A Phase 3, INterVentional, Double-Blind, Placebo Controlled Study to Assess the Safety and Efficacy of DCC-2618 In Patients with AdvanCed Gastrointestinal Stromal TUmorS who have Received Treatment with Prior Anticancer Therapies

DCC-2618, an inhibitor of KIT and PDGFRA kinases, is being developed for the
treatment
of patients with GIST, in addition to other advanced malignancies driven by
proto-oncogene
tyrosine-protein kinases. In addition to KIT and PDGFRA, the drug inhibits
CSF1R (FMS),
VEGFR2, and TIE2, which are less frequently documented to initiate tumor
development.
Gastrointestinal stromal tumors represent the most common form of sarcoma, a
relatively
rare subset of cancers arising from mesenchymal cells in the body. Adult GIST
occurs
with an incidence rate of ~3,000-6,000 new cases per year in the US, generally
presents around age 50-70, and occurs in men and women at similar rates.
Surgery is the
primary treatment for localized GIST and can be curative, though local and/or
distant
recurrence occurs in more than half of patients. For metastatic or unresectable
GIST, which is present in about half of patients at diagnosis, radiotherapy and
traditional
chemotherapy are not effective. The era of targeted cancer therapies has
ushered in
several new effective treatments for metastatic and recurrent GIST, though CRs
are rarely
achieved. Resistance to therapy occurs in a large majority of patients within a
few
months to years depending on treatment, similar to that observed in other
cancers
successfully treated with targeted therapies.

DCC-2618 is a novel, oral inhibitor of KIT kinase and PDGFRA kinases, developed
by
Deciphera Pharmaceuticals, LLC (hereafter referred to as the *Sponsor*), using
its
proprietary kinase switch control inhibitor technology platform. DCC-2618
comprehensively
and potently inhibits a broad range of primary and secondary mutants of KIT and
PDGFRA
kinases, including KIT primary mutations in exons 9 and 11 and secondary
resistance
mutations in exon 13 and 14 of the KIT ATP binding/switch pocket region and
primary or
secondary mutations in exons 17 and 18 of the activation loop
conformation-controlling
switch region. DCC-2618 also inhibits the PDGFRA primary exon 18 mutation D842V
in the
conformation-controlling switch region and exon 12 mutations in the auxiliary
inhibitory
switch. DCC-2618 exhibits this broad profile of mutant KIT/PDGFRA inhibition by
binding
as an advanced Type II kinase inhibitor that penetrates the embedded KIT/PDGFRA
switch
pockets.

DCC-2618, and its active metabolite, DP-5439, were evaluated in vitro in
recombinant
kinase assays and in cellular assays with GIST cell lines from
treatment-resistant patients,
AML and mastocytosis cell lines, or cell lines transfected with KIT or PDGFRA
mutants.
These studies provided a comprehensive profile of inhibition versus clinically
relevant KIT
and PDGFRA mutations that cause either de facto refractoriness to existing
therapies or
resistance to existing therapies. Results from evaluation in cancer cell lines
guided further
evaluation of DCC-2618 in refractory/resistant in vivo xenograft models.

A variety of cancer model systems were employed to evaluate the pharmacology of
DCC-2618 in vivo, including the evaluation of efficacy in human tumor
xenografts in nude
mice and pharmacokinetic (PK)/pharmacodynamic (PD) studies in tumor-bearing
mice to
evaluate exposures required for durable mutant KIT inhibition in vivo.

In vivo, DCC-2618 exhibited potent anti-tumor effects in mutant KIT GIST models.
Additionally, DCC-2618 showed potent inhibition of KIT phosphorylation in GIST
models.

DCC-2618 was selected for clinical development based on the efficacy and
tolerability
observed in these model systems.

Primary Objectives:
• To assess the efficacy (progression free survival [PFS]) of DCC 2618 by
independent radiologic review in patients with advanced gastrointestinal
stromal tumors (GIST) who have received prior therapies
Key Secondary Objectives:
• To assess objective response rate by independent radiologic review
Secondary Objectives:
• To assess other parameters of efficacy, including but not limited to time to
progression (TTP) and overall survival (OS)
• To assess the PD/PK relationship of DCC-2618
• To assess the robustness of efficacy using a sensitivity analysis
• To assess improvement of disease-related symptoms and quality of life
• To assess the safety of DCC-2618
Exploratory Objectives:
• To assess the efficacy of DCC 2618 in patients after dose escalation to DCC
2618 150 mg twice daily (BID)
• To characterize KIT and PDGFRA gene resistance mutations (and potentially
other gene mutations) and their DCC 2618-driven longitudinal mutation allele
frequency changes in plasma cell free DNA (cfDNA)
• To retrospectively correlate KIT and PDGFRA mutation/s and/or their frequency
(as well as of potentially other gene mutations) in baseline cfDNA with
clinical benefit
• To understand potential tyrosine kinase inhibitor (TKI) resistance
mechanisms of GIST at time of progression
• To determine concordance between KIT, PDGFRA, and other genetic mutations in
tumor and cfDNA at baseline
• To assess healthcare utilization in patients with advanced GIST who have
received approved therapies

