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A first-in-human study to investigate the safety and antitumor activity of TNG456 alone and combined with abemaciclib in patients with solid tumors with MTAP loss

This is a phase 1/2 clinical trial evaluating the safety, tolerability, and preliminary antitumor activity of TNG456 as monotherapy and in combination with abemaciclib in patients with solid tumors with methylthioadenosine phosphorylase (MTAP) loss. 

MTAP is an essential enzyme in a biochemical pathway that regenerates methionine and adenosine, which are building blocks for proteins and RNA molecules. Cells compensate for the loss of MTAP by turning to protein arginine methyltransferase 5 (PRMT5). 

MTAP loss occurs in approximately 40 percent of glioblastoma cases. These tumors also lack the cell-cycle regulator CDKN2A, which makes them susceptible to CDK4/6 inhibitors.

TNG456 is a selective oral small-molecule inhibitor of PRMT5 that crosses the blood-brain barrier. This drug binds cooperatively with a compound called MTA to inhibit PRMT5 function. Preclinical data demonstrates that TNG456 is a potent PRMT5 inhibitor and acts specifically in tumor cells with MTAP loss. 

Abemaciclib is a small-molecule inhibitor of CDK4 and CDK6, two proteins that regulate cell division. This drug was selected as the CDK4/6 inhibitor in this trial for its penetrance into the central nervous system.

