Nonhematologic Neoplasms, AdvancedPhase 1NCT02699749

A Study to Evaluate TAK-931 in Participants With Advanced Nonhematologic Tumors

A Phase 1 study testing TAK-931 in people with Nonhematologic Neoplasms, Advanced, run by Millennium Pharmaceuticals, Inc. at 2 sites in Japan.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and maximum tolerated dose (MTD) of TAK-931 in participants with advanced nonhematologic tumors. Read more about this study

Who is it for?: Ages 20 years and older
Conditions the study is for: Nonhematologic Neoplasms, Advanced
What is being tested?: TAK-931
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 80 participants
Where: 2 sitesJapan
Study dates: 24 Mar 2016to 21 Dec 2019
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 20 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Histologically confirmed diagnosis of an advanced, nonhematologic/solid tumor (with the exception of primary brain tumor).
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .
For whom no effective standard therapy is available.
Life expectancy of greater than or equal to (>=3) months.
Female participants who:
Are postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the screening visit, OR

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Are surgically sterile, OR
If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, OR
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
Male participants, even if surgically sterilized (example, status postvasectomy), who:
Agree to practice effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [example, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
Agree not to donate sperm during this study and for 120 days after receiving their last dose of study drug.
Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
Ability to swallow oral medications, willingness to undergo serial skin punch biopsies, and suitable venous access for the study-required PK and pharmacodynamic sampling.
Clinical laboratory values as specified below within 28 days before the first dose of study drug:
Bone marrow reserve consistent with absolute neutrophil count (ANC) >=1500 per millimeter cube (/mm˄3), platelet count >=100,000/mm˄3, and hemoglobin >=9 per gram deciliter (g/dL).
Total bilirubin must be less than (<) 1.5 times the upper limit of normal (ULN).
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be 3 <=ULN. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of hepatocellular carcinoma, biliary tract cancer, or metastatic disease in liver.
Serum albumin >=3.0 g/dL.
Serum creatinine <1.5 times the institutional ULN or creatinine clearance based on the Cockcroft-Gault estimate >=50 milliliter per minute (mL/minute) for participants with serum creatinine concentrations above institutional limits.
Left ventricular ejection fraction (LVEF) greater than (>) 50 percent (%) as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before receiving the first dose of study drug.
Recovered (that is, <=Grade 1 toxicity) from the reversible effects of prior anticancer therapy. Participants with ongoing toxicities at baseline may be eligible; however, any Grade 2 baseline toxicity (except for alopecia) should be discussed with the medical monitor.

Who cannot join

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.
Treatment with clinically significant enzyme inducers within 14 days before the first dose of study drug.
Treatment with any investigational products within 30 days before the first dose of study drug.
Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before the first dose of study drug.
Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
History of any of the following within the last 3 months before administration of the first dose of study drug:

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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.
Thromboembolic events (example, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events).
Significant, uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia).
Use of rate control drugs for arrhythmias (including beta blockers [such as metoprolol],acetylcholine, digoxin, and non-dihydropyridine calcium channel blockers diltiazem and verapamil).
Placement of a pacemaker for control of cardiac rhythm.
Requirement for inotropic support (including digoxin).
New York Heart Association (NYHA) Class II to IV heart failure.
Any other cardiac condition that in the opinion of the investigator could pose an additional risk for the participation in the study (example, pericardial effusion or restrictive cardiomyopathy).
Baseline prolongation of the rate-corrected QT interval (QTc; example, repeated demonstration of QTc interval >480 millisecond (msec), or history of congenital, long QT syndrome, or torsades de pointes).
With any of the following blood pressure conditions:
History of orthostatic hypotension or syncope that required medical intervention. Orthostatic hypotension is defined as a 20 millimeter of mercury (mmHg) fall in systolic blood pressure and/or a 10 mmHg fall in diastolic blood pressure within 2 to 5 minutes of quiet standing immediately after a 5-minute period of supine rest.
Postural orthostatic tachycardia syndrome (POTS) or postural tachycardia syndrome (defined as an increase in heart rate of >30 beats per minute over baseline after 10 minutes of quiet standing).
Hypertension that is unstable or not controlled by medication.
Seizures requiring antiepileptic treatment.
History of uncontrolled brain metastasis unless:
Previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery.
Stable disease for ≥60 days, without steroid use (or stable steroid dose established for ≥28 days before the first dose of TAK-931).
Symptomatic and/or progressive central nervous system (CNS) metastases.
Ongoing medical conditions, such as acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before receiving the first dose of study drug.
Known history of human immunodeficiency virus (HIV) infection.
Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C (HCV) infection viral load. Note: Participants who have positive hepatitis B core antibody or hepatitis B surface antibody can be enrolled but must have an undetectable hepatitis B viral load. Participants who have positive hepatitis C antibody must have an undetectable hepatitis C viral load.
Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI absorption of study drug, such as total gastrectomy or GI conditions that could substantially modify gastric pH.

Trial locations and contacts

2 sites in 1 country.

Japan2 sites

Study site
Chuo-ku, Tokyo
Study site
Kashiwa, Chiba

Other trials in Japan

About this study

Official title: An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in Adult Patients With Advanced Nonhematologic Tumors

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and maximum tolerated dose (MTD) of TAK-931 in participants with advanced nonhematologic tumors.

Read the detailed description

The drug being under investigation in this study is called TAK-931. The effect of TAK-931 is being evaluated in up to 100 participants who have nonhematologic (solid) neoplasms. This study will look at the safety, tolerability, and PK to determine the maximum tolerated dose (MTD) of TAK-931.

This multi-center trial will be conducted in Japan. The overall study duration is approximately 42 months for total of dose escalation cohorts and the safety expansion cohort. Participants will make multiple visits to the clinic with final visit approximately 30-40 days after last dose of study drug for a follow-up assessment.

Conditions: Nonhematologic Neoplasms, Advanced
Being tested: TAK-931
Keywords: Drug Therapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

TAK-931Drug
TAK-931 oral capsules.

Study groups in NCT02699749
Study group	Role	What they receive
TAK-931	Experimental	TAK-931 30 mg, capsules, orally, QD or BID on Days 1-14 of each 21-day treatment cycle in dosing schedule A followed by dosing schedule B, C, D, E and F. In dosing schedules B through F, starting doses and dosing escalations will vary depending on the dosing data obtained from dosing in the previous schedule. Dose escalation of TAK-931 will be based on evaluation of clinical safety and tolerability and guided by accumulating PK data. 3-4 dose cohorts are expected for each dosing schedule. If the PK from the early cohorts support BID dosing, then study drug administration in subsequent cohorts may transition to a BID dosing schedule. Receives: Drug: TAK-931

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03
Toxicity was evaluated by NCI CTCAE v4.03. DLT:any of following occurred events during Cycle 1 considered by investigator to be possibly related to therapy:1)Grade4 neutropenia,2)Febrile neutropenia lasting greater(>)1 hour,3)Grade greater than or equal to (>=)3 neutropenia with infection,4)Grade >=3 thrombocytopenia with bleeding,4)Grade 4 thrombocytopenia,5)delay in initiation of Cycle 2 by >14 days,6)Grade 2:<Grade 2 ejection fraction,7)other Grade 2 nonhematologic toxicities considered by investigator related to study drug and DLTs,8)who received <50 percent of doses of planned TAK-931 dosing in Cycle 1 for related AEs:<7 QD/<14 BID doses (Schedules A,B);<11 QD/<21 BID doses(Schedule D),<3 QD/<6 BID doses for(Schedule E),9)Grade >=3 nonhematologic toxicity except arthralgia/myalgia and fatigue, isolated >=Grade 3 laboratory abnormalities if it is asymptomatic and resolves to <=Grade 1 or baseline levels in <=7 days;inadequately treated Grade 3 nausea and/or vomiting and diarrhea.
Measured: Baseline up to Cycle 1 (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs)
Measured: Baseline up to 30 days after the last dose of study drug or before initiation of new anti-cancer therapy (up to Day 499)

Secondary outcomes (14)

Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931
Measured: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931
Measured: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931
Measured: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931
Measured: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8 and 12 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931
Measured: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931
Measured: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931
Measured: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931
Measured: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931
Measured: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931
H-score were a composite score that comprised of intensity and percentage of staining and were used for assessing amount of protein (in this case pMCM2 [Ser40]) present in a tissue sample. The composite score obtained by H-score is derived by adding of the percentages of cell staining at each intensity level multiplied by the weighted intensity of staining (0 [no staining], 1+ [weak staining], 2+ [medium staining], 3+ [strong staining]). The H-score has a range of 0 to 300. Lower H-scores represent lower expression of pMCM2 (Ser40) in the tissue sample, while higher scores represent stronger expression of pMCM2 (Ser40) in the tissue samples.
Measured: Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days)
Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931
Positive index was calculated by taking the number of cells staining positive for the marker over the total number of cells.
Measured: Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days)
Overall Response Rate (ORR)
ORR was defined as percentage of participants who had achieved complete response (CR) and partial response (PR), as measured by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V 1.1). CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (<) 10 millimeter (mm). PR: was at least a 30 percent (%) decrease in sum of diameter (SOD) of target lesions, taking as reference the baseline SOD.
Measured: From date of first dose to the date of first documentation of progressive disease (PD) or death due to any cause, which ever occurred first (up to Month 45)
Progression-free Survival (PFS)
PFS was defined as the time from the date of first dose to the date of first documentation of PD or death due to any cause, whichever occurs first, as measured by RECIST V1.1. PD: 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PFS was analyzed using the Kaplan-Meier method.
Measured: From date of first dose to the date of first documentation of PD or death due to any cause, which ever occurred first (up to Month 45)
Duration of Response (DOR)
The DOR was defined as the time from the date of first documentation of a response (CR or PR) to the date of first documentation of PD, as measured by RECIST V 1.1. CR: was disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR: was at least a 30% decrease in SOD of target lesions, taking as reference the baseline SOD. PD: 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. DOR was analyzed using the Kaplan-Meier method.
Measured: From the date of first documentation of response to the date of first documentation of PD (up to Month 45)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

24 Mar 201621 Dec 2019

First posted4 Mar 2016 (estimated)
Study start24 Mar 2016
Primary completion21 Dec 2019
Study completion21 Dec 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Nonhematologic Neoplasms, AdvancedStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Other
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 80 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02699749
Sponsor's protocol ID: TAK-931-1002 Merge to Takeda
Other IDs: U1111-1181-0269, JapicCTI-163200
Status last verified: Feb 2021
First submitted: 29 Feb 2016
Last updated: 21 Feb 2021
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: 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.

Publications

Kuboki Y, Shimizu T, Yonemori K, Kojima T, Kondo S, Koganemaru S, Iwasa S, Harano K, Koyama T, Lu V, Zhou X, Niu H, Yanai T, Garcia-Ribas I, Doi T, Yamamoto N. Safety, Tolerability, and Pharmacokinetics of TAK-931, a Cell Division Cycle 7 Inhibitor, in Patients with Advanced Solid Tumors: A Phase I First-in-Human Study. Cancer Res Commun. 2022 Nov 14;2(11):1426-1435. doi: 10.1158/2767-9764.CRC-22-0277. eCollection 2022 Nov.
PubMed 36970056
Martin JC, Sims JR, Gupta A, Bakin AV, Ohm JE. WEE1 inhibition augments CDC7 (DDK) inhibitor-induced cell death in Ewing sarcoma by forcing premature mitotic entry and mitotic catastrophe. Cancer Res Commun. 2022 Jun;2(6):471-482. doi: 10.1158/2767-9764.crc-22-0130. Epub 2022 Jun 20.
PubMed 36338546

Study at a glance

From the registry record, last updated by the sponsor on 21 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: An Open-Label, Phase 1, Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-931, a Cell Division Cycle 7 (CDC7) Inhibitor, in Adult Patients With Advanced Nonhematologic Tumors
ClinicalTrials.gov ID: NCT02699749
Acronym / sponsor ID: TAK-931-1002 Merge to Takeda
Conditions: Nonhematologic Neoplasms, Advanced
Keywords: Drug Therapy
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 80 participants (actual)
Lead sponsor: Millennium Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
Study start: 24 Mar 2016 (actual)
Primary completion: 21 Dec 2019 (actual)
Study completion: 21 Dec 2019 (actual)
First posted: 4 Mar 2016 (estimated)
Results: Posted 21 Feb 2021

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and maximum tolerated dose (MTD) of TAK-931 in participants with advanced nonhematologic tumors.

Detailed description

Study design

Primary purpose: Other
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
TAK-931	Experimental	Drug: TAK-931TAK-931 30 mg, capsules, orally, QD or BID on Days 1-14 of each 21-day treatment cycle in dosing schedule A followed by dosing schedule B, C, D, E and F. In dosing schedules B through F, starting doses and dosing escalations will vary depending on the dosing data obtained from dosing in the previous schedule. Dose escalation of TAK-931 will be based on evaluation of clinical safety and tolerability and guided by accumulating PK data. 3-4 dose cohorts are expected for each dosing schedule. If the PK from the early cohorts support BID dosing, then study drug administration in subsequent cohorts may transition to a BID dosing schedule.

Who may qualify

Ages: 20 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (23 listed)

Histologically confirmed diagnosis of an advanced, nonhematologic/solid tumor (with the exception of primary brain tumor).
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .
For whom no effective standard therapy is available.
Life expectancy of greater than or equal to (>=3) months.
Female participants who:

Key exclusion criteria (29 listed)

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.
Treatment with clinically significant enzyme inducers within 14 days before the first dose of study drug.
Treatment with any investigational products within 30 days before the first dose of study drug.
Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before the first dose of study drug.
Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TAK-931TAK-931 oral capsules.	Drug	TAK-931

Primary outcome

Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03
Time frame: Baseline up to Cycle 1 (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Toxicity was evaluated by NCI CTCAE v4.03. DLT:any of following occurred events during Cycle 1 considered by investigator to be possibly related to therapy:1)Grade4 neutropenia,2)Febrile neutropenia lasting greater(>)1 hour,3)Grade greater than or equal to (>=)3 neutropenia with infection,4)Grade >=3 thrombocytopenia with bleeding,4)Grade 4 thrombocytopenia,5)delay in initiation of Cycle 2 by >14 days,6)Grade 2:<Grade 2 ejection fraction,7)other Grade 2 nonhematologic toxicities considered by investigator related to study drug and DLTs,8)who received <50 percent of doses of planned TAK-931 dosing in Cycle 1 for related AEs:<7 QD/<14 BID doses (Schedules A,B);<11 QD/<21 BID doses(Schedule D),<3 QD/<6 BID doses for(Schedule E),9)Grade >=3 nonhematologic toxicity except arthralgia/myalgia and fatigue, isolated >=Grade 3 laboratory abnormalities if it is asymptomatic and resolves to <=Grade 1 or baseline levels in <=7 days;inadequately treated Grade 3 nausea and/or vomiting and diarrhea.
Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs)
Time frame: Baseline up to 30 days after the last dose of study drug or before initiation of new anti-cancer therapy (up to Day 499)

