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In Situ, Autologous Therapeutic Vaccination Against Solid Cancers With Intratumoral Hiltonol® (Poly-ICLC)

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ClinicalTrials.gov Identifier: NCT02423863
Recruitment Status : Recruiting
First Posted : April 22, 2015
Last Update Posted : November 13, 2019
Sponsor:
Collaborators:
National Institutes of Health (NIH)
Icahn School of Medicine at Mount Sinai
Bay Hematology Oncology
National Cancer Institute (NCI)
University of Missouri-Columbia
Chevy Chase Regional Cancer Care Associates LLC
Dermatologic Surgery Center of Washington LLC and Skin Cancer Treatment Center
Information provided by (Responsible Party):
Oncovir, Inc.

Tracking Information
First Submitted Date  ICMJE April 13, 2015
First Posted Date  ICMJE April 22, 2015
Last Update Posted Date November 13, 2019
Study Start Date  ICMJE March 2015
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 11, 2019)
  • 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 ]
    Wk 26 study subject's response will be defined as BOR (CR, PR, SD) or PD.
  • Evaluate therapeutic efficacy assessed by Disease Control (CR, PR, or SD) as defined by the RECIST 1.1 Criteria. [ Time Frame: 6 months ]
    Week 26 tumor assessment will be performed, an optional biopsy may be performed.
Original Primary Outcome Measures  ICMJE
 (submitted: April 21, 2015)
  • Evaluate safety of sequential intratumoral, plus intramuscular injections of Poly-ICLC, Hiltonol® for treatment of study subjects with advanced accessible solid tumors (response determined using the irRC criteria) [ Time Frame: Evaluation of response at wk 26, in the absence of possible drug induced acute inflammation ]
    At wk 26 study subjects will be assessed and response determined using the irRC 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 Immune related Response Criteria (irRC). 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 Disease Control (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.
  • To evaluate therapeutic efficacy in treated study subjects as assessed by Disease Control (CR, PR, or SD) as defined by the Immune-related Response Criteria (irRC) and recorded at the 6-month time point only, compared to baseline. [ Time Frame: 6 months ]
    Study subjects with CR, PR, or SD may be offered maintenance therapy from week 27 to 36, with administration of 1 mg IM Poly-ICLC twice weekly as per below schema. At week 36 a repeat tumor assessment, including optional tumor biopsy, will be performed.
Change History Complete list of historical versions of study NCT02423863 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 11, 2019)
  • 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 ]
    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
  • 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 ]
    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)
  • 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 ]
    Bi-dimensional measurements will be performed on injected and non-injected lesions at the indicated time points in the study calendar.
  • Determine progression free survival at 12, 24, and 36 months in treated study subjects. [ Time Frame: 12, 24 and 36 months ]
    Up to 5 visible deep measureable lesions will be designated as Target Lesions (index lesions)
  • Determine overall survival (OS) in treated study subjects. [ Time Frame: Up to 36 months ]
    Survival and disease control/progression-free survival (PFS) will be estimated using Kaplan-Meir curves.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 21, 2015)
  • Determine if 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 ]
    Serial blood samples collected at baseline, and at selected time points during and post treatment as detailed in the study calendar will be processed to collect plasma/serum and peripheral blood mononuclear cells (PBMCs) which be used to evaluate humoral and cellular immunity induced by IT and IM polyICLC injections
  • Determine if the treatments will lead to regression of injected tumor lesions as defined by change in size at 8 weeks and 26 weeks as assessed by bi-dimensional measurement. [ Time Frame: 8 weeks and 26 weeks ]
    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)
  • Determine if the treatments will lead to regression of non-injected tumor lesions, both visceral and non-visceral as defined by change in size at 8 weeks and 26 weeks as assessed by bidimensional measurement, using irRC criteria. [ Time Frame: 8 weeks and 26 weeks ]
    Bi-dimensional measurements will be performed on injected and non-injected lesions at the indicated time points in the study calendar.
  • Determine long-term progression free survival at 12, 24 and 36 months in treated study subjects. [ Time Frame: 12, 24 and 36 months ]
    Up to 10 lesions, including the target lesion, will be measured. If the target lesion is measured under ultrasound guidance, it will be measured under ultrasound guidance. Skin lesions will be measured using a ruler or calipers. Skin lesions which are completely flat, do not protrude above the skin surface and are stable in size from the prior visit will be considered scars and scored as a 0.
  • Determine overall survival (OS) in treated study subjects. [ Time Frame: Up to 36 months ]
    Overall survival will be estimated using a Kaplan-Meier curve to describe survival from enrollment to death from any cause or until censoring.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE In Situ, Autologous Therapeutic Vaccination Against Solid Cancers With Intratumoral Hiltonol®
Official Title  ICMJE In Situ, Autologous Therapeutic Vaccination Against Solid Cancers With Intratumoral Hiltonol® (Poly-ICLC): An Adaptive, Multicenter, Phase II Clinical Study
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Melanoma
  • Head and Neck Cancer
  • Sarcoma
  • Non-Melanoma Skin Cancers
Intervention  ICMJE Biological: Hiltonol

Wk 1 Days 1, 3 and 5: Poly-ICLC (Hiltonol®) 1 mg (0. 5 ml) IntraTumoral (priming treatment course). Weeks 2-25 Poly-ICLC (Hiltonol®) 1 mg (0.5 ml) IM twice a week with a 48-72 hour interval between the two injections, AND either:

No additional immunotherapy OR

ONLY ONE of the 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, OR Pembrolizumab, OR Atezolizumab, OR Cemiplimab, OR Durvalumab

Other Names:
  • Poly-ICLC
  • Nivolumab
  • Pembrolizumab
  • Atezolizumab
  • Cemiplimab
  • Durvalumab
Study Arms  ICMJE Experimental: Hiltonol Poly-ICLC

Open 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.

Intervention: Biological: Hiltonol
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 21, 2015)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date June 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Andres M Salazar, MD 202 342 1726 asalazar@oncovir.com
Contact: Rose Marie Holman, MA 917 885 9680 rmholman@oncovir.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02423863
Other Study ID Numbers  ICMJE ONC2014-001
1R44CA183075-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: No plan to share data
Responsible Party Oncovir, Inc.
Study Sponsor  ICMJE Oncovir, Inc.
Collaborators  ICMJE
  • National Institutes of Health (NIH)
  • Icahn School of Medicine at Mount Sinai
  • Bay Hematology Oncology
  • National Cancer Institute (NCI)
  • University of Missouri-Columbia
  • Chevy Chase Regional Cancer Care Associates LLC
  • Dermatologic Surgery Center of Washington LLC and Skin Cancer Treatment Center
Investigators  ICMJE
Principal Investigator: Nina Bhardwaj, MD, PhD Icahn School of Medicine at Mount Sinai
Principal Investigator: David H Smith, MD Bay Hematology Oncology
Principal Investigator: Kevin Staveley-O'Carroll, MD University Missouri
Principal Investigator: Frederick P Smith, MD Chevy Chase, RCCA
PRS Account Oncovir, Inc.
Verification Date September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP