Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL) Clinical Trial
Official title:
A Pivotal Phase 1/2, Single-Arm, Open-label Study to Evaluate the Safety and Efficacy of Ponatinib With Chemotherapy in Pediatric Patients With Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Who Have Relapsed or Are Resistant or Intolerant to a Prior Tyrosine Kinase Inhibitor-Containing Therapy, or Who Have the T315I Mutation
| Verified date | March 2024 |
| Source | Takeda |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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 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.
| Status | Active, not recruiting |
| Enrollment | 68 |
| Est. completion date | January 4, 2027 |
| Est. primary completion date | December 19, 2024 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 1 Year to 21 Years |
| Eligibility | 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. |
| Country | Name | City | State |
|---|---|---|---|
| Argentina | Hospital Italiano de Buenos Aires | Buenos Aires | |
| Argentina | Hospital Universitario Austral | Pilar | Buenos Aires |
| Australia | Perth Childrens Hospital | Nedlands | Western Australia |
| Australia | Royal Children's Hospital Melbourne - PIN | Parkville | Victoria |
| Australia | Queensland Childrens Hospital | South Brisbane | Queensland |
| Brazil | Fundacao Pio XII Hospital de Cancer de Barretos | Barretos | Sao Paulo |
| Brazil | Rua Ramiro Barcelos, 2350 | Curitiba | Parana |
| Brazil | Hospital de Clinicas de Porto Alegre (HCPA) - PPDS | Porto Alegre | Rio Grande Du Sul |
| Brazil | Irmandade Da Santa Casa de Misericordia de Porto Alegre | Porto Alegre | Rio Grande Du Sul |
| Brazil | Hospital Das Clinicas da Faculdade de Medicina de Ribeirao Preto - USP | Ribeirao Preto | |
| Brazil | Graacc Grupo de Apoio Ao Adolescente E A Crianca Com Cancer | Sao Paulo | |
| Brazil | Hospital Santa Marcelina | Sao Paulo | |
| China | West China Second University Hospital, Sichuan Univesity | Chengdu | |
| China | Children's Hospital of Chongqing Medical University | Chongqing | |
| China | The Affiliated Hospital of Guizhou Medical University | Guiyang | |
| China | The Second Hospital of Anhui Medical University | Hefei | |
| China | Qilu Hospital of Shandong University | Jinan | |
| China | Children's Hospital of Shanghai | Shanghai | |
| China | Shanghai Childrens Medical Center | Shanghai | |
| China | Children's Hospital of Soochow University | Suzhou | |
| China | Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences | Tianjin | |
| China | Tongji Hospital Tongji Medical College Huazhong University of Science and Technology | Wuhan | |
| China | Union Hospital Tongji Medical College Huazhong University of Science and Technology | Wuhan | |
| Czechia | Fakultni nemocnice Brno | Brno | |
| Czechia | Fakultni nemocnice v Motole | Praha | |
| France | Assistance Publique Hopitaux de Marseille | Marseille | |
| France | Hopital Robert Debre | Paris | |
| France | Hopital Sud | Rennes | Ille-et-Vilaine |
| France | Hopital Des Enfants | Toulouse | |
| Italy | Istituto G Gaslini Ospedale Pediatrico IRCCS - INCIPIT - PIN | Genova | Liguria |
| Italy | Fndazione MBBM (MONZA E BRIANZA PER IL BAMBINO E LA SUA MAMMA) - c/o Centro Maria Letizia Verga | Monza | Lombardia |
| Italy | IRCCS Ospedale Pediatrico Bambino Gesu - INCIPIT - PIN | Roma | Lazio |
| Italy | Ospedale Infantile Regina Margherita - INCIPIT - PIN | Torino | Piemonte |
| Korea, Republic of | Asan Medical Center - PPDS | Seoul | |
| Korea, Republic of | Seoul National University Hospital | Seoul | |
| Korea, Republic of | Severance Hospital Yonsei University Health System | Seoul | |
| Korea, Republic of | The Catholic University of Korea, Seoul St. Mary's Hospital | Seoul | |
| Mexico | Instituto Nacional de Pediatria | Ciudad De Mexico | |
| Mexico | Nuevo Hospital Civil de Guadalajara Dr. Juan I. Menchaca | Guadalajara | |
| Mexico | Hospital Universitario Dr. Jose Eleuterio Gonzalez | Monterrey | Nuevo Leon |
| Netherlands | Princess Maxima Center for Pediatric Oncology - PIN | Utrecht | |
| Poland | Uniwersytecki Szpital Dzieciecy | Krakow | |
| Poland | SPSK Nr 1 im. Prof.Stanislawa Szyszko Slaskiego Uniwersytetu Medycznego | Zabrze | |
| Portugal | Instituto Portugues de Oncologia de Lisboa Francisco Gentil, E.P.E. | Lisbon | Lisboa |
| Portugal | Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS | Porto | |
| Spain | Hospital Universitario Vall d'Hebron - PPDS | Barcelona | |
| Spain | Hospital Infantil Universitario Nino Jesus - PIN | Madrid | |
| Spain | Hospital Universitario Virgen del Rocio - PPDS | Sevilla | |
