LeukemiaPhase 1/2NCT02829840
Dose-Escalation Study of Ponatinib, a FLT3 Inhibitor, With and Without Combination of 5-Azacytidine, in Patients With FLT3-Mutated Acute Myeloid Leukemia (AML)
A Phase 1/2 study testing Ponatinib, 5-azacytidine and Phone Calls in people with Leukemia and FLT3-Mutated Acute Myeloid Leukemia, run by M.D. Anderson Cancer Center.
Trial summary
The goal of Part 1 of this clinical research study is to learn if ponatinib alone can help to control FLT3-mutated AML or FLT3-mutated high-risk MDS. The safety of this drug will also be studied. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Leukemia, FLT3-Mutated Acute Myeloid Leukemia, FLT3-Mutated High-Risk Myelodysplastic Syndrome
- What is being tested?
- Ponatinib, 5-azacytidine and Phone Calls
- Type of treatment
- Pill or oral medicine, Injection or infusion, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Sep 2016to Sep 2021
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
- Patients should have a FLT3 mutation, either ITD or kinase domain mutation or activation loop mutation.
- Age >/= 18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status </= 2
- 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.
- Left ventricular ejection fraction (LVEF) at least 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
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- Patients must provide written informed consent.
- 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.
- 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.
- 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.
- 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
- 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.
- 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.
- 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.
Who cannot join
- Patients with known allergy or hypersensitivity to ponatinib, or 5-azacytidine, or any of their components.
- Patients who have received any treatment of ponatinib prior to study entry.
- History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
- History of alcohol abuse.
- 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.
- 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.
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- 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).
- 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.
- 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).
- 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.
- Patients who have had any major surgical procedure within 14 days of Day 1.
- Patients unwilling or unable to comply with the protocol.
- 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)
- 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.
- 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.
- 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).
- Known human immunodeficiency virus (HIV) infection.
- 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.
About this study
Official title: Phase I/II, Dose-Escalation Study of Ponatinib, a FLT3 Inhibitor, With and Without Combination of 5-Azacytidine, in Patients With FLT3-Mutated Acute Myeloid Leukemia (AML)
The goal of Part 1 of this clinical research study is to learn if ponatinib alone can help to control FLT3-mutated AML or FLT3-mutated high-risk MDS. The safety of this drug will also be studied.
The goal of Part 2 of this clinical research study is to find the highest tolerable dose of ponatinib in combination with 5-azacytidine and to learn if the highest dose level found can help to control FLT3-mutated AML or FLT3-mutated high-risk MDS. The safety of this combination will also be studied.
Read the detailed description
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.
- Conditions
- Leukemia, FLT3-Mutated Acute Myeloid Leukemia, FLT3-Mutated High-Risk Myelodysplastic Syndrome
- Being tested
- Ponatinib, 5-azacytidine, Phone Calls
- Keywords
- Leukemia, FLT3-Mutated Acute Myeloid Leukemia, FLT3-Mutated High-Risk Myelodysplastic Syndrome, Acute Myeloid Leukemia, AML, Myelodysplastic Syndrome, MDS, Ponatinib, Iclusig, AP24534, 5-azacytidine, Azacitidine, 5-aza, Vidaza, 5-AZC, AZA-CR, Ladakamycin, NSC-102816, Azacytidine
- Medical subject headings
- Leukemia, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PonatinibDrug
Also called Iclusig, AP24534
Part 1: Ponatinib at starting dose of 30 mg by mouth every day for one 28 day cycle.
Part 2 Phase I Dose Escalation: Ponatinib at starting dose of 30 mg by mouth every day of a 28 day cycle.
Part 2 Phase II Dose Expansion: Ponatinib at maximum tolerated dose from Phase I by mouth every day of a 28 day cycle.
5-azacytidineDrug
Also called Azacitidine, 5-aza, Vidaza, 5-AZC
Part 2 Phase I Dose Escalation: 5-azacytidine at dose of 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) for on Days 1-7 of every 28 day cycle.
Part 2 Phase II Dose Expansion: 5-azacytidine 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) on Days 1-7 of every 28 day cycle.
Phone CallsBehavioural
About 30 days after end-of-study visit, study staff calls participant and asks if they have had any side effects and/or started any new treatment(s).
If disease appears to be responding to study drugs, study staff calls participant every 3-6 months for up to 5 years and asks how they are doing and about any side effects they may be having.
| Study group | Role | What they receive |
|---|---|---|
| Cohort #1 | Experimental | Cohort #1: Participants with no previous leukemia therapy (including no previous FLT3 inhibitor therapy) for either: a) front-line treatment of elderly (age 65 and greater) FLT3-mutated AML patients, or b) patients unable or unwilling to receive standard intensive therapy.
Part 1: Ponatinib at starting dose of 30 mg by mouth every day for one 28 day cycle. If disease does not respond to ponatinib alone, participant continues on to Part 2 of study.
Part 2 Phase I Dose Escalation: Ponatinib at starting dose of 30 mg by mouth every day of a 28 day cycle. 5-azacytidine at dose of 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) for on Days 1-7 of every 28 day cycle.
Part 2 Phase II Dose Expansion: Ponatinib at maximum tolerated dose from Phase I by mouth every day of a 28 day cycle. 5-azacytidine 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) on Days 1-7 of every 28 day cycle. Receives: Drug: Ponatinib; Drug: 5-azacytidine; Behavioral: Phone Calls |
| Cohort #2 | Experimental | Cohort #2: Participants with relapsed/refractory FLT3-mutated AML that have not received prior FLT3 inhibitor therapy.
Part 1: Participants receive Ponatinib at starting dose of 30 mg by mouth every day for one 28 day cycle. If disease does not respond to ponatinib alone, participant continues on to Part 2 of study.
Part 2 Phase I Dose Escalation: Ponatinib at starting dose of 30 mg by mouth every day of a 28 day cycle. 5-azacytidine at dose of 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) for on Days 1-7 of every 28 day cycle.
Part 2 Phase II Dose Expansion: Ponatinib at maximum tolerated dose from Phase I by mouth every day of a 28 day cycle. 5-azacytidine 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) on Days 1-7 of every 28 day cycle. Receives: Drug: Ponatinib; Drug: 5-azacytidine; Behavioral: Phone Calls |
| Cohort #3 | Experimental | Cohort #3: Participants with relapsed/refractory FLT3-mutated AML, that have received previous FLT3 inhibitor therapy (including, but not limited to, quizartinib, crenolanib, sorafenib, other FLT3 inhibitors).
Part 1: Participants receive Ponatinib at starting dose of 30 mg by mouth every day for one 28 day cycle. If disease does not respond to ponatinib alone, participant will continue on to Part 2 of study.
Part 2 Phase I Dose Escalation: Ponatinib at starting dose of 30 mg by mouth every day of a 28 day cycle. 5-azacytidine at dose of 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) for on Days 1-7 of every 28 day cycle.
Part 2 Phase II Dose Expansion: Ponatinib at maximum tolerated dose from Phase I by mouth every day of a 28 day cycle. 5-azacytidine 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) on Days 1-7 of every 28 day cycle. Receives: Drug: Ponatinib; Drug: 5-azacytidine; Behavioral: Phone Calls |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum Tolerated Dose (MTD) of Ponatinib
MTD defined as highest dose level with </= 1 out of 6 patients experience a dose limiting toxicity (DLT) during the first 28 days of treatment. DLT defined as clinically significant non-hematologic adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications.
Measured: 28 days
Rate of Composite Complete Remission (CRc)
CRc defined as complete remission (CR), complete remission with incomplete platelet recovery (CRp), or complete remission with incomplete blood count recovery (CRi). Response defined by achievement of CRc at any point in time within the first 3 cycles of therapy, or prior to going off study, for those patients discontinuing treatment before completion of 3 cycles of therapy.
