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

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.