An Open-Label, Phase 1/2 Dose Escalation and Expansion Trial to Evaluate the Pharmacokinetics, Safety, and Efficacy of Brigatinib as Monotherapy in Pediatric and Young Adult Patients With ALK+ Anaplastic Large Cell Lymphoma, Inflammatory Myofibroblastic Tumors or Other Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 发起方
- 主要终点
- Phase 1: Time of First Occurrence of Maximum Observed Plasma Concentration (Tmax) of Brigatinib
研究概览
简要总结
The purpose of this study is to estimate the maximum tolerated dose (MTD)/ recommended phase 2 dose (RP2D) regimen and characterize the pharmacokinetics (PK) of brigatinib monotherapy (film-coated tablets and age-appropriate formulation [AAF]) administered orally once daily (QD) in pediatric and young adult participants in Phase 1 and to define the efficacy of brigatinib administered as monotherapy within the disease-specific expansion arms (unresectable/recurrent anaplastic lymphoma kinase positive (ALK+) inflammatory myofibroblastic tumor (IMT); relapsed/refractory ALK+ anaplastic large cell lymphoma (ALCL) in Phase 2.
详细描述
The drug being tested in this study is called Brigatinib. Brigatinib is being tested to treat people who have Anaplastic Large Cell Lymphoma, Inflammatory Myofibroblastic Tumors or other solid tumours.
The study will enroll approximately 61 patients. Participants will be assigned to the following arm group to receive brigatinib:
- Phase 1 (Dose Escalation): Brigatinib Dose Level 1 and Dose Level 2 (based on safety and tolerability)
- Phase 2 (Dose Expansion): Unresectable/ Recurrent ALK+ IMT
- Phase 2 (Dose Expansion): Relapsed/ Refractory ALK+ ALCL
All participants will be administered brigatinib orally once daily in 28-day Cycles. Participants will receive fixed doses of brigatinib based on weight ranges. The starting doses in Phase 1 (Dose Level 1) are expected to provide systemic exposures of brigatinib in pediatric participants comparable to those achieved in adults receiving the recommended clinical dose of 90 mg once daily for 7 days followed by 180 mg once daily. One additional dose level (Dose Level 2) is planned in Phase 1 if the initial dose level is tolerated. This subsequent dose level is expected to provide systemic exposures of brigatinib in pediatric participants comparable to those achieved in adults receiving 90 mg once daily for 7 days followed by 240 mg once daily (the highest acceptably tolerated dose in adults). In Phase 2, brigatinib will be administered at the RP2D determined during Phase 1.
This multi-centre trial will be conducted worldwide. The overall time to participate in this study is approximately 36 months. Participants will make multiple visits to the clinic and will be contacted by telephone OR a final visit after receiving their last dose of brigatinib for a follow-up assessment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must have confirmed cancer histologically or cytologically diagnosed at baseline
- •Participants are required to provide prior results showing an activating ALK aberration in the tumor (bone marrow aspirate, peripheral blood samples, biopsy, etc) documented by fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) for the ALK-fusion transcript, next generation sequencing (NGS) or ALK immunohistochemistry (ALK immunohistochemistry can be used as a surrogate for FISH or NGS)
- •Phase 1, participants must be relapsed/refractory or intolerant to standard therapies or without option of established systemic therapy
- •Phase 2, participants must have measurable and/or evaluable disease:
- •Arm 1: IMT participants must not be suitable for curative surgical resection
- •Arm 2: participants must have relapsed/refractory ALCL
- •Performance Status: Karnofsky performance status ≥40% for participants >16 years of age or Lansky Play Scale ≥40% for participants ≤16 years of age
- •For participants receiving prior therapy:
- •Participants must have recovered to Grade <2 NCI CTCAE v5.0 or to baseline, from any nonhematologic toxicities (except alopecia and peripheral neuropathy) due to previous 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 brigatinib can be given
- •Participants with hematologic malignancy and prior hematopoietic stem cell transplant (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 45 days posttransplant at the time of enrollment
- •Hematopoietic growth factors: Before the first dose of brigatinib, 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:
- •Immunotherapy: Before the first dose of brigatinib, at least 30 days must have passed after the completion of any type of immunotherapy, (eg, monoclonal antibodies [anti-PD1/PDL1], tumor vaccines, chimeric antigen receptor [CAR] T cells, etc.)
