A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113
Overview
- Phase
- Phase 1
- Intervention
- Brigatinib
- Conditions
- Lymphoma, Large-Cell, Anaplastic
- Sponsor
- Ariad Pharmaceuticals
- Enrollment
- 137
- Primary Endpoint
- Recommended Phase 2 Dose (RP2D) of Brigatinib
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
- •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.
Exclusion Criteria
- •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-
- •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.
Arms & Interventions
Brigatinib 30 mg QD/60 mg QD
Brigatinib 30 mg/60 mg, tablets, orally, once daily (QD) in each cycle of 28 days (Approximately up to 7.3 years).
Intervention: Brigatinib
Brigatinib 90 mg QD
Brigatinib 90 mg, tablets, orally, QD in each cycle of 28 days (Approximately up to 7.3 years).
Intervention: Brigatinib
Brigatinib 120 mg QD/60 mg BID
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).
Intervention: Brigatinib
Brigatinib 90 mg QD-180 mg QD
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.
Intervention: Brigatinib
Brigatinib 180 mg QD/90 mg BID
Brigatinib 180 mg, once daily or 90 mg, BID, tablets, orally in each cycle of 28 days (Approximately up to 7.3 years).
Intervention: Brigatinib
Brigatinib 240 mg QD/120 mg BID/300 mg QD
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).
Intervention: Brigatinib
Outcomes
Primary Outcomes
Recommended Phase 2 Dose (RP2D) of Brigatinib
Time Frame: 28 days
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).
Objective Response Rate (ORR)
Time Frame: From Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years)
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.
Secondary Outcomes
- Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study(Up to Cycle 1 (28 days))
- Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) 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)
- Best Overall Response(Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years))
- 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))
- 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)
- 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(Cycle 1 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose)
- 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(Cycle 2 (28-days cycle): Day 1 multiple time points (up to 24 hours) post-dose)
- Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Brigatinib at Cycle 2 Day 1(Cycle 2 (28-days cycle): Day 1)
- Overall Survival (OS)(Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years))
- T1/2: Terminal Phase Elimination Half-life for Brigatinib at Cycle 2 Day 1(Cycle 2 (28-days cycle): Day 1)
- Duration of Response(Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years))
- Progression Free Survival (PFS)(Screening and at 8-week intervals thereafter up to end of the study (up to 8.4 years))
- Intracranial Objective Response Rate(Screening and at 8-week intervals thereafter (approximately up to 50 months))
- Duration of Intracranial Response(Screening and at 8-week intervals thereafter (approximately up to 50 months))
- Intracranial Progression Free Survival (PFS)(Screening and at 8-week intervals thereafter (approximately up to 50 months))