CTX-10726의 안전성 및 내약성에 대한 1상, 개방형, 다중증량 연구

Inclusion Criteria:

1. Age 18 years or older.
2. Patients must have a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic disease that is relapsed/refractory to standard therapy or for which no effective standard therapy is available, including:

2a: Renal Cell Carcinoma (RCC)

• Histologically confirmed diagnosis of renal cell carcinoma (with clear cell component) with advanced or metastatic disease that is not amenable to cure by surgery or other means.

• Patients who have progressed after a minimum of 2 doses of a programmed cell death 1 (PD-1)/ programmed cell death ligand 1 (PDL1) treatment.

• Patients must have received at least one regimen including a tyrosine kinase inhibitor (TKI).

• Patients who received immunomodulatory drugs (thymosin, interferon, interleukin, etc.) within 2 weeks before the first dose or received major surgical treatment within 3 weeks before the first dose are not eligible.

  2b: Hepatocellular Carcinoma (HCC)

• Patients who have progressed after a minimum of 2 doses of a PD-1/PDL1 treatment.

• Patient must have received one of the following regimens: ipilimumab+nivolumab, tremelimumab+durvalumab, atezolizumab+bevacizumab or lenvatinib+pembrolizumab.

• Hepatic function: Child -Pugh A and Child-Pugh B7.

• Receipt of local area treatment of the liver more than 4 weeks prior to the first dose is allowed.

  2c. Gastroesophageal Cancer (GC)

• Patients who have progressed after a minimum of 2 doses of a PD-1/PDL1 treatment.

• Patients must have received prior treatment with platinum-based chemotherapy.

  2d: Endometrial Cancer (EC)

• Patients must have received at least 1 cycle of platinum-based chemotherapy.

• Patients with newly diagnosed advanced endometrial cancer that have persistent lesion(s) after standard treatment with surgery and chemotherapy ± radiotherapy.

• Patients with MSI- high or deficient DNA mismatch repair (dMMR) tumors who have progressed after a minimum of 2 doses of a PD-1/PDL1 treatment.

  3. Patients must have measurable disease per RECIST 1.1. Tumor sites that are considered measurable must not have received prior radiation.

  4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

  5. Adequate organ function including:

• Bone marrow function defined by absolute neutrophil (ANC) of ≥ 1.5×109/L, platelet count of ≥ 100.0×109/L, and hemoglobin of ≥ 9.0 g/dL (with or without transfusion).

• Hepatic function defined as serum total bilirubin ≤ 1.5 × ULN (<3 x ULN in patients with Gilbert's syndrome), AST/ALT ≤ 2.5 × ULN (or ≤ 5 × ULN in patients with liver metastases).

• Renal function defined as creatinine clearance ≥ 30 mL/min by Cockcroft Gault equation.

• Cardiac function with Left Ventricular Ejection Fraction (LVEF) ≥ 50%.

  6. Female patients must be surgically sterile (or have a monogamous partner who is surgically sterile) or be at least 2 years postmenopausal or commits to use 2 acceptable forms of birth control (defined as the use of an intrauterine device, a barrier method with spermicide, condoms, any form of hormonal contraceptives) or abstinence for the duration of the study and for 4 months following the last dose of study treatment. Male patients must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study and for 4 months following the last dose of study treatment.

  7. Female patients who are women of childbearing potential (WOCBP) must have a negative serum pregnancy test at Screening within 7 days of dosing with CTX-10726.

  8. Prior anticancer therapy > 28 days (or 2 half-lives for proteins, whichever is shorter), radiotherapy > 7 days (concurrent localized palliative radiotherapy is allowed during CTX-10726 treatment with medical monitor approval), therapeutic surgical intervention > 21 days, blood transfusion > 14 days, or biopsy or minor surgery (excluding placement of vascular access devices) > 7 days prior to the first dose of CTX-10726.

  9. Resolution of all prior anti-cancer therapy toxicities ≤ Grade 2 (excluding alopecia).

  10. Capable of understanding and complying with protocol requirements

  11. Signed and dated institutional review board (IRB) approved informed consent form (ICF) before any protocol-directed screening procedures are performed.

Exclusion Criteria:

1. Developed clinically significant adverse reaction to prior PD-1 or PD-L1 therapy, including immune related adverse reactions (irAE), that led to discontinuation of treatment. A prior irAE may be considered not exclusionary only after consultation with the Medical Monitor if it resolved or stabilized to Grade 1 or baseline before informed consent, has been clinically stable for at least 3 months, and does not require ongoing systemic corticosteroids or other systemic immunosuppressive therapy other than protocol-permitted physiologic replacement. Participants are not eligible if the prior irAE was severe or life-threatening, involved a high-risk organ system with potentially dangerous recurrence, was recurrent or occurred after rechallenge, required second-line immunosuppressive therapy beyond corticosteroids, suggested broad immune susceptibility, or could confound safety evaluation in this first-in-human study.

