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

This is a Phase 1, multicenter, open-label dose escalation study to determine the safety and tolerability of intratumoral (IT) injection of tolododekin alfa (ANK-101) in participants with advanced solid tumors who have progressed during or after receiving standard of care (SOC) therapy or who will not benefit from such therapy. The study will be conducted in three parts; in Part 1, participants with superficial lesions will receive ANK-101 as a single agent; in Part 2, participants with visceral lesions will receive ANK-101 as a single agent; and in Part 3, participants with cutaneous squamous cell carcinoma (CSCC) will receive ANK-101 in combination with cemiplimab.

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 and an expansion cohort at the RDE. 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 will be dosed in a Part 1 dose expansion cohort at the RDE, and in Part 2, the dose expansion cohort at the RDE will include 10 participants with non-small cell lung cancer (NSCLC).

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.

Eligibility Criteria:
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