MC# 20-23 - An Open-Label, Multicenter Phase I/II Dose Escalation and Expansion Study of THOR-707 as a Single Agent and as a Combination Therapy in Adult Subjects with Advanced or Metastatic Solid Tumors

  • Agent(s): THOR-707
  • Disease Type(s): Solid Tumor
  • Phase(s): I, II
  • Drug Classification(s): Immunotherapy, Targeted Therapy
  • Molecular Target(s): IL-2
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Mechanism of Action

THOR-707, the IL-2 variant moiety binds to dimers containing the IL-2 receptor beta and gamma chains (IL2Rbg; IL2Rbetagamma) on immune cells activating these cells and inducing their expansion.  It also induces the expression of certain cytotoxic cytokines.  The addition of the novel amino acid and the concurrent pegylation prevents the binding of the IL-2 moiety to the IL-2 receptor alpha chain (IL2Ra), thereby blocking the IL2Ra- mediated activation of CD4-positive regulatory and immunosuppressive T cells (Tregs).  Since it cannot bind to IL2Ra expressed on innate lymphoid cells in the vascular endothelium, THOR-707  prevents IL-2-mediated recruitment and activation of  eosinophils, and inhibits the induction of eosinophil-mediated vascular leak syndrome.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of THOR-707 given alone, or in combination with pembrolizumab or cetuximab
  • How proteins that indicate the status of your disease are affected with use of THOR-707
  • If THOR-707 given alone, or in combination with pembrolizumab or cetuximab, prevents or delays tumor growth or shrinks existing tumors
  • How much of THOR-707 is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from THOR-707
Inclusion Criteria
  1. Willing and able to provide informed consent and comply with protocol requirements for the duration of the study
  2. Males or females aged ≥ 18 years at screening
  3. Prior anti-cancer therapy is allowed (eg, radiotherapy, chemotherapy, surgery, targeted therapy), including prior immunotherapy treatment.  If previously treated with any anti-cancer therapy, at least one of the following must be met:
    • Treatment related toxicity resolved to grade 0 or 1 (alopecia excepted) according to NCI CTCAE v5.0
    • Treatment related toxicity resolved to at least grade 2 according to NCI CTCAE v5.0 with prior approval of the Medical Monitor
  4. For Part 2 exclusively: While it is highly preferred to enroll subjects who are naïve to PD-1 inhibitors into a Part 2 dose escalation cohort, this is not an enrollment requirement.  However, subjects who enroll into a Part 2 safety expansion cohort must be naïve to PD-1 inhibitors.  If such subject is unable to meet this requirement but otherwise remains a good candidate for study enrollment, the Investigator should discuss with the Sponsor whether the subject may be enrolled.
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  6. Life expectancy greater than or equal to 12 weeks as determined by the Investigator
  7. Histologically or cytologically confirmed diagnosis of advanced and/or metastatic solid tumors with at least one tumor lesion with location accessible to safely biopsy per clinical judgment of the Investigator. (Caution: Cohort D only: patients with KRAS mutant colon cancer have not typically benefitted from the addition of cetuximab in earlier lines of therapy)
  8. Subjects with advanced or metastatic solid tumors who have refused standard of care; or for whom no reasonable standard of care exists that would confer clinical benefit; or for whom standard therapy is intolerable, not effective, or not accessible
  9. Measurable disease per RECIST v1.1
  10. Adequate laboratory parameters including:
    • Absolute lymphocyte count ≥0.5 times lower limit of normal
    • Platelet count ≥ 100 x 109/L
    • Hemoglobin ≥ 9.0 g/dL (absence of growth factors or transfusions within 2 weeks; 1-week washout for ESA and CSF administration is sufficient)
    • Absolute neutrophil count ≥ 1.5 x 109/L (absence of growth factors within 2 weeks)
    • Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 times upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN except if liver metastases are present may be ≤ 5 times ULN
    • Total bilirubin ≤ 1.5 x ULN
  11. Females of childbearing potential and men who are not surgically sterile must agree to use medically-accepted method of birth control during the study and for at least 3 months after last dose of treatment
  12. [Females] Negative serum pregnancy test within 7 days prior to initiating study treatment in premenopausal women and women less than 12 months after menopause
  13. [Males] Agreement to refrain from donating or banking sperm during the treatment period and for at least 3 months after last dose of study treatment
Exclusion Criteria
  1. Radiotherapy ≤ 14 days prior to first dose of study drug (palliative radiation or stereotactic radiosurgery within 7 days prior to start of study treatment)
