Intratumoral Microdosing of TAK-981 in Head and Neck Cancer

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 TAK-981 and TAK-981 combined with cetuximab or avelumab when administered intratumorally in microdose quantities via the CIVO device. 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 localized or metastatic primary tumors of the head and neck (who will be undergoing previously planned tumor and regional nodes dissection), we will evaluate TAK-981's ability to activate innate immune effector cells within the local tumor microenvironment. Additionally, this study will examine TAK-981 in combination with cetuximab or avelumab to study whether TAK-981 enhances the localized immune responses compared to those of either immunotherapy alone. TAK-981 singly and in combination with cetuximab or avelumab 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 (one or three 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 primary cancers of the head and neck.
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 tumor, recurrent tumor, or effaced metastatic lymph node) ≥ 2 cm in the shortest diameter that is surface accessible for CIVO injection that may be guided by ultrasound if appropriate and for which there is a planned surgical intervention. Treatment plan may include adjuvant radiation or chemotherapy and patients must have no medical contraindication to surgery.
6. ECOG (Eastern Cooperative Oncology Group) performance status of 0-2.
7. Female patients who:

   * Are postmenopausal for at least one year before the screening visit, OR
   * Are surgically sterile, OR
   * If they are of childbearing potential, agree to practice two effective methods of contraception, at the same time, from the time of signing of the informed consent through four months after the tumor injection procedure, OR agree to completely abstain from heterosexual intercourse.
   * Agree to refrain from donating ova during study participation.

Male patients, even if surgically sterile (i.e., status post-vasectomy), who:

* Agree to practice effective barrier contraception during the entire study treatment period through four months after the tumor injection procedure, OR
* Agree to completely abstain from heterosexual intercourse.
* 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. Patients who have received prior treatment with cetuximab or immune checkpoint inhibitors.
3. Female patients who are both lactating and breastfeeding or have a positive serum pregnancy during the screening period or a positive urine pregnancy test on Day 1 before the tumor injection procedure.
4. 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.
5. Patients with uncontrolled autoimmune diseases requiring treatment.
6. Patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) with uncontrolled viral load and CD4 (Cluster of Differentiation 4) less than 200.
7. Patients that have received a live vaccine within 4 weeks of the baseline/screening visit.
8. Patients with a sensitivity to Captisol.
9. Use of any of the following ≤ 2 weeks prior to CIVO injection:

   1. Immunosuppressive drugs (e.g., calcineurin inhibitors)
   2. Biological response modifiers for autoimmune disease
   3. Systemic glucocorticoids: oral or parenteral corticosteroids at a dose ≥ 20 mg/day prednisone, or equivalent Note: physiologic replacement dosing of steroids (≤ 3mg/m2/d prednisone or equivalent), low-dose corticosteroids for dye allergies prior to staging scans or use in anti-emetic prophylaxis for patients undergoing chemotherapy, or topical steroids, are allowed
   4. Hematopoietic growth factors