Primary Objectives:Part 1- Estimate the relative bioavailability of the tablet formulation of TAK-931 in reference to the PIC formulation.Part 2- Assess the effect of a high-fat meal on the single dose PK of TAK-931 administered as the tablet…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1
* Ratio of geometric mean of the following PK parameters for TAK-931 tablets in
reference to PIC and
associated 90% CIs:
* Maximum observed concentration (Cmax).
* AUC from time 0 to time of the last quantifiable concentration (AUClast).
* AUC from time 0 to infinity (AUC*).
Part 2
* Ratio of geometric mean of the following PK parameters for TAK-931 tablets
under fed and fasted conditions and associated 90% CIs:
* Cmax.
* AUClast.
* AUC*.
* Ratio of geometric mean of the following PK parameters for TAK-931 tablets in
the presence and absence of esomeprazole and associated 90% CIs:
* Cmax.
* AUClast.
* AUC*.
* Summary statistics of the following PK parameters for TAK-931:
* Cmax.
* AUClast.
* AUC*.
Secondary outcome
Part 1
* PK parameters of TAK-931 following single-dose administrations as PIC and
tablets at 80 mg:
* Time of first occurrence of Cmax (tmax).
* Apparent clearance after extravascular administration (CL/F).
* Terminal disposition phase half-life (t1/2z).
* Antitumor activity:
* Overall response rate (ORR).
* PFS.
* Disease control rate (DCR).
* Duration of response (DOR).
* Safety:
* Percentage of serious adverse events (SAEs), treatment-emergent adverse
events (TEAEs), Grade *3 TEAEs, TEAEs leading to discontinuation or dose
modification, and percentage of laboratory abnormalities.
Part 2
* PK parameters:
* tmax, CL/F, and t1/2z of TAK-931 tablets following single-dose administration
under fasting and fed conditions.
* tmax, CL/F, and t1/2z of TAK-931 tablets following single-dose administration
in the absence and in the presence of esomeprazole.
* Antitumor activity:
* ORR.
* PFS.
* DCR.
* DOR.
* Safety:
* Percentage of serious adverse events (SAEs), treatment-emergent adverse
events (TEAEs), Grade *3 TEAEs, TEAEs leading to discontinuation or dose
modification, and percentage of laboratory abnormalities.
Background summary
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda
Pharmaceutical Company Limited, the study Sponsor is paying the study hospital
and the investigator to carry out this research study.
TAK-931, the study drug, is an investigational drug. This means that it has not
been approved by the FDA (US Food and drug Administration), EMA (European
Medicines Agency) or other regulatory authorities for use by the general public
and is still being tested. This study is not intended to improve the health but
is necessary for the further development of TAK-931.
TAK-931 is being studied as a new medication in humans with advanced solid
tumors. TAK-931 decreases the activity of a chemical in the body that is called
CDC7 kinase, which is important for the survival of cancer cells.
This study is an open-label study, which means that both the patient and the
study doctor know which treatment the patient is receiving.
The study consists of 2 parts. Approximately 20 patients will participate in
part 1 and 24 patients in part 2 of this research study. The doctor will tell
the patient if he/she is being invited to participate in Part 1 or in Part 2.
Patients cannot participate in both parts. The study will only be conducted in
the Netherlands.
Study objective
Primary Objectives:
Part 1
- Estimate the relative bioavailability of the tablet formulation of TAK-931 in
reference to the PIC formulation.
Part 2
- Assess the effect of a high-fat meal on the single dose PK of TAK-931
administered as the tablet formulation.
- Assess the effect of esomeprazole, a proton pump inhibitor (PPI) on the
single dose PK of TAK-931 administered as the tablet formulation.
Secondary Objectives:
Part 1
- Further characterize the PK of TAK-931 administered as PIC or the tablet
formulation.
- Assess the safety and tolerability of TAK-931 administered as the tablet and
PIC formulations.
- Assess the antitumor activity of TAK-931 in patients with locally advanced or
metastatic solid tumors.
Part 2
- Further characterize the PK of TAK-931 administered as the tablet formulation
under fasted and fed conditions.
- Further characterize the PK of TAK-931 administered as the tablet formulation
in the presence or absence of esomeprazole, a PPI.
- Assess the safety and tolerability of TAK-931 administered as the tablet
formulation under fed and fasted conditions.
- Assess the antitumor activity of TAK-931 in patients with locally advanced or
metastatic solid tumors.
Study design
Part 1: Assessment of Relative Bio-availability of TAK-931 Tablets in Reference
to Powder-in-Capsule
Approximately 20 patients (to ensure 14-16 patients evaluable for
pharmacokinetics [PK]) will be randomized in a crossover fashion to receive in
Cycle 0 a single dose of TAK-931 80 mg powder-in-capsule (PIC) or tablet on Day
1 and a single dose of TAK-931 80 mg with the alternate formulation on Day 3
(PIC to tablet, or tablet to PIC; n of ~10/sequence). Blood samples will be
collected predose and up to 48 hours postdose at predetermined time points to
measure plasma drug concentrations to evaluate the relative bioavailability of
TAK-931 tablets in reference to the PIC formulation. There will be no TAK-931
dosing on Day 2 or Day 4. Starting on Day 5, patients will continue to receive
TAK-931 50 mg PIC once daily (QD) for 12 days followed by a 7-day rest period.
Starting at Cycle 1, patients will 50 mg PIC QD for 14 days, followed by 7-day
rest period, in 21-day treatment cycles until one of the discontinuation
criteria is met.
Part 2: Assessment of the Effect of Food and Esomeprazole, a Proton Pump
Inhibitor, on the PK of TAK-931 as a Tablet
After the preliminary PK data from part 1 have been analyzed to estimate the
relative bioavailability of the tablet formulation in reference to PIC, the
dose of TAK-931 tablet will be calculated to provide total exposure (area under
the concentration-time curve [AUC]) comparable to the 80-mg dose of PIC. In
part 2, approximately 24 patients (to ensure 14-16 patients evaluable for PK)
will be randomized in a crossover fashion to receive in Cycle 0 a single dose
of the TAK-931 tablet formulation with or without a standard high-fat breakfast
on Day 1, with the alternate food intake condition and dosing on Day 3 (fasted
to fed or fed to fasted; n of ~12/sequence). Blood samples will be collected
predose and for up to 48 hours postdose at predetermined time points to measure
plasma drug concentrations to characterize the effect of food on the PK profile
of TAK-931 tablet. Starting from Day 5, patients will receive esomeprazole 40
mg QD through Day 13. On Day 12, each patient will receive a single dose of the
TAK-931 tablet formulation, and PK samples will be collected up to 48 hours
postdose (Day 14 predose). Starting on Day 14, patients will continue to
receive TAK-931 tablets at a dose expected to achieve exposures comparable to
50 mg PIC QD for
11 days, followed by a 7-day rest period, until a discontinuation criterion is
met.
Starting at Cycle 1, patients will receive the TAK-931 tablet formulation at a
dose expected to achieve exposures comparable to 50 mg PIC QD for 14 days,
followed by 7-day rest period, in 21-day treatment cycles.
Intervention
Part 1: 80 mg single dose on Day1 and Day 3 respectively followed by 50 mg QD
thereafter.
Part 2: Tablet single dose providing an AUC comparable to the 80-mg single dose
of PIC on Day 1, Day 3, and Day 12 followed by a tablet QD dose providing an
AUC comparable to 50-mg dose of PIC.
Study burden and risks
During the study, the patient may have discomforts and risks from TAK-931 and
from the study procedures. Most of these are listed here, but there may be
others that we cannot predict.
Discomforts and risks may vary from person to person. Everyone taking part in
the study will be watched carefully for side effects; however, doctors do not
know all the discomforts and risks that may happen. There is always the
possibility that unknown risks may occur. These may be mild or very serious,
and in some cases may be very serious, long-lasting, or may never go away.
There is also a risk of death. Serious adverse reaction may occur upon
resumption of TAK-931 treatment even after dose reduction or dose interruption.
If any discomforts or risks occur, the patient must tell the study doctor.
The doctor may give the patient medications to help lessen some of the
discomforts and risks. If a severe reaction to TAK-931 occurs, the doctor may
stop TAK-931.
TAK-931 has been given to some patients already, however, the exact effects are
unknown.
The following discomforts and risks have been reported in the limited number of
patients taking TAK-931 in a single agent clinical trial studying the drug in
humans:
Very common (Incidence 10% and above)
* Decrease in the number of white blood cells which may increase the patients
risk of infection and may be associated with fever
* Decrease in the number of red blood cells, which may make the patient feel
tired or lose your energy; have pale skin; or experience shortness of breath
and/or a faster heart rate.
* Hair loss
* Nausea
* Vomiting
* Decreased appetite
* Diarrhoea: watery and frequent bowel movements
* Tiredness
* Fever
* Low levels of blood protein called albumin which can cause generalized
swelling
* Swelling of arms or legs
* Constipation
* A vague feeling of bodily discomfort
Landsdowne Street 40
Cambridge MA 02139
US
Landsdowne Street 40
Cambridge MA 02139
US
Listed location countries
Age
Inclusion criteria
1. Adult patients with histologically or cytologically confirmed metastatic or locally advanced or metastatic solid tumors for whom there is no available standard treatment with proven survival benefit, this therapy is not indicated, or it is refused by the patient.
2. Eastern Cooperative Oncology Group performance status of 0 to 1.
3. Adequate bone marrow reserve and renal and hepatic function based on the following laboratory parameters:
* Absolute neutrophil count *1.5 × 109/L, platelet count *75.0 × 109/L, and hemoglobin *85 g/L.
* Total bilirubin *1.5 times the institutional upper limit of the normal range (ULN) or total bilirubin <3.0 times ULN in patients with well documented Gilbert*s Syndrome.
* Serum alanine aminotransferase or aspartate aminotransferase *3.0 times the ULN (<5 times ULN if liver enzyme elevations are due to hepatocellular cancer, biliary tract cancer, or metastatic disease in the liver).
* Creatinine <1.5 times the institutional ULN or estimated creatinine clearance using the Cockcroft-Gault formula *30 mL/min for patients with serum creatinine concentrations above institutional limits.
4. Left ventricular ejection fraction *50% as measured by echocardiogram or multiple gated acquisition scan within 4 weeks before receiving the first dose of study drug.
5. Recovered to Grade 1 or baseline from all toxic effects of previous therapy (except alopecia or neuropathy).
Exclusion criteria
1. Patients who require continuous use of PPIs or histamine-2 receptor antagonists and patients 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, enzalutamide, mitotane, ritonavir, rifampin, or St John's wort within 14 days before the first dose of study drug.
3. Treatment with systemic anticancer treatments or any investigational products within 28 days before the first dose of study drug or 5 half-lives, whichever is shorter.
4. Patients with hypertension that is unstable or not controlled despite appropriate medical therapy.
5. Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after central nervous system-directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging or computed tomography) during the screening period.
6. Known history of HIV infection.
7. Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C infection viral load. Note: Patients who have positive hepatitis B core antibody or hepatitis B surface antigen antibody can be enrolled but must have an undetectable hepatitis B viral load.
8. 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 or GI transit.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-004629-34-NL |
| CCMO | NL66709.091.18 |