Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL), Ph+ Mixed Phenotype Acute Leukemia (MPAL), Philadelphia Chromosome-Like ALL (Ph-like ALL)
Conditions
Keywords
Drug Therapy
Brief summary
This study is about an anticancer drug called ponatinib which is a tyrosine kinase inhibitor given with chemotherapy to children, teenagers, and young adults up to 21 years of age with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia who have relapsed or are resistant to other treatment. The main aims of this study are to confirm the highest dose of ponatinib tablets and minitablet capsules that can be given to participants with acceptable side effects, and to evaluate if participant's leukemia achieves remission. Participants will take ponatinib tablets with chemotherapy. For participants who cannot swallow tablets or who are receiving less than a 10 milligrams (mg) dose, a capsule with small ponatinib minitablets inside will be provided. Participants will take ponatinib for 10 weeks in combination with chemotherapy (reinduction and consolidation blocks) and will be followed up for at least 3 years.
Detailed description
The drug being tested in this study is called ponatinib. Ponatinib is being tested to treat pediatric population who have Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), Ph+ mixed phenotype acute leukemia (Ph+ MPAL), or Philadelphia chromosome-like ALL who have relapsed or are resistant or intolerant to a prior tyrosine kinase inhibitor (TKI)-containing therapy, or who have the T315I mutation. The study will enroll approximately 68 participants. Participants will be assigned to a treatment group either in phase 1 or phase 2. Participants unable to swallow the ponatinib tablets or who are receiving less than a 10 mg dose will receive the age-appropriate formulation, capsule with ponatinib minitablets inside: • Ponatinib + Chemotherapy All participants will be asked to take ponatinib once daily. In phase 1 ponatinib will be administered in combination with a chemotherapy backbone to determine the recommended phase 2 dose (RP2D) of ponatinib. In both phase 1 and phase 2, treatment consists of two 35-day blocks of therapy (reinduction block and consolidation block). Each block will include 29 days of treatment of daily ponatinib and a chemotherapy backbone regimen followed by a rest period from chemotherapy for a minimum of 6 days consisting of daily ponatinib only. This is a multi-center trial and will be conducted worldwide. The overall time to participate in this study is 6.5 years. Participants will make multiple visits to the clinic, and may be contacted by telephone in at least 36 months of follow-up after treatment.
Interventions
DRUGPonatinib
Ponatinib tablets.
Chemotherapy agents for reinduction include vincristine, dexamethasone, polyethylene glycol (PEG)-asparaginase (Erwinia asparaginase when PEG-asparaginase is not available), daunorubicin. Agents for intrathecal (IT) chemotherapy, central nervous system (CNS)-1/2: IT methotrexate chemotherapy, or CNS-3: triple intrathecal (ITT) methotrexate, hydrocortisone, cytarabine. Chemotherapy agents for consolidation include dexamethasone, vincristine, methotrexate, PEG-asparaginase (Erwinia asparaginase when PEG-asparaginase is not available), cyclophosphamide, etoposide, CNS-1/2: IT methotrexate chemotherapy, CNS-3: ITT chemotherapy methotrexate, hydrocortisone, cytarabine. The doses for chemotherapy agents for reinduction will be given as per standard of care.
