Study Groups:
If participant is found to be eligible to take part in this study, they will be assigned to
either Part 1 or Part 2 based on when they join this study.
If participant is enrolled in Part 1, they will receive ponatinib alone for the first cycle.
If the doctor thinks it is needed, the dose level may be increased. If the disease does not
respond to ponatinib alone, participant will continue on to Part 2 of this study.
Part 2 of this clinical research study will have 2 phases: Phase 1 (dose escalation) and
Phase 2 (dose expansion).
In Part 2, participant will be assigned to a study group based on when they join this study.
Up to 3 groups of 30 participants will be enrolled in Phase 1 of Part 2, and up to 60
participants will be enrolled in Phase 2.
If participant is enrolled in Phase 1, the dose of ponatinib they receive will depend on when
they join this study. The first group of participants will receive the lowest dose level of
ponatinib. Each new group will receive a higher dose of ponatinib than the group before it,
if no intolerable side effects were seen. This will continue until the highest tolerable dose
of ponatinib is found.
If participant is enrolled in Phase 2, they will receive ponatinib at the highest dose that
was tolerated in Phase 1.
All participants in Part 2 will receive the same dose level of 5-azacytidine.
Study Drug Administration:
Each study cycle is 28 days.
Participant will take ponatinib tablets by mouth 1 time every day while they are on study.
Participant should swallow the tablets whole. Participant should not crush them.
If participant is enrolled in Part 2, they will receive 5-azacytidine either by vein over
about 1 hour or as an injection under the skin on Days 1-7 of each study cycle or on Days
1-5, 8, and 9 of each study cycle (if the clinic is closed on a weekend).
If the doctor thinks it is needed, the dose level, dosing schedule, or study cycle may be
changed and/or delayed. The study doctor will discuss any changes with participant.
Study Visits:
On Day 1 of each cycle (+/- 4 days), participant will have a physical exam.
On Day 1 (+/-1 day) of Cycles 1-3 and then every 3 cycles after that (Cycles 6, 9, 12, and so
on), participant will have an EKG.
On Day 1 of Cycle 2 and then every 3 cycles after that, participant will have an ECHO or MUGA
performed.
One (1) time each week during Cycles 1-3 and then 1 time every 2-4 weeks after that, blood
(about 1 tablespoon) will be drawn for routine tests. Participant may be able to have these
blood draws performed at a local lab or clinic that is closer to their home. The results of
the testing will be sent to MD Anderson for review.
On Day 28 (+/- 7 days) of Cycles 1, 3, and then every 1-3 cycles after that, participant will
have a bone marrow aspiration/biopsy to check the status of the disease.
One (1) time every 3 cycles, if participant can become pregnant, blood (about 1-2
tablespoons) will be drawn for a pregnancy test.
At any time while participant is on study, if the doctor thinks it is needed:
- Blood (about 1-2 tablespoons) will be drawn for routine tests.
- Participant may have a bone marrow aspiration/biopsy to check the status of the disease.
Length of Study:
Participant will receive ponatinib alone or ponatinib and 5-azacytidine for as long as the
doctor thinks it is in their best interest. Participant will no longer be able to take the
study drugs if the disease gets worse, if intolerable side effects occur, or if they are
unable to follow study directions.
Patient's participation on the study will be over after the follow-up visits.
End-of-Study Visit:
Within 14 days after participant's last dose of study drug(s):
- Participant will have a physical exam.
- Blood (about 2-3 tablespoons) will be drawn for routine tests.
- If the doctor thinks it is needed, participant will have a bone marrow aspirate/biopsy
to check the status of the disease.
Follow-Up:
About 30 days after the end-of-study visit, a member of the study staff will call participant
to ask if they have had any side effects and/or started any new treatment(s). This call
should last about 5 minutes. If the study staff thinks it is needed, participant may also be
asked to come into the clinic for a physical exam.
Long-Term Follow-Up:
If the disease appears to be responding to the study drugs, a member of the study staff will
call participant every 3-6 months for up to 5 years to ask how they are doing and about any
side effects they may be having. Each call should last about 5 minutes. Participant may also
be asked to come into the clinic for a physical exam, if the study staff thinks it is needed.
This is an investigational study. 5-azacytidine is FDA approved and commercially available
for the treatment of myelodysplastic syndrome (MDS). Ponatinib is commercially available and
FDA approved for the treatment of specific groups of chronic myeloid leukemia (CML)
participants. Their use in this study is considered investigational. The study doctor can
explain how the study drugs are designed to work.
Up to 132 participants will take part in this study. All will be enrolled at MD Anderson.
Inclusion Criteria:
1. Patients should have a diagnosis of AML (de novo or transformed from hematologic
malignancies), MDS or chronic myelomonocytic leukemia (CMML) with one of the following
features: (A) Patients with MDS or CMML should have failed prior therapy with a
hypomethylating agent and/or with lenalidomide (Cohorts 2 and 3). (B) Patients with
AML should have failed any prior therapy or have relapsed after prior therapy (Cohorts
2 and 3). For patients in Cohort 3 prior therapy should have included a FLT3
inhibitor. (C) Patients with MDS or CMML who received therapy with a hypomethylating
agent and progress to AML are eligible at the time of diagnosis of AML regardless any
prior therapy for AML. The World Health Organization (WHO) classification will be used
for AML. These patients will be assigned to Cohort 1. Patients with MDS, CMML or AML
who have received no prior therapy are eligible if age 65 and greater or if, at the
time of enrollment, are not candidates to receive or refuse standard therapy (Cohort 1
only)
2. Patients should have a FLT3 mutation, either ITD or kinase domain mutation or
activation loop mutation.
