Clinical trial NCT04682405: Uproleselan (GMI-1271) for GI Toxicity Prophylaxis During Melphalan-Conditioned Autologous Hematopoietic Cell Transplantation (Auto-HCT) for Multiple Myeloma (MM)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: GlycoMimetics Incorporated
name: The Foundation for Barnes-Jewish Hospital
First posted: 2020-12-23
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in Diarrhea as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
Secondary outcomes:
measure: Change in Oral Mucositis as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Esophagitis as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Gastritis as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Esophageal Pain as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Abdominal Pain as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Nausea as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Vomiting as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Enterocolitis as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Proctitis as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Hemorrhoids as Assessed Per CTCAE v5.0
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Time to Neutrophil Engraftment
timeFrame: Through date of discharge (up to be 18 days)
measure: Change in Nutritional Status as Assessed by Total Parenteral Nutrition (TPN) Days
timeFrame: Before conditioning and at day +14 or date of discharge (whichever is sooner) (up to be 18 days)
measure: Duration of Hospital Length of Stay
timeFrame: From date of admission for auto-HCT to date of discharge (up to be 18 days)
measure: Change in Bristol Stool Scale
timeFrame: From day -3 to date of discharge or day 14 (whichever is sooner) (up to be 18 days)
measure: Change in Nutritional Status as Assessed by Change in Standing Weight
timeFrame: Day -3, Day 8, and date of discharge or Day 14 (whichever is sooner) (up to be 18 days)
measure: Incidence of Infection Assessed by Rates of Bacteremia (With Organism Reported When Available)
timeFrame: Through date of discharge (upto be 18 days)
measure: Time to First Antibiotics
timeFrame: Through date of discharge (up to be day 18)
measure: Incidence of Clostridium Difficile Infections
timeFrame: Through date of discharge (up to be 18 days)
measure: Median Daily Dose of Anti-diarrheal Medications
timeFrame: Through date of discharge (up to be 18 days)
measure: Median Daily Dose of Pain Medications
timeFrame: Through date of discharge (up to be 18 days)
measure: Median Change in Scores of Patient Reported Outcomes as Measured by the CTCAE Pro Form v1.0
timeFrame: Day -3, Day +8, date of discharge or Day +14 (whichever is sooner) (up to 18 days)
measure: Median Change in Scores of Quality of Life as Measured by the CTCAE Pro Form v 1.0
timeFrame: Day -3, Day +8, date of discharge or Day +14 (whichever is sooner) (up to 18 days)
measure: Median Change in Scores of Patient Reported Outcomes as Measured by the CTCAE Pro Form v1.0
timeFrame: Day -3, Day +8, date of discharge or Day +14 (whichever is sooner) (up to 18 days)
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Keith Stockerl-Goldstein, M.D.
role: PRINCIPAL_INVESTIGATOR
References: