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Report for Clinical Trial NCT01449461

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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.

NCT01449461 Lymphoma, Large-Cell, Anaplastic Carcinoma, Non-Small-Cell Lung
MeSH:Lymphoma Carcinoma, Non-Small-Cell Lung Lymphoma, Large-Cell, Anaplastic
HPO:Anaplastic large-cell lymphoma Lymphoma Non-small cell lung carcinoma

1 Interventions

Name: Brigatinib

Description: Brigatinib tablets and capsules
Type: Drug
Group Labels: 6

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


Primary Outcomes

Description: 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).

Measure: Recommended Phase 2 Dose of Brigatinib

Time: 28 days

Description: ORR assessed by the investigator, is defined as the proportion 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.

Measure: Objective Response Rate (ORR)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Secondary Outcomes

Description: 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.

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

Time: Any adverse event reported on or after the day of first dose of study drug (approximately up to 50 months)

Description: 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). Evaluable participants must complete at least 75% of their planned doses, unless missed doses are due to AEs. The cohort may be expanded to better define the safety profile for confirmation of the MTD. The maximum administered dose in the trial will likely exceed the MTD.

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

Time: Up to Cycle 1 (28 days)

Description: 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.

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

Time: Up to Cycle 1 (28 days)

Measure: Cmax: Maximum Observed Plasma Concentration for Brigatinib

Time: Cycle 1 Day 1

Measure: Cmax: Maximum Observed Plasma Concentration for Brigatinib

Time: Cycle 2 Day 2

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib

Time: Cycle 1 Day 1

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib

Time: Cycle 2 Day 1

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

Time: Cycle 1 Day 1, 8, 15 and 22 pre-dose and Day 1 multiple timepoints (up to 48 hours) post-dose; Cycle 2 Day 1 and 3 pre-dose and Day 1 multiple time points (up to 48 hours) post-dose

Measure: Terminal Phase Elimination Half-life (T1/2) for Brigatinib

Time: Cycle 2 Day 1

Description: Best overall response is defined as proportion 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.

Measure: Best Overall Response

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: Duration of response is defined as time interval from the 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 at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions.

Measure: Duration of Response

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: 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). PFS was calculated by Kaplan-Meier estimation.

Measure: Progression Free Survival (PFS)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

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

Measure: Overall Survival (OS)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: Intracranial objective response rate is defined as the proportion 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. Meta.=Metastases.

Measure: Intracranial Objective Response Rate

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: 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.

Measure: Duration of Intracranial Response

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: 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.

Measure: Intracranial Progression Free Survival (PFS)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There is one SNP

SNPs


1 T790M

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. --- T790M ---

Documented evidence of an EGFR-T790M mutation following disease progression on the most recent EGFR TKI therapy; iv. --- T790M ---



HPO Nodes


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