Overview

This is a phase II trial of durvalumab and tremelimumab in combination of platinum-based chemotherapy. Patients with stage IV Non-Small-Cell-Lung Cancer (NSCLC) with human immunodeficiency virus (HIV) infection (cohort 1) or hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (cohort 2) will be eligible. Patients will receive standard platinum-based chemotherapy plus durvalumab for 4 cycles (every 3 weeks), followed by durvalumab (with or without pemetrexed for non-squamous NSCLC) maintenance therapy. It is hypothesized that Durvalumab and tremelimumab in combination with standard chemotherapy is safe and effective for the treatment of stage IV NSCLC in patients with HIV, HBV, or HCV infection.

Eligibility

Inclusion Criteria:

1. Patients with stage IV NSCLC who had undergone no previous systemic therapy for stage IV disease.
2. Cohort 1: Patients with HIV must be on an effective combination anti-retroviral therapy (cART) regimen for ≥ 4 weeks. Also, patients need to meet the following criteria.
   • Documented HIV viral load < 400 copies/mL
   • No AIDS-defining opportunistic infections within the last 12 months
   • No concurrent incurable AIDS-defining malignancy

Cohort 2:

             HBV: Patients with chronic HBV infection (defined by persistence of HBsAg for more
             than six months) will be eligible. Patients with positive hepatitis B core antibody
             (anti-HBc) but negative surface antigen (HBsAg) will also be eligible. Those with
             detectable HBV DNA who are negative for HBsAg will also be eligible.
             o HBV-positive patients who are HBsAg positive with evidence of active disease should
             be on anti-HBV therapy prior to starting study therapy.
             HCV: Patients with detectable HCV RNA will be eligible if they are on appropriate
             anti-HCV therapy. Those who have completed antiviral therapy for HCV and undetectable
             HCV RNA will also be eligible.
          3. Age > 18 years at time of study entry.
          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
          5. Body weight >30kg
          6. Adequate normal organ and marrow function as defined below:
               -  Hemoglobin ≥ 9.0 g/dL
               -  Absolute neutrophil count (ANC) ≥ 1,000 per mm3
               -  Platelet count ≥ 100,000 per mm3
               -  CD4 T-cell count ≥ 100 per mm3 for HIV-infected patients
               -  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 unless liver
                  metastases are present, in which case it must be ≤5x ULN
               -  Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40
                  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)] / [72 x serum creatinine
             (mg/dL)] Females: Creatinine CL (mL/min) = [Weight (kg) x (140 - Age) x 0.85] / [72 x
             serum creatinine (mg/dL)]
          7. 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 <50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).
               -  Women ≥50 years of age would be considered post-menopausal if they have been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year ago, had
                  chemotherapy-induced menopause with last menses >1 year ago, or underwent
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
                  hysterectomy).
          8. 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.
          9. Must have a life expectancy of at least 12 weeks.
        Exclusion Criteria:
          1. Sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q)
             and/or ALK translocations by locally approved laboratory testing including blood-based
             liquid biopsy.
          2. 2. Coinfection of HIV + HBV (coinfection of HIV and HBV allowed if the patient is on
             appropriate anti-viral therapy for HBV) or HIV + HCV (coinfection of HIV and HCV
             allowed if HCV is cured or patient is on appropriate anti-viral therapy for hepatitis
             C). Coinfection of HBV and HCV is allowed if otherwise eligible.
          3. No measurable disease.
          4. Receipt of the last dose of anticancer therapy (chemotherapy, targeted therapy) ≤ 21
             days prior to the first dose of study treatment.
          5. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy
             (chemotherapy, targeted therapy, radiation therapy) with the exception of alopecia,
             vitiligo, and the laboratory values defined in the inclusion criteria.
          6. Patients who have had whole brain radiation therapy (WBRT) during the previous 2 weeks
             before treatment (no washout period is required for patients who have received
             stereotactic body radiation therapy).
          7. Subject has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic)
             within 4 weeks prior to starting study drug or has not recovered from side effects of
             such procedure (≥ grade 2 AE related to such procedure). Video-assisted thoracic
             surgery (VATS) and mediastinoscopy will not be counted as major surgery and subject
             can be enrolled in the study ≥ 1 week after the procedure.
          8. History of allogenic organ transplantation.
          9. Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], 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:
             i. Patients with vitiligo or alopecia ii. Patients with hypothyroidism (e.g.,
             following Hashimoto syndrome) stable on hormone replacement iii. Any chronic skin
             condition that does not require systemic therapy iv. Patients without active disease
             in the last 5 years may be included
         10. 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, 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.
         11. Patients with prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial.
         12. Previously untreated central nervous system (CNS) metastases or leptomeningeal
             disease. Patients who have had whole brain radiation therapy (WBRT) during the
             previous 2 weeks before treatment (no washout period is required for patients who have
             received stereotactic body radiation therapy).
         13. Active tuberculosis (clinical evaluation that includes clinical history, physical
             examination and radiographic findings, and TB testing in line with local practice).
         14. Current or prior use of immunosuppressive medication within 7 days before the first
             dose of durvalumab. The following are exceptions to this criterion:
             i. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
             articular injection) ii. Systemic corticosteroids at doses not to exceed 20 mg/day of
             prednisone or its equivalent iii. Steroids as premedication for hypersensitivity
             reactions (e.g., CT scan premedication) iv. Decreasing dose of systemic
             corticosteroids after radiation therapy for brain metastasis.
         15. Receipt of live attenuated vaccine within 30 days prior to the first dose of
             investigational product (IP). Note: Patients, if enrolled, should not receive live
             vaccine whilst receiving study treatment and up to 30 days after the last dose of IP.
         16. Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential who are not willing to employ effective birth control.
         17. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
             excipients.
         18. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4 within 12 months
             of the first dose of durvalumab.
         19. 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.