Advanced solid tumors Cancer
Conditions
Interventions
Phase 1a - DOSE ESCALATION
Description:
Single arm dose escalation of TH9619 as monotherapy.
TH9619 will be administered as an intravenous infusion. Multiple doses will be tested.
Dosing will be given
Sponsors
One-carbon Therapeutics AB
Eligibility
Sex/Gender
All
Age
18 Years to 120 Years
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 14/05/2025: 1. Willing and able to give written informed consent for participation in the study before performance of any study-specific screening procedures 2. Male or female subject aged =18 years of age 3. Histopathologically confirmed CRC, HNSCC, NSCLC, and gastric cancer with metastatic and/or unresectable disease (not amenable to treatment with curative intent), except for: 3.1. NSCLC with EGFR driver mutations including but not limited to del19, L858R 3.2. Gastrointestinal Stromal cell Tumors (GIST) 3.3. CRC with MSI-H 4. Treatment with at least one prior line of cytotoxic systemic therapy for metastatic/unresectable disease, including but not limited to pemetrexed, capecitabine, MTX, 5-FU, tegafur, oxaliplatin, irinotecan, cisplatin, and carboplatin 5. Prior systemic neoadjuvant or adjuvant therapy will be considered as one line of therapy if radiological progression occurred either during that treatment or within 6 months of completion 6. Progressive disease as per investigator assessment after latest given therapy 7. At least one measurable lesion by RECIST v1.160 8. Must have tumor lesion(s) or metastases amenable to biopsy, excluding bone metastases, as confirmed by a radiologist, if appropriate, and as deemed safe by the investigator 9. Mandatory pre-treatment and on-treatment biopsies (except for subjects treated at the lowest dose levels within the accelerated titration 10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 11. Life expectancy of at least 12 weeks as judged by the investigator 12. The following safety laboratory parameters must be met during screening (within 15 days) and also immediately before first IMP administration: 12.1. Total bilirubin =1.5 x upper limit of normal (ULN), or unconjugated bilirubin of = 3 x ULN in subjects diagnosed with Gilbert’s syndrome 12.2. Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) = 3.0 x ULN (=5 x ULN allowed in patients with metastases in the liver) 12.3. Renal function: Estimated creatinine clearance by eGFR =50 mL/min 12.4. Absolute neutrophil count (ANC) =1500 cells/mm³ (1.5 x 10?/L) 12.5. Platelet count =100000 cells/mm³ (100 x 10?/L) 12.6. Hemoglobin =90 g/L 12.7. Albumin levels 3.4-5.4 g/dL in the normal range of institutional standards 12.8. Folic acid levels 3.1-17.5 ng/mL (7.0-39.7 nmol/L) in the normal range of institutional standards 12.9. Vitamin B12 levels of >250 pg/mL (>185 pmol/L) 13. Contraceptive measures 13.1. Women of childbearing potential (WOCBP) must: 13.1.1. Have a negative pregnancy test within 1 week before first dose of study drug 13.1.2. Use highly effective method(s) of birth control consistently and correctly during the study and for at least 6 months after the last dose of treatment 13.1.3. Agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 6 months after the last study drug administration 13.1.4. Agree to not breastfeed and not plan to become pregnant during the study and for at least 6 months after the last study drug administration 13.2. Males who are sexually active must: 13.2.1. Agree to use a condom with spermicidal foam/gel/film/cream/suppository during the study and for at least 90 days after the last study drug administration 13.2.2. Agree to not donate sperm during the study and for at least 90 days after the last study drug administration 13.2.3. Have no plan to father a child during
Exclusion criteria
Exclusion criteria: 1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject’s ability to participate in the study 2. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of first administration of IMP, as judged by the Investigator 2.1. Any toxicities from prior treatment(s) (incl surgery, RT and systemic therapies) grade >2 by NCI CTCAE v5.0 criteria prior to first dose of study treatment 2.2. Clinically significant cardiovascular disease, defined as any of the following: 2.2.1. Major ECG abnormalities (e.g., symptomatic or sustained atrial or ventricular arrhythmias, second- or third-degree atrioventricular block, clinically significant bundle branch blocks, clinically significant ventricular hypertrophy) 2.2.2. Including dihydropyrimidine dehydrogenase polymorphisms (DDP) and fluoropyrimidine toxicity 3. Primary brain malignancy or known, untreated central nervous system (CNS) or leptomeningeal metastases, or symptoms suggesting CNS involvement for which treatment is required. Screening of asymptomatic patients without history of CNS metastases is not required. Subjects with previously treated brain metastases are eligible, provided they have not experienced a seizure, had no significant change in neurological status, and have not required steroids for management of brain metastases in the last 2 weeks prior to enrollment 4. Active known second malignancy with the exception of any of the following: 4.1. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer 4.2. Adequately treated Stage 1 cancer from which the patient is currently in remission and has been in remission for =2 years 4.3. Low-risk prostate cancer with a Gleason score <7 and a prostate-specific antigen (PSA) level <10 ng/mL 4.4. Any other cancer from which the patient has been disease-free for =3 years. Malignancy (other than the one diagnosed) within the past 5 years, with the exception of any other malignancy that has been treated with no signs of relapse within 3 years (e.g., superficial melanoma, low grade cervix cancer) 5. Any planned major surgery within the duration of the study (i.e., from screening to end of study visit) 6. Active and uncontrolled infection requiring intravenous antibiotic or antiviral treatment within 2 weeks prior to first IMP administration 7. Subjects with known active HBV (screening for HBV is not required for subjects who do not have a history of HBV, unless required by local regulations) and with treated/chronic HBV are eligible provided they meet the following criteria: 7.1. Subjects with positive HBsAg must be on permitted suppressive antiviral therapy prior to first IMP administration, remain on the same antiviral treatment throughout the study and should follow local standards for continuation of therapy after completion of IMP 7.2. Note: while HBsAg-negative, anti-HBc–positive subjects are at lower risk of HBV reactivation compared with HBsAg-positive subjects, risk of HBV reactivation should be considered in all subjects and the need for anti-HBV prophylaxis should be carefully assessed prior to the initiation of the IMP 7.3. Undetectable HBV DNA = 14 days of C1D1 7.4. Note: subjects who are HBsAg positive and HBV DNA positive (detectable) will be excluded 8. Known
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Frequency of treatment-emergent adverse events (TEAEs) is measured using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 2. Severity of treatment-emergent adverse events (TEAEs) is measured using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 3. Causality of treatment-emergent adverse events (TEAEs) is measured using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 4. Frequency of serious adverse events (SAEs) is measured using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 5. Severity of serious adverse events (SAEs) is measured using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 6. Causality of serious adverse events (SAEs) is measured using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 7. Clinically significant findings on clinical laboratory tests at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 8. Clinically significant findings on vital signs parameters at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 9. Clinically significant findings on electrocardiogram (ECG) at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 10. Clinically significant findings on physical examinations at baseline, C1D1, safety follow-up visit (EOT), or early withdrawal 11. Tolerability is assessed by treatment-emergent adverse events ( | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Maximum concentration (Cmax) is measured using pharmacokinetic (PK) analysis at baseline, C1D1, and at specified timepoints post-dose 2. Time to maximum concentration (Tmax) is measured using pharmacokinetic (PK) analysis at baseline, C1D1, and at specified timepoints post-dose 3. Area under the curve (AUC) is measured using pharmacokinetic (PK) analysis at baseline, C1D1, and at specified timepoints post-dose 4. Maximum percentage tumor shrinkage from baseline is measured using imaging (e.g., CT/MRI) at baseline and at specified intervals during treatment 5. Objective Response Rate (ORR) is measured using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by Investigator assessment at baseline and at specified intervals during treatment 6. Duration of response (DOR) is measured using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by Investigator assessment at baseline and at specified intervals during treatment 7. Progression Free Survival (PFS) is measured using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by Investigator assessment at baseline and at specified intervals during treatment 8. Clinical benefit rate (CBR) is measured using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by Investigator assessment at baseline and at specified intervals during treatment 9. Time to response (TTR) is measured using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by Investigator assessment at baseline and at specified intervals during treatment 10. Overall Survival (OS) is measured using survival status assessments at baseline and at specified intervals up to 2 years 11. Disease progression is measured using imaging (e.g., CT/MRI) and clinical assessments at baseline and at specified intervals up to 2 years 12. Survival status is measured using follow-up assessments at baseline and at specified intervals up to 2 years | — |
Countries
France, Spain, United Kingdom
Contacts
Public ContactAna Slipicevic
Outcome results
None listed