Clinical trial NCT01449461: 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)
Official title: A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Lymphoma, Large-Cell, Anaplastic
Carcinoma, Non-Small-Cell Lung
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-10-10
Enrollment: 137
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

General Eligibility Criteria

1. 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.
2. Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).
3. Male or female participants ≥ 18 years old.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
5. Minimum life expectancy of 3 months or more.
6. Adequate renal and hepatic function.
7. Adequate bone marrow function.
8. Normal QT interval on screening electrocardiogram (ECG) evaluation.
9. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
10. 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.
11. Signed and dated informed consent indicating that the participant has been informed of all pertinent aspects of the study.
12. Willingness and ability to comply with scheduled visits and study procedures.

Cohort-specific Eligibility Criteria

PART 1: Dose Escalation Phase:

1. Histologically confirmed advanced malignancies. All histologies except leukemia;
2. Refractory to available therapies or for whom no standard or available curative treatments exist;
3. Tumor tissue available for analysis.

PART 2: Expansion cohorts (5 additional cohorts):

1. Expansion cohort 1: Non-small cell lung cancer (NSCLC) participants whose tumors exhibit anaplastic lymphoma kinase (ALK) rearrangements and who have not been treated with previous ALK inhibitors.

i. Histologically or cytologically confirmed NSCLC; ii. Tumor tissue available for analysis (see General Eligibility Criterion 1; iii. History of ALK rearrangement by fluorescence in situ hybridization (FISH); iv. No prior ALK inhibitor therapy; 2. Expansion cohort 2: NSCLC participants whose tumors exhibit ALK rearrangements and who are resistant to crizotinib: i. Histologically or cytologically confirmed NSCLC; ii. Tumor tissue available for analysis (see General Eligibility Criterion 1); iii. History of ALK rearrangement by FISH; iv. Resistant to crizotinib (and have not received any other prior ALK inhibitor therapy); 3. Expansion cohort 3: NSCLC participants whose tumors exhibit an epidermal growth factor receptor EGFR-T790M mutation and who are resistant to 1 prior EGFR TKI: i. Histologically or cytologically confirmed NSCLC ii. Previous treatment with only 1 EGFR TKI for which the last administration was within 30 days of the initiation of brigatinib; iii. Documented evidence of an EGFR-T790M mutation following disease progression on the most recent EGFR TKI therapy; iv. No intervening systemic therapy between cessation of the EGFR TKI and initiating brigatinib; v. Tumor tissue available for analysis (see General Eligibility Criterion 1). 4. Expansion cohort 4: Participants with any cancers with abnormalities in ALK or other brigatinib targets. Examples include, but are not limited to, anaplastic large cell lymphoma (ALCL), diffuse large-cell lymphoma (DLCL), inflammatory myofibroblastic tumors (IMT), and other cancers with ALK abnormalities, or tumors with ROS1 fusions: i. Histologically confirmed lymphomas and other cancers, with the exception of leukemias; ii. Tumor tissue available for analysis (see General Eligibility Criterion 1). 5. Expansion Cohort 5: NSCLC participants whose tumors exhibit ALK rearrangements and who have active, measurable brain metastases: i. Histologically or cytologically confirmed NSCLC: ii. Tumor tissue available for analysis (see General Eligibility Criterion 1); iii. History of ALK rearrangement by FISH; iv. Either crizotinib naive or resistant; v. Have at least one measurable brain lesion (≥ 10 mm by contrast enhanced, T1 weighted magnetic resonance imaging \[cMRI\]). Previously treated brain lesions by stereotactic radiosurgery (SRS) or surgical resection should not be included as a target or non-target lesion; vi. Previously untreated brain metastases with radiologically documented new or progressing brain lesions. Unequivocal progression of previously treated lesions (non-SRS and non-surgically treated lesions) at least 3 months after the last treatment; vii. Neurologically stable. Participants must be on a stable or deceasing dose of corticosteroids and/or have no requirement for anticonvulsants for 5 days prior to the baseline MRI and for 5 days prior to initiating brigatinib.

Exclusion Criteria:

1. Received an investigational agent ≤ 14 days prior to initiating brigatinib.
2. 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.
3. 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.
4. Major surgery within 28 days prior to initiating brigatinib.
5. Brain metastases that are neurologically unstable or require anticonvulsants or an increasing dose of corticosteroids.

   1. Participants with previously treated brain metastases without evidence of disease or recurrence are allowed for cohorts 1-4.
   2. 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.
6. Significant uncontrolled or active cardiovascular disease.
7. Uncontrolled hypertension (diastolic blood pressure \[BP\] \> 100 mm Hg; systolic \> 150 mm Hg).
8. Prolonged QT interval, or being treated with medications known to cause Torsades de Pointes.
9. History or presence of pulmonary interstitial disease or drug-related pneumonitis.
10. Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection.
11. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history.
12. Pregnant or breastfeeding.
13. Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of brigatinib.
14. Any condition or illness that, in the opinion of the Investigator, would compromise participant safety or interfere with the evaluation of the safety of the drug.
15. Leptomeningeal carcinomatosis and spinal cord compression. In the case of suspected meningeal involvement, a negative lumbar puncture prior to study entry is required.

Primary outcomes:
measure: Recommended Phase 2 Dose (RP2D) of Brigatinib
timeFrame: 28 days
measure: Objective Response Rate (ORR)
timeFrame: From Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
Secondary outcomes:
measure: Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)
timeFrame: 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)
measure: Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study
timeFrame: Up to Cycle 1 (28 days)
measure: Number of Participants With Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study
timeFrame: Up to Cycle 1 (28 days)
measure: Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 1 Day 1
timeFrame: Cycle 1 (28-days cycle): Day 1
measure: Cmax: Maximum Observed Plasma Concentration for Brigatinib at Cycle 2 Day 1
timeFrame: Cycle 2 (28-days cycle): Day 1
measure: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 1 Day 1
timeFrame: Cycle 1 (28-days cycle): Day 1
measure: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 2 Day 1
timeFrame: Cycle 2 (28-days cycle): Day 1
measure: 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
timeFrame: Cycle 1 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose
measure: 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
timeFrame: Cycle 2 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose
measure: T1/2: Terminal Phase Elimination Half-life for Brigatinib at Cycle 2 Day 1
timeFrame: Cycle 2 (28-days cycle): Day 1
measure: Best Overall Response
timeFrame: Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
measure: Duration of Response
timeFrame: Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
measure: Progression Free Survival (PFS)
timeFrame: Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
measure: Overall Survival (OS)
timeFrame: Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
measure: Intracranial Objective Response Rate
timeFrame: Screening and at 8-week intervals thereafter (approximately up to 50 months)
measure: Duration of Intracranial Response
timeFrame: Screening and at 8-week intervals thereafter (approximately up to 50 months)
measure: Intracranial Progression Free Survival (PFS)
timeFrame: Screening and at 8-week intervals thereafter (approximately up to 50 months)
Other outcomes:
Locations:
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.