A First-in-human, Phase I/II, Multicenter, Open-label, Dose Escalation, Confirmation and Expansion Study to Evaluate the Safety, Pharmacokinetics and Antitumor Activity of TH9619 in Subjects With Advanced Solid Tumors

Study Identifier:
TH9619-0101
CT.gov Identifier:
NCT07151040
EudraCT Identifier:
202452000000
EU Trial (CTIS) Number:
2024-519639-40-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

This is a first in human, multi-center, open-label, dosage escalation study to determine the recommended dose range of TH9619 in subjects with advanced cancer.

This is a Phase 1a (dose escalation)/Phase Ib (dose expansion) single arm study of TH9619 in patients with selected tumor types who have been treated with available standard of care therapies. This study drug, TH9619, was tested in laboratory and animal studies and will now be tested for the first time in humans to evaluate its safety, antitumor activity and pharmacokinetics (PK) in patients. PK is an analysis of how a drug is absorbed, distributed, and eliminated from the body. A single-arm study is one in which the activities of the study drug are not compared to those of another.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Solid Tumor
  • Bowel (Colorectal)
  • HNSCC
  • Non-Small Cell Lung Cancer
  • Gastric
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I/II
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: Single arm dose
    • Read More
  • Drug: Drug: TH9619
  • Drug: Description:
  • Drug: Single arm dose escalation of TH9619 as monotherapy.
  • Drug: Phase 1b - DOSE EXPANSION
  • Drug: Single arm dose expansion of TH9619 as monotherapy in selected tumor types. The objectives and endpoints for the expansion cohort(s) will be defined in a protocol amendment, once data from Phase 1a are available.
  • Drug: Phase 1a - DOSE ESCALATION
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Recruiting

    Requirements information
    Inclusion criteria
    • * Must have given written informed consent
    • * Histopathologically confirmed advanced cancer (colorectal cancer, head and neck squamous cell cancer, non-small cell lung cancer and gastric cancer (including gastroesophageal junction cancer))
    • * Prior treatment with at least one line of cytotoxic systemic therapy for metastatic/unresectable cancer
    • * Adult patients (≥18 years of age)
    • * Must be willing to comply with study procedures
    • Willing and able to give written informed consent for participation in the study before performance of any study-specific screening procedures
    • Male or female subject aged ≥18 years of age
    • Histopathologically confirmed CRC, HNSCC, NSCLC, and gastric cancer with metastatic and/or unresectable disease (not amenable to treatment with curative intent), except for:
    • NSCLC with EGFR driver mutations including but not limited to del19, L858R
    • Gastrointestinal Stromal cell Tumors (GIST)
    • CRC with MSI-H
    • 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
    • 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
    • Progressive disease as per investigator assessment after latest given therapy
    • At least one measurable lesion by RECIST v1.160
    • 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
    • Mandatory pre-treatment and on-treatment biopsies (except for subjects treated at the lowest dose levels within the accelerated titration
    • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
    • Life expectancy of at least 12 weeks as judged by the investigator
    • The following safety laboratory parameters must be met during screening (within 15 days) and also immediately before first IMP administration:
    • Total bilirubin ≤1.5 x upper limit of normal (ULN), or unconjugated bilirubin of ≤ 3 x ULN in subjects diagnosed with Gilbert’s syndrome
    • Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤ 3.0 x ULN (≤5 x ULN allowed in patients with metastases in the liver)
    • Renal function: Estimated creatinine clearance by eGFR ≥50 mL/min
    • Absolute neutrophil count (ANC) ≥1500 cells/mm³ (1.5 x 10⁹/L)
    • Platelet count ≥100000 cells/mm³ (100 x 10⁹/L)
    • Hemoglobin ≥90 g/L
    • Albumin levels 3.4-5.4 g/dL in the normal range of institutional standards
    • Folic acid levels 3.1-17.5 ng/mL (7.0-39.7 nmol/L) in the normal range of institutional standards
    • Vitamin B12 levels of >250 pg/mL (>185 pmol/L)
    • Contraceptive measures
    • Women of childbearing potential (WOCBP) must:
    • Have a negative pregnancy test within 1 week before first dose of study drug
    • Use highly effective method(s) of birth control consistently and correctly during the study and for at least 90 days after the last dose of treatment
    • Agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 90 days after the last study drug administration
    • Agree to not breastfeed and not plan to become pregnant during the study and for at least 90 days after the last study drug administration
    • Males who are sexually active must:
    • 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
    • Agree to not donate sperm during the study and for at least 90 days after the last study drug administration
    • Have no plan to father a child during the study and for at least 90 days after the last study drug administration
    Exclusion criteria
    • History or presence of any clinically significant disorders as judged by the Investigator.
    • 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
    • Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of first administration of IMP, as judged by the Investigator
    • 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
    • Clinically significant cardiovascular disease, defined as any of the following:
    • 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)
    • Including dihydropyrimidine dehydrogenase polymorphisms (DDP) and fluoropyrimidine toxicity
    • 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
    • Active known second malignancy with the exception of any of the following:
    • Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer
    • Adequately treated Stage 1 cancer from which the patient is currently in remission and has been in remission for ≥2 years
    • Low-risk prostate cancer with a Gleason score <7 and a prostate-specific antigen (PSA) level <10 ng/mL
    • 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)
    • Any planned major surgery within the duration of the study (i.e., from screening to end of study visit)
    • Active and uncontrolled infection requiring intravenous antibiotic or antiviral treatment within 2 weeks prior to first IMP administration
    • 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:
    • 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
    • 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
    • Undetectable HBV DNA ≤ 14 days of C1D1
    • Note: subjects who are HBsAg positive and HBV DNA positive (detectable) will be excluded
    • Known hepatitis C or human immunodeficiency virus (HIV) infection
    • Subjects with known positivity for HIV and who have well-controlled HIV infection/disease
    • Subject with a history of Kaposi Sarcoma and/or multicentric Castleman Disease is excluded
    • Subjects with known active HCV and previously treated for HCV
    • Prolonged QTcF (> 450 ms), or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator
    • History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to TH9619
    • Any anti-cancer therapy (chemotherapy, targeted agents, radiotherapy, immunotherapy) within 28 days or 5 times the half-life (whichever is shorter) before study treatment
    • Planned treatment or treatment with another investigational drug within 28 days or 5 times the half-life such as other anti-cancer therapy prior to first IMP administration. Subjects consented and screened but not dosed in previous Phase 1 studies will not be excluded
    • Current alcohol and/or drug abuse, as judged by the Investigator
    • The Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements

    Clinical Study Information for Healthcare Providers

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Madrid, Spain (FJD)
    Madrid, Spain, 28040
    Investigator
    Victor Moreno Garcia
    Status
    Recruiting
    Condition(s) Treated at Site
    Solid Tumor
    Bowel (Colorectal)
    HNSCC
    Non-Small Cell Lung Cancer
    Gastric