This is a 2 arm, randomized, placebo-controlled, double blind, international,
multicenter study comparing the efficacy of DCC 2618+best supportive care
(hereafter referred to as *DCC 2618*) to placebo+best supportive care
(hereafter referred to as *placebo*) in patients with advanced gastrointestinal
stromal tumors (GIST) who have received treatment with prior anticancer
therapies. Prior anticancer therapies must include treatment with imatinib,
sunitinib, and regorafenib (3 prior therapies). Up to 40% of enrolled patients
may have received prior treatment with imatinib, sunitinib, regorafenib, and
other drugs (>=4 prior therapies).Approximately 120 patients will be randomized
in a 2:1 ratio to DCC 2618 150 mg once daily (QD) or placebo (see Figure 1).
Randomization will be stratified by:
• Patients who have received 3 prior anticancer treatments versus patients who
have received >=4 prior anticancer treatments
o It should be noted that enrollment for patients who have received >=4 prior
anticancer treatments will be limited to 40% of the overall sample size.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS)=0 versus
ECOG PS=1 or 2
The primary response for the study will be evaluated using the modified
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - GIST
specific (hereafter referred to as *modified RECIST*) based on independent
radiologic review.
Upon disease progression by modified RECIST based on independent
radiologic review, study drug treatment will be unblinded. At that time:
• Patients randomized to DCC 2618 150 mg QD will be given the option to:
o continue DCC 2618 at an increased dose of 150 mg BID, or
o continue treatment on study with the same dose if the Investigator feels the
patient is receiving benefit from DCC 2618 or if dose escalation may not be
tolerable for the patient (dose escalation is not permitted at a later time
during the study), or
o discontinue DCC 2618.
• Patients randomized to placebo will be given the option to:
o cross over to receive DCC 2618 150 mg QD, or
o discontinue the study.
Patients randomized to placebo who cross over to receive DCC 2618 150
mg QD and have disease progression by modified RECIST based on Investigator
assessment will be given the option to:
o continue DCC-2618 at an increased dose of 150 mg BID, or
o continue treatment on study with the same DCC 2618 dose if the Investigator
feels the patient is receiving benefit from DCC 2618 or if dose escalation may
not be tolerable for the patient (dose escalation is not permitted at a later
time during the study), or
o discontinue DCC 2618.

This is a 2-arm, randomized, placebo-controlled, double-blind, international,
multicenter
study comparing the efficacy of DCC-2618 to placebo in patients who have
received
treatment with prior anticancer therapies. Prior anticancer therapies must
include treatment
with imatinib, sunitinib, and regorafenib (3 prior therapies). Up to 40% of
enrolled patients
may have received prior treatment with imatinib, sunitinib, regorafenib, and
other drugs (>=4
prior therapies). Approximately 120 patients will be randomized in a 2:1 ratio
to DCC-2618
150 mg QD or placebo. Randomization will be stratified by:
• Patients who have received 3 prior anticancer treatments versus patients who
have
received >=4 prior anticancer treatments
• It should be noted that enrollment for patients who have received >=4 prior
anticancer
treatments will be limited to 40% of the overall sample size.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS)=0 versus
ECOG
PS=1 or 2
The primary response for the study will be evaluated using the modified RECIST
Version 1.1
- GIST-specific (hereafter referred to as *modified RECIST*) based on
independent
radiologic review.
Upon disease progression by modified RECIST based on independent radiologic
review,
study drug treatment will be unblinded. At that time:
Patients randomized to DCC-2618 150 mg QD will be given the option to:
• continue DCC-2618 at an increased dose of 150 mg BID, or
• continue treatment on study with the same dose if the Investigator feels the
patient is
receiving benefit from DCC-2618 or if dose escalation may not be tolerable for
the
patient (dose escalation is not permitted at a later time during the study), or
• discontinue DCC-2618.
Patients randomized to placebo will be given the option to:
• cross over to receive DCC-2618 150 mg QD, or
• discontinue the study.
Patients randomized to placebo who cross over to receive DCC-2618 150 mg QD and
have disease progression by modified RECIST based on Investigator assessment
will be
given the option to:
• continue DCC-2618 at an increased dose of 150 mg BID,
• continue treatment on study with the same DCC-2618 dose if the Investigator
feels
the patient is receiving benefit from DCC-2618 or if dose escalation may not be
tolerable for the patient (dose escalation is not permitted at a later time
during the
study), or,
• discontinue DCC-2618

The side effects may be mild, moderate, severe, long-lasting, permanent or
fatal. Many side effects may go away shortly after the drug is stopped, but in
some cases, side effects can last longer. Sometimes they can be permanent or
serious. DCC-2618 is still being studied in humans and not all the side effects
are known. There is a risk of a rare or previously unknown side effect
occurring.