- •Other: before the first dose of brigatinib, at least 7 days must have passed since the last dose of a biologic agent. For agents that have known adverse events (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
- •Immunosuppressive therapy: Before the first dose of brigatinib, at least 14 days must have passed after the completion of immunosuppressive therapy (including regimens following stem cell transplant)
- •For symptomatic participants that urgently need relief (eg, airway obstruction), therapeutic doses of corticosteroids may be administered for a short course (up to 5 days)
- •Radiotherapy (XRT): No washout period is necessary for radiation given to any extramedullary site other than the CNS and lungs; ≥6 weeks must have passed if participants received prior total body irradiation or craniospinal or cranial XRT; ≥28 days must have passed if participants received radiotherapy to the lung(s)
- •Normal QT interval corrected per Fridericia method (QTcF) on screening electrocardiogram (ECG), defined as QTcF of ≤450 ms
- •Have life expectancy of ≥3 months.
排除标准
- •Participants receiving systemic treatment with strong or moderate cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days prior to the first dose of study drug
- •Previous treatment with brigatinib or other ALK inhibitors (except for participants in Phase 1)
- •Participants with completely resected stage-1 (ALCL and other lymphomas) disease
- •Participants with disease limited to skin (ALCL and other lymphomas)
- •Diagnosis of another concurrent primary malignancy
- •Clinically significant cardiovascular disease, including any of the following:
- •Myocardial infarction or unstable angina within 6 months of study entry
- •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
- •Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or immunotherapy while participant is on study treatment
- •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).
- •Any illness that affects gastrointestinal absorption
- •Ongoing or active systemic infection, active seropositive HIV, or known active hepatitis B or C infection.
研究组 & 干预措施
Phase 1: Brigatinib
Brigatinib tablet or age-appropriate formulation (AAF), orally once daily in 28-day Cycles with reference to adult dose of 90 mg in Week 1 and 180 mg starting in Week 2 based on participant's weight as dose level 1. Participants could receive dose level 2 based on safety and tolerability of dose level 1 in dose escalation phase (Ph).
干预措施: Brigatinib AAF (Drug)
Phase 1: Brigatinib
Brigatinib tablet or age-appropriate formulation (AAF), orally once daily in 28-day Cycles with reference to adult dose of 90 mg in Week 1 and 180 mg starting in Week 2 based on participant's weight as dose level 1. Participants could receive dose level 2 based on safety and tolerability of dose level 1 in dose escalation phase (Ph).
干预措施: Brigatinib (Drug)
Ph 2:Brigatinib (Unresectable/Recurrent ALK+ IMT) Participants
Brigatinib recommended phase 2 dose (RP2D) determined during phase 1, tablet or AAF orally QD in participants with Unresectable/ Recurrent ALK+ IMT for up to 2 years in dose expansion phase.
干预措施: Brigatinib (Drug)
Ph 2:Brigatinib (Unresectable/Recurrent ALK+ IMT) Participants
Brigatinib recommended phase 2 dose (RP2D) determined during phase 1, tablet or AAF orally QD in participants with Unresectable/ Recurrent ALK+ IMT for up to 2 years in dose expansion phase.
干预措施: Brigatinib AAF (Drug)
Ph 2 :Brigatinib (Relapsed/Refractory ALK+ ALCL) Participants
Brigatinib RP2D determined during phase 1, tablet or AAF orally QD in participants with Relapsed/ Refractory ALK+ ALCL for up to 2 years in dose expansion phase.
干预措施: Brigatinib (Drug)
Ph 2 :Brigatinib (Relapsed/Refractory ALK+ ALCL) Participants
Brigatinib RP2D determined during phase 1, tablet or AAF orally QD in participants with Relapsed/ Refractory ALK+ ALCL for up to 2 years in dose expansion phase.
