A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients with Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
- Conditions
- Bloodcancerbone marrow cancer10024324
- Registration Number
- NL-OMON39645
- Lead Sponsor
- ARIAD Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 10
1. Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL (defined in Sections 12.3 and 12.4).
a. All patients must have screening bone marrow (BM) cytogenetics with conventional banding performed within 42 days prior to beginning treatment
b. Examination of at least 20 metaphases is required. If less than 20 metaphases are examined, the BM aspirate should be repeated.
Patients must either meet criterion 2 or 3:
2. Be previously treated with and resistant, or intolerant, to either dasatinib or nilotinib:
2.1 Resistance is defined for CML CP patients (CP at the time of initiation of dasatinib or nilotinib therapy) as follows. Patients must meet at least 1 criterion.
a. Three months after the initiation of therapy: No cytogenetic response (>95% Ph+) or failure to achieve CHR.
b. Six months after the initiation of therapy: Less than a minor cytogenetic response (>65% Ph+).
c. Twelve months after the initiation of therapy: Less than a PCyR (>35% Ph+).
d. At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of CCyR.
e. At any time after the initiation of therapy, the development of new clonal evolution in the absence of CCyR.
f. At any time after the initiation of therapy, the loss of any cytogenetic response [from complete (0%), partial (1% to 35%), minor (36% to 65%), or minimal (66% to 95%) to a
response at least 1 grade worse], confirmed in at least 2 consecutive analyses separated by at least 4 weeks.
g. At any time after the initiation of therapy, progression of disease (to AP or BP).
2.2 Resistance is defined for CML AP patients (AP at the time of initiation of dasatinib or nilotinib therapy) as follows. Patients must meet at least 1 criterion.
a. Three months after the initiation of therapy: failure to achieve a MaHR.
b. At any time after the initiation of therapy, the loss of a MaHR, confirmed in at least 2 consecutive analyses separated by at least 4 weeks.
c. At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of a MaHR.
2.3 Resistance is defined for CML BP patients (BP at the time of initiation of dasatinib or nilotinib therapy) and Ph+ ALL patients as follows. Patients must meet at least 1 criterion.
a. One month after the initiation of therapy: failure to achieve a MaHR.
b. At any time after the initiation of therapy, the loss of a MaHR, confirmed in at least 2 consecutive analyses separated by at least 1 week.
c. At any time after the initiation of therapy, the development of new BCR-ABL kinase domain mutations in the absence of a MaHR.
2.4 Intolerance to dasatinib or nilotinib is defined as: a. Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal) in the absence of a CCyR for CP patients or MaHR for AP, BP or Ph+ ALL patients.
b. Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by manufacturer (80 mg daily [QD] for dasatinib; 400 mg QD for nilotinib) in the absence of a CCyR for CP patients or MaHR for AP
Patients are not eligible for participation in the study if they meet any of the following
exclusion criteria:
1. Received TKI therapy within 7 days prior to receiving the first dose of onatinib, or have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs except alopecia) due to agents previously administered.
2. Received other therapies as follows:
a. For CP and AP patients, received hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of ponatinib, interferon, cytarabine, or immunotherapy within 14 days, or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib.
b. For BP patients, received chemotherapy within 14 days prior to the first dose of ponatinib. Otherwise 2a applies.
c. For Ph+ ALL patients, received corticosteroids within 24 hours before the first dose of ponatinib, or vincristine within 7 days prior to the first dose of ponatinib, or received other chemotherapy within 14 days prior to the first dose of ponatinib. Otherwise, 2a applies.
d. All patients are excluded if they have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs (except alopecia) due to agents previously administered.
3. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of ponatinib; any evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy.
4. Take medications that are known to be associated with Torsades de Pointes. These prohibited medications are listed in Attachment B.
5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
6. Have previously been treated with ponatinib.
7. Patients with CML CP are excluded if they are in CCyR.
8. Patients with CML AP, CML BP, or Ph+ ALL are excluded if they are in MaHR.
9. Have active central nervous system (CNS) disease as evidenced by cytology or pathology. In the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.
10. Have significant or active cardiovascular disease, specifically including, but not restricted to:
a. Myocardial infarction within 3 months prior to first dose of ponatinib,
b. History of clinically significant atrial arrhythmia or any ventricular arrhythmia,
c. Unstable angina within 3 months prior to first dose of ponatinib,
d. Congestive heart failure within 3 months prior to first dose of ponatinib.
11. Have a significant bleeding disorder unrelated to CML or Ph+ ALL.
12. Have a history of pancreatitis or alcohol abuse.
13. Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL).
14. Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered ponatinib.
15. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years).
16. Are pregnant or lactating. Women of childbearing potential must agree to effective contraception from the time of signing informed consent through the Follow-up Visit, approximately 30 days after last dose of ponatinib.
17. Underwent major surgery (with the e
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary Endpoint:<br /><br>- For CML patients in CP at study entry: major cytogenetic response (MCyR),<br /><br>defined as complete cytogenetic response (CCyR) or partial cytogenetic response<br /><br>(PCyR). CP patients in CCyR are not eligible for this study.<br /><br>- For CML patients in AP at study entry: major hematologic response (MaHR),<br /><br>defined as complete hematologic response (CHR) or no evidence of leukemia<br /><br>(NEL). AP patients in MaHR are not eligible for this study.<br /><br>- For CML patients in BP at study entry or Ph+ ALL patients: MaHR, consisting<br /><br>of CHR or NEL. BP and Ph+ ALL patients in MaHR are not eligible for this<br /><br>study.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary Endpoints:<br /><br>* For CML patients in CP:<br /><br>- Hematologic responses: CHR;<br /><br>- Cytogenetic responses: confirmed MCyR; and<br /><br>- Molecular responses: major molecular response (MMR).<br /><br>* For CML patients in AP or BP or Ph+ ALL patients:<br /><br>- Cytogenetic responses: CCyR, PCyR, confirmed MCyR; and<br /><br>- Molecular responses: MMR.<br /><br>* For all patients: time to response, duration of response, progression-free<br /><br>survival, and overall survival.<br /><br>* For all patients: safety and tolerability.<br /><br><br /><br>Exploratory Endpoints:<br /><br>* For all patients: BCR-ABL sequence;<br /><br>* For all patients: allele-specific oligonucleotide (ASO) polymerase chain<br /><br>reaction (PCR) for T315I; and<br /><br>* For all patients: molecular genetic analyses.</p><br>