| Eligibility |
Inclusion Criteria:
- 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 myeloproliferative neoplasm
(MPN) who transformed to AML, therapy received for MDS, CMML, or MPN is NOT considered
as prior therapy for AML with the exception of MDS or CMML treated with
hypomethylating agents (HMAs). Patients with MDS or CMML treated with HMA therapies
who progress to AML, and have no available therapies or are not candidates for
available therapies, will be eligible at the time of progression to AML.
- Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g.
FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is
permitted.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
- Total bilirubin =< 2.0 times upper limit of normal (x ULN).
- Aspartate aminotransferase or alanine aminotransferase =< 2.5 x ULN (aspartate
aminotransferase or alanine aminotransferase =< 5.0 x ULN if deemed related to
leukemia by the treating physician).
- Adequate renal function defined by an estimated creatinine clearance >= 40 mL/min
according to the Cockcroft-Gault formula (or local institutional standard method).
- Patients must provide written informed consent.
- 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 hydroxyurea 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,
venetoclax 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.
- Concurrent therapy for central nervous system (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 lumbar punctures (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).
- 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.
- 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
contraception.
- 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.
- Combination of any of the two following:
- 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.
- Placement of an intrauterine device (IUD) or intrauterine system (IUS).
- 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 treatment.
- 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.
Exclusion Criteria:
- 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 National Cancer
Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]
4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features
of partially controlled asthma).
- 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 principal investigator
(PI).
- Clinically significant (i.e., active) cardiovascular disease: acute cerebral vascular
accident/stroke (< 6 months prior to enrollment) excluding transient ischemic attack
(TIA), myocardial infarction (< 6 months prior to enrollment), unstable angina,
congestive heart failure (>= New York Heart Association classification class II), or
serious cardiac arrhythmia requiring medication.
- Ejection fraction < 50% on screening echocardiography (ECHO) or multigated acquisition
scan (MUGA).
- Persisting toxicity related to prior therapy of grade > 1 NCI-CTCAE v 4.03; however,
alopecia and sensory neuropathy grade =< 2 is acceptable.
- Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent: * Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid
disease not requiring immunosuppressive treatment are eligible
- Current use of immunosuppressive medication, EXCEPT for the following:
- Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,
intra-articular injection);
- Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or
equivalent;
- Steroids as premedication for hypersensitivity reactions (e.g., computed
tomography [CT] scan premedication).
- Prior organ transplantation including allogenic stem-cell transplantation within 3
months prior to planned enrollment.
- Patients with symptomatic CNS leukemia or patients with poorly controlled CNS
leukemia.
- 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.
- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome.
- Known history of 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.
- Vaccination within 4 weeks of the first dose of avelumab and while on trials is
prohibited except for administration of inactivated vaccines.
- 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.
- Patients unwilling or unable to comply with the protocol.
- Pregnant or breastfeeding.
- Known alcohol or drug abuse within the last 1 year.
- Acute promyelocytic leukemia (APL).
- 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, cerebrovascular accident (CVA), transient ischemic attack or symptomatic
pulmonary emboli, as well as bradycardia defined as < 50 bpms on screening or day 1
electrocardiography (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 corrected QT interval by Fridericia's
correction formula (QTcF) interval > 470 msec within 4 weeks prior to starting the
study drug
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