Inclusion Criteria
  1. Has a tumor with confirmed MTAP loss.
  2. Is ≥18 years of age.
  3. Can understand the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements.
  4. Has had progression or an inadequate response to or is intolerant of the approved standard of care therapy, no standard of care therapy exists, or the investigator has determined that treatment with the standard of care therapy is not appropriate, the reason for which must be documented in the eCRF. There is no limit to lines of prior therapy for patients in dose escalation and non-glioblastoma patients in dose expansion. Patients with glioblastoma are limited to their first or second recurrence per RANO 2.0 without limitation to the types of prior therapy with the exception of bevacizumab, PRMT5, MAT2a, and CDK4/6i.
  5. Prior therapies:
    1. The elapsed time from the last dose of prior therapies until the first dose of study drug must meet the following criteria:
      1. Cytotoxic therapies: 28 days, or 21 days if patient has adequate bone marrow function, except 42 days for nitrosoureas.
      2. Radiation therapy: 14 days for all tumors other than glioblastoma; >3 months for glioblastoma.
      3. Any investigational agent or other antitumor therapies, including antibodies: the shorter of 28 days or 5 half-lives.
      4. Bevacizumab (glioblastoma only) limited to 1 to 3 doses for radiation related pseudoprogression (not as a glioblastoma treatment regimen). The last dose must be at least 3 months from the screening imaging.
    2. All adverse effects related to prior therapies (e.g., chemotherapy, radiotherapy, or surgery) must have resolved to Grade 1 or baseline, except for the following:
      1. Alopecia (Grade ≤2).
      2. Sensory neuropathy (Grade ≤2).
      3. Other persistent adverse effects that have resolved to Grade ≤2 that, according to the clinical judgment of the investigator, do not constitute a safety risk to the participant.
      4. Lymphopenia (Grade ≤3).
  6. Is able to swallow tablets.
  7. Organ function reserve:
    1. Bone marrow (within the 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 for TNG456 monotherapy, ≥100 × 106/mL for TNG456 in combination with abemaciclib. Note: Platelet transfusion is not allowed within 7 days before the first dose of the study treatment.
    2. Hepatic:
      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
      3. Albumin and INR ≤Grade 1 (for patients participating in the FE substudy and PPI substudy)
    3. Renal:
      1. iEstimated creatinine clearance (by Cockcroft-Gault) ≥60 mL/min
    4. Cardiac:
      1. Baseline QTcF ≤470 msec
  8. Pregnancy:
    1. Women of childbearing potential must have a negative serum pregnancy test result at screening, and the test must be performed within 72 hours before Cycle 1 Day 1 of study treatment.
    2. Women not of childbearing pontential 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.
  9. Contraception:
    1. Male patients with a partner who is a women of childbearing potential must use a highly effective form of 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 a highly effective form of contraception during their participation in the study and for 6 months following the last dose of the study treatment.
  10. 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.
  11. Has a Karnofsky performance status score ≥70.
  12. Has a confirmed glioblastoma (IDH-wildtype) with radiographic evidence of disease progression or recurrence:
    1. Limited to first or second confirmed recurrence.
    2. Progression must be identified >3 months from end of radiation, or have progression that is outside the prior high dose radiation field, or is confirmed by biopsy/resection to be viable recurrent/progressive mitotically active glioblastoma and confirmed by the medical monitor.
    3. Confirmed measurable disease and progression as defined by RANO 2.0: serial imaging demonstrating tumor growth with ≥25% increase in the sum of products of the perpendicular diameters or ≥40% increase in total volume of enhancing lesions as compared with the most recent previous scan or a new lesion that is at least 1 cm × 1 cm, at least 4 weeks after the initial radiographic progression.
  13. Prior therapy with bevacizumab must be limited to 1 to 3 doses from radiation related pseudoprogression (not as a glioblastoma treatment regimen). There must be a washout of at least 3 months before the screening imaging.
  14. Must be willing to provide historic scans for central imaging and/or provide bidirectional historic lesion measurements for entry into the study database.
Exclusion Criteria
  1. Is pregnant, lactating, breastfeeding, intends to become pregnant, or is of childbearing potential and not using adequate contraceptive methods.
  2. Is unwilling or unable to comply with the scheduled visits, study treatment administration plan, laboratory tests, biopsy, or other study procedures and study restrictions.
  3. Has impaired GI function or disease that may significantly alter the absorption of oral study treatment(s).
  4. 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, impair the assessment of study results or compliance with the protocol.
  5. Has an active infection requiring systemic therapy.
  6. Has received prior treatment with a PRMT5 inhibitor or a MAT2A inhibitor.
  7. Is receiving treatment with any of the following prohibited medications. If a patient is receiving any treatment a washout period of 5 half-lives is required.
    1. Drugs known to prolong QTc (Cycle 1 Day 1 to Cycle 1 Day 15)
    2. Proton pump inhibitors (except as used in the PPI sub-study)
    3. Strong CYP3A inhibitors
    4. Moderate CYP3A inhibitors
    5. Strong CYP3A inducers
    6. Moderate CYP3A inducers
    7. Strong P-glycoprotein inhibitors
    8. Strong breast cancer resistance protein (BCRP) inhibitors
    9. Histamine type 2 receptor antagonist
  8. Is currently participating in or has planned concurrent participation in a study of another investigational agent or device.
  9. Patients with recurrent glioblastoma for whom contrast-enhancing MRIs are contraindicated.
  10. Patients with history of a seizure disorder, including those with glioblastoma, may be included if adequately controlled on a stable regimen on non-enzyme-inducing anticonvulsant drug(s).
  11. Has an 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 may be eligible for this study, if approved in writing by the sponsor. Malignancies that do not require written sponsor approval include basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and early-stage prostate cancer undergoing watchful waiting. Patients with a completely treated prior malignancy and no evidence of disease for >2 years prior to the first dose of TNG456 are also eligible.
  12. Patients that require corticosteroids to manage symptoms related to CNS disease must remain on a stable dose of corticosteroids for at least 14 days for patients with solid tumors other than glioblastoma and for 5 days for patients with glioblastoma prior to their baseline scan and must be ≤4 mg dexamethasone or equivalent.
  13. Has had a red blood cell transfusion within 14 days prior to first dose of TNG456.
  14. Had a platelet transfusion or administration of colony-stimulating growth factor (G-CSF or GM-CSF) within 7 days prior to first dose for TNG456.
  15. Had a major surgery within 14 days of the first dose of TNG456.
  16. Has received an experimental treatment in a clinical trial within the last 4 weeks or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1, or is currently enrolled in any other type of medical research (eg, medical device) judged by the sponsor not to be scientifically or medically compatible with this study.
  17. Has known history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
  18. 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.
  19. The patient has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (eg, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel).
  20. The patient has active systemic bacterial infection, fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [eg, hepatitis B surface antigen positive]). Screening is not required for enrollment.
  21. Patients should avoid concomitant use of CYP3A4 inducers and consider alternative agents. Note that strong and moderate inducers are prohibited in this study.
  22. Has been treated with a CDK4/6 inhibitor (dose expansion phase only; prior CDK4/6 inhibitor use is allowed in dose escalation and for patients assigned to TNG456 monotherapy).
  23. Has a tumor with a known retinoblastoma 1 (RB1) loss-of-function mutation (patient may be considered for TNG456 monotherapy).
Investigator(s)

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