The purpose of this study is to assess the safety and efficacy of ponatinib in Japanese patients with chronic myeloid leukemia (CML) who have experienced failure of dasatinib or nilotinib or with Ph+ acute lymphoblastic leukemia (ALL) following failure of prior tyrosine kinase inhibitors (TKIs).
This multi-center, phase 1/2, open-label study will consist of two phases. The first will be a dose escalation phase employing a modified 3+3 design with two dose cohorts (30mg and 45mg). After 6 patients complete the first cycle in a cohort, safety events will be evaluated before opening the next dose cohort. Patients will continue on treatment as long as it is tolerated and disease progression has not occurred. Phase 2 will occur at the recommended dose determined in phase 1 in an additional 25 patients. Another 3 patients will be dosed at 15mg for collection of pharmacokinetic data. These patients may also escalate to the recommended dose and be assessed for efficacy and safety as phase 2 patients. Efficacy measures include molecular, cytogenetic, and hematologic response rates at various time points; time to response; duration of response; and survival follow-up. Safety measures include routine physical and laboratory evaluations, adverse event monitoring, and ECGs. Other measures include mutation testing and molecular genetic assessment. Accrual is expected to take approximately 12 months, and patients will be followed for survival for up to 60 months from the last dose of study drug; therefore, the estimated duration of the trial is 72 months.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
35
30 mg dose of ponatinib taken orally once daily for at least the first 6 patients. If no dose-limiting toxicities are observed, the next patients will receive 45 mg dose of ponatinib taken orally once daily. Once the recommended dose is confirmed, all patients may receive the recommended dose, at the investigators' discretion.
Recommended dose of ponatinib as determined in the dose escalation phase. In addition, 3 patients will receive 15 mg dose once daily for 8 days for PK testing. These PK patients may be allowed to receive the recommended dose after PK testing is complete, at the investigators' discretion.
Aichi Cancer Center Hospital
Nagoya, Aichi-ken, Japan
Akita University Hospital
Akita, Akita, Japan
Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital
Hiroshima, Hiroshima, Japan
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) as a Measure of Safety Profile to Determine Recommended Dose of Ponatinib
DLT was evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 and was defined as any of the following events: 1. Grade greater than or equal to (\>=) 3 non-hematologic, with the exception of medically controllable toxicities (example; nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting \<=3 days, but excluding alopecia; 2. Missed doses: \>25% of planned ponatinib doses over 28 days due to AEs in the first cycle; 3. Febrile neutropenia (the occurrence of an ANC \<500/microliter concurrently with a temperature elevation of \>101 degree Fahrenheit), when neutropenia is not related to underlying acute leukemia, as defined hematologic toxicity: Dose-limiting hematologic toxicity is the occurrence of a Grade 4 cytopenia \>28 days, not related to underlying disease according to the investigator. Bone marrow examination must demonstrate \<5% cellularity.
Time frame: Cycle 1 (Cycle length= 28 days)
Phase 2, CP-CML Participants: Percentage of Participants With Major Cytogenetic Response (MCyR)
MCyR was defined as percentage of participants who achieved a complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR) after the initiation of study treatment. Cytogenic response was the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow. CCyR: no Ph+ cells. PCyR: 1% to 35% Ph+ cells. Participants entering the study already in PCyR had to achieve a CCyR in order to be considered a success for the confirmed MCyR rate.
Time frame: Baseline up to 60 months
Phase 2, BP-CML and Ph+ALL: Percentage of Participants With Major Hematologic Response (MaHR)
MaHR was defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). MaHR response was confirmed by a peripheral blood complete blood count (CBC) and differential no earlier than 28 days after the response was observed. Response criteria for CHR was reported as white blood cells (WBC)\<=institutional upper limit of normal (ULN), absolute neutrophil count (ANC)\>=1000/mm\^3, platelets\>=100,000/mm\^3, no blasts or promyelocytes in peripheral blood, BM blasts \<=5%, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, no extramedullary involvement; Response criteria for NEL reported as WBC\<=institutional ULN, no blasts or promyelocytes in peripheral blood, BM blasts \<=5%, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm\^3\<=platelets\<100,000/mm\^3; (ii) 500/mm\^3\<=ANC\<1000/mm\^3.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Kyushu University Hospital
Hukuoka-shi, Hukuoka, Japan
Kinki University Hospital, Faculty of Medicine
Osakasayama-shi, Osaka, Japan
The Cancer Institute Hospital Japanese Foundation for Cancer Research
Koto, Tokyo, Japan
The University of Tokyo, The Institute of Medical Science
Minato-ku, Tokyo, Japan
Keio University Hospital
Shinjuku-ku, Tokyo, Japan
Osaka City University Hospital
Shinjuku-ku, Tokyo, Japan
National Cancer Center Hospital
Chuo-ku, Tokyo, Japan
...and 1 more locations
Time frame: Baseline up to 60 months
CP-CML Participants: Percentage of Participants With CHR
Hematologic response was defined as CHR for CP-CML participants. Participants who entered the trial in CHR and continued to meet the criteria for CHR on study were analyzed as responders. Response criteria for CHR was reported as WBC \<=institutional ULN, platelets \<450,000 per cubic millimeter (/mm\^3), no blasts or promyelocytes in peripheral blood, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, no extramedullary involvement (including no hepatomegaly or splenomegaly).
