CIMAvax Vaccine, Nivolumab, and Pembrolizumab in Treating Patients With Advanced Non-small Cell Lung Cancer or Squamous Head and Neck Cancer
CIMAvax Vaccine, Nivolumab, and Pembrolizumab in Treating Patients With Advanced Non-small Cell Lung Cancer or Squamous Head and Neck Cancer
This phase I/II trial studies the best dose and side effects of recombinant human
 EGF-rP64K/montanide ISA 51 vaccine (CIMAvax) and nivolumab and to see how well they work in
 treating patients with non-small cell lung cancer or squamous head and neck cancer that has
 spread to other places in the body. Vaccine therapy, such as CIMAvax vaccine may help slow
 down and stop tumor growth. Immunotherapy with monoclonal antibodies, such as nivolumab and
 pembrolizumab, may help the body's immune system attack the cancer, and may interfere with
 the ability of tumor cells to grow and spread. Giving CIMAvax vaccine together with nivolumab
 or pembrolizumab may work better in treating patients with non-small cell lung cancer or
 squamous head and neck cancer.
PRIMARY OBJECTIVES:

 I. To identify the maximum dose of CIMAvax in combination with nivolumab based on dose
 limiting toxicities (DLTs) as assessed by Common Terminology Criteria for Adverse Events
 version 4.03 (CTCAE version [v] 4.03). (Phase I) II. To evaluate the 12-month overall
 survival of CIMAvax combined with nivolumab in patients with advanced non-small cell lung
 cancer (NSCLC). (Phase II-Study A) III. To evaluate the 6-month progression free survival
 (PFS) of CIMAvax combined with nivolumab in patients with advanced recurrent squamous cell
 carcinoma of the head and neck. (Phase II-Study B) IV. To evaluate the objective response
 rate of pembrolizumab in combination with CIMAvax as first-line therapy in patients with
 advanced NSCLC (PD-L1 expression >= 50%). (Phase II-Study C)

 SECONDARY OBJECTIVES I. To assess the toxicity of CIMAvax combined with nivolumab using the
 Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common Terminology
 Criteria for Adverse Events (CTCAE version 4.03). (Phase I) II. Determine the preliminary
 efficacy of the combination of anti-PD1 therapy with CIMAvax. (Phase I) III. To evaluate
 progression free survival (PFS) for the combination of CIMAvax and nivolumab in patients with
 advanced NSCLC. (Phase II-Study A) IV. To evaluate the 12-month overall survival of patients
 with advanced recurrent squamous cell carcinoma of the head and neck who received nivolumab
 in combination with CIMAvax. (Phase II-Study B) V. To evaluate the PFS and 12-month overall
 survival of CIMAvax in combination with pembrolizumab as first-line therapy in patients with
 advanced NSCLC (PD-L1 expression >= 50%). (Phase II-Study C) VI. To assess the toxicity of
 CIMAvax combined with nivolumab using the CTEP NCI Common Terminology Criteria for Adverse
 Events (CTCAE version 4.03). (Phase II)

 TERTIARY OBJECTIVES:

 I. To conduct correlative studies comparing blood EGF levels, platelet levels, markers of
 immune response and functionality of antibody response. (Phase I) II. To examine the
 association of EGFR (total and activated), PD-1 and PD-L1 expression and mutations in tumor
 tissue with biomarkers of genetic and immune response. (Phase I and II) III. Comparison of
 response assessment criteria for a prospective analysis (immune-related [ir] Response
 Evaluation Criteria in Solid Tumors [RECIST] response assessment versus [vs.] immune-related
 Response Criteria [irRC] vs. RECIST 1.1). (Phase I and II) IV. To characterize the blood EGF
 levels and other blood-based biomarkers of patients censored from the trial because of low
 titer response. (Phase II)

 OUTLINE: This is a phase I dose escalation study of CIMAvax followed by a phase II study.

 LOADING PHASE I: Patients receive CIMAvax intramuscularly (IM) and nivolumab intravenously
 (IV) over 60 minutes on day 1. Treatment repeats every 2 weeks for up to 4 doses in the
 absence of disease progression or unacceptable toxicity. Within 4 weeks after the 4th dose,
 patients receive CIMAvax IM at the same time as the next nivolumab dose.

