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An Open-Label, Phase 2, Parallel Arm Study to Evaluate the Safety, Tolerability, and Activity of TAK-931 Single Agent in Patients with Metastatic Pancreatic Cancer, Metastatic Colorectal Cancer, and Other Advanced Solid Tumors

A Study to Evaluate the Safety, Tolerability, and Activity of TAK-931 in Participants with Metastatic Pancreatic Cancer, Metastatic Colorectal Cancer, and Other Advanced Solid Tumors

101

More than half (60.4%) of the overall population was male, and the median age was 63 years with a range of 36 to 88 years. Overall, 63.4% of the patients were white, 25.7% were Japanese, and 7.9% were Black. The most common disease type at diagnosis was colon cancer (23.8%), followed by esophageal cancer (20.8%), pancreatic cancer (17.8%), and sqNSCLC (16.8%). All other diagnoses were reported in <10% of patients. The majority (91.1%) of patients had Stage IV cancer at study entry.

A total of 101 patients with histologically confirmed, nonhematologic tumors were enrolled in the study, received at least 1 dose of TAK 931, and were included in the safety population. All 101 patients (100%) discontinued study treatment, the primary reason being progressive disease (PD) (80.2%).

In the Western safety cohort, 12 patients (100%) experienced at least 1 TEAE. Ten patients (83.3%) experienced drug related TEAEs. Eleven patients (91.7%) experienced Grade 3 or higher TEAEs, and 5 patients (41.7%) experienced at least 1 drug related Grade 3 or higher TEAE. One patient in the Western safety cohort experienced Grade 4 neutropenia that lasted for more than 7 consecutive days and therefore met the criteria for a DLT. Among the most commonly reported TEAEs in the Western safety cohort were nausea, decreased appetite, abdominal pain (50.0% each), fatigue, myalgia (41.7% each), vomiting, neutrophil count decreased, dyspnea, back pain, dizziness, weight decreased (33.3% each), constipation, headache, insomnia, pruritus, upper respiratory tract infection, and depression (25.0% each). The most frequently reported all Grade drug related TEAEs were nausea, fatigue (41.7% each), and myalgia (25.0%). The most commonly reported Grade 3 or higher TEAEs in the Western safety cohort were neutrophil count decreased (33.3%), hyponatremia, and malignant pleural effusion (16.7% each). The most commonly reported Grade 3 or higher drug related TEAE was neutrophil count decreased (33.3%). In the Western safety cohort, 7 patients (58.3%) experienced at least 1 treatment emergent SAE. The most common treatment emergent SAE in the Western safety cohort was malignant pleural effusion (2 patients, 16.7%). Other treatment emergent SAEs in the Western safety cohort were reported in 1 patient each. In the Western safety cohort, 1 patient (8.3%) experienced a TEAE (neutrophil count decreased) leading to study drug discontinuation. The event was considered related to the study treatment. In the Western safety cohort, 4 patients (33.3%) experienced a TEAE leading to study drug modification. Three patients (25.0%) experienced neutrophil count decreased and 1 patient experienced neutropenia that was related to neutrophil count decreased but coded under a separate MedDRA term. All other TEAEs leading to study drug modifications were experienced by 1 patient each in the Western safety cohort. No deaths on study treatment occurred in the Western safety cohort. Across all study cohorts, 98 patients (97.0%) reported at least 1 TEAE. Eighty two patients (81.2%) experienced drug related TEAEs. Sixty one patients (60.4%) experienced Grade 3 or higher TEAEs, and 34 patients (33.7%) experienced at least 1 drug related Grade 3 or higher TEAE. Across all study cohorts, the most commonly reported TEAEs were nausea (47.5%), vomiting (35.6%), decreased appetite (33.7%), neutrophil count decreased (26.7%), fatigue (23.8%), and abdominal pain (20.8%). The most frequently reported all Grade drug-related TEAEs were nausea (37.6%), neutrophil count decreased (26.7%), and decreased appetite (22.8%). The most commonly reported Grade 3 or higher TEAEs were neutrophil count decreased (20.8%), white blood cell count decreased (10.9%), and abdominal pain (5.9%). The most commonly reported Grade 3 or higher drug-related TEAEs were neutrophil count decreased (19.8%), white blood cell count decreased (10.9%), anemia (7.9%), and neutropenia (5.0%). The neutropenia reported in this study was related to neutrophil count decreased but coded under a separate MedDRA term. Across all study cohorts, 29 patients (28.7%) experienced at least 1 treatment-emergent SAE. The most common treatment-emergent SAEs overall were abdominal pain (3 patients [3%]), upper gastrointestinal hemorrhage, small intestinal obstruction, nausea, and dyspnea (2 patients [2%] each). Other treatment-emergent SAEs were reported in 1 patient each. Eight patients overall (7.9%) had TEAEs that led to discontinuation of study drug, including 3 patients with events that were assessed by the investigators as related to study drug (neutrophil count decreased and ejection fraction decreased). Six on-study treatment deaths occurred across all study cohorts. Five patient deaths were considered by the investigators to be unrelated to the study drug: 1 patient died of worsening of sepsis and 4 patients died of the disease under study (2 patients of CRC, 1 patient of pancreatic cancer, and 1 patient of sqEC). One patient death due to alveolar hemorrhage and pneumonitis was considered by the investigators to be related to the study drug.