Sponsors
Takeda
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
1. Participants must have a diagnosis of Ph+ ALL, Philadelphia chromosome-positive plus mixed phenotype acute leukemia (Ph+ MPAL), or Ph-like ALL with: a) Involvement of BM with ALL, including one of the following: i. M2 BM (5%-24% lymphoblasts): by morphology with confirmatory testing consisting of at least one of the following: flow cytometry lymphoblasts ≥5%, or BCR-ABL1 fluorescence in situ hybridization, or ≥10-2 leukemic clone identified by immunoglobulin heavy chain-T-cell receptor polymerase chain reaction, OR ii. M3 BM (≥25% lymphoblasts): by morphology, OR iii. Participants with combined BM (as defined above) and extramedullary disease. b) Evidence of Ph+ ALL, MPAL, or Ph-like ALL: i. Definite evidence of BCR-ABL1 fusion (Ph) for Ph+ ALL and MPAL, OR ii. Definite evidence of Ph-like ALL with targetable kinase-activating lesions involving any of the following kinase genes: ABL1, ABL2, CSF1R, and PDGFRB. Ph-like ALL diagnosis requires the identification of specified targetable kinase-activating lesions preferably by ribonucleic acid (RNA) sequencing or by alternative accredited method used by the site. c) Disease status: (i) For non-US sites: participants who have relapsed (post 0 or 1 HSCT) or are resistant or intolerant to at least one prior therapy that contained a BCR-ABL-targeted tyrosine kinase inhibitor (TKI), or for US sites: participants who have relapsed (post 0 or 1 HSCT) or are resistant or intolerant to at least one prior therapy that contained a second-generation BCR-ABL1-targeted TKI (i.e, dasatinib, nilotinib, and bosutinib); OR (ii) Have a BCR-ABL1 T315I mutation irrespective of relapse, resistance/intolerance, or transplant status and irrespective of any prior TKI use. Notes: A participant will be defined as intolerant if they had a Grade ≥3 nonhematologic toxicity or a Grade 4 hematologic toxicity considered related to the last TKI and lasting for \>2 weeks, and led to discontinuation of therapy. 2. Weight: Participants must be weighing at least 5 kg at the time of enrollment. 3. Performance Status: Karnofsky performance status ≥50% for participants ≥16 years of age or Lansky Play Scale ≥50% for participants \<16 years of age. 4. Have recovered to less than Grade 2 National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) Version 5.0, or to baseline, from any nonhematologic toxicities (except alopecia) due to previous therapy. 5. Participants must meet the following criteria related to prior therapies: * Cytoreduction with hydroxyurea: Hydroxyurea can be initiated and continued for up to 24 hours before the start of protocol therapy. * Participants who relapsed while receiving cytotoxic therapy: At least 14 days must have passed since the completion of the last dose of chemotherapy before the first dose of ponatinib can be given except for the following: intrathecal (IT) chemotherapy and/or maintenance therapy such as vincristine, mercaptopurine, methotrexate, or glucocorticoids. There is no waiting period for those relapsing on maintenance-like therapy. * HSCT: Participants who have experienced relapse after a HSCT are eligible, provided they have no evidence of acute or chronic graft-versus-host disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90 days posttransplant at the time of enrollment. * Hematopoietic growth factors: Before the first dose of ponatinib, at least 7 days must have passed since completion of therapy with granulocyte colony-stimulating factor or other growth factors, and at least 14 days must have passed since completion of therapy with pegfilgrastim. * Biologics and targeted therapies: Before the first dose of ponatinib, at least 7 days must have passed since the last dose of a biologic agent. For agents that have known AEs occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the sponsor's medical monitor/designee. * Monoclonal antibodies: After the last dose of monoclonal antibody, at least 3 half-lives of the administered antibody must have passed before the first dose of ponatinib. * Immunotherapy: Before the first dose of ponatinib, at least 30 days must have passed after the completion of any type of immunotherapy (eg, tumor vaccines, chimeric antigen receptor T-cell \[CAR-T-cell\]). * Immunosuppressive therapy: Before the first dose of ponatinib, at least 14 days must have passed after the completion of immunosuppressive therapy (including regimens following stem cell transplant). * Radiotherapy: No washout period is necessary for radiation given to any extramedullary site other than central nervous system (CNS); ≥90 days must have passed if participant received prior total body irradiation or craniospinal or cranial radiotherapy. * Anthracyclines: Participants must have had a lifetime exposure of \<400 milligrams per square meter (mg/m\^2) of doxorubicin equivalents of anthracyclines. 6. a) Adequate renal function defined as: Estimated glomerular filtration rate (eGFR) using the Schwartz formula, OR radioisotope glomerular filtration rate (GFR)≥70 mL/min/1.73 m\^2, OR a normal serum creatinine based on age and sex. b) Adequate liver function defined as: Direct bilirubin ≤1.5 times the upper limit of normal (ULN) for age AND ALT ≤5 times the ULN for age. 7. No clinical, radiological or laboratory evidence of pancreatitis, including: 1. Serum lipase must be \<2 times the ULN, AND 2. Serum amylase must be \<2 times the ULN. 8. Adequate cardiac function defined as shortening fraction ≥27% by echocardiogram (ECHO) OR left ventricular ejection fraction of ≥50% by ECHO or multigated acquisition scan (MUGA). 9. Normal QT interval with Fridericia correction method (QTcF) on screening electrocardiogram (ECG), defined as QTcF of ≤450 milliseconds (ms).
