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Mitogens

Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 120 mg, once daily or 60 mg, twice daily (BID), tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally once daily in Cycle 1 of 28 days followed by brigatinib 180 mg, orally once daily in cycle 2 and onward cycles of 28 days.

Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 240 mg, QD or 120 mg, BID or 300 mg once daily, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib

Medical Director

The purpose of this study is 2-fold: initially, in the dose escalation phase, the goal is to determine the safety profile of orally administered brigatinib, including: the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile. Then, once the RP2D is established, an expansion phase will assess the preliminary anti-tumor activity of brigatinib, both in non-small cell lung cancer (NSCLC) with ALK gene rearrangement (including participants with active brain metastases) or mutated EGFR, and in other cancers with abnormal targets against which brigatinib is active.

The drug being tested in this study is called brigatinib (AP26113). Brigatinib is being tested to treat people with NSCLC. This study will look at the safety, tolerability and efficacy of brigatinib.

The study enrolled 137 patients. Participants were assigned to one of the following treatment groups:

* Brigatinib 30 mg once daily (QD)/60 mg QD
* Brigatinib 90 mg QD
* Brigatinib 120 mg QD/60 mg twice daily (BID)
* Brigatinib 90 mg QD-180 mg QD
* Brigatinib 180 mg QD/90 mg BID
* Brigatinib 240 mg QD/120 mg BID/300 mg QD

This multi-center trial will be conducted worldwide. The overall expected time to participate in this study is approximately 4 years. Participants will make multiple visits to the clinic, and 30 days after the End-of-Treatment visit. Follow-up is intended to continue for at least 2 years after the initial dose.

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral Anaplastic Lymphoma Kinase (ALK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Brigatinib (AP26113)

A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1).

ORR assessed by the investigator, is defined as the percentage of the participants with complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid tumors (RECIST) v1.1 after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to \<10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (\<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. Crzb=Crizotinib.

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

The MTD is defined as the highest dose at which ≤ 1 of 6 evaluable participants experience a DLT within the first 28 days of treatment (end of Cycle 1).

DLT include any toxicity that is possibly, probably, or definitely drug-related. Toxicity grades will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. DLTs are defined by the following: A) Non-hematologic toxicities: Any grade ≥3 non-hematologic toxicity, with the exception of self-limiting or medically controllable toxicities (eg, nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting \< 3 days, and excluding alopecia. B) Hematologic toxicities: Febrile neutropenia not related to underlying disease (fever, \> 101°F; ANC\<500); Prolonged grade 4 neutropenia (\> 7 days); Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection; Thrombocytopenia ≥ grade 3 with bleeding or grade 4 lasting ≥ 7 days. C) Missed ≥ 25% of planned doses of brigatinib over 28 days due to treatment-related AEs in the first cycle.

Best overall response is defined as percentage of participants with CR, PR, stable disease (SD) or progressive disease (PD) as per of RECIST v1.1 as evaluated by investigator. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to \<10 mm in short axis. CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (\<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. Disease progression for target lesion: SLD increased by at least 20% from smallest value on study and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions. SD for neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Duration of response is defined as time interval from time that measurement criteria are first met for CR/PR (whichever is first recorded) until first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at last valid response assessment.CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to \<10 mm in short axis.CR for non-target lesion:disappearance of all extranodal non-target lesions,all lymph nodes must be non-pathological in size(\<10mm short axis) and normalization of tumor marker level.PR:at least a 30% decrease in SLD of target lesions.PD for target lesion:SLD increased by at least 20% from smallest value and must also demonstrate an absolute increase of \>=5 mm or development of any new lesion.PD for non-target lesion:unequivocal progression of existing non-target lesions.Duration of response calculated by Kaplan-Meier estimation.

PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader).

OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause.

Intracranial objective response rate is defined as the percentage of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 after the initiation of study drug. CR for target lesion: disappearance of all extranodal lesions. CR for non-target lesion: disappearance of all extranodal non-target lesions and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters.

Intracranial duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR in brain metastases (whichever is first recorded) until the first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at the last valid response assessment. Duration intracranial of response was calculated by Kaplan-Meier estimation.

PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression in brain, or death due to any cause, whichever occurs first. Intracranial PFS was calculated by Kaplan-Meier estimation.

Ariad Pharmaceuticals

Brigatinib 30 mg/60 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 30 mg QD/60 mg QD

Brigatinib 90 mg QD

Brigatinib 120 mg, once daily or 60 mg, BID, tablets, orally, in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 120 mg QD/60 mg BID

Brigatinib 90 mg, tablets, orally, once daily for 7 days followed by brigatinib 180 mg, orally QD in Cycle 1 of 28 days followed by brigatinib 180 mg, orally QD in cycle 2 and onward cycles of 28 days (Approximately up to 7.3 years).

