In Situ, Autologous Therapeutic Vaccination Against Solid Cancers With Intratumoral Hiltonol®

In Situ, Autologous Therapeutic Vaccination Against Solid Cancers With Intratumoral Hiltonol® (Poly-ICLC): An Adaptive, Multicenter, Phase II Clinical Study

The purpose of this study is to evaluate the safety of sequential intratumoral (IT) plus intramuscular (IM) Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC, Hiltonol®) for treatment of study subjects with accessible solid tumors, with or without checkpoint blockers. Enrolled study subjects will receive Poly-ICLC (Hiltonol®) treatment alone or in combination with anti-PD-1 (Nivolumab, Pembrolizumab or Cemiplimab) or anti-PD-L1 (Atezolizumab or Durvalumab) over 6 months as defined in study treatment described below. MRI or CT imaging will be done per SOC at screening, 3 and 6-month time points.

For purposes of analysis patients enrolled in Stage II of this study will be prospectively identified at initial screening as belonging to statistical Cohorts A, B, or C, which are based on patient status with regard to aPD1/aPDL1 therapy at study entry, (PD, SD, or treatment naïve) per section 11.5. For purposes of this study, patient status is considered to be the primary eligibility variable, although sub analyses will also consider histology and particular checkpoint blocker used when possible. Please see section 12 (Statistical Analysis) for further discussion.

Week 1 Days 1, 3 and 5: Poly-ICLC (Hiltonol®) 1 mg (0. 5 ml) IntraTumoral (priming treatment course).

Weeks 2-25:

1. Poly-ICLC (Hiltonol®) 1 mg (0.5 ml) IM twice a week with a 48-72 hour interval between the two injections, AND either:

2. No additional immunotherapy OR

3. ONLY ONE of the following Anti-PD1 or anti-PDL-1 regimens will be administered, per manufacturer's dosing and clinical oncologist's discretion as follows: (Not to be Administered on the same day as Poly-ICLC [Hiltonol®])

   • Either Nivolumab (Opdivo), OR
   • Pembrolizumab (Keytruda), OR
   • Atezolizumab (Tecentriq) OR
   • Cemiplimab (Libtayo) OR
   • Durvalumab (Imfinzi)

NOTE: It is recognized that some patients will have already been on anti-PD-1 or anti-PD-L1 at the time of study entry. Such patients will not have their checkpoint blocker therapy interrupted, but will be started on Poly-ICLC on week one, as above

If well tolerated they continue at full dose of 1 mg IM twice weekly through week 25. Anti-PD-1 or anti-PD-L1 per manufacturers package insert begins on week two and continues through week 25 or beyond per standard of care at physician's discretion. After the end of Poly-ICLC treatment at week 25, aPD1 or aPDL1 can be continued at the discretion of the patient and treating physician, per SOC, independent of this protocol.

At week 26 study subjects will be assessed and response determined using the RECIST 1.1 criteria. This will include measurement of accessible lesions as well as CT scan of the chest, abdomen and pelvis and extremities or neck to assess for response, using RECIST 1.1. MRI of the brain may also be obtained as part of clinical follow of their disease, if clinically indicated as per standard clinical protocol. Study subject's response will be defined as BOR (CR, PR, SD) or PD. If tumors are present and accessible, biopsies of the injected tumor as well as of a non-targeted/non-injected tumor will also be obtained at week 26.

Study subjects with CR, PR, or SD may be offered an additional treatment cycle depending on study subject's health status, costs and/or drug availability. At week 26 a repeat tumor assessment will be performed, an optional biopsy may be performed.

Follow up Period:

After completion of study treatment, study subjects may be contacted by telephone at least twice over 12 months, or longer with patient consent to inquire on their health status (e.g., alive, remission, progressive disease, on new cancer treatment). Study subjects with an initial tumor response but then long-term recurrence during the follow up period may be offered additional cycles of treatment depending on the study subject's health status, costs and/or drug availability.

