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Anaplastic Lymphoma Kinase Positive (ALK +) Anaplastic Large Cell LymphomaPhase 1/2NCT04260009

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

A Phase 1/2 study testing Brigatinib and Brigatinib AAF in people with Anaplastic Lymphoma Kinase Positive (ALK +) Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumors, run by Takeda.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 1 year to 25 years
What is being tested?
Brigatinib and Brigatinib AAF
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
1 Sep 2020to 1 Sep 2025
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 25 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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:
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  • 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.

About this study

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

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.

Read the 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.

Being tested
Brigatinib, Brigatinib AAF
Keywords
Drug Therapy
Medical subject headings
Lymphoma, Large-Cell, Anaplastic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BrigatinibDrug

    Brigatinib tablets

  • Brigatinib AAFDrug

    Brigatinib age-appropriate formulation (AAF)

Study groups in NCT04260009
Study groupRoleWhat they receive
Phase 1: BrigatinibExperimentalBrigatinib 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).
Receives: Drug: Brigatinib; Drug: Brigatinib AAF
Ph 2:Brigatinib (Unresectable/Recurrent ALK+ IMT) ParticipantsExperimentalBrigatinib 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.
Receives: Drug: Brigatinib; Drug: Brigatinib AAF
Ph 2 :Brigatinib (Relapsed/Refractory ALK+ ALCL) ParticipantsExperimentalBrigatinib 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.
Receives: Drug: Brigatinib; Drug: Brigatinib AAF

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 35 days

  2. 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.

    Measured: Up to 35 days

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

    Measured: 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)

  4. Phase 1: Time of First Occurrence of Maximum Observed Plasma Concentration (Tmax) of Brigatinib

    Measured: 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)

  5. Phase 1: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Plasma Concentration (AUClast) of Brigatinib

    Measured: 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)

  6. 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.

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

Secondary outcomes (9)

  1. Phase 1: Number of Participants with Dose Limiting Toxicity (DLTs)

    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.

    Measured: Up to 35 days

  2. Phases 1 and 2: Percentage of Participants With One or More Adverse Events (AEs) and Serious Adverse Events (SAEs)

    An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. A SAE is any AE that results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.

    Measured: From the first dose of study drug up to 30 days after last dose of study drug (Up to approximately 2 years)

  3. Overall Acceptability and Palatability as Assessed by Acceptability and Palatability Questionnaire Score

    Acceptability is defined as the overall ability of the participant to use the medicine as intended. Acceptability and palatability (taste and smell) will be assessed using a 5-point facial hedonic scale, where 1 indicates 'bad', and 5 indicates 'good'.

    Measured: Days 1 and 8 (Cycle 1)

  4. Phase 2: Duration of Response (DOR)

    DOR is defined as the time from the initial assessment of CR response until subsequent disease progression or relapse. Per RECIST 1.1, CR is defined as disappearance of all target lesions and per IPNHL, response criteria CR is defined as disappearance of all residual disease and tumor lesions. Disease progression as per RECIST 1.1, is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Disease progression as per IPNHL response criteria, is defined as development of new morphologic evidence of disease in bone marrow.

    Measured: From the first dose of study drug up to disease progression or death (Up to 36 months)

  5. Phase 2: Time to Response

    Time from the start of treatment with brigatinib to the first objective tumor response observed for participants who achieved a CR or PR. 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 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.

    Measured: From the first dose of study drug up to disease progression or death (Up to 36 months)

  6. Phase 2: Disease Control Rate in Unresectable/ Recurrent ALK+ IMT Participants

    DCR is defined as the percentage of participants who are confirmed to have achieved CR or PR or have a best overall response of stable disease (SD). 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. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

    Measured: From the first dose of study drug up to disease progression or death (Up to 36 months)

  7. Phase 2: Progression Free Survival (PFS) in Unresectable/ Recurrent ALK+ IMT Participants

    PFS is defined as the time from the date of first dose to the date of PD per RECIST v1.1, or the date of death due to any cause, whichever occurs first. PD is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

    Measured: From the first dose of study drug up to disease progression or death (Up to 36 months)

  8. Phase 2: Event-free Survival in Relapsed/ Refractory ALK+ ALCL Participants

    EFS is defined as the time from the date of first dose to any treatment failure including disease progression, or discontinuation of treatment for any reason (eg, disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death). Participants without any treatment failure events will be censored at last known alive date before data cutoff date.

    Measured: From the first dose of study drug up to disease progression or death (Up to 36 months)

  9. Phase 2: Overall Survival

    Overall survival in months is defined as the time from the date of first dose to the date of death due to any cause. Participants without documentation of death at the time of analysis will be censored at the date last known to be alive.

    Measured: Up to 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Feb 2020
  2. Study start1 Sep 2020 (estimated)
  3. Primary completion1 Sep 2023 (estimated)
  4. Study completion1 Sep 2025 (estimated)

Why it stopped: Business reason unrelated to product safety

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04260009
Sponsor's protocol ID
Brigatinib-1002
Status last verified
Mar 2020
First submitted
22 Jan 2020
Last updated
5 Mar 2020
Results posted
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Brigatinib and Brigatinib AAF in people with Anaplastic Lymphoma Kinase Positive (ALK +) Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumors, run by Takeda.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 5 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase 1: Maximum Tolerated Dose (MTD) Regimen of Brigatinib Monotherapy (time frame: Up to 35 days). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04260009.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Mar 2020.

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Clinical Trial NCT04260009 | AzTrials