Durvalumab and Tremelimumab for Adjuvant Therapy of Resected NSCLC

Inclusion Criteria:

• Written informed consent and any locally-required authorization (e.g., HIPAA in the USA, EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
• Adequate tissue must have been obtained from surgical intervention to satisfy biospecimen requirements of study (collected under biospecimen collection protocols; either AAAO5706 or AAAR1327).
• Histologically or cytologically confirmed squamous or non-squamous NSCLC.
• Stage IB-IIIA
• R0 or R1 resection
• Patients must have completed surgical resection and adjuvant chemotherapy (adjuvant radiotherapy excluded) with no significant persisting treatment related toxicity (grade 1 toxicity per CTCAE v4.0 allowed) as determined by the treating physician.
• Study treatment must begin within 30 days of surgical resection or adjuvant treatment. This timeline may be extended if further time for recovery from treatment related toxicities is required.
• Age ≥18 years; as no dosing or adverse event data are currently available on the use of durvalumab-tremelimumab in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• ECOG performance status ≤1 (Karnofsky ≥70%).

• Patients must have normal organ and marrow function as defined below:

  • Hemoglobin >or = 9.0 g/dL
  • Absolute neutrophil count ≥1.5 x 109/L
  • Platelets ≥100 x 109/L
  • Total bilirubin within normal institutional limits
  • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal
  • Serum creatinine CL > or = 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
• The effects of durvalumab-tremelimumab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 6 months after completion of durvalumab + tremelimumab administration or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of durvalumab + tremelimumab administration or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period.
• Ability to understand and the willingness to sign a written informed consent document.
• Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
• Subject 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.

Exclusion Criteria:

• Pre- or post-operative radiotherapy.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Participation in another clinical study with an investigational product during the last 4 weeks
• Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab
• Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction
• Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
• Any unresolved toxicity ( > CTCAE grade 2) from previous anti-cancer therapy.
• Any prior Grade ≥ 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
• Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
• Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
• Active hepatitis B or C (defined as positive Hepatitis B surface antigen, hepatitis C antibody)
• History of HIV infection
• History of interstitial lung disease/pneumonitis from any cause
• Never-smokers if EGFR/ALK testing results are unknown
• Patients with NSCLC that harbors an ALK rearrangement, or sensitizing EGFR mutation.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because durvalumab-tremelimumab are investigational agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with durvalumab-tremelimumab, breastfeeding should be discontinued if the mother is treated with these agents.
• History of allogeneic organ transplant
• History of hypersensitivity to durvalumab or any excipient
• History of hypersensitivity to the combination or comparator agent
• Known history of active tuberculosis
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
• Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
• Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period