A Phase I/II Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Anti-Tumor Activity of TNG908 in Patients with MTAP-deleted Advanced or Metastastic Solid Tumors

1. Age: ≥18 years of age at the time of signature of the main study ICF.
2. Karnofsky performance status score ≥ 70.
3. Patient has a prior histologically confirmed diagnosis of a grade 4 GBM or a prior histologically confirmed diagnosis of a grade 2 or 3 malignant glioma and now has radiographic progression consistent with a grade 4 GBM (IDH wild type), grade 4 diffuse astrocytoma (IDH mutant), or has a unifocal relapse of GBM.
4. Relapsed or refractory disease per modified RANO criteria after treatment in the adjuvant (eg, postsurgery) setting. Prior therapies are restricted to radiation, temozolomide, and the Optune device at a maximum.
5. Progression on prior therapy documented per modified RANO (ie, radiographic evidence of recurrence/progression on contrast-enhancing MRI with measurable disease per mRANO after standard therapy (radiation and/or temozolomide; ≥12 weeks after completion of front-line radiation therapy). Sites need to provide information on prior locoregional treatment for evaluation of the baseline scan, including the type of treatment, location of treatment, and whether the patient progressed in the treatment field after completion of locoregional therapy.
6. If there is either a history or high risk (as deemed by the investigators) of disease- related seizures, the patients must be on a non-EIAED; patients previously on an EIAED must be fully switched to non-EIAED at least 2 weeks prior to study treatment.
7. If steroids are needed, patients must be on a stable dose of corticosteroids for at least 5 days prior to the baseline MRI.
8. Documented bi-allelic (homozygous) deletion of MTAP in a tumor detected by a validated NGS test, or absence of MTAP protein in a tumor detected by a validated IHC test. Sponsor’s approval is required for laboratories and assay methods other than the study-designated central NGS or IHC laboratory to perform this assessment.
9. Has an archival tissue sample available with sufficient tumor tissue for central NGS testing and optional biomarker analyses. If patients do not have sufficient archival material and are not providing the optional on-treatment biopsy, all efforts should be made to obtain a pre-treatment biopsy to satisfy this requirement. In such cases, if it is not medically feasible or safe for patients to undergo a pre-treatment biopsy, this should be discussed with the Sponsor prior to enrollment.
10. If a patient with relapsed or refractory GBM undergoes a resection during the study, the patient must be willing to provide tumor tissue.
11. At least one of the following criteria for standard-of-care therapy(ies):
    1. Progression or an inadequate response to an approved standard-of-care therapy; no more than three lines of prior systemic therapy.
    2. No approved standard-of-care therapy.
    3. Patient is intolerant of standard-of-care therapy(ies).
    4. Investigator has determined that treatment with the standard-of-care therapy is not appropriate.
    5. Note: For (c) and (d) the reason(s) must be documented in the electronic case report form.
12. Prior therapies:
    1. Elapsed time from the last dose of prior therapies until the first dose of TNG908 must meet the following criteria:
       1. Cytotoxic therapies: 21 days, provided that patient's labs demonstrate adequate bone marrow function. Patients with inadequate bone marrow function at 21 days will be eligible after a 28-day washout.
       2. Nitrosureas: 42 days.
       3. Radiation therapy: 12 weeks.
       4. Any investigational agent or other anti-tumor therapy, including antibodies: the shorter of 28 days or 5 half-lives, except for prior bevicizumab therapy (which is only permitted as a single dose for edema/mass effect): 12 weeks. 
       5. Optune device: 14 days.
    2. All adverse events related to prior therapies (chemotherapy, radiotherapy, or surgery) must have resolved to Grade 1 or baseline, except for:
       1. Alopecia (Grade ≤2)
       2. Sensory neuropathy (Grade ≤2)
       3. Other adverse events that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the patient
13. Organ function/reserve:
    1. Bone marrow (within 14 days of the first dose of the study treatment):
       1. Hemoglobin levels ≥9 g/dL (5.6 mmol/L). Note: RBC transfusion is not allowed within 14 days before the first dose of the study treatment
       2. Absolute neutrophil count ≥1,500/μL. Note: Colony-stimulating growth factors (eg, G-CSF and GM-CSF) are not allowed within 7 days before the first dose of the study treatment
       3. Platelet count ≥75 × 10⁶/mL. Note: Platelet transfusion is not allowed within 7 days before the first dose of the study treatment.
    2. Hepatic:
       1. For participants in the main study:
          1. Total bilirubin ≤1.5 × ULN; except ≤3 × ULN in the presence of hepatic metastases or Gilbert’s disease
          2. AST/ALT ≤2.5 × ULN, or ≤5 × ULN in patients with hepatic metastases
       2. For participants in the phase II pharmacokinetic sub-studies:
          1. Total bilirubin ≤1.5 × ULN
          2. Aspartate aminotransferase/ALT ≤2.5 × ULN
          3. Albumin and INR ≤ Grade 1
    3. Renal:
       1. For participants in the main study:
          1. Estimated creatinine clearance (by Cockcroft-Gault) ≥45 mL/min
       2. For participants in the phase II pharmacokinetic sub-studies:
          1. Estimated creatinine clearance (by Cockcroft-Gault) ≥60 mL/min
14. Pregnancy:
    1. Women of childbearing potential must have a negative serum pregnancy test result at screening (not applicable to patients who are unable to become pregnant, including those with bilateral oophorectomy and/or hysterectomy). The test must be performed within 72 hours before Cycle 1 Day 1 of study treatment.
    2. Women of non-childbearing potential must have at least 12 continuous months of natural (spontaneous) amenorrhea and an appropriate clinical profile (eg, age-appropriate or history of vasomotor symptoms) or have had surgical sterilization (bilateral oophorectomy, hysterectomy, or bilateral tubal ligation) >42 days prior to screening.
15. Contraception:
    1. Male patients with a partner who is a woman of childbearing potential must use highly effective contraception, during their participation in the study and for 3 months following the last dose of the study treatment.
    2. Women of childbearing potential must use highly effective form of contraception, during their participation in the study and for 6 months following the last dose of the study treatment.
    3. Highly effective contraception is defined as having a failure rate of less than 1% per year such as hormonal oral contraceptives, injectables, patches, intrauterine devices, double-barrier methods (eg, synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel) or male partner sterilization.
16. Gamete donation: Male patients must refrain from donating sperm during participation and for 3 months following the last dose of study treatment, and female patients must refrain from donating ova during participation in the study and for 6 months following the last dose of study treatment. It is recommended that male patients bank sperm prior to treatment in this study
17. Patient must be able to swallow tablets; Participants that require study drug administration via NG/G tubes must meet all other study requirements and may be considered for the study if documented approval by the sponsor is obtained. Additionally, participants that require drug administration via NG/G tubes may not participate in the phase II pharmacokinetic sub-studies.
18. Written informed consent must be obtained according to local guidelines and signed and dated by the patient or legal guardian prior to the performance of any study-specific procedures, sampling, or analyses.

For the most up-to-date criteria, visit clinicaltrials.gov.

1. Prior treatment with a PRMT5 inhibitor.
2. Known allergies, hypersensitivity, or intolerance to TNG908 or its excipients.
3. Uncontrolled intercurrent illness that will limit compliance with the study requirements.
4. Active infection requiring systemic therapy.
5. Patients for whom contrast-enhancing MRIs are contraindicated.
6. History of a seizure disorder; patients with relapsed or refractory GBM and a history of disease-related seizures may be included if adequately controlled on a stable regimen of non-EIAED(s).
7. Currently participating in or has planned participation in a study of another investigational agent or device.
8. Impairment of GI function or disease that may significantly alter the absorption of oral TNG908 (eg, ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
9. Active prior or concurrent malignancy. Such patients for whom the natural history of the malignancy or its treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational schedule are eligible for this study, if approved in writing by the sponsor. Patients with a completely treated prior malignancy and no evidence of disease for >2 years prior to the first dose of TNG908 are also eligible.
10. Red blood cell or erythropoietin transfusion within the 14 days prior to the first dose of TNG908.
11. Platelet or colony-stimulating growth factor (eg, G-CSF and GM-CSF) transfusion within 7 days prior to the first dose of TNG908.
12. Current active liver disease from any cause, including a positive screening test for HAV (HAV immunoglobulin), HBV (HBsAg), or HCV (HCV antibody, confirmed by HCV RNA PCR). The following are exceptions, and patients meeting the following criteria are eligible (testing is not required):
    1. Patients seropositive for HBcAb and seronegative for HBsAg if HBV DNA is undetectable.
    2. Patients seropositive for HCV antibody but negative for HCV RNA PCR.
13. Known to be HIV positive, unless all of the following criteria are met (testing is not required):
    1. CD4⁺ count ≥300/μL
    2. Undetectable viral load
    3. Receiving highly active antiretroviral therapy
14. Clinically relevant cardiovascular disease:
    1. Arrhythmias, including bradyarrhythmia, and/or patients who require anti-arrhythmic therapy (except for protocol-permitted β-blockers); controlled atrial fibrillation is not excluded
    2. Personal or immediate family history of congenital long QT syndrome or personal history of Torsades de Pointes
    3. Baseline QTcF ≥470 msec
    4. Patients with known history and current symptoms of cardiac disease or history of treatment with cardiotoxic agents should have a clinical risk assessment of cardiac function using the NYHA Functional Classification. To be eligible for this study, patients must be Class 1 or 2.
    5. Unstable angina or new onset of angina within the 3 months prior to the first dose of TNG908.
    6. Myocardial infarction within the 6 months prior to the first dose of TNG908
15. Concurrent treatment with the following prohibited medications:
    1. Proton pump inhibitors
    2. H2 blockers
    3. CYP3A4:
       1. CYP3A4 substrates with a narrow therapeutic range (drugs for which a small increase in plasma concentration may increase the incidence or severity of adverse reactions)
       2. Sensitive substrates of CYP3A4/5
       3. Strong CYP3A4/5 inducers
       4. Strong CYP3A4/5 inhibitors
    4. Sensitive substrates of OATP1B1
    5. Sensitive substrates and narrow therapeutic range substrates of CYP2B6, CYP2C8, CYP2C9, CYP2C19, P-gp, and BCRP
16. A female patient who is pregnant or lactating
17. Major surgical procedure within 14 days of the first dose of the study treatment. Note: Procedures such as central venous catheter placement, tumor needle biopsy, feeding tube placement, and placement of a cerebrospinal fluid-diverting device (eg, endoscopic third ventriculotomy or a ventriculoperitoneal shunt) are not considered major surgical procedures
18. Patient is unwilling or unable to comply with the scheduled visits, study treatment administration plan, laboratory tests, biopsy, or other study procedures and study restrictions.
19. Patient has a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator’s opinion, may affect the safety of the patient or impair the assessment of study results.

For the most up-to-date criteria, please visit clinicaltrials.gov.