Phase I Study of Tolododekin Alfa (ANK-101) in Advanced Solid Tumors

This Phase 1 first-in-human (FIH) study will: 1) evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic effects and preliminary clinical activity of tolododekin alfa (ANK-101) administered as an intratumoral (IT) injection in participants with superficial or visceral lesions; 2) determine the recommended dose for expansion (RDE) of ANK-101; and 3) to determine the safety and tolerability of ANK-101 in combination with cemiplimab.

For parts 1 and 2, the study design consists of six sequential dose-escalation cohorts. Part 1 will enroll participants with advanced solid tumors, with cutaneous, subcutaneous or nodal disease (accessible by clinical palpation or ultrasound guidance). Part 2 will start once the DLT period of dose level 1 in Part 1 is completed and dose level 2 is opened. Part 2 will enroll participants with visceral disease (accessible by interventional radiology or endoscopic techniques). Participants in Part 2 may also have superficial lesions that can be injected if in the Investigator's opinion this is clinically indicated.

Ten participants with non-small cell lung cancer (NSCLC) will be dosed in a Part 2 dose expansion cohort at the RDE.

Part 3 will start once dose escalation for Part 1 is complete and the RDE is identified. Part 3 will consist of ANK-101 in combination with cemiplimab in 15 participants with high-risk locally advanced or metastatic CSCC that have superficial lesions for injection. Participants will be treated with ANK-101 given as IT injections once every three weeks at the RDE in combination with cemiplimab.

Enrollment in Part 3 will include a safety run-in of 5 participants. Following the first dose of the 5th participant, enrollment will pause for 21 days before opening enrollment to the remaining 10 participants or stopping further enrollment.

Inclusion criteria

• ≥ 18 years of age on day of signing informed consent
• histologically or cytologically confirmed diagnosis of cutaneous, subcutaneous, soft tissue, or nodal advanced solid tumor malignancy; metastatic disease eligible
• measurable disease per RECIST v1.1 - Note: Must have at least 1 tumor lesion with longest dimension of ≥ 10 mm (≥ 15 mm for the short axis for malignant lymph node lesions) that - For Part 1 only: can be easily palpated or detected by ultrasound to facilitate IT injection of ANK-101 (i.e., tumor in skin, muscle, subcutaneous tissue, or accessible lymph node) or; - For Part 2 only: can be accessed by interventional radiologic or endoscopic procedures for injection (e.g., ultrasound or computed tomography [CT] guided). - For Part 2 Dose Expansion Cohort only: Histologically confirmed Stage III or Stage IV NSCLC
• Part 3 CSCC Combination Cohort: Histologically confirmed high-risk locally advanced or metastatic CSCC not amenable to surgical management as determined by a multidisciplinary tumor board.
• documented disease progression, be refractory to, or intolerant of existing SOC therapy(ies) known to provide clinical benefit (including surgical cure) or not be eligible for SOC therapy(ies)
• ECOG performance status 0-1
• life expectancy > 12 weeks
• adequate bone marrow, hepatic and renal function
• baseline electrocardiogram (EKG) without evidence of acute ischemia or prolonged QTc interval > 460 msec
• Human immunodeficiency virus (HIV) infected participants must be on anti-retroviral therapy (ART) and have well-controlled HIV infection/disease
• last dose of previous anticancer therapy (including investigational agents) ≥ 28 days, radiotherapy ≥ 14 days (targeted palliative radiotherapy is allowed for lesions not planned for injections), or surgical intervention ≥ 21 days prior to the start of treatment
• resolution of all prior anticancer therapy toxicities (except for alopecia or vitiligo) to ≤ Grade 1 (as per NCI CTCAE Version 5.0)
• willing to provide pre- and post-treatment tumor biopsy samples if medically feasible
• participant is capable of understanding and complying with protocol requirements

Exclusion criteria

• injectable tumors impinging upon major airways or blood vessels
• prior treatment with recombinant interleukin-12 (IL-12)
• have received systemic therapy with immunosuppressive agents ≤ 28 days before the start of treatment
• have received live vaccines within 28 days prior to the start of ANK-101 treatment
• have primary or acquired immunodeficient states (e.g., leukemia, lymphoma)
• a woman of childbearing potential (WOCBP) who has a positive serum pregnancy test (within 72 hours) prior to the start of treatment or female participant who is breastfeeding
• prior organ transplantation
• known history of hepatitis B virus, known active hepatitis C virus, or a positive serological test at screening within 28 days prior to the start of treatment
• HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease
• active autoimmune disease or medical conditions requiring chronic steroid (i.e., ≥ 20 mg/day prednisone or equivalent) or other immunosuppressive therapy within 28 days prior to the start of treatment
• known active central nervous system (CNS) metastases
• 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
• uncontrolled bleeding disorders within 4 weeks prior to the start of treatment or known bleeding diathesis - Note: Part 2 only: Participants with active bleeding diathesis or requirement for therapeutic anticoagulation that cannot be interrupted or altered for procedures
• history of hypersensitivity to compounds of similar biological composition to IL-12, aluminum hydroxide, or drugs formulated with polysorbate-20
• other systemic conditions or organ abnormalities that, in the opinion of the Investigator, may interfere with the conduct and/or interpretation of the current study
• any acute or chronic psychiatric problems or substance abuse disorder that, in the opinion of the Investigator, make the participant unsuitable for participation
• Part 3 only: prior Grade 3 or greater immune-mediated adverse events (imAEs) following treatment with an agent that blocks the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway.
• Part 3 only: hypersensitivity to cemiplimab or any of its excipients or contraindications to cemiplimab per approved local labeling