Clinical Trials /

Trial of a Personalized and Adaptive Neoantigen Dose-Adjusted Vaccine Concurrently With Pembrolizumab

NCT04266730

Description:

This is a single center, open-label phase I clinical trial designed to determine the safety of personalized and adjusted neoantigen peptide vaccine (PANDA-VAC) administered concurrently with pembrolizumab in subjects with advanced squamous non-small cell lung cancer (NSCLC) or squamous cell carcinoma of head and neck (SCCHN).

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Trial of a Personalized and Adaptive Neoantigen Dose-Adjusted Vaccine Concurrently With Pembrolizumab
  • Official Title: Phase I Trial of a Personalized and Adaptive Neoantigen Dose-Adjusted Vaccine Administered Concurrently With Pembrolizumab

Clinical Trial IDs

  • ORG STUDY ID: LCCC1804
  • NCT ID: NCT04266730

Conditions

  • Squamous Cell Lung Cancer
  • Squamous Non-small Cell Lung Cancer
  • Squamous Cell Carcinoma of Head and Neck

Interventions

DrugSynonymsArms
PANDA-VACPANDA-VAC

Purpose

This is a single center, open-label phase I clinical trial designed to determine the safety of personalized and adjusted neoantigen peptide vaccine (PANDA-VAC) administered concurrently with pembrolizumab in subjects with advanced squamous non-small cell lung cancer (NSCLC) or squamous cell carcinoma of head and neck (SCCHN).

Detailed Description

      Subjects will be offered clinical trial participation if per RECIST 1.1 they are determined
      to have stable disease, mixed response, oligoprogressive state (defined as disease
      progression at a limited number of anatomic sites, with continued response or stable disease
      at other sites) or non-threatening progressive disease (defined as progression that fits a
      clinical pattern where the treating physician believes that PD-1 therapy post-progression is
      appropriate (e.g. multiple sub-centimeter nodules that do not compromise the bronchus)) to an
      anti-PD-1 or anti-PD-L1 therapy. Eligible subjects will initiate or continue pembrolizumab
      monotherapy and will have archival tissue and a buccal swab sample (matched normal sample
      genomic DNA) collected. Whole exome and single cell sequencing studies will be performed
      using the archival tumor and matched normal sample to identify tumor specific mutations and
      predict personalized human leukocyte antigen (HLA) binding proteins. Based on this
      information, 6 neoantigens will be selected for inclusion in the primary personalized
      vaccine. The primary therapeutic neoantigen vaccine product (PANDA-VAC) will be comprised of
      6 peptides at a dose of 300 micrograms (µg) per peptide admixed with local adjuvant
      Poly-ICLC. PANDA-VAC will be administered subcutaneously to six subjects after their first
      protocol-mandated disease assessment on pembrolizumab monotherapy. The subjects will receive
      five priming doses and two booster vaccinations of PANDA-VAC in combination with continued
      pembrolizumab treatment. Enrollment of the first 3 subjects to receive PANDA-VAC will be
      staggered by 4 weeks to monitor for acute and subacute adverse events. Subjects with partial
      response, stable disease, mixed response, oligoprogressive state or non-threatening
      progressive disease (in the opinion of the treating physician) following the full series of
      vaccinations may receive adapted vaccine adjusted to address neoantigens emerging during
      initial PANDA-VAC and pembrolizumab combination therapy. Subjects will have tissue collected
      for DNA and RNA sequencing and prediction of HLA binding proteins, as delineated above for
      the initial vaccine production. The therapeutic neoantigen vaccine product will be comprised
      of up to 2 additional peptides at a dose of 300 μg per peptide (up to 8 total peptides).
      Peptides targeting neoantigens no longer represented in sequencing data may no longer be
      included in the neoantigen vaccine product. The primary endpoint of this trial aims to
      evaluate the safety of the vaccination administered concurrently with pembrolizumab therapy,
      by estimating the unacceptable toxicity rate.

      As generation of either the primary therapeutic or adapted neoantigen vaccine requires: (1)
      whole exome sequencing studies of the tumor and a matched normal sample from a buccal swab
      pre-treatment; (2) RNA sequencing of the tumor pre-treatment; and (3) whole exome sequencing
      of circulating cell-free DNA and DNA derived from circulating tumor cells, information gained
      from these analyses will also provide extensive exploratory data. With this data, we will
      study relationships of mutational and genes expression profiles with depth of response to
      therapy. The purpose of these studies is to generate initial data that will allow us to
      estimate effect size and variance of the change in immune features with therapeutic
      neoantigen vaccine treatment in order to design prospective correlative studies in future
      trials.
    

Trial Arms

NameTypeDescriptionInterventions
PANDA-VACExperimentalThe final primary therapeutic neoantigen vaccine product will comprise 6 peptides at a dose of 300 μg per peptide and Poly-ICLC at a dose of 500 μg formulated in an aqueous solution containing <5% DMSO in isotonic dextrose for a total volume of 750 μL. The vaccine will be administered subcutaneously via 3 equal volume (250 μL) injections, one in an arm and one in each leg. The product will be administered on the following schedule: Days 1 and 4 of Week 1, Day 1 of Week 2, Day 1 of Week 3, Day 1 of Week 4, Day 1 of Week 11, and Day 1 of Week 21.
  • PANDA-VAC

Eligibility Criteria

        Inclusion Criteria for Vaccine Generation:

          1. Subject must sign an institutional review board (IRB) approved informed consent to
             undergo tissue procurement and HIPAA authorization for release of personal health
             information.

          2. Subject must have a previously treated, histologically confirmed squamous non-small
             cell lung cancer and head and neck squamous cell carcinoma where cure is either not
             possible or curative modality therapy is declined by the subject.

          3. Subject has adequate archival tumor tissue for sequencing for vaccine generation.

          4. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.

          5. Subject has adequate bone marrow function as demonstrated by:

               -  Absolute neutrophil count (ANC) ≥1.5 x 10^9/L

               -  Absolute lymphocyte count (ALC) ≥1.0 x 10^9/L

               -  Hemoglobin >8 g/dL (use of transfusion to reach this threshold prior to study
                  initiation is acceptable)

               -  Platelet count ≥100 x 10^9/L

          6. Subject has radiographically measurable according to RECIST 1.1 and iRECIST.

          7. Subjects must per RECIST 1.1 have stable disease, mixed response, oligoprogressive
             state (defined as disease progression at a limited number of anatomic sites, with
             continued response or stable disease at other sites of disease) or non-threatening
             progression (progression that fits a clinical pattern where the treating physician
             believes that PD-1 therapy post-progression is appropriate (e.g. multiple
             sub-centimeter nodules that do not compromise the bronchus)) on a PD-1, PDL-1 or
             PD-1/L containing regimen.

          8. Subject must meet the following criteria:

             For squamous non-small cell lung cancer (NSCLC):

               -  Tumor expressing PD-L1 (Tumor Proportion Score/TPS ≥1%) as determined by an
                  FDA-approved test, with no EGFR or ALK genomic tumor aberrations

               -  Subjects with EGFR or ALK genomic tumor aberrations should have disease
                  progression on FDA-approved therapy for these aberrations.

             Squamous cell carcinoma of head and neck (SCCHN):

               -  As 1st line treatment for tumors expressing PD-L1 [Combined Positive Score (CPS)
                  ≥1] as determined by an FDA-approved test

               -  As non-1st line treatment for recurrent or metastatic HNSCC with disease
                  progression on or after platinum containing chemotherapy

          9. Age ≥18 years.

         10. Female subject of childbearing potential must agree to use adequate contraception
             during the study. Adequate contraception is defined by the concomitant use of at least
             2 effective methods of contraception from the time of informed consent until 90 days
             after pembrolizumab or PANDA-VAC discontinuation, whichever is longer. The two
             contraception methods can be comprised of two barrier methods, or a barrier method
             plus a hormonal method or an intrauterine device that meets <1% failure rate for
             protection from pregnancy in the product label. Females of non-childbearing potential
             are those who are postmenopausal greater than 1 year or who have had a bilateral tubal
             ligation or hysterectomy or bilateral oophorectomy. Female subjects must refrain from
             egg cell donation while on pembrolizumab or PANDA-VAC and for at least 90 days after
             the last dose of investigational product, based on whichever product was last given.

         11. Male subjects with female partners must have had a prior vasectomy or agree to use an
             adequate method of contraception (i.e., double barrier method: condom plus spermicidal
             agent) starting with the first dose of pembrolizumab through 90 days after the last
             dose of pembrolizumab or PANDA-VAC, whichever is longer. Male subjects should agree to
             refrain from sperm donation while taking pembrolizumab and/or PANDA-VAC and for at
             least 90 days after the last dose of pembrolizumab or PANDA-VAC, whichever is longer.
             Should a female partner of a male subject become pregnant or suspect she is pregnant
             while participating in the study, he should inform his treating physician and the
             female partner should call her physician immediately.

         12. Subject is willing and able to comply with the protocol including undergoing treatment
             and scheduled visits and examinations.

         13. Subject is willing to consent to study-required blood draws and consent for the use of
             any residual material from biopsy or prior resections for vaccine generation and
             correlative studies.

