BR101801 in Adult Patients With Advanced Hematologic Malignancies( Phase I)

A Phase I, Open-label, Multi-center, Dose Escalation, and Expansion Study of BR101801 in Adult Patients With Advanced Hematologic Malignancies

This is a Phase I-II, multi-center, open-label, FIH study comprising of 2 study parts (Phase Ia, Phase Ib).

The Phase Ia (dose escalation) part of the study is designed to determine the safety, tolerability, and maximum tolerated dose (MTD)/recommended dose for expansion (RP2D) of BR101801 in subjects with relapsed/refractory B cell lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), and peripheral T cell lymphoma (PTCL).

The Phase Ib (dose expansion) part of the study is designed to assess tumor response and safety in specific advanced relapsed/refractory Peripheral T-cell lymphoma(PTCL) at a dose of BR101801 identified in Phase Ia. Once the RP2D has been determined in Phase Ia (dose escalation), Phase Ib (dose expansion) will commence.

Study Overview

• Status: Active, not recruiting
• Conditions: Follicular Lymphoma; B Cell Lymphoma; Waldenstrom Macroglobulinemia; Marginal Zone Lymphoma; Chronic Lymphocytic Leukemia; Diffuse Large B Cell Lymphoma; Peripheral T Cell Lymphoma; Small Lymphocytic Leukemia
• Intervention / Treatment: Drug: BR101801 (Phase Ia); Drug: BR101801 (Phase Ib)

Detailed Description

1. Phase Ia (Dose Escalation)

   Primary Objectives

   • To assess the safety and tolerability of BR101801 in patients with relapsed/refractory B-cell lymphoma, CLL/SLL, and PTCL.
   • To assess DLT and to determine the MTD and/or the RDE dose for BR101801 when administered orally on a daily schedule in 4-week cycles until disease progression.

   SecondaryObjectives

   • To characterize the plasma and urine PK of BR101801.
   • To assess the preliminary antitumor activity of BR101801.
2. Phase Ib (Dose Expansion)

Primary Objectives

• To assess the safety and tolerability of BR101801 at the RP2D dose in subjects with relapsed/refractory Peripheral T-cell lymphoma (PTCL).

SecondaryObjectives

• To assess clinical activity of BR101801 when administered orally on a daily schedule in 4-week cycles until disease progression.
• To assess the plasma PK of BR101801.

OUTLINE: This is a Phase I, multi-center, open-label, FIH study. The safety monitoring committee(SMC) will be responsible for safety oversight.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Bong-Seog Kim; Phone Number: +82-2-708-8204; Email: seog9270@boryung.co.kr

Study Locations

• Korea, Republic of
  • Busan, Korea, Republic of
    • Inje University Busan Paik Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Severance Hospital, Yonsei University Health System
  • Gyeonggi-do
    • Goyang-si, Gyeonggi-do, Korea, Republic of
      • National Cancer Center
    • Seongnam-si, Gyeonggi-do, Korea, Republic of
      • Seoul National University Bundang Hospital
  • Jeollanam-do
    • Hwasun, Jeollanam-do, Korea, Republic of
      • Chonnam National University Hwasun Hospital
• United States
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital

Participation Criteria

Eligibility Criteria

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

Description

<Inclusion Criteria>

1. Patients must sign an informed consent document
2. Female or male patients aged ≥ 18 years.
3. ECOG performance status ≤ 2.
4. Life expectancy more than 3 months.
5. Phase Ia:Patients with relapsed and/or refractory relapsed/refractory B-cell lymphoma, CLL/SLL, and PTCL diagnosed with World Health Organization (WHO) classification
6. Phase Ib: Subjects with PTCL NOS, PTCL AITL, Nodal PTCL with TFH and PTCL FTCL.
7. Patients have measurable disease based on the appropriate tumor type criteria( Phase Ib only)
8. Have a current need for systemic therapy, the assessment of the investigator.
9. An archival or fresh tumor tissue (ie, tissue block or series of at least 5 slides, up to 15 slides) is required and should be provided during the Screening Visit for Lymphoma subjects. Local review of pathology is required for study entry in Phase Ib only.
10. Phase Ia subjects should be prepared to undergo a fresh tumor biopsy during the study (tumor biopsies will be obtained from 1 to 2 subjects per cohort in Phase Ia).

11. Subject having laboratory values defined as:

    • Creatinine clearance (measured or calculated per institutional standard practice) ≥ 60 mL/min. GFR can also be used in place of creatinine clearance.
    • Total bilirubin < 1.5 × ULN, except for subjects with Gilbert's syndrome who are excluded if total bilirubin > 3.0 × ULN or direct bilirubin < 1.5 × ULN.
    • ALT < 2.5 × ULN, except for subjects who have tumor involvement of the liver, who are included if ALT < 5 × ULN.
    • AST < 2.5 × ULN, except for subjects that have tumor involvement of the liver, who are included if AST < 5 × ULN.
    • Absolute neutrophil count > 1.0 × 109/L.
    • Platelet count > 75 × 109/L.
    • Hemoglobin > 8 g/dL.

<Exclusion Criteria>

1. Presence of overt leptomeningeal or active CNS metastases, or CNS metastases that require local CNS-directed therapy or increasing doses of corticosteroids within the prior 2 weeks. Patients with treated brain metastases should be neurologically stable and off steroids for at least 2 weeks before administration of any study treatment.
2. Impaired cardiac function or clinically significant cardiac disease
3. Patients with interstitial pneumonia or history of drug-induced interstitial pneumonia/pneumonitis.
4. Human immunodeficiency virus (HIV) infection.
5. Patients who are positive for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus antibody (HCVAb).
6. Chronic liver disease or chronic hepatitis
7. Any gastrointestinal disorders interfering with study drug absorption or are unable to swallow tablets or capsules.
8. Malignant disease, other than that being treated in this study.
9. Prior PI3K inhibitor will be accepted in the dose escalation part of the study (Phase Ia) only.