Efficacy Results: DCR: Across all study cohorts, the DCR was 52.2% (48 patients). Safety Results: Refer to "Adverse Events"

Efficacy Results: ORR: The ORR was 2.2% across all cohorts, with a total of 2 patients (1 patient each in the Western safety cohort and sqEC cohort) achieving PR. No patients achieved CR. PFS: Overall, 97 patients (96.0%) experienced PD or death; 4 patients (4.0%) were censored. The overall median (95% CI) time to event was 1.64 months (1.38, 2.60). OS: Overall, the median survival was 7.03 months. A total of 63 patients (62.4%) died; 38 patients (37.6%) were censored. Pharmacokinetic Results: Following oral administration of TAK 931 at 50 mg, the peak plasma concentration of TAK 931 was generally achieved approximately 2 hours post-dose in cancer patients in the 3 cohorts. The t1/2 of TAK-931 was 4 to 6 hours. The accumulation ratio was 1.1 to 1.3 following multiple-dose administration, which is consistent with the estimated t1/2 of TAK 931. The CLss/F was 37, 42 and 34 L/h in patients in the Western safety, pancreatic and metastatic CRC, respectively. The CLss/F was comparable in the 3 cohorts, indicating that cancer type had no impact on TAK 931 PK. The CLr of TAK 931 was approximately 4% of the apparent oral clearance, indicating that CLr plays a minor role in eliminating TAK 931. Safety Results: Refer to "Adverse Events" Conclusion (continued) - The overall response rate was 2.2% across all cohorts. Overall, 96.0% of patients experienced progressive disease or death and the median survival follow up time was 7.03 months. A total of 63 patients (62.4%) died; 38 patients (37.6%) were censored. - Following oral administration of TAK 931, time to first occurrence of maximum plasma concentration was generally achieved 2 hours post dose. The terminal disposition phase half life of TAK-931 was 4 to 6 hours and the accumulation ratio was 1 to 1.3 following multiple-dose administration. The renal clearance was approximately 4% of the apparent oral clearance.

The results of this study are summarized as follows: - TAK 931 was tolerable in Western patients with locally advanced or metastatic solid tumors and in patients of Western and Japanese ethnicity with disease-specific advanced nonhematologic tumors. TAK-931 had an acceptable safety profile for the treatment of the populations studied. - Overall, the disease control rate was 52.2%. Continued to " Secondary Outcome Measures"

Yes

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Takeda Pharmaceutical Company Limited

https://www.takeda.com/who-we-are/contact-us/

Takeda Pharmaceutical Company Limited

https://www.takeda.com/who-we-are/contact-us/

+81-6-6204-2111

completed

Oct. 25, 2017

Interventional

Open-Label, Parallel Arm Study

treatment purpose

2

1.Adult male or female participants aged >=20 years (Japan) or >=18 years (United States).
2.Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
3.Has pathologically confirmed metastatic pancreatic adenocarcinoma that has progressed after, at least, a first line of standard systemic chemotherapy for the metastatic disease, OR participants with pathologically confirmed metastatic adenocarcinoma of the colon or rectum who have progressed to at least 2 lines of standard systemic chemotherapy for the metastatic disease, OR participants with pathologically confirmed locally advanced or metastatic sqEC that has progressed after at least a first line of standard systemic therapy for metastatic disease. First-line participants can be enrolled if a platinum doublet is contraindicated or refused by the participants, OR pathologically confirmed locally advanced or metastatic sqNSCLC that has progressed after at least 2 lines of standard systemic therapy for metastatic disease.
4.For the Western safety cohort only: participants with locally advanced or metastatic solid tumor for whom no standard treatment with an established survival benefit is available or if the participant refuses other standard therapy.
5.For disease-specific cohort participants: measurable disease per RECIST V1.1
6.Left ventricular ejection fraction >50% as measured by echocardiogram (ECHO) or multiple gated acquisition (MUGA) scan within 4 weeks before receiving the first dose of study drug.
7.Recovered to Grade 1 or baseline from all toxic effects of previous therapy (except alopecia or neuropathy).
8.Suitable venous access for the study-required blood sampling.
9.For the Western safety cohort only: willingness to undergo serial skin tissue biopsies.
10.For disease-specific cohort participants: Must have an archival (banked) tumor sample or agree to have a new (fresh) tumor biopsy during the screening period. If a new tumor sample is needed, the disease should be accessible for a nonsignificant risk biopsy procedure (those occurring outside the brain, lung/mediastinum, and pancreas, or obtained with endoscopic procedures not extending beyond the stomach or bowel). For participants in the Western safety cohort, this biopsy is optional.

