Overview

This is a descriptive, proof of concept, open-label, randomized, 3-arm, window of opportunity trial to evaluate the immunomodulatory role of pharmacological ascorbate with Durvalumab

Eligibility

Inclusion Criteria:

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Age > 18 years at time of study entry regardless of gender or ethnic/racial background.
• Histologically or cytologically confirmed non-small cell lung cancer
• Clinical stage I with tumor size >1 cm to 4 cm (either T1b or T1c or T2a and N0 M0) according to American Joint Committee on Cancer 8th edition
• Surgically resectable with adequate lung functions to undergo surgery as determined by thoracic surgeon.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Body weight >30 kg
• Adequate normal organ and marrow function as defined below:
  • Hemoglobin ≥9.0 g/dL
  • Absolute neutrophil count (ANC) ≥1.0 × 109 /L
  • Platelet count ≥75 × 109/L
  • Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.>>
  • AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal.
  • Measured creatinine clearance (CL) ≥50 mL/min or Calculated creatinine CL≥50 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance:

    Males

Creatinine CL (mL/min)= Weight (kg) x (140 - Age) divided by 72 x serum creatinine (mg/dL)

Females

        Creatinine CL (mL/min)= Weight (kg) x (140 - Age) x 0.85 divided by 72 x serum creatinine
        (mg/dL)
          -  Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.
          -  Must have a life expectancy of at least 12 weeks
          -  Female subjects of childbearing potential and non-sterilized male subjects who intend
             to be sexually active during the study must agree to use a highly effective method of
             contraception from the time of screening, throughout the total duration of the drug
             treatment, and during the 90-day post-drug washout period.
          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
             female pre-menopausal patients. Women will be considered post-menopausal if they have
             been amenorrheic for 12 months without an alternative medical cause. The following
             age-specific requirements apply: Women 1 year ago, had chemotherapy-induced menopause
             with last menses >1 year ago, or underwent surgical sterilization (bilateral
             oophorectomy, bilateral salpingectomy or hysterectomy).
        Exclusion Criteria:
        Patients should not enter the study if any of the following exclusion criteria are
        fulfilled:
          -  Participation in another clinical study with an investigational product during the
             last 4 weeks prior to randomization
          -  Concurrent enrollment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study
          -  Prior systemic therapy for early-stage NSCLC that is under consideration for
             thisstudy.
          -  Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, clinically non-significant labs values (e.g.,
             lymphopenia), and the laboratory values defined in the inclusion criteria
               1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                  consultation with the Study Physician.
               2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
                  treatment with durvalumab may be included only after consultation with the Study
                  Physician.
          -  Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer
             treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (e.g.,
             hormone replacement therapy) is acceptable.
          -  Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
             radiation within 4 weeks of the first dose of study drug
          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to the
             first dose of IP.
          -  History of allogenic organ transplantation.
          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion:
               1. Patients with vitiligo or alopecia
               2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) clinically
                  stable on hormone replacement
               3. Any chronic skin condition that does not require systemic therapy
               4. Patients without active disease in the last 5 years may be included but only
                  after consultation with the Study Physician
               5. Patients with celiac disease controlled by diet alone
               6. Patients with type 2 DM (insulin dependent or independent) are allowed.
          -  Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, substantially increase
             risk of incurring AEs or compromise the ability of the patient to give written
             informed consent
          -  History of another primary malignancy except for
               1. Malignancy treated with curative intent and with no known active disease ≥2 years
                  before the first dose of IP and of low potential risk for recurrence
               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease
               3. Adequately treated non-melanoma skin cancer, in situ bladder, gastric, breast,
                  colon or cervical cancers/dysplasia's, noninvasive colonic polyps, superficial
                  bladdertumors,
               4. Monoclonal B-cell lymphocytosis, or monoclonal gammopathy of undetermined
                  significance.
          -  Known to have nodal or distant metastases
          -  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
          -  History of active primary immunodeficiency
          -  Known history of active hepatitis infection, positive hepatitis C virus (HCV)
             antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody
             (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined
             as the presence of antiHBc and absence of HBsAg) are eligible. Participants positive
             for HCV antibody are eligible only if polymerase chain reaction is negative for HCV
             RNA
          -  Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2
             antibodies) or active tuberculosis infection (clinical evaluation that may include
             clinical history, physical examination and radiographic findings, or tuberculosis
             testing in line with local practice).
          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. The following are exceptions to this criterion:
               1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
                  articular injection)
               2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent
               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
                  premedication)
          -  Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
        Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days
        after the last dose of IP.
          -  Participant that is pregnant or breastfeeding.
          -  Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.
          -  Prior randomization or treatment in a previous durvalumab clinical study regardless of
             treatment Arm assignment.
          -  Prior anti PD-1, PD-L1 and CTLA-4 therapy in the last 2 years
               1. Experienced a toxicity that led to permanent discontinuation of prior
                  immunotherapy.
               2. All AEs while receiving prior immunotherapy must have completely resolved or
                  resolved to baseline prior to screening for this study.
               3. Experienced a ≥Grade 3 immune related AE or an immune related neurologic or
                  ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with
                  endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on
                  appropriate replacement therapy and are asymptomatic.
               4. Required the use of additional immunosuppression other than corticosteroids for
                  the management of an AE, experienced recurrence of an AE if re-challenged, and
                  currently require maintenance doses of > 10 mg prednisone or equivalent per day.
          -  Judgment by the investigator that the patient is unsuitable to participate in the
             study and the patient is unlikely to comply with study procedures, restrictions and
             requirements.
          -  Known allergy or hypersensitivity to IP or any excipient.
          -  Clinically significant active infection requiring systemic therapy