Inclusion Criteria:

1)1) Histologically confirmed diagnosis of one of the following:

1. Melanoma

2. Squamous head and neck cancer

3. Sarcoma

4. Non-Melanoma skin cancers 2) Sarcoma Patients must be 14 years of age or older. All other patients must be 18 years of age or older.

   3) Unresectable disease. Patients with resectable disease may be enrolled after having refused surgery after a documented consultation with a surgeon.

   4) Radiographic or visually measurable disease based on Response Evaluation Criteria In Solid Tumors, Version 1.1 criteria.

   5) At least one accessible primary or metastatic tumor site that can be readily injected IT with poly-ICLC with or without ultrasound guidance. This lesion can be superficial cutaneous, subcutaneous, or within a readily accessible location, including a lymph node, and must measure ≥ 15mm short axis for target.

   6) Patients who have received at least 8 weeks of aPD1 or aPDL1 immunotherapy and who have either progressive disease, stable disease or partial response based on RECIST 1.1 criteria are elegible for participation as separate cohorts B or C, with continuation of the aPD1 or aPDL1 therapy at their physician's discretion.

   7) ECOG performance status of ≤ 2. 8) Acceptable hematologic, renal and liver function as follows: A) Absolute neutrophil count > 1000/mm3 B) Platelets > 50,000/mm3, C) Creatinine ≤ 2.5 mg/dl, D) Total bilirubin ≤ 1.5 mg/dl, E) Transaminases ≤ 2 times above the upper limits of the institutional normal. F) INR<2 if off of anticoagulation. Patients on anticoagulation therapy with an INR>2 may be enrolled at the discretion of the investigator if they have not had any episodes of severe hemorrhage and if the site to be injected is not located in the oropharynx or another area where achieving homeostasis would be complicated by local anatomy.

   9) Patients must be able to provide informed consent. 10) Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Contraception must be continued for at least 2 months following the last dose of poly-ICLC. Women of childbearing potential must have a negative pregnancy test. While animal reproductive studies have been negative, the simulated viral infection and anti-proliferative activity of this experimental drug may theoretically affect the developing fetus or nursing infant.

   Cohort Specific Inclusion Criteria (see § 11.6 Evaluation of Best Overall Response (BOR)

   Cohort A) 11) Patients who are not receiving an anti-PD-1 or anti-PD-L1 agent,

   Cohort B 12) Patients who have received at least 8 weeks of aPD1 or aPDL1 immunotherapy. 13) Patients have progressive disease based on RECIST 1.1 criteria.

   Cohort C) 14) Patients who have received at least 8 weeks of aPD1 or aPDL1 immunotherapy. 15) Patients have stable disease or a partial response based on RECIST 1.1 criteria.

   4.2 Exclusion Criteria

   Patients with any of the following are ineligible for this research study:

   1. Serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety.
   2. Bulky intracranial metastatic disease with shift of midline structures or progressive brain metastasis such that ongoing therapy for these brain metastasis is required at the time of enrollment.
   3. In the opinion of the local PI: Head and neck cancer patients with airway tumor recurrence that may compromise breathing or swallowing if inflammation or edema is transiently aggravated by Hiltonol® injection. Head and neck cancer patients with tumor invading major blood vessels for whom there may be a risk of blockage or bleeding if inflammation or edema is transiently increased by Hiltonol® injections.
   4. AIDS defined as a CD4 count less than 200 in the context of HIV sero-positivity or chronically is taking immunosuppressive medication such as steroids or transplant related medications.
   5. Life expectancy of less than 6 months in the judgment of the study physician.
   6. Persistent toxicity from recent therapy that has not sufficiently resolved in the judgment of the study physician.
   7. History of active cancer vaccine immunotherapy in the previous month. Patients who have received at least 8 weeks of aPD1 or aPDL1 immunotherapy and who have either progressive disease, stable disease or partial response based on RECIST 1.1 criteria are elegible for participation and continuation of the aPD1 or aPDL1 therapy at their physician's discretion.