 MAINTENANCE PHASE I: Patients who do not experience a DLT receive CIMAvax every 4 weeks and
 nivolumab every 2 weeks.

 PHASE II STUDY A and B: Patients receive CIMAvax IM and nivolumab IV over 60 minutes.
 Treatment with CIMAvax repeats every 2 weeks for 4 doses during the loading phase and every 4
 weeks during the maintenance phase in the absence of disease progression or unacceptable
 toxicity. Courses for nivolumab repeat every 2 weeks in the absence of disease progression or
 unacceptable toxicity. Patients in Study A with antibody titer >= 1:4000 at the end of the
 loading phase may receive CIMAvax IM every 8 or 12 weeks during the maintenance phase.

 PHASE II STUDY C: Patients with PD-L1expression >= 50% receive CIMAvax IM and pembrolizumab
 IV over 30 minutes. Treatment with CIMAvax repeats every 2 weeks for 4 doses during the
 loading phase and every 4 weeks during the maintenance phase in the absence of disease
 progression or unacceptable toxicity. Courses for pembrolizumab repeat every 2 weeks for 2
 years in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 30 days for 120 days.
Inclusion Criteria:

 -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 1 at the
 time of study treatment initiation

 -  Have pathologically confirmed diagnosis of NSCLC (Phase I, Phase II Studies A, C and
 Expansion Cohort AE) or squamous cell head and neck cancer (Phase II Study B)

 -  Must be eligible for treatment with nivolumab as standard of care (for nivolumab
 treatment groups only)

 -  Phase II Study A and Expansion Cohort AE: Patients with advanced (metastatic) NSCLC,
 whose disease progressed during or after platinum based therapy

 -  Phase II Study B: Patients with advanced recurrent head and neck squamous cell
 carcinoma

 -  Phase II Study C: Patients with unresectable NSCLC with PD-L1 expression >= 50% for
 first line therapy in advanced stage. In the rare event that there is a discrepancy in
 the results of PD-L1 testing (i.e. 2 or more specimens were tested, etc.), eligibility
 status will be per the discretion of the principal investigator (PI) after review of
 other available biomarker testing

 -  NSCLC patients in study A and expansion cohort AE with EGFR or ALK genomic tumor
 aberrations (determined through either tissue- or liquid biopsy-based platform) should
 have disease progression on Food and Drug administration (FDA)-approved therapy for
 these aberrations prior to receiving nivolumabanti-PD1 therapy; patients with smoking
 history being considered for Study C may enroll and be treated pending results of
 molecular testing

 -  Have at least 6 month life expectancy

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

 -  Platelets >= 100 x 10^9/L

 -  Hemoglobin >= 9 g/dL

 -  Serum creatinine =< 1.5 x institution upper limit of normal (ULN) or estimated
 glomerular filtration rate (GFR) (measured or calculated with Cockcroft and Gault
 formula) > 45 ml/min

 -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (ALT
 and AST =< 5 x ULN is acceptable if liver metastases are present)

 -  Total serum bilirubin =< 1.5 x ULN; for patients with well documented Gilbert's
 syndrome, total bilirubin =< 3 x ULN with direct bilirubin within normal range

 -  Troponin-I =< ULN and B-type natriuretic peptide (BNP) < 200 pg/ml

 -  Left ventricular ejection fraction (LVEF) >= lower limit of normal (LLN)
 (institutional limit)

 -  Patients enrolled onto Phase I dose escalation or Expansion Cohort (AE) must have
 presence of evaluable disease; patients enrolled onto Phase II studies A, B, or C must
 have measurable disease as defined in RECIST 1.1

 -  Participants of child-bearing potential must agree to use adequate contraceptive
 methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study
 entry; should a woman become pregnant or suspect she is pregnant while she or her
 partner is participating in this study, she should inform her treating physician
 immediately

 -  Participant or legal representative must understand the investigational nature of this
 study and sign an Independent Ethics Committee/Institutional Review Board approved
 written informed consent form prior to receiving any study related procedure

