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: October 27, 2022
• Sponsor: MapKure, LLC
• Information provided by (Responsible Party): MapKure, LLC

Tracking Information

• First Submitted Date: January 21, 2020
• First Posted Date: January 31, 2020
• Last Update Posted Date: October 27, 2022
• Actual Study Start Date: February 17, 2020
• Estimated Primary Completion Date: May 1, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 29, 2020)

• Phase 1a: Number of Participants and Severity Experiencing Adverse Events (AEs) [ Time Frame: Up to 30 days after the last dose of study drug ]
• 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 ]
• 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) ]
• 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%.
• Phase 1b: Objective Response Rate (ORR) confirmed Complete Response and Partial Response [ Time Frame: Up to 24 months ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 13, 2021)

• Phase 1a: Overall Response Rate (ORR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1a: Duration of Response (DOR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1a: Clinical Benefit Rate (CBR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1a: Best Overall Response (BOR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1a: Duration of Stable Disease (DSD) [ Time Frame: Up to 24 months ]
• Phase 1a: Progression Free Survival (PFS) [ Time Frame: Up to 24 months ]
• Phase 1a: Plasma Concentration of BGB-3245 [ Time Frame: Within 60 minutes predose up to 72 hours postdose ]
• Phase 1a: Maximum Observed Plasma Concentration (Cmax) of BGB-3245 [ Time Frame: Within 60 minutes predose up to 72 hours postdose ]
• Phase 1a: Time to Maximum Plasma Concentration (Tmax) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• 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 ]
• 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 ]
• 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 ]
• Phase 1a: Drug Clearance (CL/F) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• Phase 1a: Apparent Volume of Distribution (Vz/F) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• 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 ]
• Phase 1a: Steady State Maximum Observed Plasma Concentration (Cmax, ss) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• Phase 1a: Steady State Time to Maximum Plasma Concentration (Tmax, ss) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• Phase 1b: Progression-free survival (PFS) as Assessed by the Investigator [ Time Frame: Up to 36 months ]
• Phase 1b: Duration of Response (DOR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1b: Disease-Control Rate (DCR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1b: Duration of Stable Disease (DSD) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1b: Clinical Benefit Rate (CBR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1b: Overall Survival [ Time Frame: Up to 36 months ]
• Phase 1b: Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to 30 days after the last dose of study drug ]
• Phase 1b: Number of Participants Experiencing Serious Adverse Events (SAEs) [ Time Frame: Up to 30 days after the last dose of study drug ]
• Phase 1b: Plasma Concentration of BGB-3245 [ Time Frame: 60 minutes predose up to 3 hours postdose ]
• Phase 1b: Steady State Trough Observed Plasma Concentration (Ctrough, SS) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]

Original Secondary Outcome Measures (submitted: January 29, 2020)

• Phase 1a: Overall Response Rate (ORR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1a: Duration of Response (DOR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1a: Clinical Benefit Rate (CBR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1a: Best Overall Response (BOR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1a: Duration of Stable Disease (DSD) [ Time Frame: Up to 24 months ]
• Phase 1a: Progression Free Survival (PFS) [ Time Frame: Up to 24 months ]
• Phase 1a: Plasma Concentration of BGB-3245 [ Time Frame: Within 60 minutes predose up to 72 hours postdose ]
• Phase 1a: Maximum Observed Plasma Concentration (Cmax) of BGB-3245 [ Time Frame: Within 60 minutes predose up to 72 hours postdose ]
• Phase 1a: Time to Maximum Plasma Concentration (Tmax) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• 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 ]
• 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 ]
• 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 ]
• Phase 1a: Drug Clearance (CL/F) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• Phase 1a: Apparent Volume of Distribution (Vz/F) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• 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 ]
• Phase 1a: Steady State Maximum Observed Plasma Concentration (Cmax, ss) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• Phase 1a: Steady State Time to Maximum Plasma Concentration (Tmax, ss) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]
• Phase 1b: Progression-free survival (PFS) as Assessed by the Investigator [ Time Frame: Up to 36 months ]
• Phase 1b: Duration of Response (DOR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1b: Disease-Control Rate (DCR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1b: Clinical Benefit Rate (CBR) as Assessed by the Investigator [ Time Frame: Up to 24 months ]
• Phase 1b: Overall Survival [ Time Frame: Up to 36 months ]
• Phase 1b: Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to 30 days after the last dose of study drug ]
• Phase 1b: Number of Participants Experiencing Serious Adverse Events (SAEs) [ Time Frame: Up to 30 days after the last dose of study drug ]
• Phase 1b: Plasma Concentration of BGB-3245 [ Time Frame: 60 minutes predose up to 3 hours postdose ]
• Phase 1b: Steady State Trough Observed Plasma Concentration (Ctrough, SS) of BGB-3245 [ Time Frame: 60 minutes predose up to 72 hours postdose ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Safety, Pharmacokinetics, and Antitumor Activity of BGB-3245 in Participants With Advanced or Refractory Tumors
• 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
• 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 solid tumors
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Solid Tumor
• B-Raf Mutation-Related Tumors

Intervention

Drug: BGB-3245

administered orally (PO)

Study Arms

• Experimental: Phase 1a: Dose Escalation
  BGB-3245 administered orally (PO)
  Intervention: Drug: BGB-3245
• Experimental: Phase 1b, Group 1: Dose Expansion
  BGB-3245 administered orally (PO)
  Intervention: Drug: BGB-3245

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 13, 2021): 168
• Original Estimated Enrollment (submitted: January 29, 2020): 69
• Estimated Study Completion Date: June 1, 2024
• Estimated Primary Completion Date: May 1, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

1. Participants with histologically confirmed advanced or metastatic solid tumor who have had 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 mutation of the v-RAF murine sarcoma viral oncogene homolog B (BRAF) gene (the mutations of primary interest are the BRAF Class II mutation, Class

   III mutation or BRAF fusion). In addition, participants with tumors harboring the mutation of the neuroblastoma RAS viral oncogene homolog (NRAS) gene or the Kirsten rat sarcoma virus oncogene homolog (KRAS) are eligible for Part 1a. For patients with KRAS mutations, tumor types of colorectal cancer (CRC) and pancreatic cancer are excluded.Phase 1b: participants must have a known mutation status and meet one of the following criteria according to the group they are enrolled into:

   I. Group 1: Patients with tumor types other than colorectal cancer (CRC) that harbor BRAF V600 mutations who have been treated and progressed on prior BRAF and/or mitogen activated protein kinase (MEK) inhibition.

   II. Group 2: Patients with advanced solid tumors harboring a BRAF Class II mutation or a BRAF fusion mutation III. Group 3: Patients with cutaneous melanoma harboring a neuroblastoma RAS viral oncogene homolog (NRAS) mutation IV. Group 4: Patients with cutaneous melanoma harboring an NRAS mutation who consent to paired fresh biopsies i. .

2. Patients in Phase 1b Group 1: Patients must have received the last dose of prior BRAF and/or MEK inhibitor therapy within 90 days of initiation of BGB-3245 study treatment (Cycle 1 Day 1)
3. Participants must provide archival tumor tissue or agree to a fresh tumor biopsy for mutation and biomarkers analysis (fresh tumor biopsies

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. Systemic 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. Current evidence of symptomatic CNS metastases, leptomeningeal carcinomatosis or untreated spinal cord compression. Asymptomatic treated or asymptomatic untreated brain metastases are allowed as long as patients are clinically stable.
5. Any unstable, preexisting major medical condition that in the opinion of the investigator contraindicates the use of a study drug, including known human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Australia, United States

Administrative Information

• NCT Number: NCT04249843
• Other Study ID Numbers: BGB-3245-AU-001
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes

• Current Responsible Party: MapKure, LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: MapKure, LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: MapKure, LLC
• Verification Date: October 2022