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)

NCT01449461 | Completed Phase 1 Results FDA Drug

• 3 other identifiers: AP26113-11-1012011-005718-12U1111-1196-8197
• Study Type: interventional
• Target: 137
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Lymphoma, Large-Cell, Anaplastic; Carcinoma, Non-Small-Cell Lung

Outcome Measures

Primary Outcomes (2)

• Recommended Phase 2 Dose (RP2D) of Brigatinib

  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).

  28 days

• Objective Response Rate (ORR)

  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.

  From Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)

Secondary Outcomes (17)

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

  From first dose of study drug up to 30 days following the last dose of the study treatment or the investigator/participant decision to discontinue treatment, whichever occurs first (approximately up to 7.4 years)

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

  Up to Cycle 1 (28 days)

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

  Up to Cycle 1 (28 days)

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

  Cycle 1 (28-days cycle): Day 1

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

  Cycle 2 (28-days cycle): Day 1

Study Arms (6)

Brigatinib 30 mg QD/60 mg QD

EXPERIMENTAL

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

Drug: Brigatinib

Brigatinib 90 mg QD

EXPERIMENTAL

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

Drug: Brigatinib

Brigatinib 120 mg QD/60 mg BID

EXPERIMENTAL

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).

Drug: Brigatinib

Brigatinib 90 mg QD-180 mg QD

EXPERIMENTAL

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.

Drug: Brigatinib

Brigatinib 180 mg QD/90 mg BID

EXPERIMENTAL

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

Drug: Brigatinib

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

EXPERIMENTAL

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).

Drug: Brigatinib

Interventions

Brigatinib DRUG

Brigatinib tablets and capsules.

Also known as: ALUNBRIG™, AP26113

Brigatinib 120 mg QD/60 mg BID; Brigatinib 180 mg QD/90 mg BID; Brigatinib 240 mg QD/120 mg BID/300 mg QD; Brigatinib 30 mg QD/60 mg QD; Brigatinib 90 mg QD; Brigatinib 90 mg QD-180 mg QD

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• General Eligibility Criteria
• All participants must have tumor tissue available for analysis. If sufficient tissue is not available, participants must undergo a biopsy to obtain adequate samples. For participants in expansion cohorts 2, 3 and 5, for whom failure of prior therapy is specified (crizotinib for cohorts 2 and 5, one epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for cohort 3), tumor tissue must be available following failure of the prior therapy.
• Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).
• Male or female participants ≥ 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Minimum life expectancy of 3 months or more.
• Adequate renal and hepatic function.
• Adequate bone marrow function.
• Normal QT interval on screening electrocardiogram (ECG) evaluation.
• For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
• Female participants who are of childbearing potential and fertile male participants must agree to use an effective form of contraception with their sexual partners throughout study participation.
• Signed and dated informed consent indicating that the participant has been informed of all pertinent aspects of the study.
• Willingness and ability to comply with scheduled visits and study procedures.
• Cohort-specific Eligibility Criteria
• PART 1: Dose Escalation Phase:

You may not qualify if:

• Received an investigational agent ≤ 14 days prior to initiating brigatinib.
• Received systemic anticancer therapy (including monoclonal antibodies and irreversible TKIs such as afatinib or dacomitinib) or radiation therapy ≤ 14 days prior to initiating brigatinib.
• a. Except for a reversible TKI (ie, erlotinib or gefitinib) or crizotinib, which are allowed up to 72 hours prior to initiating brigatinib, provided that the participant is free of treatment-related toxicity that might confound the safety evaluation of brigatinib.
• Received any prior agents targeted against ALK, with the exception of crizotinib, or received more than 1 prior EGFR TKI.
• a. Re-challenge with the same TKI is allowed.
• Major surgery within 28 days prior to initiating brigatinib.
• Brain metastases that are neurologically unstable or require anticonvulsants or an increasing dose of corticosteroids.
• Participants with previously treated brain metastases without evidence of disease or recurrence are allowed for cohorts 1-4.
• Participants with evaluable but non-measurable, active brain lesions who otherwise meet the criteria for cohort 5 for CNS disease can be enrolled in other cohorts.
• Significant uncontrolled or active cardiovascular disease.
• Uncontrolled hypertension (diastolic blood pressure \[BP\] \> 100 mm Hg; systolic \> 150 mm Hg).
• Prolonged QT interval, or being treated with medications known to cause Torsades de Pointes.
• History or presence of pulmonary interstitial disease or drug-related pneumonitis.
• Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection.
• Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history.

Sponsors & Collaborators

• Ariad Pharmaceuticals: lead

Related Publications (3)

• Camidge DR, Kim DW, Tiseo M, Langer CJ, Ahn MJ, Shaw AT, Huber RM, Hochmair MJ, Lee DH, Bazhenova LA, Gold KA, Ou SI, West HL, Reichmann W, Haney J, Clackson T, Kerstein D, Gettinger SN. Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials. J Clin Oncol. 2018 Sep 10;36(26):2693-2701. doi: 10.1200/JCO.2017.77.5841. Epub 2018 May 16.

  PMID: 29768119 DERIVED

• Gettinger SN, Bazhenova LA, Langer CJ, Salgia R, Gold KA, Rosell R, Shaw AT, Weiss GJ, Tugnait M, Narasimhan NI, Dorer DJ, Kerstein D, Rivera VM, Clackson T, Haluska FG, Camidge DR. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol. 2016 Dec;17(12):1683-1696. doi: 10.1016/S1470-2045(16)30392-8. Epub 2016 Nov 8.

  PMID: 27836716 DERIVED

• Yu HA, Riely GJ. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in lung cancers. J Natl Compr Canc Netw. 2013 Feb 1;11(2):161-9. doi: 10.6004/jnccn.2013.0024.

  PMID: 23411383 DERIVED

MeSH Terms

Conditions

Lymphoma, Large-Cell, Anaplastic; Carcinoma, Non-Small-Cell Lung

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; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: September 30, 2011
• First Posted: October 10, 2011
• Study Start: September 20, 2011
• Primary Completion: November 16, 2015
• Study Completion: February 18, 2020
• Last Updated: August 17, 2021
• Results First Posted: June 21, 2017

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.