2. Prior organ transplantation.

3. History of arterial or venous thrombosis or stroke or transient ischemic attack within 6 months prior to the first dose.

4. History of other neoplasms within 3 years prior to screening, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical cancer in situ that has undergone successful surgery.

5. Symptomatic or uncontrolled central nervous system (CNS) and brain metastasis or active leptomeningeal disease. Patients with equivocal findings or with confirmed brain metastases are eligible for the study provided that they are asymptomatic and radiologically and neurologically stable without the need for corticosteroid treatment or seizure prophylaxis for >4 weeks before the first dose of study drug. Prior treatment with either surgery or radiation is permitted and all patients with a history of CNS or brain lesions require imaging during screening to confirm stability.

6. A pleural, abdominal (eg, ascites) or pericardial effusion that is clinically symptomatic or requires repeated management (puncture or drainage, etc) within 14 days of dosing with CTX-10726.

7. Imaging at screening that shows the tumor surrounds important blood vessels or had obvious necrosis and voids, and the investigators deems that it might cause bleeding risk.

8. The presence of severe, unhealed or open wounds, active ulcers, or untreated fractures at the time of screening.

9. A history of significant bleeding tendency or severe coagulopathy.

10. Current therapeutic dose of anticoagulant or thrombolytic medication within 14 days of the first dose. Note: prophylactic use of low molecular heparin (ie, enoxaparin 40 mg/day) is allowed.

11. Current or recent use of aspirin (> 325 mg/day) or other non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days of first dose.

12. Known uncontrolled diabetes mellitus despite optimized anti-diabetes medications.

13. The presence of poorly controlled hypertension (systolic blood pressure [SBP]/diastolic blood pressure [DBP]) >140/90 mmHg (eg, patient with SBP/DBP > 140/90 mmHg despite ≥3 anti-hypertensive medications within 7 days of dosing with CTX-10726).

14. Pregnant or lactating WOCBP.

15. Patients with evidence of active hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) infection. Patients with positive HBsAg and/or detectable HBV DNA are eligible only if adequately controlled on antiviral therapy according to institutional standards and liver function eligibility criteria are also met. HCV patients showing sustained viral response or patients with immunity to HBV infection may enroll.

    1. Hepatitis B subjects who meet the following criteria are also eligible for inclusion: HBV viral load must be < 1000 copies /ml (200 IU/ml) prior to initial dosing, and subjects should receive anti-HBV therapy to avoid viral reactivation throughout the duration of study chemotherapy drug treatment. For subjects with anti-HBC (+), HBsAg (-), anti-HBS (-), and HBV viral load (-), prophylactic anti-HBV therapy is not required, but close monitoring of viral reactivation is required.
    2. HIV-infected subjects who meet the following criteria are eligible for inclusion: HIV-RNA levels below the lower limit of detection.

16. Active HCV-infected subjects (HCV antibody positive and HCV-RNA levels above the lower limit of detection).

17. Patients that received attenuated vaccination within 4 weeks prior to screening or planning to receive attenuated vaccination during the study period.

18. Current or recent systemic therapy with immunosuppressive agents within 7 days before the start of CTX-10726 treatment. Topical, intranasal, intraocular, or inhaled corticosteroids and physiologic replacement (≤ 10 mg/day prednisone or equivalent) for patients with adrenal insufficiency are allowed.

19. Active autoimmune disease or medical conditions requiring chronic steroid (i.e., > 10 mg/day prednisone or equivalent) or immunosuppressive therapy. Patients with a prior history of autoimmune disease may be eligible following discussion with the Medical Monitor.

20. Active or prior documented idiopathic pulmonary fibrosis or idiopathic pneumonia; current acute lung disease, interstitial lung disease or pneumonia (except localized interstitial pneumonia due to radiotherapy induction), pulmonary fibrosis, severe respiratory distress, pulmonary insufficiency or continuous oxygenation.

21. Other medical conditions in the opinion of the Investigator and/or Sponsor Medical Monitor may interfere with the conduct and/or interpretation of the current study, including:

    1. Congestive heart failure (> New York Heart Association Class II), active coronary artery disease, unevaluated new onset angina within 3 months or unstable angina (angina symptoms at rest) or clinically significant cardiac arrhythmias.
    2. QTc interval (using Fridericia correction calculation) > 480 msec.