Uproleselan (GMI-1271) for GI Toxicity Prophylaxis During Melphalan-Conditioned Autologous Hematopoietic Cell Transplantation (Auto-HCT) for Multiple Myeloma (MM)
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Uproleselan + Standard of Care Melphalan 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
Provided by study
Other Names:
Drug: Melphalan
-Standard of care
|
| Placebo Comparator: Placebo + Standard of Care Melphalan 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
Provided by study
Drug: Melphalan
-Standard of care
|
Outcome Measures
Primary Outcome Measures
- Change in diarrhea as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
Secondary Outcome Measures
- Change in oral mucositis as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Change in esophagitis as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Change in gastritis as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Change in esophageal pain as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Change in abdominal pain as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Change in nausea as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Change in vomiting as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Change in enterocolitis as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Change in proctitis as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Change in hemorrhoids as assessed per CTCAE v5.0 [From day -3 to date of discharge or day 14 (whichever is sooner) (estimated to be 17 days)]
- Time to neutrophil engraftment [Through date of discharge (estimated to be day 17)]
-Defined as ANC ≥0.5 x 10^9/L for 3 consecutive days or ≥1.0 x 10^9/L for 1 day
- Change in nutritional status as assessed by total TPN days [Before conditioning and at day +14 or date of discharge (whichever is sooner) (estimated to be 17 days)]
- Duration of hospital length of stay [From date of admission for auto-HCT to date of discharge (estimated to be 17 days)]
- Change in Bristol Stool Scale [From Day -3 through date of discharge or Day 14 (whichever is sooner) (estimated to be 17 days)]
-Type 1:separate hard lumps, Type 2:lumpy and sausage like, Type 3:a sausage shape with cracks in the surface, Type 4:like a smooth, soft sausage or snake, Type 5:soft blobs with clear-cut edges, Type 6:mush consistency with ragged edges, Type 7:liquid consistency with no solid pieces
- Change in nutritional status as assessed by change in standing weight [Day -3, Day 8, and date of discharge or Day 14 (whichever is sooner) (estimated to be 17 days)]
- Incidence of infection assessed by rates of bacteremia (with organism reported when available) [Through date of discharge (estimated to be day 17)]
- Time to first antibiotics [Through date of discharge (estimated to be day 17)]
- Incidence of c. difficile infections [Through date of discharge (estimated to be day 17)]
- Median daily dose of anti-diarrheal medications [Through date of discharge (estimated to be day 17)]
- Median daily dose of pain medications [Through date of discharge (estimated to be day 17)]
- Median change in scores of Patient Reported Outcomes as measured by the CTCAE Pro Form v1.0 [Day -3, Day +8, date of discharge or Day +14 (whichever is sooner)]
Questions regarding gastrointestinal, pain, and psychological symptoms Responses are scored from 0-4 with 0=no symptoms to 4=severe symptoms
- Median change in scores of Quality of Life as measured by the CTCAE Pro Form v 1.0 [Day -3, Day +8, date of discharge or Day +14 (whichever is sooner)]
Questions regarding gastrointestinal, pain, and psychological symptoms Responses are scored from 0-4 with 0=no symptoms to 4=severe symptoms
Eligibility Criteria
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.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
Sponsors and Collaborators
- Washington University School of Medicine
- GlycoMimetics Incorporated
- The Foundation for Barnes-Jewish Hospital
Investigators
- Principal Investigator: Keith Stockerl-Goldstein, M.D., Washington University School of Medicine
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 202103086