Ensayos clínicos

Inclusion Criteria:

Phase 1 Dose Escalation

• Have a histologically or pathologically documented, locallyadvanced or metastatic solid tumor for which standard curative measures do not exist or are no longer effective, which may include prior immunotherapy. Preferred indications include: RCC, mesothelioma, NSCLC, cSCC, MSS-CRC, uveal melanoma, malignant melanoma, cervical adenocarcinoma, and CCA.

Phase 2a Dose Expansion

• Have a histologically or cytologically confirmed advanced (metastatic and/or unresectable) solid tumor listed below, that is incurable:
• Advanced (unresectable) or metastatic, intra or extra hepatic adenocarcinoma originating from the bile duct, CCA (Cohort 1) having progressed on at least 1 line of systemic therapy (including targeted therapy if eligible);
• Locally advanced metastatic cutaneous melanoma (Cohort 2) that has failed antiPD-1 or anti-PDL1 therapy (+/- anti-CTLA-4 therapy) and if BRAF+, having failed a BRAF/ +/-MEK inhibitor;
• Locally advanced or metastatic cSCC (Cohort 3) that has not received systemic therapy (e.g., local resection or local topical therapy is permitted);
• Locally advanced or metastatic MSS-CRC (Cohort 4) patients that have progressed on at least 2 prior lines of systemic therapy which should include irinotecan and oxaliplatin +/- targeted therapy if warranted.
  • Note: MSS disease is determined by an approved diagnostic test for identification of patients without a microsatellite instability (MSI) positive biomarker. This testing is performed locally.
• Have measurable disease based on RECIST 1.1 criteria as determined by the Investigator.
  • Note: In the event all measurable disease is situated in a previously irradiated area, these lesions are only considered measurable if progression has been demonstrated post irradiation treatment.
• Have at least one tumor amenable to safe ITu injections (Arm A, Arm B, and Phase 2a only) and biopsies (all Arms and Cohorts). Refer to the ITu Injection Procedure and Biopsy Guidance Manual for information on tumor selection, tumor size, and other procedural recommendations.
• Have ECOG performance status 0 or 1.
• Demonstrate adequate organ function:
  • WBC count ≥ 2,000 cells/mm^3;
  • ANC ≥ 1,000 cells/mm^3;
  • Hgb ≥ 8 g/dL or ≥ 4.96 mmol/L;
  • Platelet count ≥ 100,000 platelets/mm^3 (untransfused);
  • Total bilirubin ≤ 1.5× ULN;
  • AST ≤ 3× ULN and ALT ≤ 3× ULN;
  • Serum chemistries: Sodium, potassium, and calcium WNL or Grade 1;
  • Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min for patient with creatinine levels > 1.5 × institutional ULN according to Cockcroft-Gault formula.
• For ITu Arms (Arm A & B) Only: INR and aPTT WNL For IV Arms (Arm C & D) Only: INR and aPTT ≤ 1.5 ULN.
  • Note: All patients must be able to suspend anticoagulant therapy for study specific biopsies and ITu injections.
• To prevent the risk of environmental shedding, all patients must be willing to use barrier contraception during sexual activity, starting with Day 1 through 6 weeks after the last dose of TBio-6517. Additionally, to prevent pregnancy, patients who are able to conceive or father children must use a highly effective contraction method during sexual activity starting with Screening through 120 days after the last study treatment, including pembrolizumab.
• Be willing and able to attend protocol-specified visits, complete protocol procedures, and adhere to post-treatment care instructions within the informed consent to minimize the risk of transmission to caregivers and close contacts.
• Be ≥ 18 years of age (or legal age of majority in the jurisdiction) on day of signing informed consent.
• Life expectancy of at least 4 months as determined by the Investigator.
• Patients must be willing to comply with mandatory pre-treatment and on-treatment biopsies.

Exclusion Criteria:

• Has disease eligible for therapy with curative intent.
• Has had prior treatment with any oncolytic virus
• Has had prior surgery, chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to first dose, or prior anti-cancer monoclonal antibody (mAb) therapy within 45 days prior to study Day 1.
  • Note: Patients are allowed to receive any of the following treatments up to 7 days prior to the first dose:
  • Stereotactic radiosurgery (SRS);
  • Stereotactic body radiation therapy (SBRT); or
  • palliative radiation outside the chest and brain. Irradiated lesions cannot be used as a site for biopsy or TBio-6517 injection.
• Has failed to recover (e.g., to ≤ Grade 1 or to baseline status) from clinically relevant or significant AEs associated with prior cancer treatment.
  • Note: Except patients with ≤ Grade 2 neuropathy or any grade of alopecia.
• Has tumor(s) invading a major vascular structure (e.g., carotid artery) or other key anatomical structure (e.g., pulmonary airway) in the event of post-treatment tumor swelling and/or necrosis.
• Requires use of anti-platelet or anti-coagulant therapy that cannot be safely suspended for per protocol ITu injections or biopsies per standard of care, including the discontinuation of NSAIDs, including ASA, at least 7 days prior to any study biopsy or ITu injection.
• Has CNS metastases that have not been completely resected or completely irradiated and/or carcinomatous meningitis.
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected) virus infection.
• Has used excluded anti-viral medication (e.g., IFN/peg-IFN, ribavirin, etc.) within 14 days of Day 1 and that cannot be suspended throughout the initial TBio-6517 treatment period and for at least 14 days prior to and after each booster dose of TBio-6517 Note: Acyclovir is permitted.
• Has significant immunodeficiency due to underlying illness (e.g., known HIV/AIDS) or has received systemic immunosuppressive medication including high-dose corticosteroids (e.g., systemic corticosteroids > 10 mg prednisone or equivalent), other than protocol-required pre-medications, within 4 weeks prior to the first dose of trial treatment. Inhaled steroid doses ≤ 10 mg prednisone or equivalent are permitted in the absence of active autoimmune disease.
  • Note: High dose corticosteroids administered for contrast allergy prophylaxis is permitted throughout the trial prior to radiographic scans as long as the first dose of TBio-6517 is at least 7 days after the corticosteroid administration.
• Prior history of myocarditis.
• Given the potential risk of tachycardia, hypotension, and/or fluid volume loading during or following treatment with oncolytic viruses, patients with the following should be excluded:
  • Symptomatic cardiovascular disease, including but not limited to, significant coronary artery disease (e.g., myocardial infarction or other coronary artery disease requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months;
  • Asymptomatic cardiovascular disease (current or past history) unless cardiology consultation and clearance has been obtained for study participation;
  • New York Heart Association functional class III-IV heart failure on active treatment;
  • Patients who for any other reason cannot tolerate tachycardia, hypotension, and/or fluid volume loading.
• Has a known additional malignancy except basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
• Is pregnant, currently breastfeeding or intending to breastfeed, or expecting/trying to conceive or father children within the projected duration of the trial, starting with Screening through 120 days after the last dose of study treatment including pembrolizumab.
• Pulse oximetry of < 90% in room air at rest.
• Ongoing severe inflammatory skin condition or history of severe eczema requiring prior medical treatment.
• Has had prior organ transplant.
• Has evidence of active, non-infectious pneumonitis.
• Has a history of interstitial lung disease.
• Has an illness, metabolic dysfunction, physical examination finding, or clinical laboratory finding that gives reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug or that would limit compliance with study requirements Has severe atopic disease or known active milk allergy.
• Has received a live vaccine within 30 days of planned study treatment.
• Has a previously identified AVM in an organ where intratumoral injection or tumor biopsy is intended to occur.
• Has known adrenal insufficiency requiring replacement doses of corticosteroids.
• Has received > 4 prior lines of therapy for metastatic or locally advanced disease (neoadjuvant or adjuvant therapy does not count as a prior regimen in this regard).

In addition to above, the following Exclusion Criteria are applicable to patients intending to receive pembrolizumab combination (i.e., Arm B and Arm D):

• Has been intolerant to prior PD-1/PD-L1 targeted antibody therapy for which re-treatment would expose the patient to clinically significant risk in the opinion of the Investigator (please obtain Sponsor permission for enrollment of any patient with prior intolerance to anti-PD1/PD-L1 antibody treatment).
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immune-modulating drugs). Replacement therapy with thyroxine or insulinis not considered an excluded form of systemic treatment.

Eligibility last updated 10/7/21. Questions regarding updates should be directed to the study team contact.