Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication ICLUSIG ® is indicated for the treatment of adult patients with: Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Newly diagnosed Ph+ ALL in combination with chemotherapy. This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction [see Clinical Studies (14) ] . FDA label
Also known as ponatinib - Phase 1, AP24534, Iclusig
Ponatinib · 7 trials · 12 indications
MRD-negative CR was achieved when a participant met the criteria for both MRD negativity and CR. MRD-negativity: ≤0.01 % breakpoint cluster region-Abelson (BCR-ABL1/ABL1), or undetectable BCR-ABL1 transcripts in complementary deoxyribonucleic acid (cDNA) with ≥ 10,000 ABL1 transcripts. CR: meeting all the following for at least 4 weeks (that is no recurrence):1. No circulating blasts and less than (\<) 5% blasts in the bone marrow (BM). 2. Normal maturation of all cellular components in the BM. 3. No extramedullary disease (central nervous system \[CNS\] involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass). 4. Absolute neutrophil count (ANC) \> 1000 per microliter (/mcL) (or \>1.0\*10\^9/L). 5. Platelets \>100,000/mcL (or \>100\*10\^9/L).
To assess clinical benefit rate in participants with KIT exon 11-mutant GIST.It is defined as the composite of complete response(CR),partial response(PR),and stable disease(SD) lasting \>=16 weeks per modified Response Evaluation Criteria In Solid Tumors(RECIST) 1.1 as a measure of disease control.CR is complete disappearance of all target lesions and non-target disease, with the exception of nodal disease.All nodes, both target and non-target, must decrease to normal (short axis \<10millimeter \[mm\]).No new lesions.PR is \>=30% decrease under baseline of the sum of diameters of all target lesions.The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions.No unequivocal progression of non-target disease.No new lesions.SD is not qualifying for CR,PR,Progressive Disease(PD).PD is \>=20% increase from the smallest prior sum of the longest diameter(SLD)and with \>=5mm absolute increase, or appearance of a new lesion.
MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.
MaHR is defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). Response criteria for CHR is reported as white blood cells (WBC)≤institutional upper limit of normal, 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 is reported as WBC≤institutional upper limit of normal, 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.
MaHR is defined as percentage of participants with CHR or NEL. Response criteria for CHR is reported as WBC≤institutional upper limit of normal, 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 is reported as WBC≤ institutional upper limit of normal, 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.
Will be evaluated by BCR::ABL1 reverse transcriptase polymerase chain reaction.
MR2 was defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL \<=1% Breakpoint Cluster Region-Abelson Transcript Level as measured by the International Scale (BCR-ABL1IS), equivalent to a 2-log reduction in transcript.
Determine MTD dose or a recommended dose of oral ponatinib in a defined schedule (QD) in patients with refractory or advanced chronic myelogenous leukemia and other refractory hematologic malignancies.
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.
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.
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.
| Arm | Type | Description |
|---|---|---|
| Cohort A: Ponatinib 30 milligram (mg) | EXPERIMENTAL | Ponatinib 30 mg, tablets, orally, once daily (QD), with vincristine 1.4 mg/m\^2 (max 2 mg) intravenous (IV), on Days 1 and 14 and dexamethasone 40 mg (\<60 years \[yrs\]) and 20 mg (≥60 yrs), orally, once on Days 1 to 4, Days 11 to 14 for up to 3 cycles (each cycle=28 days) in induction phase (reduced dose of ponatinib 15 mg upon achievement of MRD-negative CR at end of induction) followed by ponatinib last induction phase dose with cytarabine, 1000 mg/m\^2 as 2-hour IV infusion (\<60 yrs) and 250 mg/m\^2 (≥60 yrs) every 12 hours, IV on Days 1, 3, 5 of Cycles 2,4,6 and methotrexate, 1000 mg/m\^2 (\<60 yrs) and 250 mg/m\^2 (≥60 yrs), IV infusion, on Day 1 of cycles 1, 3, 5 in consolidation phase followed by ponatinib last consolidation phase dose with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Day 1 and prednisone 200 mg (\<60 yrs), 100 mg (≥60-69 yrs) and 50 mg(≥70 yrs) on Days 1 to 5 for up to 11 cycles in maintenance phase up to data cut-off date: 12 August 2022. |
| Cohort B: Imatinib 600 mg | ACTIVE_COMPARATOR | Imatinib 600 mg, tablets, orally, QD, with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Days 1 and 14 and dexamethasone 40 mg (\<60 yrs) and 20 mg (≥60 yrs), orally, once on Days 1 to 4 and Days 11 to 14 in each 28-day cycle for up to 3 cycles in the induction phase followed by imatinib 600 mg, tablets, orally, QD, with cytarabine, 1000 mg/m\^2 every 12 hours as a 2-hour-IV infusion (\<60 yrs) and 250 mg/m\^2 every 12 hours (≥60 yrs), IV on Days 1, 3, and 5 of each 28-day even cycles (Cycles 2, 4, and 6), and methotrexate, 1000 mg/m\^2 (\<60 yrs) and 250 mg/m\^2 (≥60 yrs), IV infusion, on Day 1 of each 28-day odd cycles (Cycle 1, 3, and 5) in consolidation phase followed by imatinib 600 mg, tablets, orally, QD, along with vincristine 1.4 mg/m\^2 (max 2 mg), IV, on Day 1 and prednisone 200 mg (\<60 yrs), 100 mg (≥60-69 yrs) and 50 mg (≥70 yrs) on Days 1 through 5 in each 28-day cycle up to 11 cycles in maintenance phase up to data cut-off date: 12 August 2022. |
| Cohort A | EXPERIMENTAL | Participants with KIT exon 11-mutant GIST. |
| Cohort B | EXPERIMENTAL | Participants with GIST that lack KIT exon 11 mutations (Cohort B). |
| Cohort A: CP-CML R-I | EXPERIMENTAL | CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). |
| Cohort B: CP-CML with T315I Mutation | EXPERIMENTAL | CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). |
| Cohort C: Accelerated Phase (AP)-CML R-I | EXPERIMENTAL | AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). |
| Cohort D: AP-CML with T315I Mutation | EXPERIMENTAL | AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). |
| Cohort E: Blast Phase (BP)-CML/Ph+ ALL R-I | EXPERIMENTAL | BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). |
| Cohort F: BP-CML or Ph+ ALL with T315I Mutation | EXPERIMENTAL | BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). |
| Unassigned to Cohorts A-F | EXPERIMENTAL | Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not R-I to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months). |
| Treatment (DA-EPOCH, rituximab, ponatinib) | EXPERIMENTAL | Patients receive etoposide IV, doxorubicin IV, and vincristine IV over 96 hours on days 1-4, cyclophosphamide IV over 1 hour on day 5, and prednisone PO BID on days 1-5 and ponatinib PO QD on days 1-21 of each cycle. Patients receive filgrastim SC on day 6, 7, or 8 and continue until ANC \> 2000/µL past nadir or pegfilgrastim SC on day 6, 7, or 8 of each cycle. Patients who are CD20 positive also receive rituximab IV on day 1 or 5 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, bone marrow aspiration and biopsy and CT throughout the study. Additionally, patients may undergo PET/CT at enrollment. |
| Treatment Period: Cohort A: Ponatinib 45 milligrams (mg) | EXPERIMENTAL | Participants received ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily. |
| Treatment Period: Cohort B: Ponatinib 30 mg | EXPERIMENTAL | Participants received ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily. |
