Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT04018248
Recruitment Status : Not yet recruiting
First Posted : July 12, 2019
Last Update Posted : July 16, 2019
Sponsor:
Information provided by (Responsible Party):
Boryung Pharmaceutical Co., Ltd

Brief Summary:

This is a Phase I, multi-center, open-label, FIH study comprising of 2 study parts (Phase Ia and 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 (RDE) of BR101801 in patients with relapsed/refractory advanced hematologic malignancies except acute leukemia and multiple myeloma.

The Phase Ib (dose expansion) part of the study is designed to assess tumor response and safety in specific advanced relapsed/refractory hematologic malignances at a dose of BR101801 identified in Phase Ia. Once the RDE has been determined in Phase Ia (dose escalation), Phase Ib (dose expansion) will commence, and 3 groups will be recruited in parallel.


Condition or disease Intervention/treatment Phase
Diffuse Large B Cell Lymphoma Follicular Lymphoma Chronic Lymphocytic Leukemia Small Lymphocytic Leukemia B Cell Lymphoma Marginal Zone Lymphoma Waldenstrom Macroglobulinemia Peripheral T Cell Lymphoma Drug: BR101801 (Phase Ia) Drug: BR101801 (Phase Ib) Phase 1

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.

    Exploratory Objectives

    • To characterize the PD of BR101801.
    • To explore BR101801 metabolites.
  2. Phase Ib (Dose Expansion)

Primary Objectives

•To assess the safety and tolerability of BR101801 at the RDE dose in patients with relapsed and/or refractory B-cell lymphoma, CLL/SLL, and 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

Exploratory Objectives

  • To assess the PD of BR101801.
  • To explore BR101801 metabolites.

OUTLINE:This is a Phase I, multi-center, open-label, FIH study . Patients in Phase Ia and Phase Ib will receive BR101801 capsules orally and safety monitoring committee (SMC) will be responsible for safety oversight.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Open-label, Multi-center, Dose Escalation, and Expansion Study of BR101801 in Adult Patients With Advanced Hematologic Malignancies
Estimated Study Start Date : November 2019
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : February 2024


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)

Group A: Patients with diffuse large B-cell lymphoma (DLBCL) including MYC-altered DLBCL

Group B: Patients with follicular lymphoma.

Group C: Patients with chronic lymphocytic leukemia/small lymphocytic leukemia, other B-cell lymphoma such as, but not limited to mantle cell lymphoma, marginal zone lymphoma, Waldenstrom's macroglobulinemia, or PTCL

Drug: BR101801 (Phase Ib)
Phase Ib (dose expansion):25 and 100 mg capsules Doses administered will be determined from Phase Ia data.




Primary Outcome Measures :
  1. To determination of the MTD and RDE based on DLTs during Cycle 1 (Phase Ia ) [ Time Frame: From baseline to Week 4 ]
    The recommended dose is determined by the number of patients who experience a dose limiting toxicity (DLT).

  2. 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) [ Time Frame: through study completion, and about average of 1 year ]

    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


Secondary Outcome Measures :
  1. Cmax [ Time Frame: Cycle1( each cycle is 28 days) Day 1 and Cycle 1( each cycle is 28 days) Day 15 ]
    Maximum concentration obtained directly from the observed concentration versus time data.

  2. AUC(0-inf) [ Time Frame: Cycle1( each cycle is 28 days) Day 1 ]
    Area under the plasma concentration-time curve from time zero extrapolated to infinity, calculated by linear up/log down trapezoidal summation

  3. AUC(0-last) [ Time Frame: 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 ]
    Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration

  4. AUC(0-tau) [ Time Frame: Cycle1( each cycle is 28 days) Day 1 and Cycle 1( each cycle is 28 days) Day 15, dosing interval: 24 or 12 hours ]
    Area under the plasma concentration-time curve from time zero during a dosing interval

  5. Ae [ Time Frame: 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 ]
    Cumulative amount of unchanged drug excreted in urine



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
  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 who have received standard therapy or are intolerant of standard therapy, and/or for whom no standard therapy exists.
  6. Phase Ib:

    • Group A: Patients with DLBCL including MYC-altered DLBCL and transformed DLBCL.
    • Group B: Patients with follicular lymphoma Grade 1 to 3a
    • Group C: Patients with CLL/SLL, other B-cell lymphoma such as, but not limited to, mantle cell lymphoma, marginal zone lymphoma, Waldenstrom's macroglobulinemia, and PTCL
  7. Patients have measurable disease based on the appropriate tumor type criteria( Phase Ib only)
  8. An archival or fresh tumor tissue is required.
  9. Solid tumor patients in Phase Ia and the first 7 patients in each group of Phase Ib should be prepared to undergo a fresh tumor biopsy during the study
  10. Female patients must be surgically sterile, or have a monogamous partner who is surgically sterile, or be of postmenopausal status or commit to use an effective form of birth control for the duration of the study and for 3 months following the last BR101801 administration.
  11. Sexually active males must commit to use an effective form of birth control while taking the drug and for 3 months after stopping BR101801.
  12. Patient having laboratory values defined as:

    • Creatinine clearance > 40 mL/min.
    • Total bilirubin < 1.5 × ULN, except for patients 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 patients who have tumor involvement of the liver, who are included if ALT < 5 × ULN.
    • AST < 2.5 × ULN, except for patients 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, including any of the following:

    • Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade ≥ 2), left ventricular ejection fraction < 50% as MUGA or ECHO, uncontrolled hypertension, or clinically significant arrhythmia.
    • QTcF > 450 ms ECG or congenital long QT syndrome at the Screening Visit.
    • A marked baseline prolongation of QT/QTc interval
    • The obligatory use of concomitant medications that prolong the QT/QTc interval.
    • Acute myocardial infarction or unstable angina pectoris < 3 months prior to study entry.
  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. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
  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 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). Topical, inhaled, nasal, and ophthalmic steroids are allowed.
  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. If erythroid-stimulating agents were initiated more than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, they can be maintained.
  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. Patients with active CMV infection.
  17. Patients receiving moderate or potent CYP 3A4 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
  19. Radiotherapy within 2 weeks of the first dose of study drug, 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 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 patient'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 (hCG) laboratory test.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04018248


Contacts
Layout table for location contacts
Contact: Jayhyuk Myung +82-31-491-2271 (Ext. 501) jhmyung@boryung.co.kr
Contact: Evertin Kim +8227088095 evertin@boryung.co.kr

Sponsors and Collaborators
Boryung Pharmaceutical Co., Ltd
Investigators
Layout table for investigator information
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

Layout table for additonal information
Responsible Party: Boryung Pharmaceutical Co., Ltd
ClinicalTrials.gov Identifier: NCT04018248     History of Changes
Other Study ID Numbers: BR-101801-CT-101
First Posted: July 12, 2019    Key Record Dates
Last Update Posted: July 16, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Layout table for MeSH terms
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Plasma Cell
Lymphoma
Leukemia
Lymphoma, Follicular
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, T-Cell
Lymphoma, Large B-Cell, Diffuse
Waldenstrom Macroglobulinemia
Lymphoma, T-Cell, Peripheral
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Leukemia, B-Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders