Primary Objectives:The primary objective of this study is to characterize the effect of repeated oral administration of TAK-788 160 mgQD on the single oral- and IV-dose PK of midazolam.Secondary Objectives:The secondary objective of this study is to…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main Criteria for Evaluation and Analyses:
The primary endpoints of the study include, but are not limited to the
following midazolam PK parameters after oral
or IV administration in the presence and absence of TAK-788:
Primary Endpoints
* The geometric mean ratios and 90% CI of Cmax and AUC* for midazolam
administered orally with TAK-788
and when orally administered as midazolam alone.
* The geometric mean ratios and 90% CI of Cmax and AUC* for midazolam
administered intravenously with
TAK-788 and when intravenously administered as midazolam alone
Secondary outcome
Secondary Endpoints
The secondary endpoints of the study encompass the safety profile of TAK-788
and are as follows:
* AEs.
* Clinical laboratory tests (hematology and clinical chemistry).
* Vital signs.
Background summary
TAK-788 is an investigational drug which means that it is not approved yet by
FDA or/and any other Regulatory Agency across the world. It is a novel drug
which has potency to substantially reduces activity of one of the tyrosine
kinases * a category of protein (enzyme) playing important roles in development
of the tumors including NSCLC (Non Small Cell Lung Cancer) which you are
suffering from. TAK-788 will be tested during this study to evaluate for
effectiveness on the types of NSCLC which relapsed or spread to other regions
of your body after the routine treatment (such as chemotherapy or radiotherapy)
so is considered resistant to the types of treatment which were used so far.
Midazolam is approved by the US FDA (United States Food and Drug
Administration) for anesthesia, sedation, trouble sleeping, and severe
agitation. In the Netherlands it is approved for anesthesia, sedation and
trouble sleeping.
Study objective
Primary Objectives:
The primary objective of this study is to characterize the effect of repeated
oral administration of TAK-788 160 mg
QD on the single oral- and IV-dose PK of midazolam.
Secondary Objectives:
The secondary objective of this study is to assess the safety and tolerability
of TAK-788 in patients with advanced
NSCLC.
Study design
Study Design:
This open-label, multicenter, drug-drug interaction study will consist of 2
parts: Part A (Cycle 1: PK Cycle) and Part
B (Cycle 2 to Cycle 24: Treatment Cycles).
In Part A of the study, a fixed-sequence design over a single 30-day treatment
cycle will be used (Cycle 1: PK Cycle
and Cycle 2 Day1). After screening, eligible patients will be enrolled and will
receive a single oral dose of
midazolam 3 mg on Days 1 and 24 and a single IV dose of midazolam 1 mg as a
5-minute infusion on Days 2 and
25. Patients will also receive TAK-788 160 mg QD orally on Days 3 through 30.
Serial PK blood samples will be
collected to measure plasma concentrations of midazolam and its metabolite
1-hydroxymidazolam in the absence
and presence of TAK-788 on study Days 1, 2, 24, and 25. TAK-788 PK blood
samples to assess TAK-788 plasma
concentrations and its active metabolites AP32960 and AP32914 will be collected
predose on Days 24, 25, and 26 of
cycle 1 as well as Day 1 of cycle 2 and postdose on Cycle 1 Day 24.
Further, biomarker blood samples will be collected on Days 1 and 24 predose to
measure plasma concentrations of
4*-hydroxycholesterol and cholesterol, in addition to samples collected to
assess for circulating tumor DNA as part
of Cycle 1, 3, 5, and disease progression assessments.
After completion of Part A, patients may continue into Part B to to continue
treatment with TAK-788 (Cycle 2 to
Cycle 24: Treatment Cycles). Any patients who are not PK-evaluable due to
incomplete PK sample collections in
Part A will be eligible to continue into Part B.
Part B of the study will consist of 28-day treatment cycles in which patients
will continue to receive TAK-788 QD
for up to 23 months (ie, Cycle 24) or until progressive disease, intolerable
toxicity, or another discontinuation
criterion is met, whichever is sooner.
TAK-788 dose may be reduced based on protocol-defined dose modification
guidelines during the study. Safety and
tolerability will be evaluated during the study by AE monitoring, clinical
laboratory tests, vital signs, and physical
examinations. The study will include a 30-day follow-up period after EOT for
reporting of AEs.
Exploratory radiological disease assessments will be performed by
contrast-enhanced computed tomography (CT)
and/or magnetic resonance imaging (MRI) (unless contrast media is
contraindicated) at 8-week intervals during
treatment through Cycle 14; radiological assessments will then be performed
every 12 weeks (ie, every 3 cycles)
thereafter, and at EOT. Imaging of the brain (contrast-enhanced MRI is
preferred) is required at screening for all
patients, and will be repeated post-baseline for patients with CNS metastases
at baseline.
Intervention
/
Study burden and risks
see section E9.
Landsdowne Street 40
Cambridge, MA 02139
US
Landsdowne Street 40
Cambridge, MA 02139
US
Listed location countries
Age
Inclusion criteria
1. Male or female patients aged *18 years.
2. Histologically or cytologically confirmed locally advanced NSCLC in which
the patient is not a candidate for definitive therapy; or, the patient has
recurrent or metastatic (Stage IV) disease.
3. Refractory or intolerant to standard available therapies.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
5. Minimum life expectancy of 3 months or more.
6. Adequate organ function as defined by the protocol criteria.
a) Total serum bilirubin *1.5 × upper limit of normal (ULN) (*3 × ULN for
patients with Gilbert syndrome or if liver function abnormalities are due to
underlying malignancy);
b) Alanine aminotransferase and aspartate aminotransferase *2.5 × ULN (or *5 ×
ULN if liver function abnormalities are due to underlying malignancy);
c) Estimated creatinine clearance *30 mL/min (calculated by using the
Cockcroft-Gault equation);
d) Serum albumin *2 g/dL;
e) Serum lipase *1.5 × ULN; and
f) Serum amylase *1.5 × ULN unless the increased serum amylase is due to
salivary isoenzymes.
7. Adequate bone marrow function, as defined by the protocol criteria.
a) Absolute neutrophil count *1.5 × 109/L;
b) Platelet count *75 × 109/L; and
c) Hemoglobin *9.0 g/dL.
8. Normal QT interval on screening ECG, defined as QTcF of *450 msec in males
or *470 msec in females. (as conducted and interpreted in accordance to local
institutional practices and confirmed by PI).
9. All toxicities from prior anticancer therapy must have resolved to *Grade 1
according to the NCI CTCAE version 5.0 [1], or have resolved to baseline, at
the time of first dose of TAK-788. Note: treatment-related Grade 2 or 3
alopecia and treatment-related Grade 2 peripheral neuropathy are allowed if
deemed irreversible.
10. Female patients who are of childbearing potential, agree to comply with
protocol-defined contraception criteria or practice true abstinence.
11. Male patients agree to practice effective barrier contraception during the
entire study treatment period and through 30 days after the last dose of study
drug, or agree to practice true abstinence.
12. If female, a negative serum or urine pregnancy test result during the
screening period.
13. Suitable venous access for study-required blood sampling (ie, including for
PK, pharmacodynamics, and clinical laboratory tests).
14. Willingness and ability to comply with scheduled visits and study
procedures.
15. Signed and dated the informed consent indicating that the patient has been
informed of all pertinent aspects of the study. 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
patient at any time without prejudice to future medical care.
Exclusion criteria
1. Previously received TAK-788.
2. Received a strong or moderate CYP3A inhibitor or strong or moderate CYP3A
inducer within 2 weeks prior to the first dose of TAK-788.
3. Received small-molecule anticancer therapy (including but not limited to
cytotoxic chemotherapy and investigational agents) within 2 weeks prior to the
first dose of TAK-788.
4. Received antineoplastic monoclonal antibodies including check point
inhibitors within 28 days of the first dose of TAK-788.
5. Received radiotherapy *14 days prior to the first dose of TAK-788. However,
patients are allowed to receive any of the following treatments up to 7 days
prior to the first dose: (a) Stereotactic radiosurgery (SRS), (b) stereotactic
body radiation therapy (SBRT), or (c) palliative radiation outside the chest
and brain.
6. Major surgery within 28 days prior to the first dose of TAK-788. Minor
surgical procedures, such as catheter placement or minimally invasive biopsy,
are allowed.
7. Diagnosed with another primary malignancy other than NSCLC except for
adequately treated non-melanoma skin cancer or cervical cancer in situ;
definitively treated non-metastatic prostate cancer; or another primary
malignancy and is definitively relapse-free with at least 3 years elapsed since
the diagnosis of the other primary malignancy.
8. Have known active brain metastases (have either previously untreated
intracranial CNS metastases or previously treated intracranial CNS metastases
with radiologically documented new or progressing CNS lesions). Brain
metastases are allowed if they have been treated with surgery and/or radiation
and have been stable without requiring corticosteroids to control symptoms
within 7 days before the first dose of TAK-788, and have no evidence of new or
enlarging brain metastases.
9. Current spinal cord compression (symptomatic or asymptomatic and detected by
radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).
10. Have uncontrolled hypertension. Patients with hypertension should be under
treatment on study entry to control blood pressure.
11. Significant, uncontrolled, or active cardiovascular disease.
12. Treatment with medications known to be associated with the development of
torsades de pointes.
13. Current or history of interstitial lung disease, radiation pneumonitis that
required steroid treatment, or drugrelated pneumonitis.
14. Ongoing or active infection including, but not limited to, the requirement
for IV antibiotics, or a known history of human immunodeficiency virus
infection. Testing is not required in the absence of history. Patients who are
positive for hepatitis B surface antigen or anti-hepatitis C virus antibody may
be eligible (see full protocol for further details).
15. Gastrointestinal illness or disorder that could affect oral absorption of
TAK-788 or midazolam.
16. If female, the patient is lactating and breastfeeding. Female patients who
are lactating will be eligible if they discontinue breastfeeding.
17. History of, or suspected, hypersensitivity or allergy to midazolam or its
excipients or TAK-788.
18. Any condition or illness that, in the opinion of the investigator, might
compromise patient safety or interfere with the evaluation of the safety of the
study drug.
19. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
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 | EUCTR2019-000725-44-NL |
| CCMO | NL70465.031.19 |