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
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 percutaneously 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.
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 or effaced metastatic lymph node) ≥ 2 cm in the
shortest diameter that is accessible for ultrasound-guided percutaneous CIVO injection
and for which there is a planned surgical intervention. Treatment plan may include
adjuvant radiation or chemotherapy.
6. ECOG (Eastern Cooperative Oncology Group) performance status of 0-2.
7. Acceptable bone marrow, renal, and hepatic function based upon screening lab tests as
demonstrated by the following:
- Absolute neutrophil count ≥ 1,000 cells/μL
- Platelet count ≥ 75,000 per μL
- Hemoglobin ≥ 10g/dL
- Creatinine ≤ 1.5x the age-adjusted upper limit of normal
- Total bilirubin ≤ 1.5x the upper limit of normal (with the exception of patients
with Gilbert's syndrome for which higher bilirubin values would be acceptable
provided the patient has normal liver function)
- AST (Aspartate Aminotransferase)/SGOT (Serum Glutamate Oxaloacetate Transaminase)
and ALT (Alanine Aminotransferase)/SGPT (Serum Glutamate Pyruvate Transaminase) ≤
2.5x the upper limit of normal
8. 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.
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.
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
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
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
7. Patients that have received a live vaccine within 4 weeks of the baseline/screening
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
5. Anticoagulants such as warfarin or low-molecular-weight heparin