         14. Subject is willing to consent to a mandatory biopsy that is required for adapted
             vaccine generation and correlative studies if the subject has partial response, stable
             disease, mixed response, or oligoprogressive state following the full series of five
             priming and two booster vaccinations.

         15. Subject must have recovered from all reversible acute toxic effects of the previous
             cancer treatment regimen (other than alopecia) to Grade ≤ 1 or baseline.

        Exclusion Criteria for Vaccine Generation:

          1. Subject is currently participating in or has participated in a study of an
             investigational agent within 4 weeks of study pembrolizumab treatment initiation.

          2. Subject has active infection requiring systemic therapy.

          3. Subject is pregnant or breastfeeding (Note: breast milk cannot be stored for future
             use while the mother is being treated on the study).

          4. Subject has a known additional malignancy that is active and/or progressive requiring
             treatment; exceptions include basal cell or squamous cell skin cancer, in situ
             cervical cancer, or other cancer for which the subject has been disease-free for at
             least five years.

          5. Subject has active central nervous system (CNS) metastases. Treated metastases without
             evidence of progression will be allowed. Asymptomatic, subcentimeter metastases not
             requiring treatment will be allowed. Any leptomeningeal disease will be excluded.

          6. Subject is currently using systemic corticosteroids at doses ≥10mg prednisone daily or
             its equivalent, or other immunosuppressive medications including, but not limited to
             methotrexate, azathioprine, calcineurin inhibitor, and TNF-α blockers.

          7. Subject has known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or
             evidence of active hepatitis B virus (HBV).

          8. Subject has a history of primary immunodeficiency.

          9. Subject has a history of organ transplant, bone marrow transplant or hematopoietic
             stem cell transplantation.

         10. Subject has active autoimmune disease that has required systemic treatment in the past
             2 years (i.e. with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
             physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
             etc.) is not considered a form of systemic treatment.

         11. Subject has received a live attenuated vaccines within 30 days of on study
             pembrolizumab dosing. Inactivated vaccines, such as the injectable influenza vaccine,
             are permitted.

         12. Subject has any condition that, in the opinion of the investigator, would interfere
             with evaluation of study treatment or interpretation of subject safety or study
             results.

         13. Subject is not a good candidate for treatment with pembrolizumab and PANDA-VAC per
             investigator's discretion.

        Eligibility Criteria for Vaccination:

          1. Subject must sign written informed consent to enroll in the PANDA-VAC therapy trial.

          2. Subject must have completed at least two cycles of standard of care therapy with
             pembrolizumab.

          3. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

          4. Subject has radiographically measurable disease according to RECIST 1.1 and iRECIST.

          5. Subjects must per RECIST 1.1 have stable disease, mixed response, oligoprogressive
             state (defined as disease progression at a limited number of anatomic sites, with
             continued response or stable disease at other sites of disease) or progressive
             disease.

          6. Subject has adequate bone marrow function as demonstrated by:

               -  Absolute neutrophil count (ANC) ≥1.5 x 10^9/L

               -  Absolute lymphocyte count (ALC) ≥0.5 x 10^9/L

               -  Hemoglobin >8 g/dL (use of transfusion to reach this threshold prior to study
                  initiation is acceptable)

               -  Platelet count ≥50 x 10^9/L

          7. Subject has adequate hepatic and renal function as demonstrated by:

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper
                  limit of normal (ULN) (unless liver metastases are present, in which case they
                  must be ≤ 5 x ULN);

               -  Total serum bilirubin ≤1.5 mg/dL (subjects with Gilbert's syndrome may be
                  enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin
                  is <1.5 × ULN));

               -  Creatinine clearance (CrCl) >40mL/min as measured according to Cockcroft-Gault
                  equation.

          8. Subject has negative serum βhCG pregnancy test within 72 hours of day 1 of initial
             administration of vaccine in women of childbearing potential.

          9. Subject does not have active infection requiring systemic therapy (In the case of such
             infection, it is acceptable to delay vaccine administration. The use of additional
             interim pembrolizumab prior to vaccine administration will be at the discretion of the
             treating physician).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of personalized and dose adjusted antitumor peptide vaccine (PANDA-VAC) administered concomitantly with nivolumab in subjects with advanced squamous non-small cell lung cancer, and head and neck squamous cell carcinoma
Time Frame:8 weeks
Safety Issue:
Description:Safety will be assessed by events occurring after initial treatment. Toxicity will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • lung cancer
  • head and neck cancer
  • neoantigen
  • vaccine
  • pembrolizumab

Last Updated

February 10, 2020