3. Age >/= 18 years
4. Eastern Cooperative Oncology Group (ECOG) Performance Status </= 2
5. Adequate hepatic (serum total bilirubin < 2.0 x upper limit normal (ULN) (or < 3.0 x
ULN if deemed to be elevated due to leukemia or Gilbert's syndrome), alanine
aminotransferase and/or aspartate transaminase < 3.0 x ULN (or < 5.0 x ULN if deemed
to be elevated due to leukemia), and renal function (creatinine 2x ULN or glomerular
filtration rate (GFR) > 50) function.
6. Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition
(MUGA) scan or echocardiogram (ECHO)
7. Patients must provide written informed consent.
8. In the absence of rapidly progressing disease, the interval from prior treatment to
time of initiation of ponatinib administration will be at least 2 weeks for cytotoxic
agents OR at least 5 half-lives for cytotoxic/non-cytotoxic agents. Use of one dose of
cytarabine (up to 2 g/m2) or hydroxyurea for patients with rapidly proliferative
disease is allowed before the start of study therapy and for the first eight weeks on
study therapy from the day of enrollment, either prior to or concomitantly with
ponatinib administration initially to control the peripheral blast count. Concurrent
therapy for central nervous system (CNS) prophylaxis or continuation of therapy for
controlled CNS disease is permitted. Controlled CNS leukemia is defined by the absence
of active clinical signs of CNS disease and no evidence of CNS leukemia on the most
recent 2 simultaneous cerebrospinal fluid (CSF) evaluations.
9. Women of childbearing potential must practice contraception. Females of childbearing
potential: Recommendation is for 2 effective contraceptive methods during the study.
Adequate forms of contraception are double barrier methods (condoms with spermicidal
jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or
injectable contraceptives, intrauterine devices, and tubal ligation. Male patients
with female partners who are of childbearing potential: Recommendation is for male and
partner to use at least 2 effective contraceptive methods, as described above, during
the study.
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 urine
pregnancy test within 72 hours or serum pregnancy test within 2 weeks of signing the
Informed Consent document.
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: (A) 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. (B) 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
12. 11 (Cont'd): (C) 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 (D) Combination of any of the two following (a+b or a+c or b+c): (1) 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
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.
13. 11 (Cont'd) 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.
14. 1 (Cont'd) not considered candidates for intensive remission induction chemotherapy at
time of enrollment based on EITHER: 1. >/= 75 years of age OR 2. <75 years of age with
at least 1 of the following: A. Poor performance status (ECOG) score of 2-3 B.
Clinically significant heart or lung comorbidities, as reflected by at least 1 of: (i)
Left ventricular ejection fraction </= 50%, (ii) Lung diffusing capacity for carbon
monoxide (DLCO) </= 65% of expected, (iii) forced expiratory volume in 1 second (FEV1)
</= 65% of expected, (iv) congestive heart failure (CHF) C. Serum creatinine >2 mg/dL,
are on dialysis or have history of renal transplant. D. Other contraindication(s) to
anthracycline therapy (must be documented). E. Other comorbidity the investigator
judges incompatible with intensive remission induction chemotherapy, which must be
documented and approved by the PI before randomization.
Exclusion Criteria:
1. Patients with known allergy or hypersensitivity to ponatinib, or 5-azacytidine, or any
of their components.
2. Patients who have received any treatment of ponatinib prior to study entry.
3. History of acute pancreatitis within 1 year of study or history of chronic
pancreatitis.
4. History of alcohol abuse.
5. Uncontrolled infection at the time of enrollment. Infections controlled on concurrent
anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional
guidelines is acceptable.
6. Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or
squamous cell carcinoma) that in the investigator's opinion will shorten survival to
less than 1 year.
7. Cardiac Symptoms: Patients meeting the following criteria are not eligible: History of
unstable angina, myocardial infarction, transient ischemic attack (TIA), stroke,
peripheral arterial occlusive disease, venous thromboembolism or pulmonary embolism.
Any history of clinically significant ventricular arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or Torsades de pointes). Prolonged corrected QT
interval (QTc) interval on pre-entry electrocardiogram (> 470 msec) on both the
Fridericia and Bazett's correction. Symptomatic congestive heart failure within 3
months prior to first dose of ponatinib (NYHA class III or IV).
8. Patients with uncontrolled hypertension (defined as sustained stage 2 hypertension,
i.e., systolic BP >/=160 mmHg or diastolic BP >/=100 mmHg) with or without medical
therapy.
9. Patients currently taking drugs that are generally accepted to have a risk of causing
Torsades de Pointes (unless these can be changed to acceptable alternatives).
10. Taking any medications or herbal supplements that are known to be strong inhibitors of
CYP3A4 within at least 14 days before the first dose of ponatinib.
11. Patients who have had any major surgical procedure within 14 days of Day 1.
12. Patients unwilling or unable to comply with the protocol.
13. History of significant bleeding disorder unrelated to cancer, including: • Diagnosed
congenital bleeding disorders (e.g., von Willebrand's disease) • Diagnosed acquired
bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
14. Patients with inflammatory or chronic functional bowel disorder, such as Crohn
disease, inflammatory bowel disease, or gastrointestinal graft versus host disease
that in the opinion of the investigator may interfere with absorption of ponatinib or
increase the risk of serious complications.
15. Any other medical, psychological, or social condition that may interfere with study
participation or compliance, or compromise patient safety in the opinion of the
investigator.
16. Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be
positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen).
17. Known human immunodeficiency virus (HIV) infection.
18. Patients who at the time of enrollment, are willing and eligible to receive a stem
cell transplant will not be eligible to participate in this study.