Exclusion criteria
1. A history or current diagnosis of Burkitt leukemia/lymphoma or mature B-cell leukemia. 2. A history or current diagnosis of chronic myeloid leukemia (CML). 3. Diagnosis of ALL, MPAL, or Ph-like ALL with targetable kinase-activating lesions after treatment with cytotoxic therapy for another cancer. 4. Diagnosis of another concurrent primary malignancy. 5. Clinically significant cardiovascular disease, including but not limited to: 1. Any history of myocardial infarction (MI) or unstable angina. 2. History of or presence of heart block, and/or clinically significant ventricular or atrial arrhythmias. 3. Uncontrolled hypertension, defined as persistent elevation of systolic and/or diastolic blood pressures to ≥95th percentile based on age, sex, and height percentiles despite appropriate antihypertensive management. 6. Current systemic use of drug(s) that are known to have a risk of causing prolonged corrected QT interval (QTc) or torsades de pointes unless drug(s) can be changed to acceptable alternatives (ie, an alternate class of agents that do not affect the cardiac conduction system) or the participants can safely discontinue the drug(s). 7. Uncontrolled hypertriglyceridemia (triglycerides ≥450 milligrams per deciliter (mg/dL)). 8. Current systemic use of any medications or herbal supplements that are known to be strong inhibitors or strong inducers of cytochrome P450 3A (CYP3A) within 7 days before the first dose of study drug. 9. Previous treatment with ponatinib. 10. Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or immunotherapy while participant is on study treatment. 11. Known gastrointestinal disease or gastrointestinal procedure that could interfere with the oral absorption of ponatinib. 12. Participants with deoxyribonucleic acid (DNA) fragility syndromes, such as Fanconi anemia and Bloom syndrome. 13. Participants with Down syndrome. 14. Participants with uncontrolled systemic infection, or known laboratory and/or clinical evidence of active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. 15. Participants with pre-existing significant CNS pathology, including history of severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination/movement disorder, or autoimmune disease with CNS involvement, are not eligible. 16. Participants with a history of cerebrovascular ischemia/hemorrhage with residual deficits are not eligible. (Participants with a history of cerebrovascular ischemia/hemorrhage remain eligible provided all neurologic deficits and causative factor(s) have resolved). 17. Uncontrolled seizure disorder. (Participants with seizure disorders that do not require antiepileptic drugs or are well controlled with stable doses of antiepileptic drugs are eligible). 18. History of severe coagulopathy or cardiovascular or peripheral vascular events. 19. Treatment with live attenuated vaccinations within 30 days prior to initiation of study treatment regimen.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy | Up to Day 35 in Phase 1 | The RP2D is the maximum tolerated dose (MTD) or less. |
| Phase 2: Percentage of Participants With Complete Remission (CR) at the End of the Reinduction Block | Up to Day 35 in Phase 2 | CR was defined as no circulating blasts and less than (\<)5 percent (%) blasts in the bone marrow (BM); normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) greater than (\>)1000 cells/microliter (μL) (or \>1.0 × 10\^9 cells/liter \[L\]); Platelets \>100,000/μL (or \>100 × 10\^9 platelets/L). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Percentage of Ph+ ALL Participants With Negative Minimal Residual Disease (MRD) Among Those Who Achieved CR | Up to Day 70 (end of consolidation block) in Phase 2 | MRD negative rate is the percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirate at \<0.01% threshold. |
| Phase 2: Percentage of Participants Who Relapsed or Progressed Following Reinduction and Consolidation | Up to 3 years of follow-up in Phase 2 | — |
| Phase 2: Event-free Survival (EFS) | Up to 3 years of follow-up in Phase 2 | EFS was defined as time from date of enrollment until death due to any cause; refractory to treatment (defined as failure to achieve CR by end of the consolidation block) or relapse from CR. CR was defined as no circulating blasts and \<5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000 platelets/μL (or \>100 × 10\^9 platelets/L). |
| Phase 2: Progression-free Survival (PFS) | Up to 3 years of follow-up in Phase 2 | PFS was defined as time from date of enrolment until death related to disease under study; disease progression (clinical deterioration associated with disease process, including evidence of increasing blasts in the bone marrow from baseline and/or evidence of new organ involvement) or relapse from CR. CR was defined as no circulating blasts and \<5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000 platelets/μL (or \>100 × 10\^9 platelets/L). |
| Phase 2: Overall Survival (OS) | Up to 3 years of follow-up in Phase 2 | OS was defined as time from first dose of ponatinib until death due to any cause. |
| Phase 2: Duration of Response (DOR) | Up to 3 years of follow-up in Phase 2 | DOR was defined as the interval between the first assessment at which the criteria for CR are met until the time at which relapse from CR occurs. CR was defined as no circulating blasts and \<5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000 platelets/μL (or \>100 × 10\^9 platelets /L). |
| Phase 1: Number of Participants With CR at the End of Reinduction Block | Day 35 in Phase 1 | CR was defined as no circulating blasts and \<5% blasts in the BM; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000/μL (or \>100 × 10\^9 platelets/L). |
| Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib | Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1 | — |
| Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib | Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1 | — |
| Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib | Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1 | — |
| Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | Up to 34.8 months in Phase 1 | An adverse event (AE) is defined as any untoward medical occurrence in clinical study participant, temporally associated with use of study intervention, whether or not occurrence was considered related to the study intervention including any unfavorable & unintended sign (e.g., clinically significant abnormal laboratory finding), symptom/disease. TEAE: any AE that occurs after administration of first dose of any study drug & through 30 days after last dose of any study drug. Serious TEAE:AE that at any dose resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent/significant disability or incapacity, was congenital anomaly/birth defect, was medically important event. AESI: Protocol-defined AEs resulting in compromise of organ function or other significant consequences. VTEs were identified as AESIs for ponatinib and included arterial, VTEs that meet criteria for serious TEAEs. |
| Phase 2: Number of Participants With TEAEs, Serious TEAEs, VTEs, and AESIs | Up to 30 days after last dose of ponatinib in Phase 2 | An AE is defined as any untoward medical occurrence in clinical study participant, temporally associated with use of study intervention, whether or not occurrence was considered related to the study intervention including any unfavorable & unintended sign (e.g., clinically significant abnormal laboratory finding), symptom/disease. TEAE: any AE that occurs after administration of first dose of any study drug & through 30 days after last dose of any study drug. Serious TEAE:AE that at any dose resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent/significant disability or incapacity, was congenital anomaly/birth defect, was medically important event. AESI: Protocol-defined AEs resulting in compromise of organ function or other significant consequences. VTEs were identified as AESIs for ponatinib and included arterial, VTEs that meet criteria for serious TEAEs. |
| Phase 2: Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplantation (HSCT) | Up to 3 years of follow-up in Phase 2 | — |
| Phase 2: Percentage of Ph+ ALL Participants Who Achieved CR at the End of Consolidation Block | Day 70 in Phase 2 | CR was defined as no circulating blasts and \<5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000 platelets/μL (or \>100 × 10\^9 platelets/L). |
Countries
Argentina, Australia, Brazil, China, Czechia, France, Italy, Mexico, Netherlands, Poland, Portugal, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants with a diagnosis of Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) took part in the study at various investigative sites globally from 24 February 2021 to 19 July 2024.
Pre-assignment details
Participants were enrolled in Phase 1 and received ponatinib per protocol specifications (presented per dose regimen here). Due to the observation of multiple dose-limiting toxicities (DLTs) in Phase 1, study enrollment was terminated per protocol and no recommended phase 2 dose (RP2D) could be determined. The Sponsor terminated the study following a 6-month follow-up and no participants were enrolled in Phase 2 of the study, thus, no Phase 2 results are presented here as it was not conducted.
Participants by arm
| Arm | Count |
|---|---|
| Ponatinib 30 mg Adult-Equivalent Participants received weight-based dose of ponatinib tablets 30 mg adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator's discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1. | 7 |
| Ponatinib 15 mg Adult-Equivalent Participants received weight-based dose of ponatinib tablets 15 mg adult-equivalent, orally, once daily in combination with chemotherapy backbone per standard regimen at the investigator's discretion in both reinduction block and consolidation block (35 days each including 29 days of treatment in combination with chemotherapy followed by a minimum 6-day rest period from chemotherapy with daily ponatinib only) up to Day 70 (end of consolidation) followed by optional ponatinib continuation in Phase 1. | 4 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study Terminated by Sponsor | 6 | 3 |
| Overall Study | Withdrawal by Participant (Parent/Legal Guardian) | 1 | 1 |
Baseline characteristics
| Characteristic | Ponatinib 15 mg Adult-Equivalent | Total | Ponatinib 30 mg Adult-Equivalent |
|---|---|---|---|
| Age, Continuous | 13.5 years STANDARD_DEVIATION 3.7 | 12.6 years STANDARD_DEVIATION 2.84 | 12.1 years STANDARD_DEVIATION 2.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 9 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 6 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 4 |
| other Total, other adverse events | 7 / 7 | 4 / 4 |
| serious Total, serious adverse events | 5 / 7 | 2 / 4 |
Outcome results
Primary
Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy
The RP2D is the maximum tolerated dose (MTD) or less.
Time frame: Up to Day 35 in Phase 1
Population: The Safety Population included all participants who received at least 1 dose of ponatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy | NA milligrams per square meter (mg/m^2) |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy | NA milligrams per square meter (mg/m^2) |
Primary
Phase 2: Percentage of Participants With Complete Remission (CR) at the End of the Reinduction Block
CR was defined as no circulating blasts and less than (\<)5 percent (%) blasts in the bone marrow (BM); normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) greater than (\>)1000 cells/microliter (μL) (or \>1.0 × 10\^9 cells/liter \[L\]); Platelets \>100,000/μL (or \>100 × 10\^9 platelets/L).
Time frame: Up to Day 35 in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
Secondary
Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib
Time frame: Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1
Population: The PK Analysis Population included all participants in the Phase 1 portion of the study who had sufficient ponatinib dosing data and concentration-time data to permit the calculation of ponatinib PK parameters. Number analyzed is the number of participants with data available for analysis for the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ponatinib 30 mg Adult-Equivalent | Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib | Day 1 | 883 hours*nanograms/milliliter (h*ng/mL) | Geometric Coefficient of Variation 22.8 |
| Ponatinib 30 mg Adult-Equivalent | Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib | Day 22 | 2800 hours*nanograms/milliliter (h*ng/mL) | — |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib | Day 1 | 264 hours*nanograms/milliliter (h*ng/mL) | Geometric Coefficient of Variation 62.1 |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib | Day 22 | 815 hours*nanograms/milliliter (h*ng/mL) | Geometric Coefficient of Variation 83.2 |
Secondary
Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib
Time frame: Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1
Population: The Pharmacokinetic (PK) Analysis Population included all participants in the Phase 1 portion of the study who had sufficient ponatinib dosing data and concentration-time data to permit the calculation of ponatinib PK parameters. Number analyzed is the number of participants with data available for analysis for the specified timepoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib | Day 1 | 65.8 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 29.5 |
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib | Day 22 | 183 nanograms/milliliter (ng/mL) | — |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib | Day 1 | 24.9 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 71.1 |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib | Day 22 | 47.7 nanograms/milliliter (ng/mL) | Geometric Coefficient of Variation 92.8 |
Secondary
Phase 1: Number of Participants With CR at the End of Reinduction Block
CR was defined as no circulating blasts and \<5% blasts in the BM; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000/μL (or \>100 × 10\^9 platelets/L).
Time frame: Day 35 in Phase 1
Population: The Safety Population included all participants who received at least 1 dose of ponatinib. Overall number of participants analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Number of Participants With CR at the End of Reinduction Block | 1 Participants |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Number of Participants With CR at the End of Reinduction Block | 2 Participants |
Secondary
Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs)
An adverse event (AE) is defined as any untoward medical occurrence in clinical study participant, temporally associated with use of study intervention, whether or not occurrence was considered related to the study intervention including any unfavorable & unintended sign (e.g., clinically significant abnormal laboratory finding), symptom/disease. TEAE: any AE that occurs after administration of first dose of any study drug & through 30 days after last dose of any study drug. Serious TEAE:AE that at any dose resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent/significant disability or incapacity, was congenital anomaly/birth defect, was medically important event. AESI: Protocol-defined AEs resulting in compromise of organ function or other significant consequences. VTEs were identified as AESIs for ponatinib and included arterial, VTEs that meet criteria for serious TEAEs.
Time frame: Up to 34.8 months in Phase 1
Population: The Safety Population included all participants who received at least 1 dose of ponatinib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | TEAEs | 7 Participants |
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | Serious TEAEs | 5 Participants |
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | VTEs | 0 Participants |
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | AESIs | 0 Participants |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | AESIs | 0 Participants |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | TEAEs | 4 Participants |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | VTEs | 0 Participants |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | Serious TEAEs | 2 Participants |
Secondary
Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib
Time frame: Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1
Population: The PK Analysis Population included all participants in the Phase 1 portion of the study who had sufficient ponatinib dosing data and concentration-time data to permit the calculation of ponatinib PK parameters. Number analyzed is the number of participants with data available for analysis for the specified timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib | Day 1 | 6.00 hours |
| Ponatinib 30 mg Adult-Equivalent | Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib | Day 22 | 4.08 hours |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib | Day 1 | 3.99 hours |
| Ponatinib 15 mg Adult-Equivalent | Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib | Day 22 | 3.92 hours |
Secondary
Phase 2: Duration of Response (DOR)
DOR was defined as the interval between the first assessment at which the criteria for CR are met until the time at which relapse from CR occurs. CR was defined as no circulating blasts and \<5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000 platelets/μL (or \>100 × 10\^9 platelets /L).
Time frame: Up to 3 years of follow-up in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
Secondary
Phase 2: Event-free Survival (EFS)
EFS was defined as time from date of enrollment until death due to any cause; refractory to treatment (defined as failure to achieve CR by end of the consolidation block) or relapse from CR. CR was defined as no circulating blasts and \<5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000 platelets/μL (or \>100 × 10\^9 platelets/L).
Time frame: Up to 3 years of follow-up in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
Secondary
Phase 2: Number of Participants With TEAEs, Serious TEAEs, VTEs, and AESIs
An AE is defined as any untoward medical occurrence in clinical study participant, temporally associated with use of study intervention, whether or not occurrence was considered related to the study intervention including any unfavorable & unintended sign (e.g., clinically significant abnormal laboratory finding), symptom/disease. TEAE: any AE that occurs after administration of first dose of any study drug & through 30 days after last dose of any study drug. Serious TEAE:AE that at any dose resulted in death, was life-threatening, required inpatient hospitalization/prolongation of existing hospitalization, resulted in persistent/significant disability or incapacity, was congenital anomaly/birth defect, was medically important event. AESI: Protocol-defined AEs resulting in compromise of organ function or other significant consequences. VTEs were identified as AESIs for ponatinib and included arterial, VTEs that meet criteria for serious TEAEs.
Time frame: Up to 30 days after last dose of ponatinib in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
Secondary
Phase 2: Overall Survival (OS)
OS was defined as time from first dose of ponatinib until death due to any cause.
Time frame: Up to 3 years of follow-up in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
Secondary
Phase 2: Percentage of Participants Who Relapsed or Progressed Following Reinduction and Consolidation
Time frame: Up to 3 years of follow-up in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
Secondary
Phase 2: Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplantation (HSCT)
Time frame: Up to 3 years of follow-up in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
Secondary
Phase 2: Percentage of Ph+ ALL Participants Who Achieved CR at the End of Consolidation Block
CR was defined as no circulating blasts and \<5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000 platelets/μL (or \>100 × 10\^9 platelets/L).
Time frame: Day 70 in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
Secondary
Phase 2: Percentage of Ph+ ALL Participants With Negative Minimal Residual Disease (MRD) Among Those Who Achieved CR
MRD negative rate is the percentage of participants who achieve MRD negative status by evaluation of bone marrow aspirate at \<0.01% threshold.
Time frame: Up to Day 70 (end of consolidation block) in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.
Secondary
Phase 2: Progression-free Survival (PFS)
PFS was defined as time from date of enrolment until death related to disease under study; disease progression (clinical deterioration associated with disease process, including evidence of increasing blasts in the bone marrow from baseline and/or evidence of new organ involvement) or relapse from CR. CR was defined as no circulating blasts and \<5% blasts in the bone marrow; normal maturation of all cellular components in the bone marrow; no extramedullary disease; ANC \>1000 cells/μL (or \>1.0 × 10\^9 cells/L); Platelets \>100,000 platelets/μL (or \>100 × 10\^9 platelets/L).
Time frame: Up to 3 years of follow-up in Phase 2
Population: The study enrollment was terminated per protocol due to DLTs observed in both dose cohorts in Phase 1 and the RP2D could not be determined leading to study termination by the Sponsor before Phase 2 could be initiated. No data was collected as no participants were enrolled in Phase 2.