PF-04449913 B1371012 Final Protocol Amendment 7, 14 June 2018 AN OPEN-LABEL PHASE 1B STUDY OF PF-04449913 (GLASDEGIB) IN COMBINATION WITH AZACITIDINE IN PATIENTS WITH PREVIOUSLY UNTREATED HIGHER-RISK MYELODYSPLASTIC SYNDROME, ACUTE MYELOID LEUKEMIA, OR CHRONIC MYELOMONOCYTIC LEUKEMIA Compound: PF-04449913 Compound Name: Glasdegib United States (US) Investigational New 105,453 Drug (IND) Number: European Clinical Trials Database 2014-001345-24 (EudraCT) Number: Protocol Number: B1371012 Phase: 1b This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, by accepting or reviewing this document, you agree to hold this information in confidence and not copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified. PFIZER CONFIDENTIAL Page 1 PF-04449913 B1371012 Final Protocol Amendment 7, 14 June 2018 Document History Document Version Date Summary of Changes Original protocol 15-July-2014 N/A Amendment 1 21 October 2014 Figures 1 and 3: Study Schematic updated to include the 2 additional safety analyses during the Randomized Phase 2 component. Added in all appropriate sections that patients with >30% BM blasts OR a rapidly progressive increase in the proportion of BM blasts at any point during the trial, must discontinue the study drug combination and enter follow-up. Added in all appropriate sections that two safety analyses will be performed following commencement of the randomized Phase 2 component of the study in order to carry out an early assessment of the safety profile of the study treatment combination in addition to the one performed at the end of the lead-in phase. One analysis will be carried out after 12 patients have completed 2 cycles of treatment, and one after 24 patients have completed 2 cycles of treatment. The EDMC will review the results of both analyses. Deleted all references to allowing the continuation of single agent PF-04449913/placebo in the event that azacitidine is permanently discontinued for reasons other than objective disease progression, patient refusal, or consent withdrawal. Updated in all appropriate sections that the Patient Dosing Diary for PF-04449913/placebo will now be required for all treatment cycles. Previously the Patient Dosing Diary was optional after Cycle 6. End of Treatment Visit added to Table 4. PFIZER CONFIDENTIAL Page 2 PF-04449913 B1371012 Final Protocol Amendment 7, 14 June 2018 Document Version Date Summary of Changes The following Exclusion Criteria was added: “Patients with AML who are candidates for standard induction chemotherapy”. The following clarification of the definition of a missed dose was added to Section 5.5.1 General Guidelines in reference to PF-04449913: “If a patient forgets to take their dose at the regularly scheduled time, and if less than 10 hours have passed since the scheduled dosing time, that dose should be taken as soon as possible. If more than 10 hours have passed since the scheduled dosing time, the dose should be skipped and the patient should continue on their normal dosing schedule.” For clarification the following sentence was added to Section 5.5.2.3.2: PF-04449913 or Placebo: “PF-04449913/placebo treatment should be interrupted for ANC <100/mm3 and /or platelets < 10,000/mm3 regardless of when it occurs.” In Section 5.5.2.3.2. PF-04449913 or Placebo: Investigator judgment allowing re-commencement of PF-04449913/placebo treatment for non-hematological toxicities if returned to baseline or ≤ Grade 2 (if not considered a safety risk) was removed. Re-commencement can only occur when the non-hematological toxicity has returned to baseline or ≤ Grade 1. In Section 5.5.2.4. Dose Reduction for Azacitidine and PF-04449913 or Placebo the following sentence was deleted: “No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity. Investigators should, however, manage their patients according to their medical judgment based on the clinical circumstances.” PFIZER CONFIDENTIAL Page 3 PF-04449913 B1371012 Final Protocol Amendment 7, 14 June 2018 Document Version Date Summary of Changes Table 7 was updated to include additional and new PF-04449913/placebo dose modification instructions. Table 7 Footnote was updated to include both definitions of recovery as well as clarification on PF-04449913/placebo interruption criteria. Table 8: Section referring to PF-04449913/placebo related Other Non-Hematologic Toxicities was updated to also exclude muscle spasms and myalgia. Table 9. Recommended Dose Modifications for PF-04449913/placebo related QTcF prolongation was updated. Table 10. Recommended Dose Modifications for PF-04449913/placebo in case of drug class related AEs was added. Section 7.6. Triplicate (12 Lead) ECGs was updated to agree with the updated Table 9. Minor administrative corrections adding clarifications and correction of typos. Amendment 2 15 December 2014 In Section 3.3.2 Breaking the Blind and Section 5.2 Breaking the Blind the following sentence was removed: “Whenever possible, the Investigator or sub investigator consults with the Sponsor prior to breaking the blind.” In Sections 3.3.2 Breaking the Blind and 5.2 Breaking the Blind the following sentence was added: “Immediate unblinding for patient safety can occur via the IRT system.” In the Protocol Summary; Study Treatments, Section 3.3.1 Study Treatments, Section 5.5.1.3 Treatment Duration and Section 6.4 Follow-Up the following sentence was added: “In cases of unacceptable toxicity or pregnancy, the patient must be withdrawn from study drug combination and entered into the follow-up phase of the study.” PFIZER CONFIDENTIAL Page 4 PF-04449913 B1371012 Final Protocol Amendment 7, 14 June 2018 Document Version Date Summary of Changes Throughout the document when referring to study endpoints and objectives the terms Objective Response Rate (ORR) and Objective Response (OR) were changed to Response Rate (RR) and Response respectively. Under Protocol Summary and under Section 2.2: Endpoints for the Phase 1b (Safety Lead-In Cohort [LIC]) Secondary Endpoints: Clarified the definition of Response Rate by adding the following in bold: “Response Rate (percentage of patients achieving Complete Remission (CR) + Partial Remission (PR)) as defined by modified International Working Group (IWG) criteria (2006) Appendix 2:” Under Protocol Summary and under Section 2.4: Endpoints for the Randomized Phase 2 Primary Endpoint: Clarified the definition of Response Rate by adding the following in bold: “Response Rate (percentage of patients achieving CR + PR) as defined by modified IWG criteria (2006) Appendix 2.” Section 4.2 Exclusion Criteria 1 (updated in bold) to:” Patients with AML who are candidates for standard induction chemotherapy as first line treatment.” Minor administrative corrections adding clarifications and correction of typos. Amendment 3 17 February 2015 Section 5.5.2.4 Table 9 and Section 7.6: Will be updated with the following sentence: “If Grade 3 QTcF prolongation (>500 msec) occurs, continuous ECG monitoring and cardiology specialist evaluation and guidance are recommended.” Minor administrative corrections adding clarifications and correction of typos. PFIZER CONFIDENTIAL Page 5 PF-04449913 B1371012 Final Protocol Amendment 7, 14 June 2018 Document Version Date Summary of Changes Updates to safety and communication of results by Pfizer text to incorporate latest template changes. Amendment 4 04 January 2016 Study Title updated to include the drug International Nonproprietary Name (INN), Glasdegib. Abbreviations list updated. Table 1- Schedule of Activities for the Phase 1b Safety LIC: Footnotes 14 and 25 updated to clarify that study treatment refers to PF-04449913 + Azacitidine Footnote 25, corrected to remove mention of PRO assessment collection in the Long-Term Follow Up period of the Phase 1b Safety LIC. Table 2 “Pharmacokinetics and ECG Schedule for the Safety LIC” updated to expand ECG collection to Day 1 of every cycle and clarify that PK collection ends after Cycle 6. Table 4 “Pharmacokinetics & ECG Schedule for the Randomized Phase 2” updated to expand ECG collection to Day 1 of every cycle. Section 1.2.12 Summary of Benefit-Risk Assessment updated with information concerning QTc interval prolongation. Section 4.0 Patient Selection. The following statement was added to clarify that eligibility criteria must be met both at Screening and on Cycle 1 Day 1: “These criteria must also be met prior to dosing on Cycle 1 Day 1.” Section 4.2 Exclusion Criterion 19 revised to include exclusion of all bundle branch blocks. PFIZER CONFIDENTIAL Page 6 PF-04449913 B1371012 Final Protocol Amendment 7, 14 June 2018 Document Version Date Summary of Changes Section 5.5.2 Dose Modifications updated: 1. The section heading and titles for Table 7- Dose Modifications for Hematologic Toxicities and Table 8-Dose Modifications for Non-Hematologic Toxicities amended to remove the term “Recommended”. The term “Recommended” was also removed from all dose modification references throughout the protocol. 2. The following statement was added “If there is a need to deviate from any of the dose modifications this first must be discussed with the Sponsor Medical Monitor.” 3. Table 9- Recommended Dose Modifications for PF-04449913/placebo related QTcF prolongation replaced with a new table entitled PF-04449913/placebo Dose Modifications for mean QTcF (mQTcF) Prolongation. 4. Table 10-Recommended Dose Modifications for PF-04449913/placebo in Case of Drug Class Related AEs updated to remove the term “Recommended” from the title and replaced with a new table. 5. Sub-Section 5.5.2.3.2 PF-04449913 or Placebo, added sub heading entitled “QTcF Interval Monitoring and Management” language concerning the monitoring of potential cardiovascular symptoms and guidance on the use of moderate/strong CYP3A4/5 inhibitors or drugs with a known risk of Torsade de pointes are added as concomitant therapy with PF-04449913/placebo.