An Open-Label, Dose Escalation, Phase 1, First-in-Human Study of TAK-164, an Antibody-Drug Conjugate, in Patients with Advanced Gastrointestinal Cancers Expressing Guanylyl Cyclase C

Scientific Background
Antibody-directed cancer chemotherapy in the form of antibody-drug conjugates
(ADCs) can improve therapeutic indices, with the potential to enhance efficacy
and decrease systemic toxicity. After the ADC is internalized by the target
tumor cell and shuttled to the lysosomal compartment, enzymatic cleavage of the
chemical linker releases the cytotoxic drug [4]. In an effort to further
exploit ADC technology to improve treatment of gastrointestinal (GI)
malignancies, Takeda Pharmaceuticals Inc (Takeda) has developed TAK-164, a new
ADC which targets guanylyl cyclase C (GCC) and consists of a human monoclonal
antibody (mAb) specifically targeting GCC, a potent cytotoxic agent, and a
linker. Prior and ongoing clinical studies evaluating an ADC-based therapy with
another cytotoxic agent, monomethylauristatin E have shown promising results
[5]. The mechanism of action of TAK-164 should result in potent
target-dependent eradication of GCC-expressing tumor cells.

Disease Under Treatment
TAK-164 is being developed to be a standard of care in the metastatic and
adjuvant setting for patients with GI cancers that express GCC.
The expression of GCC is maintained throughout the spectrum of adenoma and
carcinoma in the colorectum [6,7]. Also, GCC expression has been observed in
lymph nodes harboring metastatic cells and is being studied as a potential
marker for more accurate staging of this disease [8]. In
addition to colorectal carcinoma (CRC), other GI malignancies have been found
expressing GCC, such as gastric, esophageal, small intestine, and pancreatic
carcinomas.

Study Drug
TAK-164, a novel ADC consists of a mAb that specifically targets GCC, linked to
a cytotoxic DNA-damaging agent by a peptide linker. TAK-164 is designed to
internalize into tumor cells and to release the cytotoxic agent, which binds to
DNA, resulting in DNA damage due to
alkylation, ultimately leading to apoptosis-driven cell death.
GCC is expressed throughout the GI tract and plays an important role in
maintaining fluid ion homeostasis and genomic integrity in intestinal cells.
GCC binds to the endogenous ligands, guanylin and uroguanylin, as well as to
the heat-stable enterotoxin [45,46]. In normal epithelial
cells, GCC is localized on the apical side of intestinal epithelium. This
anatomically distinct location is accessible from the luminal side, but not
from the vascular compartment due to the presence of the epithelial tight
junctions [47]. The anatomically distinct apical localization is
altered in malignant intestinal cells in which normal tissue architecture and
tight junctions are disrupted. Therefore, a systemic intravenous (IV)
administration of TAK-164 targeting GCC should affect both primary and
metastatic GI carcinoma without affecting normal epithelia
(where GCC would not be accessible to the drug). By accessing malignant cells
but not normal GI cells due to GCC localization and tight junctions, TAK-164 is
expected to have improved treatment efficacy while minimizing toxicity of the
treatment.
In a broad range of GI cancer cells expressing GCC, TAK-164 has demonstrated
antitumor activity at picomolar range. Based on preclinical studies, TAK-164 is
expected to have a manageable safety profile (as described in Section 4.6) when
administered IV to patients.
Preclinical studies have been completed to refine the flexibility of the dose
and schedule of TAK-164 that could be adopted in the clinical setting to
support administration of single-agent TAK-164 as part of this study, as well
as a subsequent combination study. Several pharmacodynamic biomarkers have been
found to be modulated in response to single-agent TAK-164, as shown by
nonclinical studies. These include gamma-H2AX and Chk1. Robust and long-lasting
increases in both of these markers are observed in human tumor xenografts. The
increases are sustained for longer than 24 hours in response to various doses
of TAK-164.
Studies which evaluated a range of response across a spectrum of tumor
xenografts as well as baseline variability of GCC expression in human tumors
have suggested that a majority of tumor models that responded to TAK-164
treatment generally had a GCC H-score of higher or equal to 100.

Primary Objective:
* To evaluate the safety of TAK-164 and to determine the MTD and/or RP2D.

Part C (imaging substudy) secondary objectives are:
* To determine the biodistribution of 89Zr-TAK-164 in patients with mCRC and/or
metastatic gastric carcinomas.
* To determine the tumor targeting of 89Zr-TAK-164.
* To determine dosimetry of 89Zr-TAK-164.

This is a multicenter, nonrandomized, open-label, phase 1 study of TAK-164 in
patients with advanced guanylyl cyclase C (GCC)-positive gastrointestinal (GI)
cancer for whom standard treatment is no longer effective or for whom there is
no available standard therapy. This study will be the first to administer
TAK-164 to humans. For the dose escalation portion of the study (Part A), the
patient population will consist of adults, aged 18 years or older, with any
various GI malignancies expressing GCC for whom standard treatment is no longer
effective or for whom there
is no available standard therapy. Maximum tolerated dose (MTD) and/ or
recommended phase 2 dose (RP2D) will be estimated in Part A. In the expanded
cohort (Part B), patients with colorectal carcinoma (CRC) and gastric carcinoma
will be enrolled at RP2D. In the expanded cohort (part
C-imaging substudy), patients with CRC and gastric carcinoma will be enrolled
at the recommended imaging dose (RID).

This study is designed to determine safety, tolerability, and pharmacokinetics
(PK) and to determine an MTD and/or RP2D of TAK-164 that may be safely
administered to patients with advanced GCC-positive GI cancer. The study may
also help define a therapeutic window of TAK-164 based on pharmacodynamics and
systemic exposures achieved over the evaluated dose range. It is anticipated
that approximately 100 patients could be enrolled, including the escalation
phase (Part A), the expansion phase (Part B), and the imaging substudy (Part C).

Once enrolled in the study, patients will receive TAK-164 treatment
intravenously (IV) on Day 1 of each 21-day treatment cycle or every 3 weeks
(Q3W).

Imaging Substudy (Part C, To Be Conducted in The Netherlands Only)
Up to 25 patients with GCC-expressing metastatic colorectal carcinoma (mCRC)
and/or gastric carcinoma at up to 2 investigational sites in the Netherlands
will be enrolled to determine the in vivo biodistribution and tumor targeting
of zirconium 89 (89Zr)-TAK-164 by positron emission tomography (PET) imaging.
In addition, the relationship of 89Zr-TAK-164 tumor targeting with
18-fluorodeoxyglucose (18F-FDG)-PET*determined response and RECIST version 1.1
response, and the relationship of 89Zr uptake with GCC expression, in tumor
tissues and other biomarkers will be investigated. Based on emerging data from
the dose escalation phase (part A) and in agreement between the site
investigator and sponsor, part C will be triggered at a dose that is considered
safe and having treatment potential (RID).

Initially, approximately 6 patients (including 3 dosimetry patients) will be
enrolled for dosimetry and imaging optimization (DIO). This DIO subgroup will
receive only 89Zr-TAK-164 (mass dose <50% of the RID) 14 days before to the
first regularly scheduled study dose at Cycle 1 Day 1 and a second
89Zr-TAK-164 administration on Cycle 1 Day 1 in combination with unlabeled
TAK-164 at a maximum mass dose of 100% of the
RID. Imaging will be performed 1 hour after end of infusion (EOI) of the first
89Zr-TAK-164 administration for dosimetry in the first 3 patients and for all
patients at 2 time points between Day 2 and Day 7 after EOI. Imaging time
points and mass dose of TAK-164 can be adjusted to optimize imaging conditions.
Up to 19 additional patients will be enrolled into Part C to receive a single
dose of 89Zr-TAK-164 at Cycle 1 Day 1 in addition to unlabeled TAK-164 as
determined for optimal imaging. Once the RP2D of TAK-164 is determined, part C
patients who have received TAK-164 at an RID lower than the RP2D of TAK-164 may
dose-escalate to the RP2D in the absence of PD or unacceptable
treatment-related toxicity at the investigator*s discretion and with the
sponsor*s approval. If the full RID/RP2D is not administered at Cycle 1 Day 1,
the differential will be provided after the second image acquisition. Part C
patients will continue treatment with the RID/RP2D of TAK-164 at Cycle 2 Day 1
and beyond.

TAK-164 will be given as an infusion in the vein; the administration could last
up to 90 minutes.
The patient will receive the study drug on day 1 of each treatment cycle. Each
treatment cycle is 21 days. For the first treatment cycle the dose may be split
into multiple infusions over the first week. This is to optimize the scanning
procedure to detect the study drug in the body. If the dose the patient
received is lower than what is later considered the recommended dose, the dose
may be increased on recommendation of the treating physician and with approval
of Takeda. The patient can have up to 12 treatment cycles or more if the doctor
thinks it is beneficial. The patient will be asked to stay at the hospital for
around 8 hours after the first administration and for 2 hours during the
subsequent cycles, as a consequence, per site standard of care and depending on
assessment timing, 1 to 2 overnight stays might be required.

The first group participating in this study will receive a low dose of study
drug 14 days prior to the first treatment cycle.

The following group (up to 19 additional patients) will start with the first
treatment cycle and a dose that may be split into multiple infusions over the
first week. For every subsequent treatment cycle, everyone will receive a
single dose of study medication on day 1.

There is limited experience with TAK-164 in humans and therefore the benefits
and risks are not yet known. During the study there is a risk that the patient
may have discomfort and side effects from the study drug and from the study
procedures. Discomfort and side effects 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 side effects that may happen. There is
always the possibility that an unknown risk or side effect may occur. These may
be mild or very severe, and in some cases may be very serious, long-lasting,
delayed, or may never go away. There is also a risk of death.

The study doctor may give the patient medications to help lessen some of the
possible discomfort and side effects. If a severe reaction to TAK-164 occurs,
the study doctor may stop the study drug.

The study doctor or health care provider will inform the patient of some foods
and other drugs that the patient may not consume during the trial as they may
interfere with TAK-164.
TAK-164 has been administered to a limited number of humans in the current
clinical trial. Not all of the clinical benefits and risks have been determined

Potential side effects based on the clinical study
Liver Injury, including liver failure:
* Treatment with TAK-164 has resulted in liver injury in some patients,
sometimes requiring hospitalization and resulting in liver failure. Liver
injury is identified by elevations in liver blood test results. Abnormally high
levels of liver blood test results can mean that your liver is not functioning
properly. Symptoms associated with poor liver function can include fatigue and
jaundice (yellowing of the skin and eyes). Although liver injury can be mild
and reversible, it can also be serious or life threatening and lead to liver
failure and death.
* In the current clinical trial, one patient treated with TAK-164 developed
severe liver failure requiring hospitalization. Another patient whose cancer
had spread to the liver also developed liver failure and passed away due to
progression of their cancer.
* Liver blood tests are done to monitor the health of the liver and this
monitoring will be done at various time points throughout the entire duration
of your participation in the study. Some abnormal liver tests indicate possible
liver damage. If you have abnormal liver tests, your study doctor may request
you to have additional follow up and testing.
* Patients with abnormal liver blood tests may or may not have clinical
symptoms. It is very important that you contact your study doctor immediately
if you do experience symptoms such as nausea (a strong urge to vomit),
vomiting, pain in the upper part of your stomach, loss of appetite, fatigue
(feeling tired), fever, rash, dark coloration of your urine, or yellowing of
the skin or eyes. Depending on your liver test results and symptoms, if any,
your study doctor may ask you to stop taking the study drug.
* It is always important that any time you start taking any new medication,
including all over-the-counter medicines such as vitamins, herbal preparations
or natural remedies, you bring this to the attention of your study doctor. This
will help your study doctor have the most complete information while evaluating
abnormal liver blood test results.

Potential side effects based on animal studies:
Based on animal studies with TAK-164, it may be possible to predict some of the
discomforts and side effects. Animal studies do not always predict what happens
in humans. We do not know if these side effects will occur in patients taking
TAK-164.
* Decrease in the number of white blood cell count which may increase the 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 energy; have pale skin; or experience shortness of breath and/or
a faster heart rate.
* Decrease in the number of platelets (a type of blood cell), which could
increase the chance of bruising and bleeding (eg. nosebleeds, bleeding from
gums).
* Skin sores and scabbing at injection sites which may persist even after
stopping TAK-164.
* Bleeding at blood collection sites which may persist even after stopping
TAK-164.
* Generalized bruising which may persist even after stopping TAK-164.
* Darkening of the skin sometimes with sores and scabbing, present on the face,
arms legs or all over the body, which may persist even after stopping TAK-164.
* Diarrhea.
* Inability to become pregnant, or to impregnate a female partner.
* Changes in salivary and tear glands, leading to painful red eyes.

Potential side effects based on other drugs in the same class
* Any drug can cause an allergic reaction. Symptoms of an allergic reaction may
include shortness of breath, wheezing, dizziness, fainting, skin rash, hives,
itching lip or face swelling, throat tightness and swallowing difficulties.
Allergic reactions may require treatment with medications. If a severe allergic
reaction does not respond to treatment, it may result in death. It may happen
in the course of the first infusion or later on after repeated doses.
* Your body may make a protein against TAK-164 that can reduce the activity of
the drug.
* TAK-164 may be a risk to an unborn child or breast-feeding baby.

Risks or inconveniences from study procedures
Blood Samples:
Drawing blood may cause pain, bruising or infection at the site where the
needle enters the body. It is also possible that the patient may feel
lightheaded or faint.

MRI or CT scans:
During the study, the patient will have MRI or CT scans more frequent as he/she
would have them if he/she were not in a clinical trial. There are some side
effects or risks associated with these scans. Some people cannot have an MRI
because they have some type of metal in their body. Often people who have an
MRI scan experience feelings of claustrophobia (fear of being confined in any
space). The scan may be uncomfortable because the patient has to stay still.
Most people experience no unusual side effects or complications from the
contrast dye used in these procedures. However, as with any medical procedure,
some risk is involved such as allergic type reaction with itching and/or hives,
swelling of eyes and lips, sneezing, or difficulty breathing. Some patients may
feel uncomfortable during the CT scan because they are surrounded by moving
technical equipment. The patient will be exposed to a small amount of radiation
from CT scans. The number of tests required as part of the study is
representative of standard of care for this disease. Fatal complications are
rare with this procedure.

PET-scan:
The scan is painless but can be uncomfortable because the patient has to stay
still for around 30 minutes. Some patients may also feel uncomfortable during
the PET scan because they are surrounded by moving technical equipment. The
PET scan involves radioactive tracers. Most people experience no unusual side
effects or complications from the tracer used in these procedures. However, as
with any medical procedure, some risk is involved such as allergic type
reaction with itching and/or hives, swelling of eyes and lips, sneezing, or
difficulty breathing.

Radiation Risks:
CT scan/MRI scan and PET involves using X-rays and radioactive markers. The
radiation used during the study may lead to damage to the patient's health.
However, this risk is small. We nevertheless advise the patients not to
participate in another scientific study involving exposure to radiation in the
near future. Examinations or procedures involving radiation for medical reasons
are not a problem.

Tumor Biopsy Risks:
There are several procedures the study doctor may use to get the tumor biopsy.
The study doctor will discuss the risks of anesthesia and the procedure
involved with getting a biopsy of the patient's specific type of cancer. Tissue
biopsies have the potential to lead to local discomfort, pain, bleeding and
infection. In some cases, complications from a biopsy could be severe.

Study drug administration risk:
Skin lesions with ulceration (sores) or necrosis (tissue death) are a potential
risk and are presumed associated with accidental or inadvertent leakage of
injection fluid.

ECG Risks:
There is a small risk that redness or swelling could develop from the ECG
electrodes (pads) that will be placed on the skin.