Locally Advanced Solid Tumor
Conditions
Keywords
MTAP deletion, PRMT5, cholangiocarcinoma, NSCLC, mesothelioma, MPNST, Tango, pancreatic, sarcoma, urothelial, gallbladder, liver, renal, breast
Brief summary
This is a first in human study in patients with advanced or metastatic solid tumors known to have an MTAP deletion. The first part of the study is an open-label, dose escalation and the second part is an open label dose expansion in specific MTAP-deleted tumor types. The study drug, TNG462, is a selective PRMT5 inhibitor administered orally. The study is planned to treat up to 225 participants.
Detailed description
This is a Phase 1/2 multi-center, open label study in solid tumor patients who have a confirmed homozygous MTAP deletion in their tumor. The Phase 1 portion is a dose escalation study of oral TNG462 administered as a single agent and in combination with pembrolizumab in patients with confirmed MTAP-deleted solid tumors. In Phase 2, 6 expansion arms defined by confirmed MTAP-deleted tumor types will enroll in parallel at the RP2D(s) of TNG462 and in combination. In both parts of the study participants who tolerate the drug may continue treatment until disease progression.
Interventions
DRUGTNG462
TNG462, a selective PRMT5 inhibitor, will be administered orally
DRUGPembrolizumab
An anti PD-1 antibody, will be administered intravenously
Sponsors
Tango Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1 dose escalation (sequential) followed by phase 2 dose expansion in 5 arms (parallel)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age: ≥18 years-of-age at the time of signature of the main study ICF 2. Performance status: ECOG Performance Score of 0 to 1 3. Confirmed histologic or cytologic diagnosis of a locally advanced, metastatic, and/or unresectable solid tumor 4. Prior standard therapy, as available 5. Documented bi-allelic (homozygous) deletion of MTAP in a tumor detected by next- generation sequencing or absence of MTAP protein in a tumor detected by IHC. 6. Adequate organ function/reserve per local labs 7. Adequate liver function per local labs 8. Adequate renal function per local labs 9. Negative serum pregnancy test result at screening 10. Written informed consent must be obtained according to local guidelines
Exclusion criteria
1. Known allergies, hypersensitivity, or intolerance to TNG462, or its excipients or to pembrolizumab in the combination treatment arms 2. Uncontrolled intercurrent illness that will limit compliance with the study requirements 3. Active infection requiring systemic therapy 4. Currently participating in or has planned participation in a study of another investigational agent or device 5. Impairment of GI function or disease that may significantly alter the absorption of oral TNG462 6. Active prior or concurrent malignancy. 7. Central nervous system metastases associated with progressive neurological symptoms 8. Current active liver disease from any cause 9. Known to be HIV positive, unless all of the following criteria are met: 1. CD4+ count ≥300/μL 2. Undetectable viral load 3. Receiving highly active antiretroviral therapy 10. Clinically relevant cardiovascular disease 11. A female patient who is pregnant or lactating 12. Patient is unwilling or unable to comply with the scheduled visits, drug administration plan, laboratory tests, biopsy, or other study procedures and study restrictions 13. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 Maximum Tolerated Dose | 28 days and 21 days | To determine the maximum tolerated dose (MTD) of TNG462 when administered as a single agent and in combination with pembrolizumab |
| Phase 1 Dosing Schedule | 28 days | To determine the dosing schedule of TNG462 |
| Phase 2 Anti-neoplastic Activity | 16 weeks and 18 weeks | To assess anti-neoplastic activity of TNG462 administered single agent and in combination with pembrolizumab in patients with MTAP-deleted advanced solid tumors by RECIST v1.1, iRECIST or mRECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 and 2 Time to Achieve Maximal Plasma Concentration | 16 days | Measure the time to achieve maximal plasma concentration (Tmax) |
| Phase 1 and 2 Maximum Observed Plasma Concentration | 16 days | Measure the maximum observed plasma concentration (Cmax) |
| Phase 1 and 2 Terminal Elimination Half-life | 16 days | Determine the terminal elimination half-life (t1/2) |
| Phase 1 Anti-neoplastic Activity | 16 weeks | To assess preliminary evidence of anti-neoplastic activity of TNG462 as a single agent and when administered in combination with pembrolizumab in patients with MTAP-deleted advanced solid tumors by RECIST v1.1, iRECIST or mRECIST v1.1 |
| Phase 1 and 2 Volume of Distribution | 16 days | Determine the apparent volume of distribution when dosed orally (Vz/F) |
| Phase 1 and 2 SDMA Levels | 28 days | SDMA levels in tumor tissue will be assessed pre-treatment and post treatment with TNG462 |
| Phase 1 and 2 Total Plasma Clearance | 16 days | Determine the apparent total plasma clearance when dosed orally (CL/F) |
| Phase 1 and 2 Adverse Event Profile | 28 days and 21 days | To describe the safety and tolerability profile of TNG462 by frequency and severity of AEs |
| Phase 1 and 2 Concentration versus Time Curve | 16 days | Measure the area under the plasma concentration versus time curve (AUC) |
Countries
France, Spain, United States
Contacts
Primary ContactTango Clinical Trials
Outcome results
None listed