| Treatment Period: Cohort C: Ponatinib 15 mg | EXPERIMENTAL | Participants received ponatinib 15 mg orally once daily in each 28 day Cycle. |
| Close-out Period: Cohort A: Ponatinib 45 mg | EXPERIMENTAL | Participants received ponatinib 45 mg orally once daily in each 28-day cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily. |
| Close-out Period: Cohort B: Ponatinib 30 mg | EXPERIMENTAL | Participants received ponatinib 30 mg orally once daily in each 28 day Cycle until achievement of ≤1% BCR-ABL1IS. Once ≤1% BCR-ABL1IS was achieved, participants received reduced dose of ponatinib 15 mg orally once daily. |
| Close-out Period: Cohort C: Ponatinib 15 mg | EXPERIMENTAL | Participants received ponatinib 15 mg orally once daily in each 28 day Cycle. |
| ponatnib | EXPERIMENTAL | Comparison of different dosages of ponatinib given orally once per day. |
| Phase 1 dose escalation | EXPERIMENTAL | Phase 1 |
| Phase 2 expansion | EXPERIMENTAL | Phase 2 |
| Name | Type | Description |
|---|---|---|
| Ponatinib | DRUG | Ponatinib Tablets. |
| Imatinib | DRUG | Imatinib Tablets. |
| Vincristine | DRUG | Vincristine IV injection. |
| Dexamethasone | DRUG | Dexamethasone Tablets. |
| Cytarabine | DRUG | Cytarabine IV infusion. |
| Methotrexate | DRUG | Methotrexate IV infusion. |
| Prednisone | DRUG | Prednisone Tablets. |
| Cyclophosphamide | DRUG | Given IV |
| Doxorubicin | DRUG | Given IV |
| Etoposide | DRUG | Given IV |
| Filgrastim | BIOLOGICAL | Given SC |
| Pegfilgrastim | BIOLOGICAL | Given SC |
| Rituximab | BIOLOGICAL | Given IV |
| Biospecimen Collection | PROCEDURE | Undergo blood sample collection |
| Bone Marrow Aspiration | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Bone Marrow Biopsy | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Computed Tomography | PROCEDURE | Undergo CT and PET/CT |
| Positron Emission Tomography | PROCEDURE | Undergo PET/CT |
| ponatinib - Phase 1 | DRUG | 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. |
| ponatinib - Phase 2 | DRUG | 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. |
Inclusion Criteria: 1. Newly diagnosed Philadelphia chromosome-positive (Ph+) or BCR-ABL1-positive ALL, as defined by the 2017 national comprehensive cancer network (NCCN) guidelines. 2. Eastern Cooperative Oncology Group (ECOG) performance status of \<=2. Exclusion Criteria: 1. With a history or...
Ponatinib is an oral small molecule studied in several blood cancers and in gastrointestinal stromal tumor. Its development focuses on Philadelphia chromosome positive acute lymphoblastic leukemia, chronic phase chronic myeloid leukemia, and B acute lymphoblastic leukemia with the t(9;22)(q34.1;q11.2); BCR-ABL1 abnormality, plus GIST.
Ponatinib targets ABL1 and BCR. It is an inhibitor of these proteins, which are linked to the BCR-ABL1 fusion that drives Philadelphia chromosome positive leukemias. By inhibiting this target, the drug is designed to interfere with the signaling that supports these cancer cells.
Ponatinib is developed by Takeda Pharmaceutical Company Limited, which trades under the ticker TAK. Takeda is the company listed as the developer of the ponatinib clinical program across the leukemia and GIST studies.
Ponatinib is in Phase 2 development overall, with one active Phase 2 trial and completed Phase 2 studies. A Phase 3 study of ponatinib versus imatinib in adults with Philadelphia chromosome positive acute lymphoblastic leukemia is also listed as active but not recruiting. Ponatinib is investigational.
Ponatinib trials include NCT07224100, a recruiting Phase 2 study of dose-adjusted EPOCH with or without rituximab plus ponatinib in newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoma, and NCT03589326, a Phase 3 study of ponatinib versus imatinib in adults with Ph+ALL.
Yes. Ponatinib is also referred to as ponatinib - Phase 1 and ponatinib- Phase 1. These are alternate names for the same agent, so searches using those labels refer to the ABL1 and BCR inhibitor developed by Takeda.