The goal of this clinical research study is to learn about the safety and tolerability of 8
different drug combinations when given to patients with acute myeloid leukemia (AML).
Researchers also want to learn if these drug combinations can help to control the disease.
The drug combinations being studied are:
- PF-04518600 (OX40 agonist monoclonal antibody) alone
- PF-04518600 and avelumab (anti-PDL1 mAb)
- PF-04518600 and azacitidine
- PF-04518600 and utomilumab (anti-41BB mAb)
- avelumab and utomilumab
- PF-04518600, avelumab, and azacitidine
- gemtuzumab ozogamicin (anti-CD33 mAb) and glasdegib (smoothened inhibitor)
- glasdegib and avelumab
This is an investigational study. Avelumab is FDA approved and commercially available for the
treatment of advanced Merkel cell carcinoma and urothelial carcinoma. Azacitidine is FDA
approved and commercially available for the treatment of myelodysplastic syndrome (MDS).
Gemtuzumab ozogamicin is FDA approved and commercially approved for the treatment of AML.
PF-04518600, utomilumab, and glasdegib are not FDA approved or commercially available.
It is considered investigational to use these drugs to treat AML. The study doctor can
describe how the drugs are designed to work.
Up to 138 participants will be enrolled in this study. All will take part at MD Anderson.
If you are found to be eligible to take part in this study, you will be assigned to 1 of 8
study groups based on when you join the study and what the study doctor thinks is in your
- Group A will receive PF-04518600.
- Group B will receive PF-04518600 and avelumab.
- Group C will receive PF-04518600 and azacitidine.
- Group D will receive PF-04518600 and utomilumab.
- Group E will receive avelumab and utomilumab.
- Group F will receive PF-04518600, avelumab, and azacitidine.
- Group G will receive gemtuzumab ozogamicin and glasdegib.
- Group H will receive glasdegib and avelumab.
Study Drug Administration:
Each study cycle is 28 days.
PF-04518600 will be given by vein over about 60 minutes on Days 1 and 14 of each cycle. If
given with other drugs, PF-04518600 will be given first.
Avelumab will be given by vein over about 60 minutes on Days 1 and 14 of each cycle.
Azacitidine will be given either by vein over about 10-40 minutes or as an injection under
the skin on Days 1-7 or Days 1-5 and 8-9 of each cycle. The study doctor will tell you which
azacitidine administration and schedule you will follow.
Utomilumab will be given by vein over about 60 minutes on Days 1 and 14 of each cycle.
Gemtuzumab ozogamicin will be given by vein over about 2 hours on Days 1, 4, and 7 of each
Glasdegib tablets will be taken by mouth with a cup (about 8 ounces) of water every morning.
Length of Study:
You may continue taking the study drug(s) for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug(s) if intolerable side effects
occur, or if you are unable to follow study directions.
Your participation in this study will be over after follow-up.
On Day 1 of all cycles:
- You will have a physical exam.
- You will have an EKG.
- Blood (about 3 teaspoons) and urine will be collected for routine tests.
Two (2) times each week during Cycles 1-3 and then 1-2 times each week after that during
Cycles 4 and beyond, blood (about 3-4 teaspoons) will be drawn for routine tests. This blood
draw may be performed at a local doctor's office or lab closer to your home if that is more
convenient for you. If this is done, the results will be sent to the study doctor.
On Day 28 of Cycles 1, 2, 4 and 8, you will have a bone marrow aspirate to check the status
of the disease. If the disease appears to get worse or at any time the doctor thinks it is
needed, you will have this test repeated.
On Day 1 of Cycle 4 and every 3 cycles after that (Cycles 7, 10, 13, and so on), you will
have an ECHO or MUGA scan.
Within 30 days after your last dose of study drug(s):
- You will have a physical exam.
- Blood (about 5 teaspoons) will be drawn for routine, PD, and biomarker testing.
- If the doctor thinks it is possible, you will have a core tumor biopsy performed for
biomarker and PD testing.
- If you can become pregnant, blood (about 1 teaspoon) or urine will be collected for a
Every 3-6 months after your last of study drug(s) for up to 5 years, you will be called by a
member of the study staff to ask how you are doing and if you have started any new
medications. The call should take about 15-20 minutes.
1. Arms A - G: RR AML: Patients with AML who are refractory or relapsed (any salvage)
with no available therapies or not candidates for available therapies. For patients
with prior MDS or chronic myelomonocytic leukemia (CMML) or MPN who transformed to
AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy for
2. Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g.
FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is
permitted in all arms of the study.
3. Age >/=18 years
4. Eastern Cooperative Oncology Group (ECOG) Performance Status </=2
5. Adequate hepatic (serum direct bilirubin </= 1.5 x upper limit normal (ULN) (or </=
3.0 x ULN if deemed to be elevated due to leukemia), alanine aminotransferase and/or
aspartate transaminase </= 2.5 x ULN (or </= 5.0 x ULN if deemed elevated due to
leukemia). Note: Subjects with Gilbert's Syndrome may have a bilirubin > 1.5 × ULN .
6. Adequate renal function defined by an estimated creatinine clearance >/= 40 mL/min
according to the Cockcroft-Gault formula (or local institutional standard method)
7. Patients must provide written informed consent.
8. In the absence of rapidly progressive disease, the interval from prior treatment to
the time of initiation of protocol therapy will be at least 14 days for prior
anti-leukemic therapy, with the exception of hydrea as noted below, OR at least 5
half-lives for cytotoxic/noncytotoxic agents, whichever is shorter. The half-life for
the therapy in question will be based on published pharmacokinetic literature
(abstracts, manuscripts, investigator brochure's, or drug-administration manuals) and
will be documented in the protocol eligibility document. The toxicity from prior
therapy should have resolved to Grade </=1, however alopecia and sensory neuropathy
Grade </=2 not constituting a safety risk based on investigators judgement is
acceptable. Since the effect of most IO-agents, HMA-therapies, SMO-inhibitors may be
delayed, use of hydroxyurea for patients with rapidly proliferative disease is allowed
before the start of study therapy and will not require a washout.
9. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS
disease is permitted. Patients with a known history of CNS disease or leukemic brain
metastasis must have been treated locally, have at least 3 consecutive LPs with no
evidence of CNS leukemia, and must be clinically stable for at least 4 weeks prior to
enrollment and have no ongoing neurological symptoms that in the opinion of the
treating physician are related to the CNS disease (sequelae that are a consequence of
the treatment of the CNS disease are acceptable).
10. Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
at least 12 months) or if of childbearing potential, must have a negative serum or
urine pregnancy test within 72 hours before the start of the treatment.
11. Women of childbearing potential must agree to use an adequate method of contraception
during the study and until 3 months after the last treatment. Males must be surgically
or biologically sterile or agree to use an adequate method of contraception during the
study until 3 months after the last treatment. Adequate methods of contraception
include: • Total abstinence when this is in line with the preferred and usual
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
12. Continued from No. 11; • Female sterilization (have had surgical bilateral
oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, 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 patients on the
study, the vasectomized male partner should be the sole partner for that patient
13. Continued from No. 12; • Combination of any of the two following (a+b or a+c or b+c)
a. Use of oral, injected or implanted hormonal methods of contraception or other forms
of hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception b. Placement of an
intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of
contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with
spermicidal foam/gel/film/cream/ vaginal suppository In case of use of oral
contraception, women should have been stable on the same pill before taking study
14. Continued from No. 13; Note: Oral contraceptives are allowed but should be used in
conjunction with a barrier method of contraception due to unknown effect of drug-drug
interaction. Women are considered post-menopausal and not of child bearing potential
if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at
least six weeks ago. In the case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment is she
considered not of child bearing potential.
1. Patients with a known allergy or hypersensitivity to the protocol therapies or any of
their components to be used in the arm the patient is to be enrolled on. Known severe
hypersensitivity reactions to monoclonal antibodies (Grade >/= 3 NCI CTCAE v 4.03),
any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of
partially controlled asthma).
2. Patients with a known history of severe interstitial lung disease or severe
pneumonitis or active pneumonitis/pneumonia or pulmonary pathology that is not well
controlled in the opinion of the treating physician and/or PI.
3. Patients who have previously been treated with any of the agents or same class of
agents they are scheduled to receive will be excluded. For example, a patient
previously treated with a PD1 or PDL1-based therapy will not be eligible for
avelumab+4-1BB or avelumab+OX40 arms. A patient previously treated with an OX40 based
therapy will not be eligible for any of the OX40 single-agent or combination arms.
4. Clinically significant (i.e., active) cardiovascular disease: acute cerebral vascular
accident/stroke (< 6 months prior to enrollment) excluding TIA, myocardial infarction
(< 6 months prior to enrollment), unstable angina, congestive heart failure (>/= New
York Heart Association Classification Class II), or serious cardiac arrhythmia
5. Ejection fraction < 50% on screening ECHO or MUGA
6. Persisting toxicity related to prior therapy of Grade >1 NCI-CTCAE v 4.03; however,
alopecia and sensory neuropathy Grade </= 2 is acceptable
7. Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent: a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid
disease not requiring immunosuppressive treatment are eligible b. Current use of
immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled,
topical steroids, or local steroid injection (e.g., intra-articular injection); b.
Systemic corticosteroids at physiologic doses </=10 mg/day of prednisone or
equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
8. Prior organ transplantation including allogenic stem-cell transplantation within 3
months prior to planned enrollment.
9. Patients with symptomatic CNS leukemia or patients with poorly controlled CNS
10. Active and uncontrolled disease (active infection requiring systemic therapy, fever
likely secondary to infection within prior 48 hours, uncontrolled hypertension despite
adequate medical therapy as judged by the treating physician.
11. Known history of testing positive for HIV or known acquired immunodeficiency syndrome
12. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive
13. Vaccination within 4 weeks of the first dose of avelumab and while on trials is
prohibited except for administration of inactivated vaccines
14. Other severe acute or chronic medical conditions that is active and not well
controlled including colitis, inflammatory bowel disease, or psychiatric conditions
including recent (within the past year) or active suicidal ideation or behavior; or
laboratory abnormalities that may increase the risk associated with study
participation or study treatment administration or may interfere with the
interpretation of study results and, in the judgment of the investigator, would make
the patient inappropriate for entry into this study.
15. Patients unwilling or unable to comply with the protocol.
16. Pregnant or breastfeeding
17. Known alcohol or drug abuse within the last 1 year
18. Acute promyelocytic leukemia (APL).
19. Cardiac exclusions specific to Glasdegib and OX40 containing arms: Any one of the
following ongoing or in the previous 6 months: congenital long QT syndrome, Torsades
de pointes or any clinically significant ventricular fibrillation, sustained
ventricular tachyarrhythmia requiring medical intervention, right bundle branch block
+ left anterior hemiblock (i.e. bifascicular block): isolated RBBB without a
bifascicular block will not be an exclusion criterion; complete left bundle branch
block, unstable angina or myocardial infarction, coronary/peripheral artery bypass
graft, CVA, transient ischemic attack or symptomatic pulmonary emboli, as well as
bradycardia defined as <50 bpms on screening or Day 1 EKG. Known history of second or
third degree heart block (may be eligible if the patient currently has a pacemaker).
Active cardiac dysrhythmias of NCI CTCAE grade >/= 2 (eg, atrial fibrillation) or QTc
interval > 470 msec within 4 weeks prior to starting the study drug.