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

Phase 1

Recruiting

• Conditions: Malignant Neoplasm of Brain; Malignant Neoplasm
• Interventions: Drug: NBM-BMX Capsule; Drug: Temozolomide; Radiation: Standard radiotherapy

• Registration Number: NCT06012695
• Lead Sponsor: Novelwise Pharmaceutical Corporation

Brief Summary

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.

Study Timeline

• Study Start: 2023-08-11
• Study First Submitted: 2023-08-11
• Study First Submitted QC: 2023-08-22
• Study First Posted: 2023-08-25
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-12
• Last Update Posted: 2024-11-14
• Primary Completion: 2028-05-30
• Study Completion: 2029-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 79

Inclusion Criteria

Arm A (advanced solid tumors)

1. Having signed and dated the informed consent form.

2. Females or males > 18 years old.

3. Histologically or cytologically confirmed advanced solid tumors refractory to standard of care therapy, or for which no standard of care therapy is available.

4. 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).

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.

6. Adequate organ function as defined by the following criteria:

   1. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 × upper limits of normal (ULN), unless liver metastases present, then ≤ 5 × ULN
   2. Total serum bilirubin ≤ 1.5 × ULN unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin ≤ 3 × ULN
   3. Absolute neutrophil count (ANC) ≥ 1,000/μL
   4. Platelets ≥ 75,000/μL
   5. Hemoglobin ≥ 8.0 g/dL
   6. 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.

7. QTcF ≤ 480 msec

8. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.

Arm B (newly diagnosed GBM)

1. Having signed and dated the informed consent form.

2. Females or males > 18 years old.

3. Newly diagnosed, histologically confirmed glioblastoma, non-resectable, partially resected or resected.

4. Karnofsky performance status (KPS) ≥ 60 at screening and before the initiation (Day 1) of concomitant therapy.

5. Disease that is measurable or evaluable as defined by Response Assessment in Neuro-Oncology (RANO) criteria.

6. Adequate organ function as defined by the following criteria:

   1. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3 × upper limit of normal (ULN), unless liver metastases present, then ≤ 5 × ULN
   2. Total serum bilirubin ≤ 1.5 × ULN unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin ≤ 3 × ULN
   3. Absolute neutrophil count (ANC) ≥ 1,500/μL
   4. Platelets ≥ 100,000/μL
   5. Hemoglobin ≥ 8.0 g/dL
   6. 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.

7. QTcF ≤ 480 msec

8. Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.

Exclusion Criteria

Arm A (advanced solid tumors)

1. 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.

2. Curative radiation therapy within 28 days or palliative RT within 7 days of the first dose of NBM-BMX.

3. Currently taking strong inhibitors (e.g., gemfibrozil) or inducers of CYP2C8.

4. 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.

5. 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.

6. Known history of human immunodeficiency virus (HIV) infection.

7. 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.

8. Females who are pregnant or breastfeeding.

9. 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)

1. Prior systemic therapy (including Gliadel wafer implant), immunotherapy, investigational agents, or radiotherapy for glioblastoma.

2. Currently taking strong inhibitors (e.g., gemfibrozil) or inducers of CYP2C8.

3. Corticosteroid use of > 8 mg/day dexamethasone or equivalent within 5 days before the first dose of NBM-BMX.

4. A history of hypersensitivity reaction to temozolomide or dacarbazine.

5. 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.

6. 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.

7. Known history of human immunodeficiency virus (HIV) infection. Note: HIV testing is not required.

8. 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.

