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

Studies

Study First Submitted Date 2020-02-10
Study First Posted Date 2020-02-12
Last Update Posted Date 2023-06-18
Start Month Year April 22, 2024
Primary Completion Month Year June 1, 2024
Verification Month Year June 2023
Verification Date 2023-06-30
Last Update Posted Date 2023-06-18

Detailed Descriptions

Sequence: 20845058
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.

Facilities

Sequence: 201223085
Name Lineberger Comprehensive Cancer Center at University of North Carolina – Chapel Hill
City Chapel Hill
State North Carolina
Zip 27599
Country United States

Browse Interventions

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Mesh Term Pembrolizumab Mesh Term Antineoplastic Agents, Immunological Mesh Term Antineoplastic Agents Mesh Term Immune Checkpoint Inhibitors Mesh Term Molecular Mechanisms of Pharmacological Action
Downcase Mesh Term pembrolizumab Downcase Mesh Term antineoplastic agents, immunological Downcase Mesh Term antineoplastic agents Downcase Mesh Term immune checkpoint inhibitors Downcase Mesh Term molecular mechanisms of pharmacological action
Mesh Type mesh-list Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor

Conditions

Sequence: 52488001 Sequence: 52488002 Sequence: 52488003
Name Squamous Cell Lung Cancer Name Squamous Non-small Cell Lung Cancer Name Squamous Cell Carcinoma of Head and Neck
Downcase Name squamous cell lung cancer Downcase Name squamous non-small cell lung cancer Downcase Name squamous cell carcinoma of head and neck

Id Information

Sequence: 40385036
Id Source org_study_id
Id Value LCCC1804

Countries

Sequence: 42820728
Name United States
Removed False

Design Groups

Sequence: 55944164
Group Type Experimental
Title PANDA-VAC combined with pembrolizumab
Description The 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.

Interventions

Sequence: 52796856 Sequence: 52796857
Intervention Type Biological Intervention Type Drug
Name PANDA-VAC Name Pembrolizumab
Description The primary therapeutic neoantigen vaccine product, Personalized and Adaptive Neoantigen Dose-Adjusted Vaccine (PANDA-VAC), will be comprised of 6 peptides at a dose of 300 micrograms (µg) per peptide admixed with local adjuvant Stabilized polyriboinosinic/polyribocytidylic acid (Poly-ICLC). Description Pembrolizumab will be administered at 200 mg IV dose every three weeks. The subject may transition to 400 mg every six weeks if, after the first scan done after start of treatment, they have a partial response or better or after two scans with stable disease or better.

Keywords

Sequence: 80298063 Sequence: 80298064 Sequence: 80298065 Sequence: 80298066 Sequence: 80298067
Name lung cancer Name head and neck cancer Name neoantigen Name vaccine Name pembrolizumab
Downcase Name lung cancer Downcase Name head and neck cancer Downcase Name neoantigen Downcase Name vaccine Downcase Name pembrolizumab

Design Outcomes

Sequence: 178566196 Sequence: 178566197 Sequence: 178566198 Sequence: 178566199
Outcome Type primary Outcome Type secondary Outcome Type secondary Outcome Type secondary
Measure Number of adverse events in participants as a measure of safety of personalized and dose adjusted antitumor peptide vaccine (PANDA-VAC) administered concomitantly with pembrolizumab. Measure Response rate in subjects with advanced squamous non-small cell lung cancer, and head and neck squamous cell carcinoma treated with PANDA-VAC and pembrolizumab Measure Overall survival of subjects with advanced squamous non-small cell lung cancer, and head and neck squamous cell carcinoma treated with PANDA-VAC and pembrolizumab Measure Progression-free survival of subjects with advanced squamous non-small cell lung cancer, and head and neck squamous cell carcinoma treated with PANDA-VAC and pembrolizumab
Time Frame 8 weeks Time Frame 2 years Time Frame 10 years Time Frame 10 years
Description Safety will be assessed by events occurring after initial treatment for subjects with advanced squamous non-small cell lung cancer, and head and neck squamous cell carcinoma. Toxicity will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Description Response rate will be measured by RECIST 1.1 and iRECIST. Complete response rate (CRR) will also be reported. In the case of treatments beyond progression, the Response Rate 2 (RR2) will be reported. Description Overall survival will be calculated starting from day 1 of PANDA-VAC and pembrolizumab therapy until death from any cause Description Progression-free survival (PFS) is defined as the time from day 1 of PANDA-VAC and pembrolizumab until evidence of disease progression per iRECIST (see Appendix C). In the case of treatment beyond progression, PFS1 and PFS2 (defined as the time from progression until next progression) will be reported.

Browse Conditions

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Mesh Term Lung Neoplasms Mesh Term Squamous Cell Carcinoma of Head and Neck Mesh Term Respiratory Tract Neoplasms Mesh Term Thoracic Neoplasms Mesh Term Neoplasms by Site Mesh Term Neoplasms Mesh Term Lung Diseases Mesh Term Respiratory Tract Diseases Mesh Term Carcinoma, Squamous Cell Mesh Term Carcinoma Mesh Term Neoplasms, Glandular and Epithelial Mesh Term Neoplasms by Histologic Type Mesh Term Head and Neck Neoplasms
Downcase Mesh Term lung neoplasms Downcase Mesh Term squamous cell carcinoma of head and neck Downcase Mesh Term respiratory tract neoplasms Downcase Mesh Term thoracic neoplasms Downcase Mesh Term neoplasms by site Downcase Mesh Term neoplasms Downcase Mesh Term lung diseases Downcase Mesh Term respiratory tract diseases Downcase Mesh Term carcinoma, squamous cell Downcase Mesh Term carcinoma Downcase Mesh Term neoplasms, glandular and epithelial Downcase Mesh Term neoplasms by histologic type Downcase Mesh Term head and neck neoplasms
Mesh Type mesh-list Mesh Type mesh-list Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor Mesh Type mesh-ancestor

Sponsors

Sequence: 48613316
Agency Class OTHER
Lead Or Collaborator lead
Name UNC Lineberger Comprehensive Cancer Center

Overall Officials

Sequence: 29450949
Role Principal Investigator
Name Jared Weiss, MD
Affiliation UNC Chapel Hill

Central Contacts

Sequence: 12090681 Sequence: 12090682
Contact Type primary Contact Type backup
Name Catherine Cheng Name Caroline Babinec
Phone 919-445-4208 Phone 919-962-7426
Email catherine_cheng@med.unc.edu Email caroline_babinec@med.unc.edu
Role Contact Role Contact

Design Group Interventions

Sequence: 68581778 Sequence: 68581779
Design Group Id 55944164 Design Group Id 55944164
Intervention Id 52796856 Intervention Id 52796857

Eligibilities

Sequence: 30946686
Gender All
Minimum Age 18 Years
Maximum Age N/A
Healthy Volunteers No
Criteria Inclusion Criteria for Vaccine Generation: Subject must sign an institutional review board (IRB) approved informed consent to undergo tissue procurement and HIPAA authorization for release of personal health information. 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. Subject has adequate archival tumor tissue for sequencing for vaccine generation. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1. 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 Subject has radiographically measurable according to RECIST 1.1 and iRECIST. 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. 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 Age ≥18 years. 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. 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. Subject is willing and able to comply with the protocol including undergoing treatment and scheduled visits and examinations. 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. 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. 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: Subject is currently participating in or has participated in a study of an investigational agent within 4 weeks of study pembrolizumab treatment initiation. Subject has active infection requiring systemic therapy. Subject is pregnant or breastfeeding (Note: breast milk cannot be stored for future use while the mother is being treated on the study). 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. 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. 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. Subject has known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or evidence of active hepatitis B virus (HBV). Subject has a history of primary immunodeficiency. Subject has a history of organ transplant, bone marrow transplant or hematopoietic stem cell transplantation. 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. 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. 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. Subject is not a good candidate for treatment with pembrolizumab and PANDA-VAC per investigator’s discretion. Eligibility Criteria for Vaccination: Subject must sign written informed consent to enroll in the PANDA-VAC therapy trial. Subject must have completed at least two cycles of standard of care therapy with pembrolizumab. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Subject has radiographically measurable disease according to RECIST 1.1 and iRECIST. 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. 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 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. Subject has negative serum βhCG pregnancy test within 72 hours of day 1 of initial administration of vaccine in women of childbearing potential. 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).
Adult True
Child False
Older Adult True

Calculated Values

Sequence: 254313764
Number Of Facilities 1
Registered In Calendar Year 2020
Were Results Reported False
Has Us Facility True
Has Single Facility True
Minimum Age Num 18
Minimum Age Unit Years
Number Of Primary Outcomes To Measure 1
Number Of Secondary Outcomes To Measure 3

Designs

Sequence: 30692283
Allocation N/A
Intervention Model Single Group Assignment
Observational Model
Primary Purpose Treatment
Time Perspective
Masking None (Open Label)

Intervention Other Names

Sequence: 26829205
Intervention Id 52796856
Name Personalized and adaptive neoantigen dose-adjusted vaccine

Links

Sequence: 4412086
Url https://unclineberger.org/
Description Related Info

Responsible Parties

Sequence: 29059033
Responsible Party Type Sponsor