Measured: 84 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jul 2016 (estimated)
- Study startSep 2016
- Primary completionSep 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for LeukemiaStudies of the same condition, open and under way.
- More trials run by M.D. Anderson Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- M.D. Anderson Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- Ariad Pharmaceuticals
- Responsible party
- Sponsor
- Investigators
- Naval Daver, MD, Principal investigator, M.D. Anderson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02829840
- Sponsor's protocol ID
- 2014-1083
- Other IDs
- NCI-2016-01187
- Status last verified
- Jun 2017
- First submitted
- 5 Jul 2016
- Last updated
- 2 Jun 2017
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II, Dose-Escalation Study of Ponatinib, a FLT3 Inhibitor, With and Without Combination of 5-Azacytidine, in Patients With FLT3-Mutated Acute Myeloid Leukemia (AML)
- ClinicalTrials.gov ID
- NCT02829840
- Acronym / sponsor ID
- 2014-1083
- Conditions
- Leukemia, FLT3-Mutated Acute Myeloid Leukemia, FLT3-Mutated High-Risk Myelodysplastic Syndrome
- Keywords
- Leukemia, FLT3-Mutated Acute Myeloid Leukemia, FLT3-Mutated High-Risk Myelodysplastic Syndrome, Acute Myeloid Leukemia, AML, Myelodysplastic Syndrome, MDS, Ponatinib
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Withdrawn
- Enrolment
- 0 participants (actual)
- Lead sponsor
- M.D. Anderson Cancer CenterUniversity, hospital or other
- Collaborators
- Ariad Pharmaceuticals
- Study start
- Sep 2016
- Primary completion
- Sep 2021 (estimated)
- First posted
- 12 Jul 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of Part 1 of this clinical research study is to learn if ponatinib alone can help to control FLT3-mutated AML or FLT3-mutated high-risk MDS. The safety of this drug will also be studied.
The goal of Part 2 of this clinical research study is to find the highest tolerable dose of ponatinib in combination with 5-azacytidine and to learn if the highest dose level found can help to control FLT3-mutated AML or FLT3-mutated high-risk MDS. The safety of this combination will also be studied.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Cohort #1 | Experimental | Drug: Ponatinib, Drug: 5-azacytidine, Behavioral: Phone CallsCohort #1: Participants with no previous leukemia therapy (including no previous FLT3 inhibitor therapy) for either: a) front-line treatment of elderly (age 65 and greater) FLT3-mutated AML patients, or b) patients unable or unwilling to receive standard intensive therapy. Part 1: Ponatinib at starting dose of 30 mg by mouth every day for one 28 day cycle. If disease does not respond to ponatinib alone, participant continues on to Part 2 of study. Part 2 Phase I Dose Escalation: Ponatinib at starting dose of 30 mg by mouth every day of a 28 day cycle. 5-azacytidine at dose of 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) for on Days 1-7 of every 28 day cycle. Part 2 Phase II Dose Expansion: Ponatinib at maximum tolerated dose from Phase I by mouth every day of a 28 day cycle. 5-azacytidine 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) on Days 1-7 of every 28 day cycle. |
| Cohort #2 | Experimental | Drug: Ponatinib, Drug: 5-azacytidine, Behavioral: Phone CallsCohort #2: Participants with relapsed/refractory FLT3-mutated AML that have not received prior FLT3 inhibitor therapy. Part 1: Participants receive Ponatinib at starting dose of 30 mg by mouth every day for one 28 day cycle. If disease does not respond to ponatinib alone, participant continues on to Part 2 of study. Part 2 Phase I Dose Escalation: Ponatinib at starting dose of 30 mg by mouth every day of a 28 day cycle. 5-azacytidine at dose of 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) for on Days 1-7 of every 28 day cycle. Part 2 Phase II Dose Expansion: Ponatinib at maximum tolerated dose from Phase I by mouth every day of a 28 day cycle. 5-azacytidine 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) on Days 1-7 of every 28 day cycle. |
| Cohort #3 | Experimental | Drug: Ponatinib, Drug: 5-azacytidine, Behavioral: Phone CallsCohort #3: Participants with relapsed/refractory FLT3-mutated AML, that have received previous FLT3 inhibitor therapy (including, but not limited to, quizartinib, crenolanib, sorafenib, other FLT3 inhibitors). Part 1: Participants receive Ponatinib at starting dose of 30 mg by mouth every day for one 28 day cycle. If disease does not respond to ponatinib alone, participant will continue on to Part 2 of study. Part 2 Phase I Dose Escalation: Ponatinib at starting dose of 30 mg by mouth every day of a 28 day cycle. 5-azacytidine at dose of 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) for on Days 1-7 of every 28 day cycle. Part 2 Phase II Dose Expansion: Ponatinib at maximum tolerated dose from Phase I by mouth every day of a 28 day cycle. 5-azacytidine 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) on Days 1-7 of every 28 day cycle. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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)
- Patients should have a FLT3 mutation, either ITD or kinase domain mutation or activation loop mutation.