Brigatinib 90 mg QD-180 mg QD

Brigatinib 180 mg QD/90 mg BID

Brigatinib 240 mg QD/120 mg BID/300 mg QD

Total

Age, Continuous

Age, Customized

Sex: Female, Male

Race/Ethnicity, Customized

United States

Spain

Region of Enrollment

ECOG assessed participant's performance status on a 5 point scale: 0 equals (=) fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, but ambulatory/able to carry out light or sedentary work; 2=ambulatory (greater than \[\>\] 50 percentage \[%\] of waking hours \[h\]), capable of all self care, but unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair \>50% of waking hours; 4= completely disabled, cannot carry on any selfcare, totally confined to bed or chair and 5=Dead.

Eastern Cooperative Oncology Group (ECOG) Performance Score

Time Since Diagnosis of Cancer

Participants with Diagnosis of Cancer Type

Number of Participants with Mutation Types

Participants with Prior Chemotherapy Regimen

Participants with Prior Radiotherapy to Brain

Safety population included all enrolled participants who received at least one dose of study drug.

All participants who received brigatinib, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).

Recommended Phase 2 Dose (RP2D) of Brigatinib

With Prior Treatment with Crizotinib

Without Prior Treatment with Crizotinib

Full analysis set (FAS) included all participants who received at least one dose of study drug. Participants with anaplastic lymphoma kinase (ALK) and non-small cell lung cancer (NSCLC) were evaluated for this outcome measure. Number analyzed is the number of participants with data evaluable for specific category.

Objective Response Rate (ORR)

Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)

All participants received brigatinib tablets, orally, once daily (QD) starting at 30 mg in each cycle of 28 days.

Safety population included all enrolled participants who received at least one dose of study drug. Participants enrolled in the dose escalation phase were included in the analysis.

Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study

Brigatinib 30 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 30 mg

Brigatinib 60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 60 mg

Brigatinib 90 mg, tablets, orally, once daily or twice daily in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 90 mg

Brigatinib 120 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 120 mg

Brigatinib 180 mg, tablets, orally once daily in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 180 mg

Brigatinib 240 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 240 mg

Brigatinib 300 mg, tablets, orally, once daily in each cycle of 28 days (Approximately up to 7.3 years).

Brigatinib 300 mg

DLT-evaluable population included participants who received ≥75% of planned study drug doses during Cycle 1.

Number of Participants With Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study

Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here number of participants analyzed is the participants who were evaluable for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.

Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 1 Day 1

Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here number of participants analyzed is the participants with data available for analysis for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.

Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 2 Day 1

Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, number of participants analyzed is the participants who were evaluable for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.

Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 1 Day 1

Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, number of participants analyzed is the participants with data available for analyses for this outcome measure. Participants of brigatinib 90 mg QD-180 mg QD arm were included as per treatment received at each time point.

Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 2 Day 1

AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib at Cycle 1 Day 1

AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib at Cycle 2 Day 1

T1/2: Terminal Phase Elimination Half-life for Brigatinib at Cycle 2 Day 1

With Prior Treatment with Crizotinib: Complete Response

Without Prior Treatment with Crizotinib: Complete Response

With Prior Treatment with Crizotinib: Partial Response

Without Prior Treatment with Crizotinib: Partial Response

With Prior Treatment with Crizotinib: Stable Disease

Without Prior Treatment with Crizotinib: Stable Disease

With Prior Treatment with Crizotinib: Progressive Disease

Without Prior Treatment with Crizotinib: Progressive Disease

Full analysis set included all participants who received at least one dose of study drug. Participants with ALK and NSCLC were evaluated for this outcome measure. Number analyzed is the number of participants with data evaluable for specific category.

Best Overall Response

Full analysis set included all participants who received at least one dose of study drug. Participants who were responders among those who had ALK and NSCLC were evaluated for this outcome measure. Number analyzed is the number of participants with data evaluable for specific category.

Duration of Response

Analysis was performed on all enrolled participants in the study who received at least one dose of brigatinib. Here, overall number of participants analyzed is the participants who were evaluable for this outcome measure.

Progression Free Survival (PFS)

Overall Survival (OS)

Measurable Brain Metastases

Only Non-Measurable Brain Metastases

Full analysis set. ALK+ NSCLC participants with measurable and non-measurable brain metastases at baseline were evaluated for this outcome measure. Here, number analyzed is the number of participants who were evaluable for specific category.

Intracranial Objective Response Rate

Full analysis set. ALK+ NSCLC participants with measurable and non-measurable brain metastases at baseline were evaluated for this outcome measure.

Spots Global Cancer Trial Database for A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral Anaplastic Lymphoma Kinase (ALK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Brigatinib (AP26113)

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