As of August 2018, 227 patients with different types of cancer have received
DCC-2618 in the Phase 1 study. The followings side effects have been reported.
These side effects may or may not be related to DCC-2618. Some may have been
considered serious.
Common side effects reported in more than 20% of patients:
• Fatigue (40%)
• Hair loss (39%)
• Pain or ache in the muscle (34%)
• Constipation (29%)
• Hand-Foot-Syndrome (blisters, redness, swelling, and pain on the palms of
hands and/or the soles of the feet, 26%)
• Nausea (25%)
• Loss of appetite (23%)
• High blood levels of an enzyme that breaks down fat (22%)
Occasional side effects reported 20% or less of patients:
• Weight loss (20%)
• Abdominal pain (18%)
• Diarrhea (17%)
• Vomiting (16%)
• Decreased iron in the blood, which may make you feel tired or short of breath
(15%)
• Joint pain (15%)
• High blood pressure (15%)
• Shortness of breath (15%)
• Rash (14%)
• Headache (13%)
• Dry skin (12%)
• Increased levels of blood bilirubin, which is a pigment produced by the
liver. Increased levels can cause possible yellowing of the skin and/or eyes
and may indicate liver injury (12%)
• Pain in extremity (12%)
• Cough (11%)
• Muscle spasms (11%)

Some side-effects were considered serious (e.g., required hospitalization or
the doctor felt they were medically important). The following is a list of
serious side effects reported in 2 or more patients. They may or may not be
related to DCC-2618.
• In 8 patients (4%): abdominal pain
• In 6 patients (3%): shortness of breath
• In 4 patients (2%): fever
• The following side effects were reported in 3 patients (1%) each: intestinal
blockage, life-threatening blood infection, urinary tract infection, decreased
iron in the blood, increased bilirubin, confusion
• The following side effects were reported in 2 patients (1%) each: fluid
accumulation in the belly, trouble swallowing, intestinal bleeding, pneumonia,
inflammation of the pancreas, vomiting, fatigue, increased levels of an enzyme
that breaks down fat, mental status changes, chest pain, heart failure, blood
clots, low blood pressure, kidney failure, falls

One patient treated with DCC-2618 was diagnosed with Stevens-Johnson Syndrome
and recovered once the drug was stopped. It is a rare, serious disorder of the
skin and mucous membranes. It begins with flu-like symptoms, followed by a
painful red or purplish rash that spreads and blisters. Then, the top layer of
the affected skin dies, sheds and then heals. This is a serious condition and
may be life-threatening.
While deaths have been reported on the Phase 1 study, none were related to
DCC-2618 treatment. As of August 2018, thirty patients died during the study
with most (22 patients) having died due to disease progression. Three patients
died suddenly due to heart failure. One patient died due to an infection of the
bile duct and one died due to cardiac arrest. Three patients died to unknown
reasons.

Skin Side Effects Observed in Participants in the Phase 1 study that May be
Related to DCC-2618
Some patients treated with DCC-2618 to date have reported changes in the skin.
As of August 2018, eleven (11) patients have had; a curable form of skin cancer
(squamous cell carcinoma). This was treated by removing the tumors using an
outpatient surgical procedure. This common cancer tends to occur in sun
exposed skin and can be seen with the naked eye as often, dry, flaky, raised or
depressed, slow-growing bumps in the skin. Other reported skin changes that are
not listed above were non-cancerous or pre-cancerous skin lesions (including
actinic keratosis and keratoacanthoma) reported in 13 other patients.

Risks for Patients with Lactose Intolerance: Study drug pills contain lactose;
therefore, patients with lactose intolerance should discuss this with their
study doctor.

Possible Drug Interaction Risks: The combination of study drug and any other
medications could be harmful.

Blood Draw Risks: Blood draws may cause pain, bleeding, and/or bruising.

Tumor Biopsy Risks: Risks associated with biopsy of tumor include bleeding,
pain, and infection.

ECG Risks: The tape used to adhere the electrodes to skin may cause some
redness and/or swelling.

CT Scan Risks: The dye used in CT scans may cause pain, burning sensation, hot
flushes, and a severe allergic reaction, particularly in those with prior
allergies to iodine.

MRI Risks: The dye used for MRIs may cause headache, nausea, stomach pain, and
convulsions. There is the possibility of a severe allergic reaction that may be
life threatening.

Pregnancy Risks: The effects of DCC-2618 on the reproductive system (sperm,
eggs), nursing infant, or the unborn child are not known and may be harmful.

Phototoxicity Risks: Your skin may be more sensitive to sunlight while taking
DCC-2618.

There may be additional risks that are unknown or unexpected.

The researchers have taken steps to minimize the risks of this study.