- Age >/= 18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status </= 2
- 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.
Key exclusion criteria (18 listed)
- Patients with known allergy or hypersensitivity to ponatinib, or 5-azacytidine, or any of their components.
- Patients who have received any treatment of ponatinib prior to study entry.
- History of acute pancreatitis within 1 year of study or history of chronic pancreatitis.
- History of alcohol abuse.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PonatinibAlso: Iclusig, AP24534Part 1: Ponatinib at starting dose of 30 mg by mouth every day for one 28 day cycle. Part 2 Phase I Dose Escalation: Ponatinib at starting dose of 30 mg by mouth every day of a 28 day cycle. Part 2 Phase II Dose Expansion: Ponatinib at maximum tolerated dose from Phase I by mouth every day of a 28 day cycle. | Drug | Cohort #1, Cohort #2, Cohort #3 |
| 5-azacytidineAlso: Azacitidine, 5-aza, Vidaza, 5-AZCPart 2 Phase I Dose Escalation: 5-azacytidine at dose of 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) for on Days 1-7 of every 28 day cycle. Part 2 Phase II Dose Expansion: 5-azacytidine 75 mg/m2/d administered subcutaneously (SQ) or intravenously (IV) on Days 1-7 of every 28 day cycle. | Drug | Cohort #1, Cohort #2, Cohort #3 |
| Phone CallsAbout 30 days after end-of-study visit, study staff calls participant and asks if they have had any side effects and/or started any new treatment(s). If disease appears to be responding to study drugs, study staff calls participant every 3-6 months for up to 5 years and asks how they are doing and about any side effects they may be having. | Behavioural | Cohort #1, Cohort #2, Cohort #3 |
Primary outcome
Maximum Tolerated Dose (MTD) of Ponatinib
Time frame: 28 days
MTD defined as highest dose level with </= 1 out of 6 patients experience a dose limiting toxicity (DLT) during the first 28 days of treatment. DLT defined as clinically significant non-hematologic adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications.
Rate of Composite Complete Remission (CRc)
Time frame: 84 days
CRc defined as complete remission (CR), complete remission with incomplete platelet recovery (CRp), or complete remission with incomplete blood count recovery (CRi). Response defined by achievement of CRc at any point in time within the first 3 cycles of therapy, or prior to going off study, for those patients discontinuing treatment before completion of 3 cycles of therapy.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jun 2017.
- University of Texas MD Anderson Cancer Center WebsiteLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Naval Daver, MD principal investigator
M.D. Anderson Cancer Center
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ponatinib, 5-azacytidine and Phone Calls in people with Leukemia and FLT3-Mutated Acute Myeloid Leukemia, run by M.D. Anderson Cancer Center.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 2 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) of Ponatinib (time frame: 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jun 2017.