 -  Phase II studies: Participant agrees to provide tumor biopsy tissue before treatment,
 blood samples at the start of treatment and at multiple times during the study and, a
 tumor biopsy at the end of the trial or after disease progression; archival
 formalin-fixed paraffin-embedded (FFPE) tissue is permitted for Expansion Cohort AE;
 archival FFPE tissue is also permitted for Study C patients provided that tissue is
 adequate and no systemic anti-cancer therapy had been administered between the time
 specimen was obtained and start of protocol therapy

 Exclusion Criteria:

 -  Receipt of anticancer chemotherapy within 4 weeks before the first administration of
 study drug

 -  Previous anti-PD1 or PD-L1 immunotherapy is not allowed; treatment with other
 investigational agents within 6 half-lives of first administration of study drug is
 not allowed

 -  Prior radiotherapy or gamma knife within 2 weeks of study treatment for non-brain
 metastasis; subjects must have recovered from all radiation related toxicities

 -  Active/untreated brain metastasis; whole brain radiation or gamma knife radiosurgery
 performed less than 4 weeks prior to first administration of study drug; previously
 treated brain metastasis allowed as long as not requiring steroids and stable on
 imaging at least 4 weeks after completing radiation therapy

 -  Leptomeningeal involvement regardless of treatment status

 -  Tumor with mutation that is known to be sensitive to FDA approved targeted therapy but
 has not yet received such targeted therapy

 -  History of autoimmune disorder, with exception of patients with vitiligo or
 endocrine-related autoimmune conditions receiving appropriate hormonal supplementation
 who are eligible; systemic use of immunosuppressant drugs such as steroids (except as
 hormone replacement therapy or short-course supportive medication such as chemotherapy
 or drug allergy, etc.), azathioprine, tacrolimus, cyclosporine, etc. within 4 weeks
 before recruitment

 -  Currently receiving or has received systemic corticosteroids within 4 weeks prior to
 starting study drug for management of brain metastases, or who have not fully
 recovered from side effects of such treatment; steroids for endocrine replacement or
 receipt of short-course of steroids during the preceding 4 week period as supportive
 medication such as for drug allergy, anti-emetic, etc. is allowed

 -  Had major surgery within 14 days prior to starting study drug or has not recovered
 from major side effects (tumor biopsy is not considered major surgery) resulting from
 a prior surgery

 -  Has known immunosuppressive disease (e.g. human immunodeficiency virus [HIV], acquired
 immune deficiency syndrome [AIDS] or other immune depressing disease); testing is not
 mandatory

 -  Active, clinically serious infections or other serious uncontrolled medical conditions

 -  Patient has known hypersensitivity to the components of the study drugs or any analogs

 -  History or current evidence of any condition, therapy, or laboratory abnormality that
 might confound the results of the study, interfere with the patient?s participation
 for the full duration of the study, or is not in the best interest of the patient to
 participate, in the opinion of the treating investigator, including, but not limited
 to:

 -  Myocardial infarction or arterial thromboembolic events within 6 months prior to
 baseline or severe or unstable angina, New York Heart Association (NYHA) class
 III or IV disease

 -  History of documented congestive heart failure (New York Heart Association
 functional classification III or IV) within 6 months prior to baseline

 -  Uncontrolled hypertension (systolic blood pressure [SBP] > 160/diastolic blood
 pressure [DBP] > 100 despite medical intervention)

 -  History of myocarditis of any etiology

 -  History of ventricular arrhythmias

 -  Phase II only: Patients diagnosed with an invasive cancer within 2 years prior to
 starting protocol therapy with the following exceptions: non-melanoma skin cancers,
 in-situ cancers, and prostate cancer gleason =< to 6 (under surveillance or treated),
 early stage node-negative estrogen receptor (ER)+/progesterone receptor (PR)+ breast
 cancer with Oncotype Dx score < 25 not taking adjuvant hormonal therapy

 -  Pregnant or nursing female participants

 -  Any condition which in the investigator?s opinion deems the participant an unsuitable
 candidate to receive study drug

 -  Unwilling or unable to follow protocol requirements