14 secondary outcomes

Cmax: Maximum Observed Plasma Concentration After First Dose of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After First Dose of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After First Dose of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUC12: Area Under the Plasma Concentration-time Curve From 0 to 12 Hours After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8 and 12 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After First Dose of TAK-931
Time frame: Cycle 1 Day 1: pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUC24: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Multiple Doses of TAK-931
Time frame: Cycle 1 Day 8 (Schedule A and D), Cycle 1 Day 7 (Schedule B), Cycle 1 Day 9 (Schedule E): pre-dose and 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])
Schedule A, B and D: Change From Baseline in Phosphorylated Minichromosome Maintenance Complex-2 (pMCM2) (Ser40) Levels in Skin Based on Histological Score Nuclei (H-score) After Multiple Doses Of TAK-931
Time frame: Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days)
Schedule A, B and D: Change From Baseline in pMCM2 (Ser40) Levels in Skin Based on Positive Index After Multiple Doses Of TAK-931
Time frame: Cycle 1 Day 1 pre-dose up to any dosing day after 3 consecutive days post-dose (up to Cycle 1 Day 8 [Schedule A and D]; Cycle 1 Day 7 [Schedule B]; Cycle 1 Day 12 [Schedule D]) (Cycle Length of Schedules A and D = 21 days; and Schedule B= 28 days)
Overall Response Rate (ORR)
Time frame: From date of first dose to the date of first documentation of progressive disease (PD) or death due to any cause, which ever occurred first (up to Month 45)
Progression-free Survival (PFS)
Time frame: From date of first dose to the date of first documentation of PD or death due to any cause, which ever occurred first (up to Month 45)
Duration of Response (DOR)
Time frame: From the date of first documentation of response to the date of first documentation of PD (up to Month 45)

Results and safety

Results posted to the registry on 21 Feb 2021, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Schedule A: TAK-931 30 mg	3	0
Schedule A: TAK-931 40 mg	3	0
Schedule A: TAK-931 50 mg	16	0
Schedule A: TAK-931 60 mg	3	0
Schedule B: TAK-931 60 mg	3	0
Schedule B: TAK-931 80 mg	9	0
Schedule B: TAK-931 100 mg	6	0
Schedule B: TAK-931 120 mg	6	0
Schedule D: TAK-931 20 mg	6	0
Schedule D: TAK-931 30 mg	6	0
Schedule D: TAK-931 40 mg	6	0
Schedule E: TAK-931 100 mg	4	0
Schedule E: TAK-931 120 mg	3	0
Schedule E: TAK-931 150 mg	6	0

Primary outcome: Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03

Time frame: Baseline up to Cycle 1 (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B]). Count of participants. Unit: Participants

Measure	Schedule A: TAK-931 30 mg n = 3	Schedule A: TAK-931 40 mg n = 3	Schedule A: TAK-931 50 mg n = 16	Schedule A: TAK-931 60 mg n = 3	Schedule B: TAK-931 60 mg n = 3	Schedule B: TAK-931 80 mg n = 9	Schedule B: TAK-931 100 mg n = 6	Schedule B: TAK-931 120 mg n = 6	Schedule D: TAK-931 20 mg n = 6	Schedule D: TAK-931 30 mg n = 6	Schedule D: TAK-931 40 mg n = 6	Schedule E: TAK-931 100 mg n = 4	Schedule E: TAK-931 120 mg n = 3	Schedule E: TAK-931 150 mg n = 6
Value	0	0	0	2	0	2	1	1	0	0	1	0	0	2

Population analysed: The DLT-evaluable population was defined as all participants who received at least 75% of their planned TAK-931 doses for their first cycle of treatment (unless interrupted by study drug-related AEs) and who had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.

Primary outcome: Number of Participants With Reporting One or More Treatment-emergent Adverse Events (TEAEs)

Time frame: Baseline up to 30 days after the last dose of study drug or before initiation of new anti-cancer therapy (up to Day 499). Count of participants. Unit: Participants

Measure	Schedule A: TAK-931 30 mg n = 3	Schedule A: TAK-931 40 mg n = 3	Schedule A: TAK-931 50 mg n = 16	Schedule A: TAK-931 60 mg n = 3	Schedule B: TAK-931 60 mg n = 3	Schedule B: TAK-931 80 mg n = 9	Schedule B: TAK-931 100 mg n = 6	Schedule B: TAK-931 120 mg n = 6	Schedule D: TAK-931 20 mg n = 6	Schedule D: TAK-931 30 mg n = 6	Schedule D: TAK-931 40 mg n = 6	Schedule E: TAK-931 100 mg n = 4	Schedule E: TAK-931 120 mg n = 3	Schedule E: TAK-931 150 mg n = 6
Value	3	3	16	3	3	9	6	6	5	6	6	4	3	6

Population analysed: The safety population was defined as all participants who received any amount of study drug.

14 secondary outcomes are reported in the full results.

Adverse events

Time frame: TEAEs are adverse events (AEs) that started after the first dose of study drug through 30 days after the last dose of study drug or before initiation of new anti-cancer therapy (whichever occurred first) (up to Day 499). Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Schedule A: TAK-931 30 mg	0 of 3 (0%)	3 of 3 (100%)	0 of 3
Schedule A: TAK-931 40 mg	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
Schedule A: TAK-931 50 mg	5 of 16 (31.3%)	16 of 16 (100%)	0 of 16
Schedule A: TAK-931 60 mg	2 of 3 (66.7%)	3 of 3 (100%)	0 of 3
Schedule B: TAK-931 60 mg	1 of 3 (33.3%)	3 of 3 (100%)	0 of 3
Schedule B: TAK-931 80 mg	2 of 9 (22.2%)	9 of 9 (100%)	0 of 9
Schedule B: TAK-931 100 mg	1 of 6 (16.7%)	6 of 6 (100%)	0 of 6
Schedule B: TAK-931 120 mg	1 of 6 (16.7%)	6 of 6 (100%)	0 of 6
Schedule D: TAK-931 20 mg	1 of 6 (16.7%)	5 of 6 (83.3%)	0 of 6
Schedule D: TAK-931 30 mg	1 of 6 (16.7%)	6 of 6 (100%)	0 of 6
Schedule D: TAK-931 40 mg	3 of 6 (50%)	6 of 6 (100%)	0 of 6
Schedule E: TAK-931 100 mg	2 of 4 (50%)	4 of 4 (100%)	0 of 4
Schedule E: TAK-931 120 mg	0 of 3 (0%)	3 of 3 (100%)	0 of 3
Schedule E: TAK-931 150 mg	3 of 6 (50%)	6 of 6 (100%)	1 of 6

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 21 Feb 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 36970056Kuboki Y, Shimizu T, Yonemori K, Kojima T, Kondo S, Koganemaru S, Iwasa S, Harano K, Koyama T, Lu V, Zhou X, Niu H, Yanai T, Garcia-Ribas I, Doi T, Yamamoto N. Safety, Tolerability, and Pharmacokinetics of TAK-931, a Cell Division Cycle 7 Inhibitor, in Patients with Advanced Solid Tumors: A Phase I First-in-Human Study. Cancer Res Commun. 2022 Nov 14;2(11):1426-1435. doi: 10.1158/2767-9764.CRC-22-0277. eCollection 2022 Nov.
Derived from this study: PubMed 36338546Martin JC, Sims JR, Gupta A, Bakin AV, Ohm JE. WEE1 inhibition augments CDC7 (DDK) inhibitor-induced cell death in Ewing sarcoma by forcing premature mitotic entry and mitotic catastrophe. Cancer Res Commun. 2022 Jun;2(6):471-482. doi: 10.1158/2767-9764.crc-22-0130. Epub 2022 Jun 20.
Individual participant dataSharing planned: 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.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Study Director study director

Takeda

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing TAK-931 in people with Nonhematologic Neoplasms, Advanced, run by Millennium Pharmaceuticals, Inc. at 2 sites in Japan.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Japan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Dose Limiting Toxicities (DLTs) Assessed by National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) Version 4.03 (time frame: Baseline up to Cycle 1 (Cycle length= 21 days [Schedules A, D and E] and 28 days [Schedule B])). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02699749, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Feb 2021.