Clinical trial NCT04260009: Pharmacokinetics, Safety, and Efficacy of Brigatinib Monotherapy in Pediatric and Young Adult Participants With ALK+ Anaplastic Large Cell Lymphoma, Inflammatory Myofibroblastic Tumors or Other Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Anaplastic Lymphoma Kinase Positive (ALK +) Anaplastic Large Cell Lymphoma
Inflammatory Myofibroblastic Tumors
Solid Tumors
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2020-02-07
Enrollment: 0
Sex: ALL
Minimum age (years): 1
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Participants must have confirmed cancer histologically or cytologically diagnosed at baseline
2. 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)
3. Phase 1, participants must be relapsed/refractory or intolerant to standard therapies or without option of established systemic therapy
4. 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
5. Performance Status: Karnofsky performance status ≥40% for participants \>16 years of age or Lansky Play Scale ≥40% for participants ≤16 years of age
6. 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)
7. Normal QT interval corrected per Fridericia method (QTcF) on screening electrocardiogram (ECG), defined as QTcF of ≤450 ms
8. Have life expectancy of ≥3 months.

Exclusion Criteria:

1. 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
2. Previous treatment with brigatinib or other ALK inhibitors (except for participants in Phase 1)
3. Participants with completely resected stage-1 (ALCL and other lymphomas) disease
4. Participants with disease limited to skin (ALCL and other lymphomas)
5. Diagnosis of another concurrent primary malignancy
6. 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
7. Planned non-protocol chemotherapy, radiation therapy, another investigational agent, or immunotherapy while participant is on study treatment
8. 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).
9. Any illness that affects gastrointestinal absorption
10. Ongoing or active systemic infection, active seropositive HIV, or known active hepatitis B or C infection.

Primary outcomes:
measure: Phase 1: Maximum Tolerated Dose (MTD) Regimen of Brigatinib Monotherapy
timeFrame: Up to 35 days
measure: Phase 1: Recommended Phase 2 Dose (RP2D) of Brigatinib Monotherapy
timeFrame: Up to 35 days
measure: Phase 1: Maximum Observed Plasma Concentration (Cmax) of Brigatinib
timeFrame: 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)
measure: Phase 1: Time of First Occurrence of Maximum Observed Plasma Concentration (Tmax) of Brigatinib
timeFrame: 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)
measure: Phase 1: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Plasma Concentration (AUClast) of Brigatinib
timeFrame: 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)
measure: Phase 2: Investigator-Confirmed Objective Response Rate (ORR)
timeFrame: Every 2 months until complete response is achieved (Up to 36 months)
Secondary outcomes:
measure: Phase 1: Number of Participants with Dose Limiting Toxicity (DLTs)
timeFrame: Up to 35 days
measure: Phases 1 and 2: Percentage of Participants With One or More Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From the first dose of study drug up to 30 days after last dose of study drug (Up to approximately 2 years)
measure: Overall Acceptability and Palatability as Assessed by Acceptability and Palatability Questionnaire Score
timeFrame: Days 1 and 8 (Cycle 1)
measure: Phase 2: Duration of Response (DOR)
timeFrame: From the first dose of study drug up to disease progression or death (Up to 36 months)
measure: Phase 2: Time to Response
timeFrame: From the first dose of study drug up to disease progression or death (Up to 36 months)
measure: Phase 2: Disease Control Rate in Unresectable/ Recurrent ALK+ IMT Participants
timeFrame: From the first dose of study drug up to disease progression or death (Up to 36 months)
measure: Phase 2: Progression Free Survival (PFS) in Unresectable/ Recurrent ALK+ IMT Participants
timeFrame: From the first dose of study drug up to disease progression or death (Up to 36 months)
measure: Phase 2: Event-free Survival in Relapsed/ Refractory ALK+ ALCL Participants
timeFrame: From the first dose of study drug up to disease progression or death (Up to 36 months)
measure: Phase 2: Overall Survival
timeFrame: Up to 36 months
Other outcomes:
Locations:
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References: