Clinical trial NCT04501614: A Study of Ponatinib With Chemotherapy in Children, Teenagers, and Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Pediatric Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia (Ph+ALL)
Ph+ Mixed Phenotype Acute Leukemia (MPAL)
Philadelphia Chromosome-Like ALL (Ph-like ALL)
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2020-08-06
Enrollment: 11
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1: Recommended Phase 2 Dose (RP2D) of Ponatinib in Combination With Chemotherapy
timeFrame: Up to Day 35 in Phase 1
measure: Phase 2: Percentage of Participants With Complete Remission (CR) at the End of the Reinduction Block
timeFrame: Up to Day 35 in Phase 2
Secondary outcomes:
measure: Phase 1: Number of Participants With CR at the End of Reinduction Block
timeFrame: Day 35 in Phase 1
measure: Phase 2: Percentage of Ph+ ALL Participants Who Achieved CR at the End of Consolidation Block
timeFrame: Day 70 in Phase 2
measure: Phase 2: Percentage of Ph+ ALL Participants With Negative Minimal Residual Disease (MRD) Among Those Who Achieved CR
timeFrame: Up to Day 70 (end of consolidation block) in Phase 2
measure: Phase 2: Percentage of Participants Who Relapsed or Progressed Following Reinduction and Consolidation
timeFrame: Up to 3 years of follow-up in Phase 2
measure: Phase 2: Event-free Survival (EFS)
timeFrame: Up to 3 years of follow-up in Phase 2
measure: Phase 2: Progression-free Survival (PFS)
timeFrame: Up to 3 years of follow-up in Phase 2
measure: Phase 2: Overall Survival (OS)
timeFrame: Up to 3 years of follow-up in Phase 2
measure: Phase 2: Duration of Response (DOR)
timeFrame: Up to 3 years of follow-up in Phase 2
measure: Phase 2: Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplantation (HSCT)
timeFrame: Up to 3 years of follow-up in Phase 2
measure: Phase 1: Cmax: Maximum Observed Plasma Concentration for Ponatinib
timeFrame: Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1
measure: Phase 1: Tmax: Time of First Occurrence of Cmax for Ponatinib
timeFrame: Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1
measure: Phase 1: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ponatinib
timeFrame: Predose and at multiple timepoints post-dose up to 24 hours on Days 1 and 22 in Phase 1
measure: 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)
timeFrame: Up to 34.8 months in Phase 1
measure: Phase 2: Number of Participants With TEAEs, Serious TEAEs, VTEs, and AESIs
timeFrame: Up to 30 days after last dose of ponatinib in Phase 2
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: San Diego
country: United States
facility: Rady Childrens Hospital San Diego - PIN
state: California
city: San Francisco
country: United States
facility: UCSF Medical Comprehensive Cancer
state: California
city: Wilmington
country: United States
facility: Alfred I Dupont Hospital For Children
state: Delaware
city: Chicago
country: United States
facility: Ann and Robert H Lurie Childrens Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital For Children
state: Indiana
city: Kansas City
country: United States
facility: Children's Mercy Hospital and Clinica
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center - PIN
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St Jude Children's Research Hospital
state: Tennessee
city: Dallas
country: United States
facility: Childrens Medical Center Research Institute at UT Southwestern
state: Texas
city: Pilar
country: Argentina
facility: Hospital Universitario Austral
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: South Brisbane
country: Australia
facility: Queensland Childrens Hospital
state: Queensland
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne - PIN
state: Victoria
city: Nedlands
country: Australia
facility: Perth Childrens Hospital
state: Western Australia
city: Curitiba
country: Brazil
facility: Rua Ramiro Barcelos, 2350
state: Parana
city: Porto Alegre
country: Brazil
facility: Irmandade Da Santa Casa de Misericordia de Porto Alegre
state: Rio Grande Du Sul
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
state: Rio Grande Du Sul
city: Barretos
country: Brazil
facility: Fundacao Pio XII Hospital de Cancer de Barretos
state: Sao Paulo
city: Ribeirao Preto
country: Brazil
facility: Hospital Das Clinicas da Faculdade de Medicina de Ribeirao Preto - USP
city: Sao Paulo
country: Brazil
facility: Graacc Grupo de Apoio Ao Adolescente E A Crianca Com Cancer
city: Sao Paulo
country: Brazil
facility: Hospital Santa Marcelina
city: Chengdu
country: China
facility: West China Second University Hospital, Sichuan Univesity
city: Chongqing
country: China
facility: Children's Hospital of Chongqing Medical University
city: Guiyang
country: China
facility: The Affiliated Hospital of Guizhou Medical University
city: Hefei
country: China
facility: The Second Hospital of Anhui Medical University
city: Jinan
country: China
facility: Qilu Hospital of Shandong University
city: Shanghai
country: China
facility: Children's Hospital of Shanghai
city: Shanghai
country: China
facility: Shanghai Childrens Medical Center
city: Suzhou
country: China
facility: Children's Hospital of Soochow University
city: Tianjin
country: China
facility: Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences
city: Wuhan
country: China
facility: Union Hospital Tongji Medical College Huazhong University of Science and Technology
city: Wuhan
country: China
facility: Tongji Hospital Tongji Medical College Huazhong University of Science and Technology
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Praha
country: Czechia
facility: Fakultni nemocnice v Motole
city: Rennes
country: France
facility: Hopital Sud
state: Ille-et-Vilaine
city: Marseille
country: France
facility: Assistance Publique Hopitaux de Marseille
city: Paris
country: France
facility: Hopital Robert Debre
city: Toulouse
country: France
facility: Hopital Des Enfants
city: Roma
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesu - INCIPIT - PIN
state: Lazio
city: Genova
country: Italy
facility: Istituto G Gaslini Ospedale Pediatrico IRCCS - INCIPIT - PIN
state: Liguria
city: Monza
country: Italy
facility: Fndazione MBBM (MONZA E BRIANZA PER IL BAMBINO E LA SUA MAMMA) - c/o Centro Maria Letizia Verga
state: Lombardia
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita - INCIPIT - PIN
state: Piemonte
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center - PPDS
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. Jose Eleuterio Gonzalez
state: Nuevo Leon
city: Ciudad De Mexico
country: Mexico
facility: Instituto Nacional de Pediatria
city: Guadalajara
country: Mexico
facility: Nuevo Hospital Civil de Guadalajara Dr. Juan I. Menchaca
city: Utrecht
country: Netherlands
facility: Princess Maxima Center for Pediatric Oncology - PIN
city: Krakow
country: Poland
facility: Uniwersytecki Szpital Dzieciecy
city: Zabrze
country: Poland
facility: SPSK Nr 1 im. Prof.Stanislawa Szyszko Slaskiego Uniwersytetu Medycznego
city: Lisbon
country: Portugal
facility: Instituto Portugues de Oncologia de Lisboa Francisco Gentil, E.P.E.
state: Lisboa
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia Do Porto Francisco Gentil Epe - PPDS
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus - PIN
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio - PPDS
city: Surrey Quays
country: United Kingdom
facility: Royal Marsden Hospital - Surrey
state: Sutton
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children (Glasgow) - PPDS - PIN
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References: