Overview

This is a multicenter, multi-arm trial evaluating anti-tumor activity, safety, and immune infiltration of IO102-IO103 in combination with pembrolizumab KEYTRUDA® as neoadjuvant and post-surgery treatment. This proof-of-concept trial will include patients with resectable tumors in at least 2 indications.

Eligibility

Melanoma-specific inclusion criteria:

        • Histologically or cytologically confirmed diagnosis of cutaneous stage III melanoma
        according to the American Joint Committee on Cancer (AJCC) 8th edition.
        Patients with resectable tumors are eligible for this trial either at presentation for
        primary melanoma with concurrent regional nodal metastasis or at the time of clinically
        detected nodal recurrence; they may belong to any of the following groups:
          -  Primary cutaneous melanoma with clinically apparent regional lymph node metastases
          -  Clinically detected recurrent melanoma at the proximal regional lymph node(s) basin
          -  Clinically detected primary cutaneous melanoma involving multiple regional nodal
             groups
          -  Clinically detected nodal melanoma (if single site) arising from an unknown primary
          -  Relapsed resectable stage III melanoma
        SCCHN-specific inclusion criteria:
        • Stage III or IVA resectable locoregionally advanced SCCHN of the oral cavity, oropharynx
        (with known HPV-negative or p16-negative status assessed per institution standard or
        centrally), hypopharynx, or larynx.
        Inclusion criteria applicable across cohorts:
        In addition to the indication-specific inclusion criteria, a patient must meet all the
        following general criteria to be eligible for participation in this trial:
          1. Measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
          2. Candidate for surgical resection with curative intent
          3. The patient (or legally acceptable representative if applicable) provides written
             informed consent for the trial.
          4. Age ≥18 years on the day of signing the informed consent form
          5. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
             of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE)
             tissue blocks are preferred to slides.
          6. Eastern Cooperative Oncology Group (ECOG) performance score status of 0 or 1
          7. Adequate organ function as defined below performed on screening labs obtained within 4
             weeks before first dose:
               -  Absolute neutrophil count (ANC) ≥1500/µL
               -  Platelets ≥100 000/µL
               -  Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (Note: Criterion must be met without packed
                  red blood cell transfusion within the prior 2 weeks. Patients can be on stable
                  dose of erythropoietin [≥ approximately 3 months].)
               -  Creatinine or measured or calculated creatinine clearance (glomerular filtration
                  rate can also be used in place of creatinine or creatinine clearance) ≤1.5 ×
                  upper limit of normal (ULN) or ≥30 mL/min for patient with creatinine levels >1.5
                  × institutional ULN
               -  Serum total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for patients with
                  total bilirubin levels >1.5 × ULN
               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN
               -  International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN unless
                  the patient is receiving anticoagulant therapy as long as PT or partial
                  thromboplastin time (PTT) is within the therapeutic range of intended use of
                  anticoagulants
               -  Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless the patient is
                  receiving anticoagulant therapy as long as PT or PTT is within the therapeutic
                  range of intended use of anticoagulants
          8. Women of childbearing potential: Negative urine or serum pregnancy within 72 hours
             prior to receiving the first dose of trial medication. If the urine test is positive
             or cannot be confirmed as negative, a serum pregnancy test will be required.
          9. Women of childbearing potential: Willing to use highly effective contraception or
             abstain from heterosexual activity for the duration of the trial and for at least 120
             days after the last dose of trial medication
         10. HIV-infected patients must be on anti-retroviral therapy (ART) and have a
             well-controlled HIV infection/disease defined as:
        a Patients on ART must have a CD4+ T-cell count >350 cells/mm3 at time of screening b
        Patients on ART must have achieved and maintained virologic suppression defined as
        confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the
        limit of detection) using the locally available assay at the time of screening and for at
        least 12 weeks prior to first dose of trial medication (Day 1) c Patients on ART must have
        been on a stable regimen, without changes in drugs or dose modification, for at least 4
        weeks prior to first dose of trial medication (Day 1) 11. Patients who are hepatitis B
        surface antigen (HBsAg) positive are eligible if they have received hepatitis B (HBV)
        antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to start
        of trial intervention.
        Note: Patients should remain on anti-viral therapy throughout trial intervention and follow
        local guidelines for HBV anti-viral therapy after completion of trial intervention.
        Hepatitis B screening tests are not required unless:
          -  Known history of HBV infection
          -  Mandated by local health authority. 12. Patients with a history of hepatitis C (HCV)
             infection are eligible if HCV viral load is undetectable at screening.
        Note: Patients must have completed curative antiviral therapy at least 4 weeks prior to
        start of trial intervention.
        Hepatitis C screening tests are not required unless:
          -  Known history of HCV infection
          -  Mandated by local health authority.
        Melanoma-specific exclusion criteria:
          -  Current or prior history of uveal, mucosal, or acral melanoma
          -  Oligometastatic stage IV melanoma
          -  History of in-transit metastases within the last 6 months
          -  Prior therapy targeting BRAF and/or MEK
        SCCHN-specific exclusion criteria:
        • Nasopharyngeal cancer, unknown primary, nasal cavity or paranasal sinus carcinoma
        Exclusion criteria applicable across cohorts:
        In addition, patients meeting any of the following criteria must be excluded:
          1. Currently participating in or has participated in a trial of an investigational agent
             or has used an investigational device within 4 weeks of the first dose of trial
             treatment Note: Patients who have entered the follow-up phase of an investigational
             trial may participate as long as it has been 4 weeks after the last dose of the
             previous investigational agent.
          2. Any prior treatment for the tumor under study
          3. Prior therapy for another tumor with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or
             with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
             CTLA-4, OX40, CD137), and discontinued from that treatment due to a grade 3 or higher
             immune-related adverse event (irAE)
          4. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
             weeks prior to first dose of trial treatment
               -  Note: Patients must have recovered from all adverse events (AEs) due to previous
                  therapies (i.e., grade ≤1 at baseline). Patients with grade ≤2 neuropathy are
                  eligible for the trial. Patients with endocrine-related AEs grade ≤2 requiring
                  treatment or hormone replacement are also eligible.
               -  Note: If the patient has had major surgery, the patient must have recovered
                  adequately from the procedure and/or complications from the surgery prior to
                  starting trial treatment.
          5. Live or live-attenuated vaccine within 30 days prior to the first dose of trial
             treatment. Note: Administration of inactivated vaccines, mRNA-based vaccines [e.g.,
             COVID-19] and vector-based vaccines are allowed.
          6. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form
             of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
             Patients who are currently receiving steroids at a dose equivalent to <5 mg/day of
             prednisone do not need to discontinue steroids prior to enrollment. Patients who
             require topical, ophthalmologic and inhalational steroids will not be excluded from
             the trial. Patients with hypothyroidism stable on hormone replacement or Sjögren's
             syndrome will not be excluded from the trial.
          7. Additional malignancy that is progressing or requires active treatment. Exceptions
             include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in
             situ cervical cancer that has undergone potentially curative therapy.
          8. History of an allogeneic tissue/solid organ transplant.
          9. Active autoimmune disease that has required systemic treatment in past 2 years (i.e.,
             with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
             Patients with type I diabetes mellitus; hypothyroidism only requiring hormone
             replacement; skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
             systemic treatment; or conditions not expected to recur in the absence of an external
             trigger are permitted to enroll.
         10. History of radiation pneumonitis
         11. History of (non-infectious) pneumonitis/interstitial lung disease that required
             steroids or has current pneumonitis/interstitial lung disease
         12. Active infection requiring systemic therapy
         13. HIV-infected patients with a history of Kaposi sarcoma and/or Multicentric Castleman
             Disease
         14. Has known active hepatitis B virus (HBV; defined as hepatitis B surface antigen
             [HBsAg] reactive and/or detectable HBV DNA) or known active hepatitis C virus (HCV)
             (defined as anti HCV Ab positive and detectable HCV ribonucleic acid [RNA]
             [qualitative]) infection.
             Note: Testing for hepatitis B and hepatitis C is not required unless
               1. Known history of HBV or HCV infection
               2. Mandated by local health authority. Patients with a history of hepatitis will be
                  screened using serology to confirm status.
         15. History or current evidence of any condition, therapy, or laboratory abnormality that
             might confound the results of the trial, interfere with the patient's participation
             for the full duration of the trial, or is not in the best interest of the patient to
             participate, in the opinion of the treating investigator
         16. Psychiatric or substance abuse disorders that would interfere with the patient's
             ability to cooperate with the trial requirements
         17. Severe hypersensitivity (grade ≥3) to pembrolizumab and/or any of its excipients