Time frame: Baseline up to 60 months
CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Confirmed MCyR
Confirmed MCyR was defined as 2 assessments of CCyR or PCyR at least 28 days apart. Participants entering the trial in PCyR must achieve two consecutive assessments of CCyR no fewer than 28 days apart in order to be considered as meeting the criteria for confirmed MCyR. Participants entering the trial in less than PCyR must achieve two consecutive assessments of PCyR or CCyR no fewer than 28 days apart in order to be considered as meeting the criteria for confirmed MCyR. CCyR: no Ph+ cells. PCyR: 1% to 35% Ph+ cells.
Time frame: Baseline up to 60 months
CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Percentage of Participants With Major Molecular Response (MMR)
MMR was defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL \<=0.1% on the International scale (equivalent to a 3-log reduction in transcript). Participants were non-responders in any of the following situations: BCR-ABL or ABL levels not detectable at baseline, no valid baseline or post-baseline assessment, and baseline assessment for e1a2 variant only.
Time frame: Baseline up to 60 months
CP-CML, AP-CML, BP-CML, and Ph+ALL Participants: Median Time to Response (TTR)
Time to response was defined as the interval from the first dose of study treatment until the criteria for response were first met, censored at the last assessment of response. Median time to response was estimated by Kaplan-Meier method.
Time frame: From the first dose of study treatment until the criteria for response were first met (up to 60 months)
CP-CML and Advanced Phase Participants: Median Duration of Response (DOR)
DOR: interval between first assessment at which criteria for response was met, until criteria for progression was met, censored at last date at which criteria for response was met. DOR was estimated using the Kaplan-Meier method. Progression criteria for CP was: death, development of AP/BP, or loss of CHR (in absence of cytogenic response), or loss of MCyR, or increasing WBC in participant without CHR (doubling of WBCs to \>20,000 on 2 occasions at least 4 weeks apart, after first week of therapy), as confirmed by development in complete blood cells (CBCs) at least 4 weeks apart; AP was: death, development of confirmed BP, loss of previous major/minor hematologic response over-2 week period, or no decrease from baseline levels in percentage blasts in peripheral blood/BM on all assessments over a 4-week period; and BP/Ph+ALL was: death/increasing blasts in peripheral blood or BM over a 4-week period. As planned, DOR is reported for all participants by entry mutation (T315I and Other).
Time frame: From the first assessment at which criteria for response was met until the criteria for progression was first met (up to 60 months)
CP-CML and Advanced Phase Participants: Median Progression-free Survival (PFS)
PFS: interval from the first dose of study treatment until the criteria for progression or death were met, censored at the last response assessment. PFS was estimated using the Kaplan-Meier method. Progression criteria for CP was: death, development of AP/BP, or loss of CHR (in absence of cytogenic response), or loss of MCyR, or increasing WBC in participant without CHR (doubling of WBCs to \>20,000 on 2 occasions at least 4 weeks apart, after first week of therapy), as confirmed by development in CBCs at least 4 weeks apart; AP was: death, development of confirmed BP, loss of previous major/minor hematologic response over-2 week period, or no decrease from baseline levels in percentage blasts in peripheral blood/BM on all assessments over a 4-week period; BP/Ph+ALL was: death or increasing blasts in peripheral blood or BM over a 4-week period. As planned, PFS is reported for all participants by entry mutation (T315I and Other).
Time frame: From the first assessment at which criteria for response was met until the criteria for progression or death was met (up to 60 months)
CP-CML and Advanced Phase Participants: Overall Survival (OS)
OS was defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive. Overall survival was estimated using the Kaplan-Meier method. As planned, OS is reported for all participants by entry mutation (T315I and Other).
Time frame: From the first dose of study treatment until death (up to 60 months)
Cmax: Maximum Observed Plasma Concentration for Ponatinib
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
Tmax: Time to Reach the Cmax for Ponatinib
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose for Ponatinib
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)
T1/2: Terminal Phase Elimination Half-life for Ponatinib
Time frame: Cycle 1 Day 1 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length= 28 days)