A Phase III Randomized, Double-Blind Trial to Evaluate the Efficacy of Uproleselan Administered with Chemotherapy versus Chemotherapy Alone in Patients with Relapsed/Refractory Acute Myeloid Leukemia

This is a Phase 3 clinical trial which continues to evaluate the effectiveness
and the safety of the study drug from what was learned in earlier research
clinical trials.

This is the seventh clinical trial in which uproleselan will be given to
humans, and the second in which it is being given to patients with AML.
Uproleselan or placebo will be given in addition to the standard chemotherapy
per investigation discretion. Treatment assignment will be randomized and
blinded to the patient and the study staff.

This research clinical trial is studying uproleselan (GMI-1271), in combination
with standard chemotherapy as a possible treatment for AML.

The names of the study treatments involved in this clinical trial are:
• Induction Cycle (first cycle):
o Uproleselan or Placebo with Mitoxantrone, Etoposide, and Cytarabine (MEC)
-OR-
o Uproleselan or Placebo with Fludarabine, Cytarabine, Idarubicin (FAI)

• Consolidation Cycles (up to 3 additional cycles of treatment following
induction if medically eligible):
o Uproleselan or Placebo with high-dose Cytarabine (HiDAC)
-OR-
o Uproleselan or Placebo with intermediate-dose Cytarabine (IDAC)

The purposes of this clinical trial are to:

• Test if trial participants taking uproleselan with standard chemotherapy
medicines live longer than those taking standard chemotherapy alone.
• Test if the number of trial participants achieving disease remission (i.e. a
reduction in disease symptoms) is increased when uproleselan is given with
standard chemotherapy medicines compared to standard chemotherapy alone.
• Measure the effect of uproleselan on oral mucositis when given with standard
chemotherapy medicines compared to standard chemotherapy alone. Oral mucositis
is a complication of chemotherapy that leads to ulcers in the mouth that may
result in pain and interfere with the ability to eat food and drink liquids.
• Learn about the safety of uproleselan and how well the patient tolerates it
when given with standard chemotherapy medicines compared to standard
chemotherapy alone.
• Find out how much uproleselan is in the blood of trial participants after
being administered uproleselan.
•Measure levels of inflammation markers in blood (a response of body tissue to
injury or irritation) and adhesion (stickiness) of cells in the body to learn
about how important these are to the effect uproleselan may have in AML.
•Measure levels of adhesion (stickiness) of cancer (AML) cells and early stage
blood cells, found in bone marrow to learn about how important these are to the
effect uproleselan may have in AML.

This trial will enroll approximately 380 randomized subjects 18 through 75
years of age at the time of randomization with primary refractory AML or
relapsed AML and eligible to receive induction chemotherapy. Subjects will
receive either uproleselan (GMI-1271) or placebo (saline solution) in a blinded
fashion administered together with chemotherapy for 1 cycle of treatment
(Induction). After induction, if subjects are medically eligible, up to three
additional cycles of consolidation treatment may be administered. At the
completion of the final consolidation cycle, an End of Treatment visit will be
performed. After the End of Treatment visit, subjects will enter the follow-up
period where they will be followed indefinitely for survival information.

Uproleselan or Placebo in conjunction with standard of care chemotherapy
options MEC or FAI.

Uproleselan is an investigational medication; how it may affect humans is being
studied. It is not known if the patient will have side effects from this
medication and if uproleselan will cause additional side effects from ones
caused by medications the patient is taking. As with any new investigational
medication, there is the possibility of side effects that are unknown or
unforeseen at this time. There is a chance that any other medications could
have a negative interaction with uproleselan. In a clinical research study like
this one, not every risk or side effect can be known. Each person*s reaction to
a study medication may be different.

The current edition of the Investigator*s Brochure (IB edition 11 dated 20 June
2023) lists the following potential side effects:

Very common (10 - 11% of study participants reported the following side
effects. That means in 100 study participants, 10 or 11 participants have
reported the following side effects):
• nausea
• diarrhea

Common (5 - 9% of study participants have reported the following side effects):
• headache
• back pain
• fever when white blood cell count is low
• fatigue (tiredness)
• decreased appetite
• low number of platelets in the blood