1.Participants who require continuous use of proton pump inhibitors (PPIs) or histamine-2 (H2) receptor antagonists and participants who are taking PPIs within 5 days before the first dose of study drug.
2.Treatment with clinically significant enzyme inducers, such as phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin, rifapentine, or Saint John's wort within 14 days before the first dose of study drug.
3.Treatment with any systemic anticancer treatment (including investigational products) within 30 days or 5 half-lives, whichever is shorter, before the first dose of study drug.
4.History of any of the following within the last 3 months before administration of the first dose of study drug:
- Ischemic myocardial event including angina requiring therapy and artery revascularization procedures, myocardial infarction, and unstable symptomatic ischemic heart disease.
- Ischemic cerebrovascular event, including transient ischemic attack and artery, revascularization procedures.
- Significant, uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
- New York Heart Association Class III to IV heart failure.
- Any other cardiac condition that, in the opinion of the investigator, could pose an additional risk for participation in the study (e.g., pericardial effusion or restrictive cardiomyopathy).
- Baseline prolongation of the QT interval corrected for heart rate (HR) using Fridericia's formula (QT interval corrected for heart rate using Fridericia's formula (QTcF); e.g., repeated demonstration of QTcF interval >480 millisecond (ms), history of congenital long QT syndrome, or torsades de pointes).
5.Hypertension that is unstable or not controlled by medication.
6.History of uncontrolled brain metastasis unless:
- Previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery, and
- Stable disease (SD) for >=30 days, without steroid use (or stable steroid dose established for >=14 days before the first dose of TAK-931).
7.Known history of human immunodeficiency virus infection.
8.Known hepatitis B virus (HBV) surface antigen seropositive or detectable hepatitis C virus (HCV) infection viral load. Note: Participants who have positive HBV core antibody or HBV surface antigen antibody can be enrolled but must have an undetectable HBV viral load.
9.Prior treatment with radiation therapy involving >=25% of the hematopoietically active bone marrow within 3 months before the first dose of study drug.
10.Participants with known microsatellite instability-high (MSI-H) genotype or known wild type tumor protein 53 (TP53) per local testing.
11.Western Safety Cohort Only: Participants with Japanese heredity.

Both

Metastatic pancreatic cancer; Colorectal cancer; Esophageal neoplasms; Carcinoma, non-small-cell lung

investigational material(s)
Generic name etc : TAK-931
INN of investigational material : -
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : TAK-931 50 mg, capsules, orally, once daily for 14 days, followed by 7-day washout period, in 21-day cycles until disease progression or unacceptable treatment-related toxicity (Up to 1 year).

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : -

safety
Percentage of Participants with Dose Limiting Toxicities (DLTs) in Western Safety Cohort
Timeframe; Cycle 1 (each cycle = 21 days)
DLT: Any following event related to TAK-931 assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03; Non-febrile Grade 4 neutropenia lasting more than 7 consecutive days; Febrile neutropenia: Grade >=3 neutropenia with fever and/or
infection; Grade 4 thrombocytopenia; Grade >=3 thrombocytopenia of any duration accompanied by Grade 2 bleeding or requiring transfusion; delay in the initiation of cycle 2 by more than 14 days due to a lack of adequate recovery of treatment-related hematological or nonhematologic toxicities; Grade 2 ejection fraction decreased by ECHO or MUGA scan; Grade 4 laboratory abnormalities; other Grade 2 nonhematologic toxicities considered by the investigator to be related to study drug and dose-limiting; Participants receiving <50% of doses (<7 doses) of the planned TAK-931 dosing in cycle 1 due to study drug-related adverse events (AEs); Grade >=3 nonhematologic toxicity with the few exceptions: Grade 3 arthralgia/ myalgia, fatigue, laboratory abnormalities, nausea and/or emesis or diarrhea.
safety
Percentage of Participants with Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), TEAEs Leading to Dose Modifications and TEAEs Leading to Treatment Discontinuation in Western Safety Cohort
Timeframe; From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.



efficacy
Disease Control Rate (DCR) in Tumor Specific Cohorts
Timeframe; Up to end of treatment (Up to approximately 14 months)
DCR is defined as percentage of participants documented to have unconfirmed complete response (CR), partial response (PR) or stable disease (SD) >=6 weeks from treatment initiation according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) as the best response.. CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of lesions, taking as reference the baseline sum LD. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started. (PD is defined as at least a 20% increase in the sum of the LD of lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions

pharmacokinetics
Cmax: Maximum Observed Plasma Concentration for TAK-931
Timeframe; Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose

pharmacokinetics
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-931
Timeframe; Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose

pharmacokinetics
AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose for TAK-931
Timeframe; Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose

pharmacokinetics
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-931
Timeframe; Cycle 1 (each cycle = 21 days) Days 1 and 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose

pharmacokinetics
CLr: Renal Clearance of TAK-931
Timeframe; Cycle 1 (each cycle = 21 days) Day 1 pre-dose and at multiple timepoints (up to 24 hours) post-dose
CLr is a measure of apparent clearance of the drug from the urine. The clearance is the rate at which waste substances are cleared from the blood.



pharmacokinetics
t1/2z: Terminal disposition phase half-life
Timeframe; Cycle 1 (each cycle = 21 days) Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose

pharmacokinetics
CLss/F: Steady-state Apparent Oral Clearance
Timeframe; Cycle 1 (each cycle = 21 days) Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose
CL/F is defined as apparent clearance of the drug from the plasma, calculated as the drug dose divided by AUC.



pharmacokinetics
Rac(AUC): Accumulation Ratio Based on AUC Over the Dosing Interval (AUCt)
Timeframe; Cycle 1 (each cycle = 21 days) Day 8 pre-dose and at multiple timepoints (up to 24 hours) post-dose

efficacy
Overall Response Rate (CR and PR)
Timeframe; Up to end of treatment (Up to approximately 14 months)
Overall Response rate is defined as percentage of participants documented to have unconfirmed CR or PR according to RECIST V1.1 as the best response.. CR is defined as disappearance of all lesions, PR is defined as at least a 30% decrease in the sum of the LD of lesions, taking as reference the baseline sum LD.



efficacy
Duration of Response (DOR)
Timeframe; From first documented response until disease progression (Up to 34 months)
DOR is defined as the time from the date of first documentation of a CR or PR to the date of first documentation of tumor progression. Per RECIST V1.1, CR is defined as disappearance of all lesions, PR is defined as at least a 30% decrease in the sum of the LD of lesions, taking as reference the baseline sum LD. PD is defined as at least a 20% increase in the sum of the LD of lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.



efficacy
Progression Free Survival (PFS)
Timeframe; From date of randomization until disease progression or death whichever occurs first (Up to approximately 34 months)
PFS is defined as the time from the date of first dose to the date of first documentation of PD (including clinical progression or clinical deterioration) or death due to any cause, whichever occurs first. Per RECIST V1.1, PD is defined as at least a 20% increase in the sum of the LD of lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.



efficacy
Overall Survival (OS)
Timeframe; From date of randomization until death due to any cause (Up to approximately 34 months)
OS is defined as the time from the date of first dose of study drug to death due to any cause.



safety
Percentage of Participants with Grade >=3 TEAEs, SAEs, TEAEs Leading to Dose Modifications, and TEAEs Leading to Treatment Discontinuation in the Tumor-Specific Cohorts
Timeframe; From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it did not necessarily have to have a causal relationship with this treatment. A TEAE was defined as an adverse event with an onset that occurred after receiving study drug. TEAEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, where Grade 3:Severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4:Life-threatening consequences, urgent intervention indicated; Grade 5:Death related to AE. A SAE was any untoward medical occurrence or effect that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was medically important due to other reasons than the above mentioned criteria.



safety
Number of Participants with Clinically Significant Changes in Laboratory Values Reported as Adverse Events in Tumor-Specific Cohorts
Timeframe; From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
Clinical laboratory tests included hematology, clinical chemistry and urinalysis. The investigator determined if the results were clinically significant. Only those categories were reported which are clinically significant at post Baseline.

safety
Percentage of Participants with Clinically Significant Changes in Vital Sign Measurements, Reported as Adverse Events in Tumor-Specific Cohorts
Timeframe; From first dose of the study drug up to 30 days after the last dose (Up to approximately 15 months)
Vital signs included assessments of systolic and diastolic blood pressure (BP), heart rate (HR), and body temperature. The investigator determined if the results were clinically significant. Only those categories were reported which are clinically significant at post Baseline.

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Jan. 31, 2018