Clinical Trials /

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

NCT02423863

Description:

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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Skin Neoplasm
  • Melanoma
  • Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ONC2014-001
  • SECONDARY ID: 1R44CA183075-01A1
  • NCT ID: NCT02423863

Conditions

  • Melanoma
  • Head and Neck Cancer
  • Sarcoma
  • Non-Melanoma Skin Cancers

Interventions

DrugSynonymsArms
HiltonolPoly-ICLC, Nivolumab, Pembrolizumab, Atezolizumab, Cemiplimab, DurvalumabHiltonol Poly-ICLC

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Hiltonol Poly-ICLCExperimentalOpen labeled, non randomized adaptive 2-stage design protocol. 21 study subjects were enrolled in stage I of the protocol. Up to an additional 60 patients. . 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). 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.
  • Hiltonol

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluate safety of intratumoral (IT) plus intramuscular (IM) Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC, Hiltonol®) for treatment of patients with accessible solid tumors, with or with
Time Frame:Evaluation of response wk 26
Safety Issue:
Description:Wk 26 study subject's response will be defined as BOR (CR, PR, SD) or PD.

Secondary Outcome Measures

Measure:Determine whether the study regimen of Poly-ICLC will induce an innate and/or an adaptive, specific anti-tumor T cell immune response in the injected tumor lesion and systemically.
Time Frame:26 weeks
Safety Issue:
Description:Serial blood samples collected at certain time points and processed and used to evaluate humoral and cellular immunity induced by IT and IM polyICLC injections
Measure:Determine the response in injected lesions as defined by change in size at 16 weeks and 26 weeks as assessed by bi-dimensional measurement using RECIST 1.1 criteria.
Time Frame:16 weeks and 26 weeks
Safety Issue:
Description:In the present protocol, we propose to induce both innate and adaptive cellular immune mechanisms with IT injections of poly-ICLC (Nierkens, den Brock et al. 2008)
Measure:Determine the response in non-injected tumor lesions, both visceral and non-visceral as defined by change in size at 16 weeks and 26 weeks as assessed by bi- dimensional measurement.
Time Frame:16 weeks and 26 weeks
Safety Issue:
Description:Bi-dimensional measurements will be performed on injected and non-injected lesions at the indicated time points in the study calendar.
Measure:Determine progression free survival at 12, 24, and 36 months in treated study subjects.
Time Frame:12, 24 and 36 months
Safety Issue:
Description:Up to 5 visible deep measureable lesions will be designated as Target Lesions (index lesions)
Measure:Determine overall survival (OS) in treated study subjects.
Time Frame:Up to 36 months
Safety Issue:
Description:Survival and disease control/progression-free survival (PFS) will be estimated using Kaplan-Meir curves.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Oncovir, Inc.

Trial Keywords

  • Cancer
  • Immunotherapy
  • Intratumoral Injection
  • Multicenter Study
  • Autovaccination
  • Solid Tumors
  • anti-PD1
  • anti-PDL1

Last Updated

November 11, 2019