Less Common (2 - 4% of study participants have reported the following side
effects):
• stomach pain or upper stomach pain
• chills
• vomiting
• constipation
• colitis (inflammation of the digestive tract)
• inflammation of the mouth and lips
• infusion site pain
• fever
• distorted sense of taste
• anemia (low numbers of red blood cells) or neutropenia (low levels of
neutrophils, a type of white blood cell)
• platelet count decreased
• increased liver enzyme (aspartate aminotransferase)
• electrolyte imbalance (low potassium levels in the blood)
• dizziness
• arthralgia (pain in a joint)
• pneumonia (an infection in the lungs)
• pruritus (itchy skin) or rash

Rare (1% of study participants have reported the following side effects):
• asthenia (physical weakness or lack of energy) or somnolence (sleepiness or
drowsiness)
• electrolyte imbalances (including low calcium, magnesium or phosphate levels
in the blood)
• musculoskeletal pain or neck pain or pain in extremity
• myalgia (muscle pain) or muscle spasms or muscular weakness
• increased liver enzyme (alanine aminotransferase)
• white blood cell or neutrophil count decreased
• sepsis (a severe type of infection)
• slow heart rate
• indigestion
• chest discomfort
• oedema peripheral (accumulation of fluid causing swelling; usually in lower
limbs)
• tumor lysis syndrome (when large amount of tumor cells are killed by
treatment and contents enter the blood stream)
• alkaline phosphatase or ALP increase (elevated levels of ALP in the blood are
most commonly caused by liver disease, bile duct obstruction, gallbladder
disease, or bone disorders)
• increased bilirubin (yellowish substance in your blood)
• dry skin or generalized itchy skin or rash with spots and bumps
• cough or dyspnea (difficult/labored breathing)
• low level of oxygen in the blood
• stomach discomfort or swelling/stretching
• pulmonary oedema (excess fluid in the lungs)
• fast heart rate
• restlessness
• high/low blood pressure.

Very Rare (Less than 1% of study participants have reported the following side
effects):
• enteritis or enterocolitis (inflammation of the digestive tract)
• stomach tenderness or symptoms
• ascites (the accumulation of fluid, causing abdominal swelling)
• digestive tract swelling or thickening or hemorrhage (bleeding)
• dry mouth or gum pain or blisters in the mouth or blisters on the tongue or
oral candidiasis (yeast/fungal infection in the mouth)
• retching (to make the sounds and movement of vomiting without actually
vomiting)
• tachycardia (fast heart rate)
• proctalgia (pain due to a spasm of the pelvic floor muscles, the muscles of
the anal sphincter, or the muscles of the rectum)
• infusion site reactions such as redness or swelling or extravasation (leakage
of intravenously infused into the tissue around the site of infusion)
• feeling hot or a burning sensation
• lack of energy
• eosinophilia (high levels of eosinophils; Eosinophils are a type of
disease-fighting white blood cell)
• lymphadenopathy (disease of the lymph nodes, in which they are abnormal in
size or consistency)
• dehydration
• hypoalbuminemia (level of albumin in the blood is low) or hyponatraemia
(level in sodium in the blood is low)
• international normalized ratio (INR) decrease (INR is a lab test to check how
your blood clots)
• liver function test increases
• musculoskeletal stiffness
• weight changes (increase or decrease)
• electrocardiogram changes
• cellulitis (painful bacterial skin infection. It may first appear as a red,
swollen area that feels hot and tender to the touch)
• clostridium difficile colitis (a bacteria that causes diarrhea and colitis
(inflammation of the colon)
• enterococcal bacteraemia or streptococcal bacteraemia (types of bacteria that
can cause a variety of infections)
• otitis media (inflammatory disease of the middle ear)
• upper or lower respiratory infections
• alopecia (hair loss)
• erythema multiforme (hypersensitivity reaction usually triggered by
infections)
• palmar erythema (rare skin condition where the palms of both hands become
reddish)
• palmar-plantar erythrodysaesthesia (hand-foot syndrome causes redness,
swelling, and pain on the palms of the hands and/or the soles of the feet.
Sometimes blisters appear)
• purpura (purple-colored spots that are mostly seen on the skin)
• erythemeous or macular rash (specific types of rash)
• skin exfoliation (peeling skin)
• acute respiratory distress syndrome (lung injury that allows fluid to leak
into the lungs)
• breathing becomes difficult and oxygen cannot get into the body or tachypnea
(faster than normal breathing)
• nasal congestion or discomfort or nose bleed
• throat pain or swelling
• dry eye or pink eye or eye swelling or blurred vision or retinal hemorrhage
(disorder of the eye in which bleeding occurs in the retina)
• anxiety or confused state
• painful urination or kidney injury or urinary tract infections
• transfusion reaction