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Tremelimumab Study Code D419AC00001 Version 08 Date 09 January 2018 Clinical Study Protocol Drug Substance Durvalumab (MEDI4736) and tremelimumab Study Code D419AC00001 Version 08 Date 09 January 2018 A Phase III Randomized, Open-Label, Multi-Center, Global Study of MEDI4736 in Combination with Tremelimumab Therapy or MEDI4736 Monotherapy Versus Standard of Care Platinum-Based Chemotherapy in First-Line Treatment of Patients with Advanced or Metastatic Non-Small- Cell Lung Cancer (NSCLC) (MYSTIC) Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden EudraCT Number: 2015-001279-39 1 (220) Clinical Study Protocol Drug Substance Durvalumab (MEDI4736) and tremelimumab Study Code D419AC00001 Version 08 Date 09 January 2018 VERSION HISTORY Version 8.0, 9 January 2018 Changes to the protocol are summarised below. Synopsis, Sections 6.1.9, 7.2.2 Updated to include further clarification on post final Data Cut Off (DCO) procedures. Section 1.3.2, Potential Risks Since the MYSTIC study was started, the durvalumab programme has developed and the emerging safety profile has become more established. As such, the “Potential Risks” section of this clinical study protocol has updated to align and be consistent with the broader durvalumab programme, including the Investigator Brochure and the clinical study protocol format of more recent studies. Section 3.10.3, Survival Status for Withdrawn Consent and Lost to Follow Up Patients Updated to clarify which analysis sets require survival status data and how and when to obtain this data. Sections 6.3.1, Time period for collection of adverse events, 6.3.2, Follow-up of unresolved adverse events Updated to clarify time period for collection of adverse events, and to clarify the follow-up of adverse events unresolved at the patient’s last visit in the study or at study completion. 6.7, Management of Investigational Product-related Toxicities Updated to include the web link to the most current Toxicity Management Guidelines. 6.7.1, MEDI4736 + tremelimumab and MEDI4736 monotherapy adverse events of special interest (AESI) Updated to align with the most current Investigator Brochure CCI Various Updated terminology from immune related Adverse Event (irAE) to immune mediated Adverse Event (imAE). 2 (220) Clinical Study Protocol Drug Substance Durvalumab (MEDI4736) and tremelimumab Study Code D419AC00001 Version 08 Date 19 December 2017 Version 7.0, 20 December 2016 Changes to the protocol are summarised below. Synopsis, Section 1.4 Clarification of the expected proportion of patients with ≥25% PD-L1 membrane-expression in tumoral tissue. With the study fully recruited there is no change in the overall patient number. Synopsis, Glossary, Figure 1, Section 1.4 The definitions for the PD-L1 tumor membrane-expression sub-groups are provided. Synopsis, Sections 1.1.5, 1.2.6, 1.3.1.1, 1.3.1.3, 2.1, 2.2, 2.3 For MEDI4733 in combination with tremelimumab the assessment of progression-free survival (PFS) and overall survival (OS) were nominated as co-primary objectives in NSCLC patients with ≥25% PD-L1 membrane-expression in tumoral tissue. For MEDI4733 monotherapy the assessment of overall survival (OS) is nominated as a co-primary objective in NSCLC patients with ≥25% PD-L1 membrane-expression in tumoral tissue . Primary and secondary objectives, endpoints and rational for endpoints were modified accordingly. Synopsis, Section 8, Table 9, Table 12, Figure 5 The statistical considerations and analyses have been updated to accommodate the nominated co-primary objectives. Section 3.1, Inclusion Criteria #3 Correction of spelling error. Section 4 Removed the set duration for treatment periods as they can be variable per protocol. Table 2 Footnote O updated for clarity. Table 4 Footnote J updated for clarity. Sections 6.7.1, 6.7.2 Updated to align with the current IB and ICF. Section 7.7 In the section on prohibited medications, the following changes have been made: A temporary period of steroids will be allowed if clinically indicated and considered to be essential for the management of the patient (eg, for chronic obstructive pulmonary disease, radiation, nausea, etc). EGFR TKIs should not be given concomitantly whilst the patient is on study treatment. In addition they should be used with caution in the 90 days after the last dose of durvalumab. (Increased incidences of pneumonitis (with third generation EGFR TKIs) and increased 3 (220) Clinical Study Protocol Drug Substance Durvalumab (MEDI4736) and tremelimumab Study Code D419AC00001 Version 08 Date 19 December 2017 Version 7.0, 20 December 2016 Changes to the protocol are summarised below. incidence of transaminase increases (with 1st generation EGFR TKIs) has been reported when durvalumab has been given concomitantly). ! Inactivated viruses, such