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

NCT04260009 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: Brigatinib-1002
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Anaplastic Lymphoma Kinase Positive (ALK +) Anaplastic Large Cell Lymphoma; Inflammatory Myofibroblastic Tumors; Solid Tumors

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (6)

• Phase 1: Maximum Tolerated Dose (MTD) Regimen of Brigatinib Monotherapy

  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.

  Up to 35 days

• Phase 1: Recommended Phase 2 Dose (RP2D) of Brigatinib Monotherapy

  The RP2D is the maximum tolerated dose (MTD) or less. MTD was highest dose of Brigatinib, at which \<=1 of 6 participants experienced DLT.

  Up to 35 days

• Phase 1: Maximum Observed Plasma Concentration (Cmax) of Brigatinib

  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: Time of First Occurrence of Maximum Observed Plasma Concentration (Tmax) of Brigatinib

  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

  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)

  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.

  Every 2 months until complete response is achieved (Up to 36 months)

Secondary Outcomes (9)

• 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)

Study Arms (3)

Phase 1: Brigatinib

EXPERIMENTAL

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).

Drug: Brigatinib; Drug: Brigatinib AAF

Ph 2:Brigatinib (Unresectable/Recurrent ALK+ IMT) Participants

EXPERIMENTAL

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.

Drug: Brigatinib; Drug: Brigatinib AAF

Ph 2 :Brigatinib (Relapsed/Refractory ALK+ ALCL) Participants

EXPERIMENTAL

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.

Drug: Brigatinib; Drug: Brigatinib AAF

Interventions

Brigatinib DRUG

Brigatinib tablets

Ph 2 :Brigatinib (Relapsed/Refractory ALK+ ALCL) Participants; Ph 2:Brigatinib (Unresectable/Recurrent ALK+ IMT) Participants; Phase 1: Brigatinib

Brigatinib AAF DRUG

Brigatinib age-appropriate formulation (AAF)

Ph 2 :Brigatinib (Relapsed/Refractory ALK+ ALCL) Participants; Ph 2:Brigatinib (Unresectable/Recurrent ALK+ IMT) Participants; Phase 1: Brigatinib

Eligibility Criteria

• Age: 1 Year - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Takeda: lead

MeSH Terms

Conditions

Lymphoma, Large-Cell, Anaplastic

Interventions

brigatinib

Condition Hierarchy (Ancestors)

Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Medical Director Clinical Science

  Takeda

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 22, 2020
• First Posted: February 7, 2020
• Study Start: September 1, 2020
• Primary Completion: September 1, 2023
• Study Completion: September 1, 2025
• Last Updated: March 5, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share