A Phase 1 Drug-Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With ALK-Positive or ROS1-Positive Solid Tumors

In vitro studies using human hepatocytes have indicated that brigatinib, at
clinically relevant concentrations of 1 to 2.5 *M, caused an increase in
cytochrome P450 3A (CYP3A4) messenger RNA levels (see the Investigator*s
Brochure for further details). Therefore, brigatinib may have
the potential for pharmacokinetic (PK) drug interactions with substrates of
CYP3A through induction of expression of this enzyme, potentially leading to
decreased systemic exposures of its substrates.

The primary purpose of this study (Brigatinib-1001) is to evaluate the effect
of repeated doses of brigatinib on the single-dose PK of midazolam, a sensitive
CYP3A probe substrate, to determine if brigatinib, at therapeutic doses,
produces clinically meaningful CYP3A induction in vivo, and if
so, to inform strategies for the management of potential drug-drug interactions
(DDIs) between brigatinib and substrates of CYP3A. Midazolam is an established
sensitive substrate of CYP3A that is commonly used in clinical DDI studies to
assess the effect of a coadministered drug on
CYP3A activity. Oral doses of midazolam ranging from 2 to 7.5 mg have generally
been used in clinical DDI studies. A 3 mg oral dose of midazolam was selected
for use in this study to allow for adequate PK characterization of midazolam
after administration in both the
absence (ie, baseline CYP3A expression levels) and presence (ie, possibly
induced CYP3A expression levels) of brigatinib.

The first part of this study (Part A) is designed to achieve the primary
objective of the study, and the second part of the study (Part B) is
exploratory and will allow patients to continue brigatinib until disease
progression (PD). In addition to ALK-positive patients with NSCLC, patients with
ROS1-positive NSCLC, and patients with ALK-positive or ROS1-positive nonlung
solid tumors*all with locally advanced or metastatic disease*are eligible for
enrollment, in an effort to gather exploratory efficacy data in these patient
populations.

Primary Objective: To characterize the effect of repeat-dose administration of
brigatinib 180 mg QD on the single-dose PK of midazolam.
Other Objectives:
Safety: To assess the safety and tolerability of brigatinib in patients with
ALK-positive or ROS1-positive solid tumors.

Study Design:
This study will consist of 2 parts: Part A (Cycle 1: pharmacokinetics [PK]
cycle) and Part B (Cycle 2 and beyond: treatment cycles). Part A of the study
will use a fixed-sequence design over a single 28-day treatment cycle. Patients
will receive a 3 mg oral dose of midazolam on Day 1 of Part A, with serial PK
sampling performed over 24 hours postdose to characterize the PK of midazolam
in the absence of brigatinib. Brigatinib 90 mg will then be orally administered
once daily (QD) on Days 2 through 8. If the 90 mg QD brigatinib dose is
tolerated by the patient, the brigatinib dose will be increased to 180 mg QD,
starting on Day 9 and continuing through Day 28 (in accordance with the United
States [US] prescribing information). For patients who have escalated to
brigatinib 180 mg QD, a 3 mg oral dose of midazolam will be administered on Day
21 of Part A, with serial PK sampling performed over 24 hours postdose to
characterize the PK of midazolam in the presence of brigatinib.
Any patients in Part A who are not PK evaluable will be replaced. Patients will
be considered PK evaluable if they receive the protocol-specified dosing
regimen during Part A (including the 180 mg QD brigatinib dose) without dose
reductions or interruptions through the completion of PK sampling (Day 22); do
not receive any excluded concomitant medications through the completion of PK
sampling; and have sufficient midazolam concentration-time data to permit the
reliable estimation of PK parameters by noncompartmental analysis methods.
After completion of Part A, patients may continue to Part B to receive the
potential therapeutic benefits of brigatinib. Any patients who are replaced
because they are not PK evaluable in Part A will also be eligible to continue
into Part B. The starting dose of brigatinib in Part B will be the dose that
was tolerated by the patient at the end of Part A. Part B of the study will
include 28-day treatment cycles in which brigatinib will continue to be dosed
QD at the highest tolerated dose (up to 180 mg QD) until disease progression
(PD), intolerable toxicity, or another discontinuation criterion is met.
Patients who cannot escalate to 180 mg QD in Part A will be maintained at 90 mg
QD or lower. The available brigatinib daily oral doses for Part A and Part B
will include 180, 120, 90, and 60 mg, allowing patients to have their dose
reduced in cases of intolerability.
Disease assessments by the investigator, using Response Evaluation Criteria in
Solid Tumors, version 1.1, and evaluated by computed tomography and/or magnetic
resonance imaging, will be performed during Screening; at 8-week intervals
during treatment (ie, on Day 28 [±3 days] of every even-numbered cycle) through
Cycle 14; and every 12 weeks (ie, every 3 cycles) thereafter, and at end of
treatment (EOT). Safety will be assessed throughout the study, including
adverse event reporting through the 30 day follow-up period after EOT.
Subsequent therapy will also be collected during the 30-day follow-up period.

Part A:
Midazolam: 2 single 3 mg doses on Day 1 and Day 21.
Brigatinib: 90 mg QD×7 days, followed by 180 mg QD× 20 days.
Part B: Brigatinib at highest tolerated dose (180, 120, 90, or 60) QD×28 days
per cycle. During Part B, patients may receive up to 23 months of treatment, or
treatment until PD, intolerable toxicity, or another discontinuation criterion
is met. If patients are still continuing to receive benefit at 23 months, they
may have the option to continue brigatinib monotherapy at the same dose.

All drugs have the possibility of complications and undesirable side effects
that are unknown at this time and could possibly occur.

The most common side effects from controlled clinical trials, (reported in 10%
and more of patients), included:
* Pneumonia or lung infection; symtoms may include cough, shortness of breath,
fevers, chills, chest pain, headache, sweating, and weakness
* Low levels of red blood cell count (which can cause you to feel tired)
* Low levels of white blood cell count (including white blood cell counts
overall, or a certain typeof white blood cells, as lymphocytes or neutrophils),
which could increase the risk of infection.
* High blood sugar levels
* High insulin levels which may cause low blood sugar, weakness, mental status
changes, and/or weight gain
* Decreased appetite
* Low levels of sodium, potassium, magnesium and phosphate in the blood
* High levels of calcium in the blood
* Headache
* Peripheral neuropathy, a condition in which damage nerves outside the brain
and spinal cord (peripheral nerves) which can result in symptoms such as
numbness, tingling, prickly sensation, weakness or pain
* Dizziness
* Visual Disturbance
* High Blood Pressure
* Cough
* Shortness of breath
* Nausea
* Diarrhea
* Vomiting
* Constipation
* Abdominal pain
* Inflammation of the oral mucosa, including cheeks, gums, tongue, lips, throat
and roof or floor of the mouth
* Increased liver enzymes (Aspartate aminotransferase (AST) increased or
Alanine aminotransferase (ALT) increased) which can suggest damage to the liver
* Increased lipase and amylase level (an enzyme measured in the blood that
reflects function of the pancreas; elevations in lipase and amylase may
indicate inflammation of the pancreas)
* Increased alkaline phosphatase level, an enzyme in the blood produced by the
liver and other organs
* Skin rash
* Itchy skin
* Increased creatine phospokinase level (an enzyme measured in the blood),
elevations may indicate injury or stress to muscle tissue, the heart, or brain
* Muscle pain (including muscle spasms)
* Joint Pain
* Increased creatinine level, which may indicate kidney damage
* Fatigue or Tiredness
* Edema (buildup of fluid in the body which causes the affected tissue to
become swollen)
* Fever (>38°C)

Common side effects (reported in 1-9% of patients) included:
* Delayed blood clotting
* Problems with memory
* Distortion of the sense of taste
* Increased or slow heart rate
* Infection involving the upper respiratory tract; symptoms may include
congestion, sneezing, coughing, fever, and sore throat
* Insomnia or inability to obtain an adequate amount or quality of sleep
* Electrocardiogram QT prolonged (a change in ECG), a study of the electrical
system of the heart that may indicate an increased risk of serious
abnormalities in the heart*s rhythm)
* Noticeably rapid, strong, or irregular heartbeats
* Pneumonitis (inflammation of the lung) or interstitial lung disease (ILD),
diseases that affect the lungs
* Indigestion or upset stomach
* Dry mouth
* Flatulence or accumulation of gas, usually in excess, that is present in the
instestinal tract and passed out of the body from the rectum
* Increased lactate dehydrogensade (LDH) level, an enzyme present in many body
tissues, especially the heart, liver, kidney, muscles, brain, blood cells, and
lungs. LDH is most often measured to check for tissue damage
* Dry skin
* Increased skin sensitivity to sunlight or lamps
* Pain in the extremity
* Musculoskeletal chest pain
* Non-cardiac chest pain
* Pain
* Chest discomfort or pain
* Loss of weight
* High levels of blood cholesterol

Uncommon side effects (reported in less than 1% of patients) included:
* Muscle and/or bone stiffness

Potential Risks of Midazolam
The potential risks associated with the use of brigatinib and midazolam in
combination is not known. For detailed information about precautions,
warnings, contraindications, and Adverse Events associated with midazolam
therapy please ask your Study Doctor or review the midazolam prescribing
information.

Discomfort from Blood Draws
There may be some discomfort such as swelling or bruising around the vein that
was used to draw your blood. You may experience lightheadedness; however,
fainting at the time of blood drawing is uncommon. Infection at the blood
drawing site could occur, but this is also uncommon. Care will be provided to
avoid these complications.
Risks associated with CT scan
CT scans are associated with exposure to a very small amount of radiation. In
addition, you may have some discomfort from lying still in an enclosed space
for a prolonged period of time.
Risks associated with MRI scan:
An MRI scan uses radio waves and a magnetic field, and will not expose you to
radiation. Some patients may feel frightened by the cramped space inside the
MRI machine or by the loud, repeated sounds the machine makes.
Risks Associated with Contrast Agents Used During Scans
There is a small risk with using a contrast agent that is injected into a vein
during the CT scan or MRI. A contrast agent is a special dye that highlights
organs, blood vessels or tissue to make them more visible. Depending on the
type of contrast agent that is used, it may cause decreased kidney function or
worsen kidney function in people who already have decreased kidney function.
Therefore, we will monitor your kidney function closely while you participate
in this study. If there is any change in your kidney function, we may have to
remove you from the study.
Uncommonly, some people have allergic reactions (such as hives and itching) to
the contrast agent. Serious reactions (for example, drop in blood pressure,
difficulty breathing or severe allergic reaction and death) are rare.
Similar Drugs
Because brigatinib shares some features with other drugs already being
investigated for non-small cell lung cancer and other cancers, it is possible
that it will cause similar side effects to those drugs. These include visual
disturbances, testosterone level decrease, inflammation of lung tissue which
can be fatal, and liver dysfunction which can be fatal. Symptoms of liver
dysfunction can include weakness, fatigue, anorexia, nausea, vomiting,
abdominal pain, yellowing of the skin, dark urine, generalized itching, and can
cause many complications including excessive bleeding.
You will be monitored closely for these side effects. If you develop symptoms,
your doctors will give you the care that you need. You must tell the Study
Doctor about any new health problems

Affects on ability to drive and use machines
There is no data on the effect of brigatinib on the ability to drive and use
machines. Visual disturbance, dizziness, and fatigue have been observed in
clinical trials. Patients should be advised not to drive or operate machines
if they experience any of these symptoms while taking brigatinib.

There may be risks from the study drug to an unborn child or breast-feeding an
infant that are not currently known. Due to unknown risks and potential harm to
the unborn child, female participants should not become pregnant or breast-feed
an infant, while participating in this study. Male participants should not try
to conceive with their female partner(s) while in participating this study.