as those in the influenza vaccine, are permitted Section 8.4.4 – 8.4.4.3 Statement that the clinical meaningfulness threshold of the PRO analyses will be described in the Statistical Analysis Plan (SAP) CCI CCI Version 6.0, 02 June 2016 Changes to the protocol are summarised below. Section 3.8 Restrictions Spermicide was removed as it is not a highly effective method of contraception. Synopsis, Section 7.2.2 Duration of treatment and criteria for retreatment To clarify that treatment through progression only applies to the immunotherapy groups (monotherapy and combination therapy arms). Updated wording in section 7.2.2. to match synopsis, indicating patients in the immunotherapy groups (rather than only the MEDI4736 group) will not be permitted to continue immunotherapy if progression occurs in a target lesion that has previously shown a confirmed response. Section 8.4.1.1 Progression-free survivalTo clarify that in the SoC group treatment can be continued, at investigator’s discretion, until disease progression in confirmed. Patients in the SoC are not allowed to continue treatment once disease progression in confirmed Version 5.0, 31 March 2016 4 (220) Clinical Study Protocol Drug Substance Durvalumab (MEDI4736) and tremelimumab Study Code D419AC00001 Version 08 Date 19 December 2017 Changes to the protocol are summarized below Title pages MEDI4736 is identified as Durvalumab in Drug substance in the header box, and referred to as MEDI4736 thereafter. Synopsis, Section 1.2.6 – Rationale for Endpoints, Section 2 – Study Objectives, Section 5.1 – Efficacy Assessments, Section 8.4 – Outcome Measures for Analysis, Section 8.5 – Methods for Statistical Analysis The primary and secondary objective endpoints have been updated to reflect changes to endpoint measures - Blinded Independent Central Review (BICR) tumor assessments rather than Investigator assessments as well as to assess the treatment benefit and efficacy of MEDI4736 as suggested by emerging immuno-oncology data. Investigator assessments will be used for sensitivity analysis. Synopsis, Section 1.4 – Study design and Section 8.2 – Sample size estimate CCI Synopsis, Section 1.4 – Study design The timing for patients to provide a tumor tissue sample was clarified as being the enrollment visit. Synopsis, Section 1.4 – Study design and Section 2 – Study objectives The assessment of progression-free survival (PFS) and overall survival (OS) were nominated as co-primary objectives. Primary and secondary objectives, endpoints and rational for endpoints were modified accordingly. Synopsis, Section 7.2.2 Duration of treatment and criteria for retreatment Duration of treatment was modified so that patients in all groups can continue therapy until disease progression rather than stopping at 12 months. Emerging data from ongoing MEDI4736 studies is suggestive of some patients losing clinical benefit after they complete the 12 months of therapy. In all groups, patients with PD (unconfirmed and confirmed) who, in the Investigator’s opinion, would continue to receive benefit from their assigned treatment, and who meet the criteria for treatment in the setting of PD, may continue to receive treatment. It was also clarified that patients on MEDI4736 alone will not be permitted to continue immunotherapy, if the progression occurs after confirmed response to immunotherapy treatment within the target lesion, and if progression events occurred in the target lesions while the patient was receiving immunotherapy during the same treatment period. Synopsis, Section 8 – Statistical methods 5 (220) Clinical Study Protocol Drug Substance Durvalumab (MEDI4736) and tremelimumab Study Code D419AC00001 Version 08 Date 19 December 2017 The statistical considerations and analyses have been updated to accommodate the new co-primary objectives and the modifications in provisions for duration of treatment and progression during treatment. CCI CCI Section 1.2.5 - Rationale of retreatment option The rationale for the retreatment option is amended to enable patients in the MEDI4736 + tremelimumab combination group who complete 4 dosing cycles (providing clinical benefit per Investigator judgement), and subsequently have PD during treatment with MEDI4736 alone, to restart combination treatment, if they also meet eligibility criteria. Section 1.3.2.1 - MEDI4736 + tremelimumab The potential risks, based on the mechanism of action of MEDI4736 and related molecules, are updated to “colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In addition, pancreatitis is an important potential risk particularly with MEDI4736 and tremelimumab combination therapy. Other inflammatory responses with potential immune-mediated etiology reported with MEDI4736 and similar molecules include myocarditis, pericarditis,
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