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About
This is a single institution, Phase 1 study for patients with Stage III/IV unresectable Kirsten rat sarcoma (KRAS) mutated NSCLC to evaluate safety of the pooled mutant-KRAS peptide vaccine (KRAS peptide vaccine) with polyinosinic-polycytidylic acid (poly-ICLC) adjuvant in combination with nivolumab and ipilimumab in the first line treatment setting. The primary objectives of this study are to determine the safety and feasibility of administering the KRAS peptide vaccine with poly-ICLC adjuvant in combination with nivolumab and ipilimumab. The secondary objectives are to estimate the progression free survival (PFS) of pooled mutant-KRAS long peptide vaccine with poly-ICLC adjuvant in combination with Ipilimumab + Nivolumab for the first line treatment of patients with unresectable Stage III/IV NSCLC whose tumors harbor selected KRAS mutations (KRAS glycine-to-cysteine substitution at codon 12 (G12C), KRAS glycine-to-valine substitution at codon 12 (G12V), KRAS glycine-to-Detoxglyphosate substitution at codon 12 (G12D), KRAS glycine-to-arginine substitution at codon 12 (G12A), KRAS glycine-to-Aspartic Acid "D" at codon 13 (G13D) or KRAS G12R) and to assess the impact of predicted KRAS mutations on mutant-KRAS specific T cell responses in the peripheral blood of these patients. Exploratory objectives will assess the impact of predicted KRAS mutations on mutant-KRAS specific T cell responses in the peripheral blood, as well as changes in circulating tumor deoxyribonucleic acid (ctDNA). Approximately 15 subjects will be enrolled to have 12 evaluable subjects for T cell response assessment. Safety analysis will include all enrolled patients who receive at least one dose of vaccine. The evaluable population for T cell response will consist of all patients who receive at least one dose of vaccine and have baseline and post-treatment T cell measures in the peripheral blood at 12 weeks.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Histologically- or cytologically-proven adenocarcinoma of the lung deemed to be locally advanced/unresectable or metastatic as per American Joint Committee on Cancer (AJCC) version 8, who has not received prior therapy for this stage of disease.
• Prior therapy for early stage NSCLC allowed. Progressive disease after at least 6 months of anti-programmed death (PD) ligand therapy (anti-PD-L1 therapy) (i.e. Durvalumab) for Stage III disease is allowed.
Must have tumor lesions amenable to repeated biopsy, and patient's acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the Principal Investigator).
Measurable disease as defined by RECIST v1.1.
Have one of the six KRAS mutations (KRAS G12C, KRAS G12V, KRAS G12D, KRAS G12A, KRAS G13D or KRAS G12R) in vaccine expressed in tumor as defined by a Clinical Laboratory Improvement Amendments (CLIA) certified tumor or plasma based genomic testing platform performed either through a local laboratory or through the investigators' central laboratory.
Age ≥18 years.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix A).
Patients must have adequate organ and marrow function as defined below:
Microliters (mcL) Microliter (uL)
Female CrCl = (140 - age in years) x weight in kg x 0.85 / 72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine in mg/dL
Exclusion criteria
Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study.
Any of the following procedures or medications:
Within 2 weeks prior to initiation of study treatment:
Within 4 weeks prior to initiation of study treatment:
Patients with a history of prior treatment with immunotherapy agents (including, but not limited to: Interleukin 2 (IL-2), interferon, anti-PD-L2, anti-cluster of differentiation 137 (anti-CD137), anti-oxidation (OX) 40 (anti-OX-40), anti-cluster of differentiation 40 (anti-CD40), anti-cytotoxic T-lymphocyte-associated (CTLA) antigen 4 (anti-CTLA-4), or anti-lymphocyte activating gene (LAG) 3 (anti-LAG-3) antibodies).
History of severe hypersensitivity reaction to any monoclonal antibodies or related compounds or to any of these agents' components (e.g., history of severe hypersensitivity reactions to drugs formulated with polysorbate 80).
Untreated or symptomatic brain metastases.
Has an active known or suspected autoimmune disease or which has required systemic therapy in the last 2 years. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
Known history of interstitial lung disease or of (non-infectious) pneumonitis that required steroids or current pneumonitis.
Has a pulse oximetry < 90% on room air.
Requires the use of home oxygen.
Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies), hepatitis B, or hepatitis C infection.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness that would limit compliance with study requirements.
Patients who have been diagnosed with another cancer or myeloproliferative disorder in the past 5 years except for superficial bladder cancer, non-melanoma skin cancers, or a low grade prostate cancer not requiring therapy.
Has a diagnosis of immunodeficiency.
Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded.
Any other sound medical or psychiatric reason as determined by the Investigator.
Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements.
Patient is unwilling or unable to follow the study schedule for any reason.
Patient is pregnant or breastfeeding.
Primary purpose
Allocation
Interventional model
Masking
12 participants in 1 patient group
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Central trial contact
Peggy Fitzpatrick, RN; Kristen Marrone, MD
Data sourced from clinicaltrials.gov
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