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Study Protocol C31002 Protocol a M End Ment 2

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Study Protocol C31002 Protocol a M End Ment 2 Title: Phase 1 Study to Evaluate the Effect of MLN0128 on the QTc Interval in Patients With Advanced Solid Tumors NCT Number: NCT02197572 Protocol Approve Date: 28 November 2017 Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from view with a black/blue bar) to protect either personally identifiable information (PPD) or company confidential information (CCI). This may include, but is not limited to, redaction of the following: Named persons or organizations associated with the study. Proprietary information, such as scales or coding systems, which are considered confidential information under prior agreements with license holder. Other information as needed to protect confidentiality of Takeda or partners, personal information, or to otherwise protect the integrity of the clinical study. M L N 0 1 2 8 Clinical Study Protocol C31002 Protocol A m end ment 2 CLINICAL STUDY PROTOCOL C31002 PROTOCOL A MEND MENT 2 M L N 0 1 2 8 A P h as e 1 St u d y t o E v al u at e t h e Eff e ct of M L N 0 1 2 8 o n t h e Q T c I nt er v al i n P ati e nts Wit h Advanced Solid Tu mors Protocol Nu mber: C 3 1 0 0 2 Indication: Ad vanced solid tu mors P h as e: 1 S p o ns o r: Mill e n ni u m P h ar m a c e uti c als, I n c. Eudra CT Nu mber: N ot a p pli c a bl e Therapeutic Area: O n c o l og y Protocol History Ori gi n al 29 October 2013 Protocol A mend ment 1 26 June 2014 Protocol A mend ment 2 28 Nove mber 2017 Mill e n ni u m P h ar m a c e uti c als, I n c. 40 Landsdo wne Street Ca mbridge, M A US A 02139 Telephone: +1 (617) 679-7000 Note: Millenniu m Phar maceuticals, Inc, a wholly o wned subsidiary of Takeda Phar maceutical Co mpany Li mited, may be referred to in this protocol as: " millenniu m”, "Sponsor" or " Takeda. ” Appro ved by: N ot e: If t his d o c u m e nt w as a p pr o v e d el e ctr o ni c all y, t h e el e ctr o ni c a p pr o v al si g n at ur es m a y b e f ou n d at t h e e n d of t h e d o c u m e nt. PPD Si g n at ur e Date D D Month YYYY Property of Takeda: For non-co m mercial use only and subject tothe applicable Ter ms of Use 1 MLN0128 Clinical Study Protocol C31002 Protocol Amendment 2 Protocol Amendment 2 Summary of Changes Rationale for Amendment 2 This document describes the changes in reference to the protocol incorporating Amendment 2. The primary purpose of this amendment is to update those sections affected by new nonclinical data for MLN0128 metabolism by specific cytochrome P450 (CYP) isoforms. The study’s exclusion criteria, list of prohibited concomitant medications, description of potential drug-drug interactions, list of relevant CYP inhibitors, and dietary restrictions related to CYP inhibitors and inducers have been updated accordingly. The required frequency of radiographic disease assessments for patients who have received at least 1 year of continuous MLN0128 treatment has also been reduced. Minor grammatical, editorial and formatting changes are included for clarification purposes only. For specific examples of changes in text and where the changes are located, see Section 14.6. The purposes of this amendment are to: 1. Remove the exclusion criterion relating to treatment with strong CYP inhibitors or inducers. 2. Update the list of concomitant medications prohibited during the study. 3. Update the description of potential drug-drug interactions. 4. Update the list of relevant CYP inhibitors and inducers. 5. Remove the dietary restrictions related to CYP inhibitors and inducers. 6. Insert language to reduce the required frequency of radiographic disease assessments for patients who have received at least 1 year of continuous MLN0128 treatment per protocol. Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use 2 MLN0128 Clinical Study Protocol C31002 Protocol Amendment 2 PROTOCOL SUMMARY Study Title: A Phase 1 Study to Evaluate the Effect of MLN0128 on the QTc Interval in Patients With Advanced Solid Tumors Number of Patients: Approximately 30 patients will be enrolled in this study. Study Objectives Primary To characterize the effect of a single dose of 40 mg MLN0128 on the electrocardiographic QT/QTc interval in patients with advanced solid tumors Secondary To evaluate the safety, tolerability, and pharmacokinetics of MLN0128 in patients with advanced solid tumors Overview of Study Design: This is an open label, single-arm, multicenter study to evaluate the effect of a single dose of 40 mg MLN0128 on the QT/QTc interval in patients with advanced solid tumors. The study will enable collection of time-matched pharmacokinetic (PK) and electrocardiogram (ECG) data before and after MLN0128 administration at the time points specified in the Schedule of Events. A central ECG reader will be used and continuous 12-lead digital ECGs will be obtained using a Holter H12+ ECG recorder. All planned 12-lead ECG collections will be obtained in triplicate. On the morning of Screening; Day -1 baseline measurements of serial triplicate ECGs (0-10 hours) will be obtained. Three Holter ECGs will be extracted at the time points that match the Cycle 1, Day 1 PK/ECG sampling times. The clock time of ECG assessments on Screening; Day -1 should coincide with the clock time of PK/ECG assessments for Cycle 1, Day 1. After collection of the planned 10-hour ECG sample on Cycle 1, Day 1, the Holter recorders will not be removed and patients will be furloughed from the study site. On Screening; Day -1 and Cycle 1, Day 1, patients will be given the option to report to the site fasted or after having a light morning meal as long as the meal has been completed at least 2 hours before the scheduled baseline triplicate ECG on each day. If patients report to the site fasted, they should do so with adequate time (approximately 3 hours before the scheduled baseline triplicate ECG) in order to eat a light, standard breakfast provided by the site that will need to be completed at least 2 hours before the scheduled baseline triplicate ECG on each day. Patients will be instructed not to eat for the next 6 hours (ie, 2 hours before the 0-hour, predose time point and until completion of the collection of the 4-hour postdose PK/ECG assessments). Light meals will be administered at the same time on Screening; Day -1 and Cycle 1, Day 1. In addition, all patients will be issued a glucometer and trained to use it to monitor their daily predose fasting blood glucose (FBG) levels at home for the days on which glucose is not measured at the clinic. Patients will be instructed to notify the study staff immediately with any abnormal readings (ie, ≥ 150 mg/dL) for further instructions on the management of hyperglycemia. In-home glucose monitoring is not required on days when fasting glucose is measured in the clinic. To mitigate nausea and vomiting known to occur at a 40 mg dose of MLN0128, patients will be administered an antiemetic agent (0.25 mg palonosetron) on Cycle 1, Day 1. Property of Takeda:After collection For non-commercial of the 10-hour postdose use PK/ECG only and assessment subject on to Cycle the1, applicable Day 1, patients Terms will be of Use furloughed from the study site. The Holter recorders will not be removed during this furlough 3 MLN0128 Clinical Study Protocol C31002 Protocol Amendment 2 period. On Cycle 1, Day 2 and Cycle 1, Day 3, patients may eat and drink up to approximately 2 hours before arriving at the study site for PK/ECG evaluations. On Cycle 1, Day 2, patients will report to the clinical facility at least 1 hour before the 24-hour postdose PK/ECG (triplicate) assessments. After the PK/ECG assessments are completed, the Holter recorders will be removed and patients will be furloughed from the study site. On Cycle 1, Day 3, patients will report to the clinical facility at least 1 hour before the 48-hour postdose assessments, which will represent the final study endpoint-specific planned PK/ECG assessments. After completing the PK/ECG assessments on Cycle 1, Day 3, patients may continue to receive MLN0128 if, in the opinion of the investigator, the patient is deriving clinical benefit, until they experience disease progression. Patients continuing treatment with MLN0128 at the discretion of the investigator will receive a dose of MLN0128 up to 30 mg every week (QW). Dose escalation will not be permitted, and a maximum of 2 dose reductions (for patients experiencing study drug-related toxicity) will be permitted. Patients will return to the study site for follow-up visits at the time points in the Schedule of Events. Treatment may continue until disease progression, unacceptable MLN0128-related toxicity, withdrawal of consent, or for up to 12 months (whichever occurs first). All patients enrolled in the study will attend the End of Study/Early Termination visit 30 (to 40) days after receiving their last dose of study drug.
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