Intratumoral Microdosing of Motolimod in HNSCC

This is a multi-center, single arm, open-label, multi-agent, localized pharmacodynamic biomarker Phase 0 trial designed to study the biological effects within the tumor microenvironment of motolimod and motolimod combined with nivolumab when administered intratumorally in microdose quantities via the CIVO device in patients with head and neck squamous cell carcinoma (HNSCC). CIVO stands for comparative in vivo oncology.

CIVO is a research tool composed of a hand-held single-use sterile injector coupled with fluorescent tracking microspheres called CIVO GLO that mark the sites of drug microdose injection, enabling rapid assessment of multiple oncology drugs or drug combinations simultaneously within a patient's tumor. In this Phase 0 intratumoral microdosing study in human patients with pathologic diagnosis of HNSCC with at least one lesion (primary, recurrent, or effaced metastatic lymph nodes) for which there is a planned surgical intervention, we will evaluate motolimod's ability to activate immune effector cells within the local tumor microenvironment. Additionally, this study will examine motolimod in combination with nivolumab to study whether motolimod enhances the localized immune responses compared to those of either immunotherapy alone. Motolimod singly and in combination with nivolumab will be delivered intratumorally in subtherapeutic microdose quantities via CIVO.

The CIVO device penetrates solid tumors and delivers subtherapeutic microdoses of up to eight anti-cancer agents or combinations of anti-cancer agents co-injected with CIVO GLO into discrete regions of the tumor. At the time of the planned surgical intervention (at least four hours to up to four days after the CIVO microdose injection), the injected tumor tissue is then excised and tumor responses are assessed via histological staining of tumor cross-sections sampled perpendicular to each injection column. Co-injection with CIVO GLO enables identification of each injection site during resection as well as in tissues stained for analysis. Because the platform delivers microdose amounts of each test agent or combination directly into the patient's tumor tissue, hypotheses can be tested earlier in the drug development process, consistent with the goals of the 2006 FDA Exploratory IND Guidance for Industry.

Eligibility Criteria:
Inclusion Criteria:

1. Ability and willingness to comply with the study's visit and assessment schedule.
2. Male or female ≥ 18 years of age at Visit 1 (Screening).
3. Pathologic diagnosis of HNSCC.
4. Ability and willingness to provide written informed consent. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
5. At least one lesion (primary or recurrent tumor) ≥ 2 cm in the shortest diameter that is accessible for ultrasound-guided percutaneous CIVO injection and for which there is a planned surgical intervention. An effaced metastatic lymph node may only be selected with prior Sponsor approval. Treatment plan may include adjuvant radiation or chemotherapy, and subjects should have no medical contraindication to surgery.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
7. Female patients who :

   * Are postmenopausal for at least 24 consecutive months (i.e., have not had menses at any time during the preceding 24 consecutive months), OR
   * Are surgically sterile, OR
   * Are of childbearing potential (FCBP) who agree to true abstinence from heterosexual intercourse (which must be source documented) or to use a highly effective contraceptive method (e.g., combined \[containing estrogen and progestogen\] or progestogen-only hormonal contraception associated with inhibition of ovulation \[oral, injectable, intravaginal, patch, or implantable\]; bilateral tubal ligation; intrauterine device; intrauterine hormone-releasing system; or vasectomized partner sterilization \[note that vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success\]) from the time of signing the Informed Consent Form (ICF) and during study participation.
   * Agree to refrain from donating ova during study participation.

Male patients who:

* Agree to practice true abstinence from heterosexual intercourse or agree to use a condom (a latex condom is recommended) during sexual contact with a pregnant female or a FCBP from the time of signing the ICF and while participating in the study, even if he has undergone a successful vasectomy.
* Agree to refrain from donating sperm during study participation.

Exclusion Criteria:

1. Tumors or effaced nodes that are anticipated by the Investigator to lack a sufficient volume of viable tumor tissue (based on available pre-operative imaging, pre-injection ultrasound imaging, or pathology reports) for CIVO injection due to size, location, necrosis, cysts, excessive stroma, fibrosis, or treatment-induced tissue changes. Lesions that have received neoadjuvant radiation therapy may lack sufficient viable tumor tissue for CIVO injection procedures.
2. Tumors near or involving critical structures for which, in the opinion of the treating clinician, injection would pose undue risk to the patient.
3. Patients with a diagnosis of nasopharyngeal carcinoma.
4. Female patients who are:

   * Both lactating and breastfeeding, OR
   * Have a positive urine β-subunit of human chorionic gonadotropin (β-hCG) pregnancy test at screening verified by the Investigator.
5. Any uncontrolled intercurrent illness, condition, serious medical or psychiatric illness, or circumstance that, in the opinion of the Investigator, could interfere with adherence to the study's procedures or requirements, or otherwise compromise the study's objectives.
6. Patients with a history of concurrent second cancers requiring active, ongoing systemic treatment.
7. Patients with active autoimmune diseases requiring treatment.
8. Patients with known human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) with uncontrolled viral load and CD4 less than 200, or known chronic hepatitis B/C.
9. Patients that have received a live vaccine within 4 weeks of the baseline/screening visit.
10. Use of any of the following ≤ 2 weeks prior to CIVO injection :

    1. Chronic systemic immunosuppressive therapy or corticosteroids (e.g., prednisone or equivalent exceeding a total dose of 140 mg over the last 14 days). Intranasal, inhaled, topical, or local corticosteroid injections (e.g., intra-articular injection), or steroids as premedication for hypersensitivity reactions (e.g., computed tomography \[CT\] scan premedication) are exceptions to this criterion.
    2. Biological response modifiers for treatment of active autoimmune disease.
    3. Hematopoietic growth factors.
    4. Anticoagulants such as warfarin or low-molecular-weight heparin.