Study of Safety, Pharmacokinetics, and Antitumor Activity of BGB-3245 in Participants With Advanced or Refractory Tumors

• ClinicalTrials.gov Identifier: NCT04249843
• Recruitment Status: Recruiting
• First Posted: January 31, 2020
• Last Update Posted: December 17, 2020
• Sponsor: MapKure, LLC
• Information provided by (Responsible Party): MapKure, LLC

Study Description

Brief Summary:

The purpose of this study is to evaluate the safety, tolerability, and antitumor activity of BGB-3245 in participants with advanced or refractory tumors harboring specific v-RAF murine sarcoma viral oncogene homolog B (B-RAF) genetic mutations.

Condition or disease	Intervention/treatment	Phase
Solid Tumor; B-Raf Mutation-Related Tumors	Drug: BGB-3245	Phase 1

Detailed Description:

This is a first-in-human, Phase 1a/1b (dose escalation and expansion) study of BGB-3245 in participants with tumors harboring B-RAF mutations that are likely to respond to a RAF dimer inhibitor. BGB-3245 is a second-generation B-RAF inhibitor that has demonstrated potent inhibitory activity against the RAF family of serine/threonine kinases preclinically. In preclinical studies, BGB-3245 showed it inhibited tumor cell lines harboring non-V600 B-RAF mutations; it was also active towards B-RAF/MAP-ERK Kinase (MEK) inhibitor-resistant tumors.

Phase 1a will consist of a dose-escalation and dose-finding component to establish the MTD and/or RP2D and to evaluate the pharmacokinetics of BGB-3245 3245 in participants with MAPK pathway aberrations. Phase 1b will consist of an expansion component to further evaluate the pharmacokinetics, safety, and tolerability of BGB-3245 at the RP2D and to assess the preliminary antitumor activity of the compound in participants with select tumor types and B-RAF mutational status.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 69 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A First-in-Human, Phase 1a/1b, Open Label, Dose-Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, and Antitumor Activity of the RAF Dimer Inhibitor BGB-3245 in Patients With Advanced or Refractory Tumors
• Actual Study Start Date: February 17, 2020
• Estimated Primary Completion Date: May 1, 2023
• Estimated Study Completion Date: June 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1a: Dose Escalation; BGB-3245 administered orally (PO) as a continuous daily administration, in 28 day and 30 day cycles	Drug: BGB-3245; Administered as specified in the treatment arm
Experimental: Phase 1b, Group 1: Dose Expansion, non-V600 B-RAF mutations; BGB-3245 administered orally (PO) as a continuous daily administration, in 28 day and 30 day cycles in participants with non-V600 B-RAF mutations including RAF fusions	Drug: BGB-3245; Administered as specified in the treatment arm
Experimental: hase 1b, Group 2: Dose Expansion, B-RAF V600 mutations; BGB-3245 administered orally (PO) as a continuous daily administration, in 28 day and 30 day cycles in participants with B-RAF V600 mutated melanoma or NSCLC B-RAF and/or MEK inhibitor resistant tumors (i.e. have progressed on a B-RAF-inhibitor and/or MEK-inhibitor)	Drug: BGB-3245; Administered as specified in the treatment arm

Outcome Measures

Primary Outcome Measures :

1. Phase 1a: Number of Participants and Severity Experiencing Adverse Events (AEs) [ Time Frame: Up to 30 days after the last dose of study drug ]
2. Phase 1a: Number of Participants and Severity Experiencing Serious Adverse Events (SAEs) [ Time Frame: Up to 30 days after the last dose of study drug ]
3. Phase 1a: number of Participants Experiencing AEs meeting protocol defined Dose-Limiting Toxicity (DLT) criteria [ Time Frame: From Cycle 1 Day to the end of Cycle 1 (Cycle 1 is 30 days) ]
4. Phase 1a: Maximum Tolerated Dose (MTD) of BGB-3245, and the recommended Phase 2 Dose (RP2D) for BGB-3245 [ Time Frame: From Cycle 1 Day to the end of Cycle 1 (Cycle 1 is 30 days) ]
   The MTD is defined as the highest dose evaluated for which the estimated toxicity rate is closest to the target toxicity rate of 33%.
5. Phase 1b: Objective Response Rate (ORR) confirmed Complete Response and Partial Response [ Time Frame: Up to 24 months ]

Secondary Outcome Measures :

1. Phase 1a: Overall Response Rate (ORR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
2. Phase 1a: Duration of Response (DOR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
3. Phase 1a: Clinical Benefit Rate (CBR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
4. Phase 1a: Best Overall Response (BOR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
5. Phase 1a: Duration of Stable Disease (DSD) [ Time Frame: Up to 24 months ]
6. Phase 1a: Progression Free Survival (PFS) [ Time Frame: Up to 24 months ]
7. Phase 1a: Plasma Concentration of BGB-3245 [ Time Frame: Within 60 minutes predose up to 72 hours postdose ]
8. Phase 1a: Maximum Observed Plasma Concentration (Cmax) of BGB-3245 [ Time Frame: Within 60 minutes predose up to 72 hours postdose ]
9. Phase 1a: Time to Maximum Plasma Concentration (Tmax) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
10. Phase 1a: Time Taken for Half the Initial Dose Administered To Be Eliminated From The Body (T1/2) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
11. Phase 1a: Area Under the Concentration-Time Curve of 0-infinity Days (AUC0-inf) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
12. Phase 1a:Area Under the Concentration-Time Curve of 0-Last hour (AUC0-last) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
13. Phase 1a: Drug Clearance (CL/F) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
14. Phase 1a: Apparent Volume of Distribution (Vz/F) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
15. Phase 1a: Steady State Area Under the Concentration-Time Curve of 0- Last hour (AUCLast, ss) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
16. Phase 1a: Steady State Maximum Observed Plasma Concentration (Cmax, ss) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
17. Phase 1a: Steady State Time to Maximum Plasma Concentration (Tmax, ss) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
18. Phase 1b: Progression-free survival (PFS) as Assessed by the Investigator [ Time Frame: Up to 36 months ]
19. Phase 1b: Duration of Response (DOR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
20. Phase 1b: Disease-Control Rate (DCR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
21. Phase 1b: Clinical Benefit Rate (CBR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
22. Phase 1b: Overall Survival [ Time Frame: Up to 36 months ]
23. Phase 1b: Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to 30 days after the last dose of study drug ]
24. Phase 1b: Number of Participants Experiencing Serious Adverse Events (SAEs) [ Time Frame: Up to 30 days after the last dose of study drug ]
25. Phase 1b: Plasma Concentration of BGB-3245 [ Time Frame: 60 minutes predose up to 3 hours postdose ]
26. Phase 1b: Steady State Trough Observed Plasma Concentration (Ctrough, SS) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion Criteria:

1. Participants with histologically or cytologically confirmed advanced or metastatic solid tumor who have experienced disease progression during or after at least 1 line of prior systemic anticancer therapy, or for whom treatment is not available or not tolerated/acceptable to the participants. In addition, participants must meet the following eligibility criteria for the corresponding phase of the study:

a. Phase 1a: Participants with a known mutation status and tumor harboring an oncogenic B-RAF or K-RAS/N-RAS mutation, or any other MAPK pathway aberrations. In Phase 1a, the study recruitment will be limited to approximately one third (1/3) participants with K-RAS/N-RAS mutation, and among these participants the study recruitment will be limited to approximately one third (1/3) colorectal cancer (CRC) or pancreatic participants.

a. Phase 1b: participants must have a known mutation status and meet one of the following criteria according to the group they are enrolled into:

1. Group 1: participants with solid tumors with non-V600 B-RAF mutations including RAF fusions,; or
2. Group 2: participants with B-RAF V600 mutated melanoma or non-small cell lung cancer (NSCLC), and have progressed on a B-RAF-inhibitor and/or MEK-inhibitor resistant tumors (i.e., mitogen-activated protein kinase/extracellular signal regulated kinase) inhibitor resistant tumors.

2. Participants must provide tumor tissue sample (archival tumor tissue or agree to a fresh tumor biopsy) for mutation and biomarkers analysis 3. Participants must have measurable disease as defined per RECIST v1.1. 4. Eastern Cooperative Oncology Group performance status of ≤1 at Screening. 5. Adequate hematologic and organ function, as indicated by the following laboratory values, prior to Cycle 1 Day 1

Key Exclusion Criteria:

1. Participants receiving cancer therapy (chemotherapy or other systemic anticancer therapies, immunotherapy, radiation therapy, or surgery) at the time of Cycle 1 Day 1.

2. All participants who have received prior systemic anticancer treatment within the following time frames will be excluded:

   1. Cyclical chemotherapy within a period of time that is shorter than the cycle length used for that treatment (i.e., 6 weeks for nitrosourea, mitomycin C) prior to Cycle 1 Day 1; and
   2. Biologic therapy (i.e., antibodies), continuous or intermittent small-molecule therapies, or any other investigational agents within a period of 5 times the half-life of the agent or ≤4 weeks (whichever is shorter) prior to Cycle 1 Day 1.
3. History or presence of gastrointestinal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
4. Leptomeningeal disease or untreated/unstable brain metastasis except participants with previously treated brain metastasis who are radiologically stable (imaging evidence required), asymptomatic and have been off steroids and antiseizure medications for longer than 28 days prior to Cycle 1 Day 1 are permitted.
5. Any unstable, preexisting major medical condition that in the opinion of the investigator contraindicates the use of an IMP, including known human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Participants who are hepatitis B surface antigen (HBsAg) positive or HCV antibody positive at Screening may be enrolled only if HBV DNA titers <500 IU/mL or negative HCV RNA polymerase chain reaction test, respectively.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Contacts

Contact: MapKure; 1-877-828-5568; clinicaltrials@mapkure.com

Locations

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

United States, New York

Memorial Sloan Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

United States, Texas

MD Anderson; Recruiting

Houston, Texas, United States, 77030

Australia

Peter MacCallum Cancer Centre; Recruiting

Melbourne, Australia, 2010

The Kinghorn Cancer Centre, St Vincent Hospital Sydney; Recruiting

Sydney, Australia, 2010

Sponsors and Collaborators

MapKure, LLC

Investigators

• Study Director: Brandon Beagle, MD; BeiGene

More Information

• Responsible Party: MapKure, LLC
• ClinicalTrials.gov Identifier: NCT04249843
• Other Study ID Numbers: BGB-3245-AU-001
• First Posted: January 31, 2020
• Last Update Posted: December 17, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by MapKure, LLC:

BGB3245; B-RAF inhibitor; B-RAF; K-RAS; N-RAS; Mitogen Activated Protein Kinase (MAPK) Pathway

Additional relevant MeSH terms:

Neoplasms