indicated. There is no grade 4 or 5 hemorrhoids defined in the CTCAE v5.0. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Time to Neutrophil Engraftment | -Defined as ANC ≥0.5 x 10^9/L for 3 consecutive days or ≥1.0 x 10^9/L for 1 day | Through date of discharge (up to be 18 days) | 
| Change in Nutritional Status as Assessed by Total Parenteral Nutrition (TPN) Days |  | Before conditioning and at day +14 or date of discharge (whichever is sooner) (up to be 18 days) | 
| Duration of Hospital Length of Stay |  | From date of admission for auto-HCT to date of discharge (up to be 18 days) | 
| Change in Bristol Stool Scale | Change in Bristol Stool Scale as measured by incidence of Type 7 Bristol Stool Scale: liquid consistency with no solid pieces. | From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days) | 
| Change in Nutritional Status as Assessed by Change in Standing Weight | Patient standing weight in kilograms was taken at specific time points to assess any changes in nutritional status. | Day -3, Day 8, and date of discharge or Day 14 (whichever is sooner) (up to be 18 days) | 
| Incidence of Infection Assessed by Rates of Bacteremia (With Organism Reported When Available) |  | Through date of discharge (upto be 18 days) | 
| Time to First Antibiotics | Measured by the time in days to the first antibiotic dose for bacteremia. | Through date of discharge (up to be day 18) | 
| Incidence of Clostridium Difficile Infections |  | Through date of discharge (up to be 18 days) | 
| Median Daily Dose of Anti-diarrheal Medications | This is defined as the number of doses of anti-diarrheal medications, such as loperamide or lomotil, that participants took daily. | Through date of discharge (up to be 18 days) | 
| Median Daily Dose of Pain Medications | The median daily dose of pain medications is provided as morphine equivalents. | Through date of discharge (up to be 18 days) | 
| Median Change in Scores of Patient Reported Outcomes as Measured by the CTCAE Pro Form v1.0 | Questions regarding gastrointestinal toxicities Responses are scored from 1-5 with 1=no symptoms to 5=severe symptoms | Day -3, Day +8, date of discharge or Day +14 (whichever is sooner) (up to 18 days) | 
| Median Change in Scores of Quality of Life as Measured by the CTCAE Pro Form v 1.0 | Questions regarding gastrointestinal, pain, and psychological symptoms interfering with daily activities Responses are scored from 1-5 with 1=not at all to 5=very much | Day -3, Day +8, date of discharge or Day +14 (whichever is sooner) (up to 18 days) | 
| Median Change in Scores of Patient Reported Outcomes as Measured by the CTCAE Pro Form v1.0 | Questions regarding gastrointestinal toxicities Responses are scored from 1-5 with 1=never and 5=almost constantly | Day -3, Day +8, date of discharge or Day +14 (whichever is sooner) (up to 18 days) |