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Clinical Study Report Page 1 of 6 SYNOPSIS STUDY INFORMATION: Long Title: A Phase 1, Open-Label, Multicenter, Dose Escalation Study to Assess the Safety and Tolerability of MLN7243, an Inhibitor of Ubiquitin-Activating Enzyme (UAE), in Adult Patients With Advanced Solid Tumors Sponsor: Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, MA USA 02139 Name of Active Ingredient: Name of Finished Product: MLN7243 (also referred to as TAK-243) Investigators: There was 1 principal investigator at each of the 6 clinical sites, who managed sub-investigators at each site. Study Sites: Six sites, all in the United States, enrolled subjects in the dose escalation part of this study. Publication Based on the Study Sarantopoulos J, Infante J, Cohen R, Haeseong P, Lockhart AC, Gourdin T, et al. First-in-human (FIH) phase 1, open-label, multicenter, dose-escalation study to assess the safety and tolerability of TAK-243, a first-in-class investigational inhibitor of ubiquitin (Ub)-activating enzyme (UAE),in adult patients (pts) with advanced solid tumors. EMBO Conference Ubiquitin and SUMO: From molecular mechanisms to system-wide responses; 15-19 September 2017; Cavtat-Dubrovnik, Croatia. Submission ID 107. Study Dates: Date first subject signed informed consent form: 13 January 2014 Date of last subject s last visit/contact: 09 November 2016 Date of last dose of study drug: 06 October 2016 Study Phase: Phase 1 Objectives: Primary Objective: The primary objective was to evaluate the safety and tolerability (ie, establish the maximum tolerated dose [MTD], inform the recommended phase 2 dose [RP2D], and identify the dose-limiting toxicity [DLT]) of MLN7243 Secondary Objectives: The secondary objectives were: To describe the pharmacokinetics (PK) of MLN7243 in plasma and urine. To investigate the pharmacodynamic effects of MLN7243 in tumor tissue. To evaluate antitumor activity that may be observed with MLN7243. Exploratory Objectives:
Clinical Study Report Page 2 of 6 Methodology: This was an open-label, multicenter, phase 1, dose escalation study of MLN7243 in adult patients with advanced malignant solid tumors to evaluate the safety, tolerability, PK, pharmacodynamics, and antitumor activity of MLN7243. This study was the first to administer MLN7243 to humans. The patient population consisted of adults previously diagnosed with any form of an advanced malignant solid tumor who had exhausted treatment with standard therapies. The study design featured 2 phases: a dose escalation phase with 2 dosing schedules (Schedule A and Schedule B) and an expansion phase. Approximately 119 patients were planned to be enrolled in this study. For reasons other than toxicity or lack of efficacy, the Sponsor decided to terminate the study and therefore Schedule B and the dose expansion phase were not initiated. Consequently, this clinical study report focuses on the procedures and analyses that were actually conducted in the Schedule A portion of the study. At the time of study closure, the totality of clinical outcomes was examined, including available tumor size reduction and progression-free survival data. Once enrolled into the study, patients were administered MLN7243 via an intravenous (IV) infusion over 10 minutes. In Schedule A, MLN7243 IV infusion was administered on Days 1, 4, 8, and 11 followed by a rest period of 10 days, for a total 21-day treatment cycle. During dose escalation, an observation interval of at least 7 days occurred between dosing of the first 2 patients in a cohort as an extra safety measure, and before dosing further patients in the cohort. For safety reasons, no dose levels were skipped, and a minimum of 3 patients must have been DLT-evaluable before escalating to the next dose level. Once at least 6 DLT-evaluable patients were treated at any dose level and the algorithm did not recommend escalation or de-escalation, this dose level was to be considered the MTD. Patients received MLN7243 until they experienced symptomatic deterioration or progressive disease (PD). The maximum duration of study treatment was 12 months. Patients could have discontinued at any time, and were to attend an End of Study visit within 30 days of their last dose of MLN7243. Number of Patients: Planned: 119 patients Enrolled in Schedule A: 29 patients Safety Population: 29 patients. PK-Evaluable Population: 29 patients. DLT-Evaluable Population: 19 patients. Response-Evaluable Population: 20 patients. Diagnosis and Main Criteria for Inclusion: Patients enrolled in this study were male or female, 18 years of age or older, and provided written informed consent. Patients must have had a histologically confirmed diagnosis of advanced, metastatic, malignant solid tumor, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate hematologic and organ function, radiographically detectable tumors, biopsy-accessible lesions, and were surgically sterile, postmenopausal or agreed to practice protocol-specified methods of birth control. Patients were excluded if they had pre-existing cardiac
Clinical Study Report Page 3 of 6 impairment; known active cardiovascular lesions; systemic antineoplastic therapy or investigational agents within 21 days; radiotherapy within 14 days; treatment with strong CYP3A4 inhibitors or inducers within 14 days; treatment with clinically significant breast-cancer resistance protein or organic anion transporting polypeptide inhibitors within 14 days; major surgery within 28 days; life-threatening illness unrelated to cancer; active infection or antibiotic therapy with 14 days; or positive for human immunodeficiency virus, hepatitis B or hepatitis C. Duration of Treatment: In Schedule A, each treatment cycle consisted of 21 days. Maximum treatment duration for each patient was up to 12 months. Study Drug, Dose and Mode of Administration, and Lot Number Study Drugs MLN7243 Product Dose Strength and Form 2 mg/ml; 5 ml vial Study Dosage Mode of Administration Manufacturer Lot Number Drug Product Lot Number 1 to 18 mg Solution for Infusion MPI 102839 9124.4 Endpoints and Criteria for Evaluation: Primary Endpoint The primary endpoint included assessment of clinical symptoms and signs, adverse events (AEs), serious adverse events (SAEs), assessments of clinical laboratory values, clinically important laboratory abnormalities, vital sign measurements, and cardiac assessments (electrocardiograms, troponin I and T, and echocardiograms) Secondary Endpoints PK parameters, including, but not limited to concentration at the end of infusion, trough plasma concentration, peak-to-trough ratio, the area under the plasma concentration curve from time zero to the last measurable concentration, the area under the plasma concentration curve over the dosing interval, the area under the plasma concentration curve from time zero to infinity (AUC inf ), clearance, renal clearance, steady-state volume of distribution, amount excreted unchanged in urine, percentage of dose excreted unchanged in urine, the accumulation ratio, and terminal disposition half-life (t 1/2 ). The study was terminated before the expansion phase, therefore urine samples were not collected for evaluation of urine PK endpoints. Pharmacodynamic endpoints include determinations by immunohistochemistry (IHC) of changes in level of MLN7243-Ub adduct, polyubiquitin, and Ub-H2B in tumor tissue following MLN7243 dosing. Measures of disease response including objective response rate and duration of response using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Statistical Methods: In the dose escalation stage, a modified Bayesian continual reassessment method was used to determine MTD and inform RP2D. Analyses were primarily descriptive in nature. No formal statistical tests were performed. Summary tabulations were presented that displayed the number of observations, mean, standard deviation, median, minimum and maximum for continuous variables, and the number and percent per category for categorical data, unless specified otherwise.
Clinical Study Report Page 4 of 6 Efficacy: This was a phase 1 study and efficacy was not a primary endpoint. Efficacy analyses were descriptive. Antitumor activity of MLN7243 was based on the best overall response per the RECIST guideline (version 1.1) at each time point and best overall response for each patient was derived programmatically from among the reported responses. Pharmacokinetics: MLN7243 PK analyses were performed on data from the PK-Evaluable population. Plasma concentrations of MLN7243 and the amount excreted in urine were to be summarized by nominal collection times according to dose, schedule, dosing cycle, and day. PK parameters were calculated for MLN7243 by non-compartmental analysis, as permitted by the data. The objectives of this analysis were to understand potential sources of PK variability, including patient-specific covariates, and to enable exploratory analysis of the relationship between PK and pharmacodynamic effects, pharmacogenomics, efficacy, and safety. Pharmacodynamics/Biomarker: Pharmacodynamic effects (IHC and DW-MRI) were to be performed on data from the respective Pharmacodynamic population. The study was terminated before the expansion phase, therefore DW-MRI data were not evaluated. Tumor biopsies were analyzed for IHC for the percentage of total area of the biopsy that was positive for the polyubiquitin and Ub-H2B markers as well as changes from the pretreatment percentage positive. Tumor biopsies were also analyzed by IHC to measure the MLN7243-Ub adduct formation. The percentage of patients in each dose level whose posttreatment biopsies were MLN7243-Ub adduct positive were summarized. Safety: AEs were evaluated according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.03). SUMMARY OF RESULTS: Disposition of Subjects: A total of 29 subjects were enrolled in Schedule A and received at least 1 dose of study medication. The most common reason for study discontinuation was PD, which was experienced by 19 patients (66%). Four patients (14%) discontinued due to AEs, 3 patients (10%) withdrew consent, and 3 patients (10%) discontinued due to other reasons. Demographic and Other Baseline Characteristics: Of the 29 patients in the Safety population, 59% were male, 76% were white, 17% were Black or African American, and in 7% of patients, race was not reported. The median age was 59 years, with a range of 39 to 75 years of age. The median time since initial diagnosis was 37 months, with a range of 11 to 177 months. The most common disease type at initial diagnosis was colon, colorectal or rectal carcinoma (6 patients [21%]), followed by non-small cell lung cancer, ovarian cancer, and uterine cancer (3 patients each [10%]). At initial diagnosis, 21 patients (72%) had Stage IV disease. The most common sites of cancer involvement were liver (15 patients [52%]), lung (14 patients [48%]), lymph nodes (11 patients [38%]), and bone (7 patients [24%]). Efficacy Results: The best overall response to treatment was based on the investigator s assessment of response. Of the 20 patients in the Response-Evaluable population, 1 patient (5%) had a partial response (PR), 11 patients (55%) had stable disease, and 8 patients (40%) had PD. For the patient with a PR (a 30% reduction from baseline in the sum of target lesions), the time to first response was 1.28 months, the duration of response was 6.24 months, and the number of cycles of response was 9.05. Mean duration of stable disease or better ranged from a low of 1.18 months in the 8 mg group to a high of 3.90 months in the 1 mg group.
