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

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.

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.

Eligibility Criteria:
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.