10. For patients with lymphoma:

    • Systemic antineoplastic therapy (including cytotoxic chemotherapy, alfa-interferon [INF], and toxin immunoconjugates) or any experimental therapy within 3 weeks or 5 half lives, whichever is shorter, before the first dose of study treatment.
    • Therapy with tyrosine kinase inhibitor within 5 half-lives before the first dose of study treatment.
    • Unconjugated monoclonal antibody therapies < 6 weeks before the first dose of study treatment.
11. Patients receiving systemic chronic steroid therapy or any immunosuppressive therapy (≥ 10 mg/day prednisone or equivalent).
12. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
13. Use of hematopoietic colony-stimulating growth factors, thrombopoietin mimetics, or erythroid-stimulating agents ≤ 2 weeks prior to start of study drug.
14. Patients with a history of stroke or having active neurological symptoms, with the exception of chronic conditions which, in the opinion of the neurologist, Investigator, and the Sponsor, would not impact ongoing neurologic assessments while on study treatment.
15. Active infection requiring systemic or antiviral antibiotic therapy.
16. Subjects with active CMV infection.
17. Subjects receiving moderate or potent CYP3A4 inhibitors or inducers and are unable to withdraw until 2 weeks or 5 times longer than the half-life, whichever is shorter, before the first dose of study treatment.
18. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery).
19. Radiotherapy within 2 weeks of the first dose of study treatment, except for palliative radiotherapy to a limited-field, such as for the treatment of bone pain or a focally painful tumor mass.
20. Presence of CTCAE ≥ Grade 2 toxicity (except alopecia, peripheral neuropathy, and ototoxicity, which are excluded if ≥ CTCAE Grade 3) due to prior cancer therapy.
21. Participation in an interventional, investigational study within 2 weeks or 5 half-lives, whichever is shorter, of the first dose of study treatment.
22. Any medical condition that would, in the Investigator's judgment, prevent the subject's participation in the clinical study due to safety concerns, compliance with clinical study procedures, or interpretation of study results.
23. Pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin laboratory test.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (BR101801): Phase Ia (dose escalation); Patients will receive BR101801 capsules orally, QD in 28-day cycles. The regimen may be changed to BID dosing based on emerging data.	Drug: BR101801 (Phase Ia); Phase Ia (dose escalation):25 mg capsules and 100 mg capsules Planned doses are 50, 100, 200, 325, and 450 mg.
Experimental: Treatment (BR101801):Phase Ib (dose expansion); • Subjects with PTCL NOS, PTCL AITL, Nodal PTCL with TFH and PTCL FTCL	Drug: BR101801 (Phase Ib); Phase Ib (dose expansion):25 and 100 mg capsules Doses administered will be determined from Phase Ia data.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determination of the MTD and RDE based on DLTs during Cycle 1 (Phase Ia )	The recommended dose is determined by the number of patients who experience a dose limiting toxicity (DLT).	From baseline to Week 4
Number of Participants With Adverse Events (AE) as a Measure of Safety and Tolerability of BR101801 when administered at the MTD or recommended dose (Phase Ia and Ib)	To evaluate safety and tolerability the aggregate review will include but is not limited to: CTCAE TEAEs, treatment-related TEAEs, Grade 3 or higher TEAEs, Grade 3 or higher treatment-related TEAEs, serious treatment-related TEAEs, and TEAEs leading to death.; Laboratory results;; Vital signs;; ECGs;; Physical examination; ECOG performance status	through study completion, and about average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax	Maximum concentration obtained directly from the observed concentration versus time data.	Cycle1( each cycle is 28 days) Day 1 and Cycle 1( each cycle is 28 days) Day 15
AUC(0-inf)	Area under the plasma concentration-time curve from time zero extrapolated to infinity, calculated by linear up/log down trapezoidal summation	Cycle1( each cycle is 28 days) Day 1
AUC(0-last)	Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration	Cycle1( each cycle is 28 days) Day 1 and Cycle 1( each cycle is 28 days) Day 15, Pre-dose to 24 hours after dosing
AUC(0-tau)	Area under the plasma concentration-time curve from time zero during a dosing interval	Cycle1( each cycle is 28 days) Day 1 and Cycle 1( each cycle is 28 days) Day 15, dosing interval: 24 or 12 hours
Ae	Cumulative amount of unchanged drug excreted in urine	Cycle 1( each cycle is 28 days)Day 15, Pre-dose to 12 hours for BID dosing and Pre-dose to 24 hours for QD dosing

Collaborators and Investigators

• Sponsor: Boryung Pharmaceutical Co., Ltd
• Investigators: Principal Investigator: TM Kim, M.D, Ph.D, Seoul National University Hospital; Principal Investigator: SJ Kim, M.D, Ph.D, Samsung Medical Center; Principal Investigator: DH Yoon, M.D, Ph.D, Asan Medical Center; Principal Investigator: Jorge Chaves, M.D, Ph.D, Northwest Medical Specialities, PLLC; Principal Investigator: Emily Curran, M.D, Ph.D, University of Cincinnati; Principal Investigator: JS Kim, M.D, Ph.D, Severance Hospital, Yonsei University Health System; Principal Investigator: EY Lee, M.D, M.S, National Cancer Center; Principal Investigator: JO Lee, M.D, Ph.D, Seoul National University Bundang Hospital; Principal Investigator: DH Yang, M.D, Ph.D, Chonnam National University Hospital; Principal Investigator: WS Lee, M.D, Ph.D, Inje University

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2020
• Primary Completion (Actual): September 21, 2023
• Study Completion (Estimated): March 1, 2024

Study Registration Dates

• First Submitted: June 14, 2019
• First Submitted That Met QC Criteria: July 10, 2019
• First Posted (Actual): July 12, 2019

Study Record Updates

• Last Update Posted (Estimated): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Neoplasms by Site; Disease Attributes; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, B-Cell; Lymphoma, T-Cell; Chronic Disease; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Hematologic Neoplasms; Leukemia; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Lymphoma, T-Cell, Peripheral
• Other Study ID Numbers: BR-101801-CT-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No