Clinical Study Report Page 5 of 6 Pharmacokinetic Results: In the 29 patients of the PK-Evaluable population, the T max of MLN7243 was reached almost immediately at the end of IV infusion independent of the administered IV dose of MLN7243. Systemic exposure to MLN7243 in terms of maximum (peak) concentration (C max ), and AUC inf was increased with the dose administered. In general, the geometric mean t 1/2 was between 5 and 8 hours after IV administration of 4 to 18 mg of MLN7243. On the basis of these results, the dose regimen of 18.0 mg twice weekly did not show apparent accumulation of MLN7243 in plasma. Safety Results: Of the 29 patients in the Safety population, all 29 patients received treatment during Cycle 1 and 19 patients received treatment during Cycle 2. The maximum number of cycles completed was 10, which was achieved by 1 patient in the 18 mg group who had stable disease for 7.3 months. The median number of doses per cycle was 4.0 (range 1 to 4). Overall, 28 patients (97%) experienced at least 1 treatment-emergent adverse event (TEAE). The most commonly reported TEAEs were anemia (28%), nausea (28%), arthralgia (24%), vomiting (24%), and fatigue (21%). Overall, 18 patients (62%) experienced at least 1 drug-related TEAE. The most commonly reported drug-related TEAEs were nausea (7 patients; 24%), fatigue (6 patients; 21%), and vomiting (5 patients; 17%). A total of 13 patients (45%) experienced at least 1 TEAE that was reported as Grade 3. The most common TEAEs Grade 3 were anemia not elsewhere classified (NEC) (10%), anemia (10%), pneumonia (7%), and dyspnea (7%). TEAEs reported as Grade 3 and considered related to study drug occurred in 3 patients (2 patients with anemia and 1 patient with hyperlipasemia). A total of 11 patients (38%) experienced at least 1 SAE. The observed SAEs were reported in patients treated with different doses of MLN7243 with no apparent association to an increase in exposure. The observed SAEs (specific preferred terms and frequency) reported in this study were expected considering the study population was composed of patients with advanced solid tumors. Only 1 patient experienced SAEs (infusion-related reaction and presyncope) that were considered related to study drug. The event of infusion-related reactions was considered a DLT in Cycle 1, and resulted in this patient discontinuing from the study. Three patients discontinued the study due to SAEs; 1 patient with abdominal and back pain, 1 patient with presyncope and infusion-related reactions (noted above), and 1 patient with small intestinal obstruction. The events of abdominal pain, back pain, and small intestinal obstruction were assessed as not related to study drug. Four patients died within 30 days of their last dose of study drug. All of these deaths were assessed by the investigator as not related to study drug: 2 deaths were attributed to disease progression and 1 each resulted from pneumonia and sepsis. CONCLUSIONS: Study C33001 was the first clinical study of MLN7243, a first-in-class antineoplastic agent with potential for broad antitumor activity. The patient population in this study consisted of adults with advanced malignant solid tumors who had been previously diagnosed and treated, and whose disease had progressed such that they had exhausted treatment with standard therapies. The primary objective of this study was to evaluate the safety and tolerability (ie, establish the MTD, inform the RP2D, and identify the DLTs) of MLN7243. At the time of study termination, 29 patients had received at least 1 dose of study medication. Dose escalation started from an initial dose level of 1 mg and escalated, in a step-wise fashion, to the highest dose level in Schedule A of 18 mg. Only 1 DLT was reported (infusion-related reaction) in 1 patient in the 4 mg dose cohort. Patients received a median of 2 treatment cycles, ranging from 1 to 10 cycles. Overall, 18 patients (62%) had drug-related AEs, most commonly
Clinical Study Report Page 6 of 6 nausea (24%), fatigue (21%), and vomiting (17%); 3 patients (10%) had drug-related Grade 3 AEs of anemia and hyperlipasaemia. Three patients (10%) discontinued due to AEs, 11 patients experienced SAEs, and 4 patients died on study (none considered treatment related). MLN7243 concentrations peaked close to the end of the infusion, followed by a rapid distribution phase and multiphasic disposition. No accumulation of MLN7243 was observed following twice-weekly dosing. Based on limited data, dose-related increases in C max and AUC were observed. Of the 20 patients in the Response-Evaluable population, 1 patient with colorectal cancer had a PR (RECIST v1.1), showing a time to response of 1.3 months with a duration of response of 6.2 months. Eleven patients had stable disease. In this FIH trial, the MTD of MLN7243 was not established as no DLTs were reported at the highest dose level and the 18 mg dose was considered safe. MLN7243 appeared tolerable in patients with advanced solid tumors. The study was halted by the sponsor for reasons other than toxicity or lack of efficacy. REPORT DATE: 08 September 2017