9. Female who are pregnant or breastfeeding.

10. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
combination therapy in newly diagnosed glioblastoma	NBM-BMX Capsule	Subjects with newly diagnosed glioblastoma will be treated with NBM-BMX at different dose levels in combination with the standard of care treatment (concomitant RT/TMZ followed by adjuvant TMZ). In the expansion study, Subjects will be treated with NBM-BMX at the recommended Phase 2 dose (RP2D) in combination with RT/TMZ.
monotherapy in advanced solid tumors	NBM-BMX Capsule	Subjects with advanced solid tumors will be treated with NBM-BMX monotherapy at different dose levels depending on the order of their enrollment.
combination therapy in newly diagnosed glioblastoma	Standard radiotherapy	Subjects with newly diagnosed glioblastoma will be treated with NBM-BMX at different dose levels in combination with the standard of care treatment (concomitant RT/TMZ followed by adjuvant TMZ). In the expansion study, Subjects will be treated with NBM-BMX at the recommended Phase 2 dose (RP2D) in combination with RT/TMZ.
combination therapy in newly diagnosed glioblastoma	Temozolomide	Subjects with newly diagnosed glioblastoma will be treated with NBM-BMX at different dose levels in combination with the standard of care treatment (concomitant RT/TMZ followed by adjuvant TMZ). In the expansion study, Subjects will be treated with NBM-BMX at the recommended Phase 2 dose (RP2D) in combination with RT/TMZ.

Primary Outcome Measures

Name	Time	Method
[Arm B, Phase II] Progression-free survival rate at 6 months (PFS6)	up to 6 months	To assess the preliminary efficacy of NBM-BMX in combination with RT and TMZ in subjects with newly diagnosed GBM, the investigators will evaluate anti-tumor activity using RANO criteria.
[Arm B, Phase Ib] Frequency of dose-limiting toxicity (DLT) at each dose level	up to 10 weeks	To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for NBM-BMX in combination with RT and TMZ in subjects with newly diagnosed GBM, toxicities will be graded according to the National Cancer Institute Common Terminology.
[Arm A, Phase Ib] Frequency of dose-limiting toxicity (DLT) at each dose level	up to 28 days	To determine the maximum tolerated dose (MTD) for NBM-BMX monotherapy in subjects with advanced solid tumors, toxicities will be graded according to the National Cancer Institute Common Terminology.

Secondary Outcome Measures

Name	Time	Method
Time to maximum plasma concentration (Tmax) of NBM-BMX	Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days)	Blood samples will be collected at each pre-specified time point for measuring concentrations of NBM-BMX in plasma using a validated bioanalytical method.
Peak plasma concentration (Cmax) of NBM-BMX	Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days)	Blood samples will be collected at each pre-specified time point for measuring concentrations of NBM-BMX in plasma using a validated bioanalytical method.
Terminal elimination half-life (T1/2) of NBM-BMX	Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days)	Blood samples will be collected at each pre-specified time point for measuring concentrations of NBM-BMX in plasma using a validated bioanalytical method.
Frequency, types, severity, and relationship to NBM-BMX of adverse events (AEs)	up to 28 days	The severity of AEs will be graded using NCI CTCAE Version 5.0 by the investigator.
Area under the plasma concentration versus time curve (AUC) of NBM-BMX	Day 1, 8 and 15 for Cycle 1 only (each cycle is 28 days)	Blood samples will be collected at each pre-specified time point for measuring concentrations of NBM-BMX in plasma using a validated bioanalytical method.
Preliminary assessment of anti-tumor activity by response evaluation criteria	at least 8 weeks	Tumor response and progression will be assessed using the RECIST v1.1 or Response Assessment in Neuro-Oncology (RANO) criteria.

Trial Locations

Locations (5)

Kaohsiung Medical University Chung-Ho Memorial Hospital; 🇨🇳 Kaohsiung City, Taiwan

Hualien Tzu Chi Hospital; 🇨🇳 Hualien City, Taiwan

Taichung Veterans General Hospital; 🇨🇳 Taichung City, Taiwan

Linkou Chang-Gung Memorial Hospital; 🇨🇳 Taoyuan City, Taiwan

Koo Foundation Sun Yat-Sen Cancer Center; 🇨🇳 Taipei City, Taiwan