NBM-BMX Administered Orally to Patients With Solid Tumors or Newly Diagnosed Glioblastoma

Official title

A Phase Ib/II, Open-label Study of NBM-BMX as Monotherapy or in Combination With Radiotherapy and Temozolomide in Subjects With Solid Tumors or Newly Diagnosed Glioblastoma

Overview

NBM-BMX is an orally available new chemical entity to inhibit histone deacetylases 8 (HDAC8) activity specifically, being developed as a potential anti-cancer therapeutic by NatureWise. This study aims to evaluate the safety, pharmacokinetics, and preliminary efficacy of NBM-BMX as monotherapy in subjects with advanced solid tumors or combination with the standard of care treatment in subjects with newly diagnosed glioblastoma.

Detailed description

This is a multi-center, open-label, 2-arm, phase Ib/II study to evaluate the safety, pharmacokinetics, and preliminary efficacy of NBM-BMX as monotherapy in the treatment of solid tumors (Arm A) or in combination with radiotherapy/temozolomide in the treatment of glioblastoma (Arm B).

Arm A consists of dose escalation cohorts in subjects with advanced solid tumors who will be treated with NBM-BMX monotherapy at different dose levels. Arm B consists of dose escalation cohorts (Phase Ib) and expansion cohorts (Phase II) in subjects with newly diagnosed glioblastoma (GBM). Subjects will be treated with NBM-BMX at different dose levels in combination with the first-line standard of care treatment (i.e., concomitant Radiotherapy (RT)/TMZ followed by adjuvant TMZ) in Phase Ib. After the recommended Phase 2 dose (RP2D) is determined in Phase Ib, additional subjects will be enrolled and treated at the RP2D to evaluate the efficacy of NBM-BMX combination therapy.

Interventions

• Drug NBM-BMX Capsule
  Each capsule contains 100 mg of the active ingredient.
• Drug Temozolomide
  TMZ will be administered orally at a 75 mg/m2 dose daily during concomitant therapy. In the maintenance period, days 1-5 of each cycle will be administered 150-200 mg/m2.
• Radiation Standard radiotherapy
  A total dose of 60 Gy will be administered in 6 weeks.

Primary outcome measures

• [Arm A, Phase Ib] Frequency of dose-limiting toxicity (DLT) at each dose level [Time frame: up to 28 days]
• [Arm B, Phase Ib] Frequency of dose-limiting toxicity (DLT) at each dose level [Time frame: up to 10 weeks]
• [Arm B, Phase II] Progression-free survival rate at 6 months (PFS6) [Time frame: up to 6 months]

Secondary outcome measures (6)

• Frequency, types, severity, and relationship to NBM-BMX of adverse events (AEs) [Time frame: up to 28 days]
• Preliminary assessment of anti-tumor activity by response evaluation criteria [Time frame: at least 8 weeks]
• Area under the plasma concentration versus time curve (AUC) of NBM-BMX [Time frame: Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days)]
• Peak plasma concentration (Cmax) of NBM-BMX [Time frame: Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days)]
• Time to maximum plasma concentration (Tmax) of NBM-BMX [Time frame: Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days)]
• Terminal elimination half-life (T1/2) of NBM-BMX [Time frame: Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days)]

Eligibility criteria

Inclusion criteria

Arm A (advanced solid tumors)

• Having signed and dated the informed consent form.
• Females or males > 18 years old.
• Histologically or cytologically confirmed advanced solid tumors refractory to standard of care therapy, or for which no standard of care therapy is available.
• Disease that is measurable or evaluable as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Response Assessment in Neuro-Oncology (RANO) criteria (for CNS tumors).
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
• Adequate organ function as defined by the following criteria:

• Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 × upper limits of normal (ULN), unless liver metastases present, then ≤ 5 × ULN
• Total serum bilirubin ≤ 1.5 × ULN unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin ≤ 3 × ULN
• Absolute neutrophil count (ANC) ≥ 1,000/μL
• Platelets ≥ 75,000/μL
• Hemoglobin ≥ 8.0 g/dL
• Non-indexed estimated glomerular filtration rate (eGFR) ≥ 50 mL/min/1.73 m2 × BSA (m2)/1.73.

