Antineoplastic Agents

All Drugs and Chemicals

TAS-119

Protein Kinase Inhibitors

Enzyme Inhibitors

Dose Escalation:

A Monotherapy Dose-Escalation Phase Performed in Approximately 5 Dose Levels (3 to 12 Patients Per Dose Level) to Determine the MTD for TAS-119 Given Orally (PO), Twice-Daily (BID) in a 28-Day Treatment Cycle; and:

Dose Expansion:

A Monotherapy Expansion Phase in Which Approximately 40 Additional Patients will be Enrolled to Further Evaluate the Recommended Phase II Dose (RP2D)

A Phase 1, Open-Label, Non-Randomized, Dose-Escalating Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of TAS-119 in Patients with Advanced Solid Tumors.

This is a Phase 1, open-label, non-randomized, dose escalation study of TAS-119 evaluating the safety, tolerability, PK, pharmacogenomics, pharmacodynamics, and preliminary antitumour activity in patients with advanced and unresectable solid tumours. The study will evaluate TAS-119 monotherapy, employing two sequential phases.

* A Dose Escalation Phase
* An Expansion Phase

An Investigation of TAS-119 Monotherapy

A Phase I, Open-Label, Non-Randomized, Dose-Escalating Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Study of TAS-119 in Patients With Advanced Solid Tumors

Identify the Maximum Tolerated Dose (MTD) and the Recommended Phase 2 Dose (RP2D) of TAS-119

Taiho Oncology, Inc.

Paclitaxel

Albumin-Bound Paclitaxel

Taxane

Tubulin Modulators

Antimitotic Agents

TAS-119 tablets, oral, dose-escalating, 28-day cycle.

Paclitaxel (90mg/m2) is administered IV in combination with TAS-119 in each of the arms.

A dose of 90 mg/m2 is used in combination with various doses of TAS-119.

The purpose of this study is to determine the safety of TAS-119 and determine the most appropriate dose in combination with Paclitaxel for subsequent studies in patients with advanced solid tumors.

TAS-119 is a novel, selective Aurora A kinase inhibitor, which has previously been demonstrated to enhance the activity of paclitaxel in preclinical studies

Background and rationale for study:

In nonclinical pharmacology studies TAS-119 significantly enhanced the antitumor activity of the microtubule stabilizer paclitaxel and TAS-119 is being developed for use in combination with paclitaxel.

TAS-119 selectively inhibits the kinase inhibitor Aurora A. AurA regulates cell division by controlling the transition from G2 to M phase. Overexpression of AurA is associated with resistance to taxanes.

The study will be conducted in two sequential phases:

Dose Escalation Phase with the purpose to determine the maximum tolerated dose and the recommended Phase 2 dose of TAS-119 given in combination with paclitaxel

An Expansion Phase in which additional patients will be enrolled to further evaluate the safety and preliminary efficacy of the recommended Phase 2 dose of TAS-119 in combination with paclitaxel, during which a subgroup of patients will be evaluated for DDI between paclitaxel and TAS-119 via PK assessment.

Dose-escalating, Safety, Tolerability and PK Study of TAS-119 in Combination With Paclitaxel in Patients With Advanced Solid Tumors

A Phase 1, Open-Label, Non-Randomized, Dose-Escalating Safety, Tolerability and Pharmacokinetic Study of TAS-119 in Combination With Paclitaxel in Patients With Advanced Solid Tumors

During Dose Escalation Phase PK blood samples will be collected from each arm during Cycle 1 (predose up to 24 hours post-dose). In the Expansion Phase, the first 12 patients (DDI Subgroup) of each arm will undergo PK sampling in Cycle 1 (predose up to 24 hours) and Cycle 2 (predose up to 48 hours post-dose).

Standard safety monitoring and grading using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 will be used.

The safety and tolerability of TAS-119 will be evaluated by the number and severity of adverse events, vital signs, physical exam, and clinical laboratory assessments.

The determination of antitumor efficacy will be based on objective tumor assessments made by the investigator according to RECIST guidelines (version 1.1, 2009).

Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Carcinoma, Hepatocellular

Liver Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Lenvatinib

Subjects with lenvatinib unresponsive or lenvatinib resistant hepatocellular HCC will receive Lenvatinib plus VIC-1911 combination therapy.

Lenvatinib: 8mg/day (≤ 60Kg), oral. VIC-1911:Groups were divided: 100mg bid（DL1, dose level 1）; 150mg bid（DL2）; 200mg bid(DL3), oral. 50mg bid is defined as DL(-1), 250mg bid is defined as DL(+1). A Bayesian Optimal Interval design schema will be followed to establish the maximum tolerated dose (MTD) of lenvatinib plus VIC-1911 combination and RP2D of VIC-1911 in HCC patients. The study would follow the Bayesian Optimal Interval Design with level size of 2 patients. The R package "BOIN" is available from CRAN.

Lenvatinib Oral Product Plus VIC1911

Lei Xia

Hao Feng

Qiang Xia, MD, PhD

Qiang XIA

This is a prospective clinical study aiming to test the safety and efficacy of lenvatinib in combination with Aurora kinase A inhibitor VIC-1911 in participate with lenvatinib-unresponsive or lenvatinib-resistant hepatocellular carcinoma(HCC).

Lenvatinib Plus VIC-1911 in Lenvatinib-unresponsive or Lenvatinib-resistant HCC

Safety and Efficacy of Lenvatinib Combined With VIC-1911 in the Treatment of Lenvatinib-unresponsive or Lenvatinib-resistant Hepatocellular Carcinoma

Length of time from the start of combination therapy to progression of disease or death

Length of time from the date of first dose of combination therapy to date of death from any cause or latest follow-up

Statistically describe the proportion of adverse events after treatment for each patient

RenJi Hospital

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.

Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2.

Alisertib

Medical Director Clinical Science

The purpose of this study was to determine the safety profile, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and to characterize the pharmacokinetic (PK) profile of alisertib twice daily (BID) dosing for 7 days in East Asian participants with advanced solid tumors or lymphomas. The secondary objective was to describe any antitumor activity that may have been observed with alisertib treatment.

The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have advanced solid tumors or lymphomas for which standard curative or life-prolonging treatment did not exist or was no longer effective or tolerable. This study evaluated the safety and pharmacokinetic (PK) profile, and maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of alisertib, as well as any antitumor activity.

The study enrolled 36 patients. Participants were assigned to one of the two treatment groups and received:

* Alisertib 30 mg
* Alisertib 40 mg All participants took two enteric-coated tablets every 12 hours each day for 7 days followed by a 14-day rest period in a 21-day cycle for up to 16 cycles.

This multi-center trial is conducted in East Asia. The overall time to participate in this study was 24 months, unless it was determined that a participant would derive benefit from continued therapy beyond 24 months. Participants made multiple visits to the clinic, and were contacted up to a maximum of 30 days after last dose of study drug for a follow-up assessment.

A Study of Alisertib (MLN8237) in Adult East Asian Participants With Advanced Solid Tumors or Lymphomas

A Phase 1 Dose Escalation and Pharmacokinetic Study of Alisertib (MLN8237), an Aurora A Kinase Inhibitor, in Adult East Asian Patients With Advanced Solid Tumors or Lymphomas

MTD was defined as highest dose at which \<2 participants experienced a dose-limiting toxicity (DLT). DLT was defined as any of the following events considered possibly related to therapy with alisertib by the investigator: 1. Grade 4 neutropenia (absolute neutrophil count \<500 cells/mm\^3) for \>7 days; 2. Grade 4 neutropenia with fever (oral or ear temperature ≥38.5°C); 3. Grade 4 thrombocytopenia (platelets \<25,000/mm\^3) for \>7 days; 4. Platelet count \<10,000 cells/mm\^3; 5. ≥Grade 3 thrombocytopenia with clinically significant bleeding; 6. Delay in initiation of subsequent cycle by \>7 days due to treatment-related toxicity; 7. ≥Grade 3 nonhematological toxicity except following: a. ≥Grade 3 nausea and/or emesis in the absence of optimal antiemetic therapy; b. ≥Grade 3 diarrhea in the absence of optimal supportive therapy; c. Grade 3 fatigue lasting \<1 week; d. Other Grade 3 nonhematological toxicity that can be safely and reliably controlled to ≤Grade 2 with appropriate treatment.

An Adverse Event (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 Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

Laboratory AEs in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, investigations, and metabolism and nutrition disorders. An abnormal laboratory value was assessed as an AE if that value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment¬-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.

Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams.

Best overall response rate is defined as the percentage of participants with complete response (CR) and/or partial response (PR) as assessed by the Investigator using Lymphoma International Working Group (IWG) Criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT, PET or MRI. IWG criteria for CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. RECIST response criteria is defined as: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions.

DOR is defined as the time from the date of first documentation of a CR response to the date of first documentation of PD according to IWG criteria or RECIST criteria 1.1. IWG PD is defined as PD is defined as any new lesion or increase by \>50% of previously involved sites from nadir. RECIST PD is defined as unequivocal progression of existing non-target lesions.

Millennium Pharmaceuticals, Inc.

At each visit the Investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Alisertib 30 mg

Alisertib 40 mg

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Not Hispanic or Latino

Singapore

Taiwan

Hong Kong

Korea, Republic of

Region of Enrollment

Height

Weight

BSA = square root \[height (cm) x weight (kg)/3600\]

Body Surface Area (BSA)

Safety Population is defined as all participants who received at least one dose of alisertib.

Medical Director

Alisertib 30 mg or 40 mg enteric-coated tablets, orally, twice a day (BID) on Days 1 through 7, followed by a 14-day rest period, in a 21-day cycle (28-day cycle with additional 7-day rest period if all alisertib-related toxicities \[except alopecia\] were not resolved to less than Grade 2), for a maximum of 24 months or until there is evidence of disease progression or unacceptable treatment related toxicity (up to 16 cycles).

Alisertib 30 mg or 40 mg

DLT-Evaluable population is defined as participants with a common race who had not used granulocyte colony-stimulating factor (G-CSF) in cycle 1, and either experienced DLT during Cycle 1 or received at least 85% of planned doses of alisertib and have sufficient follow up data to allow investigator and sponsor to determine whether a DLT occurred.

Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)

Number of Participants With Adverse Events and Serious Adverse Events

Neutropenia

Anaemia

Thrombocytopenia

Febrile neutropenia

Leukopenia

White blood cell count decreased

Aspartate aminotransferase increased

Neutrophil count decreased

Alanine aminotransferase increased

Platelet count decreased

Blood bilirubin increased

Haemoglobin decreased

Blood creatinine increased

Urine output decreased

Hypokalaemia

Hypercalcaemia

Hyponatraemia

Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events

Hypertension

Hypotension

Bradycardia

Pyrexia

Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events

Day 1

Day 7

Pharmacokinetic (PK) Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters. "n" in the category is the number of participants with data available at the given time-point.

Cmax: Maximum Observed Concentration for Alisertib

PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters. "n" in the category is the number of participants with data available at the given time-point.

Tmax: Time to First Occurrence of Cmax for Alisertib

AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib

PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.

Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib

T1/2: Terminal Half-Life for Alisertib

Rac: Accumulation Ratio for Alisertib

PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib

CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib

Best Overall Response Rate Based on Investigator Assessment

Safety Population is defined as all participants who received at least one dose of alisertib. Participants with response were evaluated.

Duration of Response

Data was not analyzed as per the change in planned analysis (protocol amendment).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
An Investigation of TAS-119 Monotherapy	NCT02448589	Advanced Solid ...	TAS-119	18 Years -	Taiho Oncology, Inc.
Dose-escalating, Safety, Tolerability and PK Study of TAS-119 in Combination With Paclitaxel in Patients With Advanced Solid Tumors	NCT02134067	Advanced Solid ...	TAS-119 Paclitaxel	18 Years -	Taiho Oncology, Inc.
Dose-escalating, Safety, Tolerability and PK Study of TAS-119 in Combination With Paclitaxel in Patients With Advanced Solid Tumors	NCT02134067	Advanced Solid ...	TAS-119 Paclitaxel	18 Years -	Taiho Oncology, Inc.
Lenvatinib Plus VIC-1911 in Lenvatinib-unresponsive or Lenvatinib-resistant HCC	NCT05718882	Liver Cancer Hepatocellular ... Resistant Cance...	Lenvatinib Oral...	18 Years - 75 Years	RenJi Hospital
Dose-escalating, Safety, Tolerability and PK Study of TAS-119 in Combination With Paclitaxel in Patients With Advanced Solid Tumors	NCT02134067	Advanced Solid ...	TAS-119 Paclitaxel	18 Years -	Taiho Oncology, Inc.
A Study of Alisertib (MLN8237) in Adult East Asian Participants With Advanced Solid Tumors or Lymphomas	NCT01512758	Advanced Solid ... Lymphomas	Alisertib	18 Years -	Takeda
A Study of Alisertib (MLN8237) in Adult East Asian Participants With Advanced Solid Tumors or Lymphomas	NCT01512758	Advanced Solid ... Lymphomas	Alisertib	18 Years -	Takeda
An Investigation of TAS-119 Monotherapy	NCT02448589	Advanced Solid ...	TAS-119	18 Years -	Taiho Oncology, Inc.
An Investigation of TAS-119 Monotherapy	NCT02448589	Advanced Solid ...	TAS-119	18 Years -	Taiho Oncology, Inc.

Spots Global Cancer Trial Database for aurora a kinase inhibitor