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

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.

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.