干预措施: Brigatinib AAF (Drug)
结局指标
主要结局
Phase 1: Time of First Occurrence of Maximum Observed Plasma Concentration (Tmax) of Brigatinib
时间窗: Cycle 1, Days 1 and 15: Predose (Day 15 only) and at multiple timepoints (Up to 24 hours) post-dose; Predose on Day 1, Cycle 2 (each cycle is of 28 days)
Phase 1: Maximum Tolerated Dose (MTD) Regimen of Brigatinib Monotherapy
时间窗: Up to 35 days
MTD will be highest dose of brigatinib, at which \<=1 of 6 participants would experience a dose-limiting toxicity (DLT). DLT is defined using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0, as: Non-Haematological events possibly or definitively brigatinib related grade ≥3 AE except fatigue, nausea, vomiting lasting for \<48 hours and nonhematologic laboratory abnormalities that resolve to Grade 1 or baseline within 7 days after study drug modification and/or supportive care; hematologic toxicities (except in participants with bone marrow involvement or MAS) as: Grade 4 neutropenia lasting longer than 7 days with supportive care, Grade ≥3 febrile neutropenia requiring antibiotics, Grade 3 platelet count (\<50,000-25,000/μL) with bleeding requiring transfusion, Grade 4 platelet count (\<25,000/μL) at any time, any delay or interruption of therapy of ≥2 weeks due to suspected treatment-related hematologic toxicities.
Phase 1: Recommended Phase 2 Dose (RP2D) of Brigatinib Monotherapy
时间窗: Up to 35 days
The RP2D is the maximum tolerated dose (MTD) or less. MTD was highest dose of Brigatinib, at which \<=1 of 6 participants experienced DLT.
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Brigatinib
时间窗: Cycle 1, Days 1 and 15: Predose (Day 15 only) and at multiple timepoints (Up to 24 hours) post-dose; Predose on Day 1, Cycle 2 (each cycle is of 28 days)
Phase 1: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Plasma Concentration (AUClast) of Brigatinib
时间窗: Cycle 1, Days 1 and 15: Predose (Day 15 only) and at multiple timepoints (Up to 24 hours) post-dose; Predose on Day 1, Cycle 2 (each cycle is of 28 days)
Phase 2: Investigator-Confirmed Objective Response Rate (ORR)
时间窗: Every 2 months until complete response is achieved (Up to 36 months)
ORR is defined as the percentage of participants with tumor size reduction of a predefined amount and for a minimum time period. ORR is determined by radiological tests and investigator assessment. ORR for unresectable/recurrent ALK+IMT participants will be the achievement of a Complete Response (CR) or Partial Response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Per RECIST 1.1, CR is defined as disappearance of all target lesions; PR is defined as atleast 30% decrease in sum of diameters (SoD) of target lesions. Per International Pediatric Non-Hodgkin Lymphoma (IPNHL) response criteria, CR is defined as disappearance of all residual disease and tumor lesions; PR is defined as 50% decrease in sum of product of greatest perpendicular diameters (SPD) of lymphoma cells.
次要结局
- Phase 1: Number of Participants with Dose Limiting Toxicity (DLTs)(Up to 35 days)
- Phases 1 and 2: Percentage of Participants With One or More Adverse Events (AEs) and Serious Adverse Events (SAEs)(From the first dose of study drug up to 30 days after last dose of study drug (Up to approximately 2 years))
- Overall Acceptability and Palatability as Assessed by Acceptability and Palatability Questionnaire Score(Days 1 and 8 (Cycle 1))
- Phase 2: Duration of Response (DOR)(From the first dose of study drug up to disease progression or death (Up to 36 months))
- Phase 2: Time to Response(From the first dose of study drug up to disease progression or death (Up to 36 months))
- Phase 2: Disease Control Rate in Unresectable/ Recurrent ALK+ IMT Participants(From the first dose of study drug up to disease progression or death (Up to 36 months))
- Phase 2: Progression Free Survival (PFS) in Unresectable/ Recurrent ALK+ IMT Participants(From the first dose of study drug up to disease progression or death (Up to 36 months))
- Phase 2: Event-free Survival in Relapsed/ Refractory ALK+ ALCL Participants(From the first dose of study drug up to disease progression or death (Up to 36 months))
- Phase 2: Overall Survival(Up to 36 months)