| United Kingdom | Cambridge University Hospitals NHS Foundation Trust | Cambridge | |
| United Kingdom | Royal Hospital for Children (Glasgow) - PPDS - PIN | Glasgow | |
| United Kingdom | Royal Marsden Hospital - Surrey | Surrey Quays | Sutton |
| United States | Ann and Robert H Lurie Childrens Hospital of Chicago | Chicago | Illinois |
| United States | Cincinnati Children's Hospital Medical Center - PIN | Cincinnati | Ohio |
| United States | Nationwide Children's Hospital | Columbus | Ohio |
| United States | Childrens Medical Center Research Institute at UT Southwestern | Dallas | Texas |
| United States | Riley Hospital For Children | Indianapolis | Indiana |
| United States | Children's Mercy Hospital and Clinica | Kansas City | Missouri |
| United States | Arkansas Children's Hospital | Little Rock | Arkansas |
| United States | Children's Hospital Los Angeles | Los Angeles | California |
| United States | St Jude Children's Research Hospital | Memphis | Tennessee |
| United States | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania |
| United States | Rady Childrens Hospital San Diego - PIN | San Diego | California |
| United States | UCSF Medical Comprehensive Cancer | San Francisco | California |
| United States | Alfred I Dupont Hospital For Children | Wilmington | Delaware |
| Lead Sponsor | Collaborator |
|---|---|
| Takeda |
United States, Argentina, Australia, Brazil, China, Czechia, France, Italy, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Spain, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy | The RP2D is the maximum tolerated dose (MTD) or less. | Up to Week 4 | |
| Primary | Phase 2: Complete Remission (CR) Rate at the end of Reinduction Block | CR rate is defined as percentage of participants with CR at end of reinduction block. CR is defined as no circulating blasts and <5% blasts in the bone marrow (BM); normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) >1000 cells/microliter (µL) (or >1.0 × 10^9 cells/liter [L]); Platelets >100,000/µL (or >100 × 10^9 platelets/L). | Up to Week 4 | |
| Secondary | Phase 1: CR Rate at the end of Reinduction Block | CR rate is defined as percentage of participants with CR at end of reinduction block. CR is defined as no circulating blasts and <5% blasts in the BM; normal maturation of all cellular components in the bone marrow; no extramedullary disease; absolute neutrophil count (ANC) >1000 cells/µL (or >1.0 × 10^9 cells/L); Platelets >100,000/µL (or >100 × 10^9 platelets/L). | Up to Week 4 | |
| Secondary | Phase 2: Percentage of Ph+ ALL Participants or who Achieved CR at the End of Consolidation Block | CR is 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). | Up to Week 8 | |
| 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. | Up to Weeks 4 and 8 | |
| Secondary | Phase 2: Percentage of Participants who Relapsed or Progressed Following Reinduction and Consolidation | Up to Weeks 4 and 8 | ||
| Secondary | Phase 2: Event-free Survival (EFS) | EFS is 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 is 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). | Up to approximately 36 months | |
| Secondary | Phase 2: Progression-free Survival (PFS) | PFS is 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 is 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). | Up to approximately 36 months | |
| Secondary | Phase 2: Overall Survival (OS) | OS is defined as time from first dose of ponatinib until death due to any cause. | Up to approximately 36 months | |
| Secondary | Phase 2: Duration of Response (DOR) | DOR is 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 is 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). | Up to approximately 36 months | |
| Secondary | Phase 2: Percentage of Participants who Underwent Hematopoietic Stem Cell Transplantation (HSCT) | Up to approximately 36 months | ||
| Secondary | Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib | Predose and at multiple timepoints (Up to 24 hours) postdose on Days 1 and 22 | ||
| Secondary | Phase 1: tmax: Time of First Occurrence of Cmax for Ponatinib | Predose and at multiple timepoints (Up to 24 hours) postdose on Days 1 and 22 | ||
| Secondary | 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 (Up to 24 hours) postdose on Days 1 and 22 | ||
| Secondary | Phase 1 and 2: Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs), Venous Thrombotic/Embolic Events (VTEs), and Adverse Events of Special Interest (AESIs) | From the first dose of study drug up to 30 days after last dose of study drug (Up to 36 months) |