  2. Treated with systemic anti-cancer therapy or an investigational agent within 2 weeks prior to start of study drug treatment (within 4 weeks for immunotherapy and tyrosine kinase inhibitor therapy)
  3. Subjects who experienced Grade 3 or higher immune-related toxicity from prior immuno- oncology therapy
  4. Major surgery ≤ 30 days prior to first dose of study drug, or has not recovered to at least Grade 1 from adverse effects from such procedure, or anticipation of the need for major surgery during study treatment
  5. Active autoimmune disease requiring systemic treatment within the past 3 months or have a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents; subjects on corticosteroids are excluded for a dose > 10 mg daily of prednisone or equivalent. Inhaled, intranasal, intraocular, and topical steroids are allowed.  Steroids as prophylaxis against contrast reactions (for disease assessments) are also allowed.
  6. Primary central nervous system (CNS) disease or leptomeningeal disease; known CNS metastases unless treated, are asymptomatic, are without evidence of radiological progression for at least 8 weeks and have had no requirement for steroids or enzyme inducing anticonvulsants in the last 14 days prior to Screening
  7. Abnormal pulmonary function within previous 6 months, including pneumonitis, active pneumonitis, interstitial lung disease requiring the use of steroids, idiopathic pulmonary fibrosis, confirmed pleural effusion, severe dyspnea at rest or requiring supplementary oxygen therapy
  8. History of allogenic or solid organ transplant
  9. Uncontrolled diabetes mellitus or other uncontrolled immune-related endocrinopathies in the opinion of the Investigator
  10. Parenteral antibiotic use ≤ 14 days prior to first dose of study drug, or any serious systemic fungal, bacterial, viral, or other infection that is not controlled or requires IV antibiotics
  11. Known human immunodeficiency virus (HIV) infection or active infection with hepatitis C
    • Known uncontrolled hepatitis B virus (HBV) infection:
      • Anti-HBV therapy started before initiation of IMP and HBV viral load < 2000 IU/mL (104 copies/mL) are eligible.  The anti-HBV therapy should continue throughout the treatment period.
      • Positive anti-HBc, positive anti HBs, negative HBsAg, and HBV virus load without HBV therapy are eligible
  12. Received a live-virus vaccination ≤ 14 days prior to first dose of study drug.  Seasonal flu and other inactivated vaccines that do not contain live virus are permitted.
  13. Clinically significant bleeding within 2 weeks prior to initial THOR-707 dose (eg, gastrointestinal bleeding, intracranial hemorrhage)
  14. Prior diagnosis of deep vein thrombosis or pulmonary embolism within 3 months
  15. Severe or unstable cardiac condition within 6 months prior to starting study treatment, such as congestive heart failure (New York Heart Association Class III or IV), cardiac bypass surgery or coronary artery stent placement, angioplasty, cardiac ejection fraction below the lower limit of normal, unstable angina, medically uncontrolled hypertension (eg ≥ 160 mm Hg systolic or ≥ 100 mm Hg diastolic), uncontrolled cardiac arrhythmia requiring medication (≥ grade 2, according to NCI CTCAE v5.0), or myocardial infarction
  16. History of non-pharmacologically induced prolonged corrected QT interval determined using Fridericia's formula (QTcF) > 450 milliseconds (msec) in males or > 470 msec in females
  17. Known hypersensitivity or contraindications to any components of THOR-707, PEG, pegylated drugs, pembrolizumab, or cetuximab for applicable cohorts
  18. Active second malignancy, or history of previous malignancy that would impact the assessment of any study endpoints. Subjects with non-melanomatous skin cancer or cervical cancer that has been curatively surgically resected are eligible
  19. Any serious medical condition (including pre-existing autoimmune disease or inflammatory disorder), laboratory abnormality, psychiatric condition, or any other significant or unstable concurrent medical illness that in the opinion of the Investigator would preclude protocol therapy or would make the subject inappropriate for the study
    • Patients with active SARS-CoV-2 (COVID-19) infections with clinically significant symptoms
  20. Is pregnant or breast-feeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 3 months after the last dose of study treatment
  21. Concurrent therapy with any other investigational agent, vaccine, or device.  Concomitant participation in observational studies is acceptable after Sponsor approval.
  22. For Cohort D only: patients with symptomatic keratitis and/or symptomatic dry eye should be excluded from enrollment. Patients who wear contact lenses should be advised to avoid contact lenses use as it could result in keratitis.
  23. Subjects with baseline oxygen saturation <92% are not eligible for enrollment.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04009681

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Re: MC# 20-23