Transfusion is not allowed to meet entry criteria.

• QTcF ≤ 480 msec
• Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.

Arm B (newly diagnosed GBM)

• Having signed and dated the informed consent form.
• Females or males > 18 years old.
• Newly diagnosed, histologically confirmed glioblastoma, non-resectable, partially resected or resected.
• Karnofsky performance status (KPS) ≥ 60 at screening and before the initiation (Day 1) of concomitant therapy.
• Disease that is measurable or evaluable as defined by Response Assessment in Neuro-Oncology (RANO) criteria.
• Adequate organ function as defined by the following criteria:

• Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 × upper limit of normal (ULN), unless liver metastases present, then ≤ 5 × ULN
• Total serum bilirubin ≤ 1.5 × ULN unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin ≤ 3 × ULN
• Absolute neutrophil count (ANC) ≥ 1,500/μL
• Platelets ≥ 100,000/μL
• Hemoglobin ≥ 8.0 g/dL
• Non-indexed estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 × BSA (m2)/1.73.

Transfusion is not allowed to meet entry criteria.

• QTcF ≤ 480 msec
• Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.

Exclusion criteria

Arm A (advanced solid tumors)

• Systemic anti-cancer treatment (investigational or approved) within 28 days or 5 half-lives of that drug (whichever is shorter) of the first dose of NBM-BMX.
• Curative radiation therapy within 28 days or palliative RT within 7 days of the first dose of NBM-BMX.
• Currently taking strong inhibitors (e.g., gemfibrozil) or inducers of CYP2C8.
• Any of the following within 6 months of the first dose of NBM-BMX: pulmonary embolism events, deep vein thrombosis (DVT) events, myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack.
• A positive test for hepatitis B (HBsAg) and/or hepatitis C (anti-HCV antibody), unless the HBV DNA level and/or HCV RNA level is below the limit of detection.
• Known history of human immunodeficiency virus (HIV) infection.
• Men and women of childbearing potential who are unwilling to use highly effective contraceptive methods during the study period.

Highly effective contraceptive methods include implants, injectables, combined oral contraceptives, intra-uterine devices (IUDs), sexual abstinence, surgical sterilization or a partner who is sterile.

• Females who are pregnant or breastfeeding.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would impart, in the judgement of the investigator and/or sponsor, excess risks associated with study participation or study drug administration.

Arm B (newly diagnosed GBM)

• Prior systemic therapy (including Gliadel wafer implant), immunotherapy, investigational agents, or radiotherapy for glioblastoma.
• Currently taking strong inhibitors (e.g., gemfibrozil) or inducers of CYP2C8.
• Corticosteroid use of > 8 mg/day dexamethasone or equivalent within 5 days before the first dose of NBM-BMX.
• A history of hypersensitivity reaction to temozolomide or dacarbazine.
• Any of the following within 6 months of the first dose of NBM-BMX: pulmonary embolism events, deep vein thrombosis (DVT) events, myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack.
• A positive test for hepatitis B (HBsAg) and/or hepatitis C (anti-HCV antibody), unless the HBV DNA level and/or HCV RNA level is below the limit of detection.
• Known history of human immunodeficiency virus (HIV) infection. Note: HIV testing is not required.
• Men and women of childbearing potential who are unwilling to use highly effective contraceptive methods during the study period and for at least 6 months after the final dose of temozolomide.

Highly effective contraceptive methods include implants, injectables, combined oral contraceptives, intra-uterine devices (IUDs), sexual abstinence, surgical sterilization or a partner who is sterile.

• Female who are pregnant or breastfeeding.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would impart, in the judgement of the investigator and/or sponsor, excess risks associated with study participation or study drug administration.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Taiwan · 4 centers

• Kaohsiung Medical University Chung-Ho Memorial Hospital — Kaohsiung City
• Taichung Veterans General Hospital — Taichung
• Koo Foundation Sun Yat-Sen Cancer Center — Taipei
• Linkou Chang-Gung Memorial Hospital — Taoyuan City

Identifiers

NCT: NCT06012695 · NBM-BMX-003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