RiMO-HNC-NEO1: Phase 2 Study of RiMO-301 and Hypofractionated Radiotherapy With Pembrolizumab for the Neoadjuvant Treatment of Resectable, Locally Advanced Head-Neck Cancer

RiMO-301 is administered intratumorally once prior to radiotherapy, with or without ultrasound/computed tomography (CT) guidance, at 30% of tumor volume(s). Radiotherapy (RT) is given starting within 1 day after RiMO-301 injection for 5 fractions of (4-5) Gray per fraction over a period of 5-15 days. PD-1 inhibitor pembrolizumab will be administered via 30-minute intravenous infusion, respectively, 200 mg once every three weeks (Q3W) with the first dose on the same day as RiMO-301 injection (+/- 1 day) for two cycles. Assessment of response will be clinically confirmed with CT imaging studies performed 5 weeks after the last radiation and pathology evaluation of the resected tumor. Event-free survival will be clinically evaluated every three months up to 12 months, CT imaging studies will be performed every 6 months after surgery up to 12 months after surgery, and overall survival will be clinically evaluated up to two years.

• RiMO-301 (Drug): RiMO-301 will be dosed at 30% of the tumor volume on Day 0 prior to radiotherapy. The injection point will be as closed to half of the tumor depth as possible.
• Pembrolizumab (Drug), also known as Keytruda: Pembrolizumab will be administered at 200 mg once every 3 weeks (Q3W) with the first dose on Day 0 +/- 1 day. Pembrolizumab will be given for a total of two cycles prior to surgery.
• Radiation (Radiation): Hypofractionated radiation will will be given within 1 day after RiMO-301 injection and will continue over a period of 5-15 days. Participants will be receive 5 fractions of radiation with a dose of 4-5 Gray per fraction.
• Surgical resection (Procedure): Surgical resection of the tumor will occur following neoadjuvant therapy.

Primary outcomes

• Efficacy of RiMO-301 when used in combination with radiotherapy and pembrolizumab as defined by clinical response rate (i.e., percentage of participants whose tumors shrink). [Treatment start until 12 months after the start of treatment]: Clinical response rate will be assessed by utilizing iRECIST criteria to measure tumor size

Secondary outcomes

• Progression-free survival rate as defined by the number of patients whose disease progresses since the start of treatment [Treatment start until 12 months after the start of treatment]: iRECIST criteria will be used to assess progression free survival rate
• Overall survival rate as defined by the number of deaths among participants [Treatment start until 24 months after the start of treatment]: Overall survival rate will be calculated based on the number of deaths
• Number of Grade 3 and Grade 4 toxicities experienced by participants as defined by CTCAE version 6 [Treatment start until 5 weeks after the last dose of radiation therapy (that is, approximately 7 weeks after treatment start)]: CTCAE version 6 will be used to assess toxicities that are experienced
• To assess the rate of Major Pathological Response (MPR) [At surgical resection]: The rate of Major Pathological Response will be defined as the proportion of participants undergoing post-neoadjuvant treatment surgical resection who are found to have no more than 10% of residual invasive cancer cells present in the collected tumor specimen
• To assess the rate of Pathological Complete Response (pCR) [At surgical resection]: The rate of Pathological Complete Response will be defined as the proportion of participants undergoing post-neoadjuvant treatment surgical resection with no residual invasive cancer within the resected primary tumor and sampled regional lymph nodes
• To assess surgical outcomes through margin measurements at surgical resection [At surgical resection]: Surgical outcomes will be assessed through margin measurements, specifically the proportion of participants who have positive surgical margins (that is, presence of invasive tumor front at resected margin) and the proportion of people who have close surgical margins (that is, the presence of invasive tumor front <2-5 mm from the resected margin)
• To evaluate the change in disease staging as assessed by the proportion of patients who have a reduction in the size or extent of tumor [Pre-treatment until 12 months after the start of treatment]: Tumor downstaging will be assessed by imaging and clinical staging by T or N status

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Diagnosis of head and neck cancer that requires surgical resection
* Must have at least one lesion that is clinically accessible to RiMO-301 injection and amenable to receiving hypofractionated radiotherapy
* The selected target lesions must be measurable on cross-sectional imaging, and repeated measurements at the same location should be achievable
* Target tumor not in the previously irradiated field or in the field irradiated at least six months prior to RiMO-301 injection, and with no complications from the prior radiation course
* Patients must have recovered from acute toxic effects (≤ grade 1 CTCAEv6) of previous cancer treatments prior to enrollment
* Patients with locally advanced, resectable head and neck cancer:

  * suitable to receive a PD-1 inhibitor (pembrolizumab) as a standard of care in the discretion of the treating physician or Principal Investigator
  * suitable to receive hypofractionated radiotherapy as a standard of care in the discretion of the treating physician or Principal Investigator
* Have adequate bone marrow reserve:

  * Absolute neutrophil count ≥1.5x109 cell/L
  * Platelet count ≥100x109 cell/L
  * Hemoglobin at least ≥9.0 g/dL unless confirmed by treating physician as not posing any increased harm to patient and approved by Sponsor (transfusion is allowed to achieve hemoglobin of ≥9.0 g/dL 14-days prior to dosing)
* Have adequate liver function:

  * Total serum bilirubin no more than 1.5x upper limit of normal (ULN)
  * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x ULN or ≤5.0x ULN in case of documented hepatic metastasis
  * Alkaline phosphatase ≤5x ULN
* Have a life expectancy of at least 12 weeks (in the opinion of the investigator)
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Females with childbearing potential should be using adequate contraceptive measures from the time of screening until 6 months after study discontinuation, should not be breastfeeding, and must have a negative pregnancy test prior to start of dosing
* Patients must sign a study-specific informed consent form prior to study entry.

Exclusion Criteria:

Diagnosis other than resectable, locally advanced head and neck cancers

* HPV associated head and neck cancer
* Nasopharynx head and neck cancer
* Have signs or symptoms of end-stage failure, major chronic illnesses other than cancer, or any severe concomitant conditions
* Symptomatic central nervous system metastases and/or carcinomatous meningitis
* Has received any approved or investigational anti-neoplastic agent or immunotherapy other than PD-1 inhibitors, pembrolizumab, within 4 weeks prior to RiMO-301 injection.
* Patients who are intolerant to pembrolizumab
* Active autoimmune disease that has required systemic treatment in the past 2 years
* Ongoing clinically significant infection at or near the incident lesion
* Major surgery over the target area (excluding placement of vascular access) ≤21 days from the beginning of the study drug or minor surgical procedures ≤7 days. No waiting is required following implantable port, enteral feeding tube, and catheter placement
* Other severe acute or chronic medical or psychiatric conditions or laboratory abnormality that would make the patient inappropriate for enrollment in this study
* Has any mental or medical condition that prevents the patient from giving informed consent or participating in the trial
* Pregnant and nursing women are excluded because of the potential teratogenic effects and potential unknown effects on nursing newborns
* Patients with a target lesion in the field that had complications from prior radiotherapy that are not amenable to repeat irradiation in the discretion of the treating physician or Principal Investigator
* Patients with lesions that have significant blood vessel involvement (such as carotid artery encasement) or other major structures

• Ameen Salahudeen, MD, PhD, Principal investigator, Principal Investigator