A Multicenter Phase 1, Open-Label Study of DCC-2618 to Assess Safety, Tolerability, Efficacy, and Pharmacokinetics in Patients with Advanced Malignancies

DCC-2618 is a novel, oral inhibitor of KIT developed by Deciphera
Pharmaceuticals, LLC, using its proprietary kinase switch pocket inhibitor
technology platform. The discovery and development of DCC-2618 was based on the
rationale of potently inhibiting a broad array of mutant forms of KIT and
PDGFRα kinases, including mutations that inevitably cause resistance to
approved targeted therapies as well as refractory primary mutations in
treatment naïve patients. This profile was achieved by optimizing the binding
of the inhibitor and forcing these oncogenic kinases into inactive
conformations.
While currently approved tyrosine kinase inhibitors have been demonstrated to
inhibit certain clinically relevant resistant mutations in KIT and/or PDGFRα,
these agents only inhibit a subset of mutant forms of the kinases and do not
broadly inhibit the full spectrum of resistance mutations that arise. DCC-2618
comprehensively and potently inhibits a wide range of primary and secondary
mutants of KIT and PDGFRα kinases, including activation loop mutations in exons
17 and 18. DCC-2618 has been evaluated in recombinant kinase assays and in
cellular assays with gastrointestinal stromal tumor (GIST) cell lines from
treatment-resistant patients, mastocytosis and acute myeloid leukemia (AML)
cell lines, and cell lines transfected with KIT or PDGFRα mutants.
In vivo, DCC-2618 exhibited robust antitumor effects in GIST models. Oral
administration of DCC-2618 in GIST and AML xenograft models demonstrated a
significant reduction in tumor volume compared to vehicle treatment, including
in exon 17 mutant KIT models. DCC-2618 showed robust inhibition of KIT
phosphorylation and signaling for approximately 12 hours after a single oral
dose in the GIST T1 xenograft model. DCC-2618 has pharmaceutical properties
amenable to oral administration. DCC-2618 is therefore a promising candidate
for the treatment of GIST and mast cell diseases, as well as other cancers
driven by KIT or PDGFRα kinases.
A series of in vitro and in vivo non-clinical experiments have been conducted
to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and toxicology
profile of DCC-2618. These studies support further development of DCC-2618
based on the efficacy and tolerability observed in these model systems.
Additional information can be found in the Investigator Brochure.

The current study is a first-in-human (FIH) study with DCC-2618. The study will
consist of an escalation phase assessing increasing doses of single agent
DCC-2618 in patients with advanced malignancies, followed by an expansion phase
testing for safety and preliminary evidence of antitumor activity in select
tumors.

It is well established that inhibition of receptor tyrosine kinases and/or
their downstream targets results in therapeutic effects in a variety of tumor
types. However, despite recent progress and the availability of targeted kinase
inhibitors for certain tumor types, ultimate drug resistance and disease
relapse develop in most tumors, underscoring the need to develop more effective
kinase inhibitors with favorable benefit-risk profiles.

DCC-2618 inhibits a broad range of primary and secondary mutants of KIT and
PDGFRα kinases, including activation loop mutations in exons 17 and 18.
DCC-2618 has been evaluated in recombinant kinase assays and in cellular assays
with GIST cell lines from treatment-resistant patients, mastocytosis and AML
cell lines, and cell lines transfected with KIT or PDGFRα mutants.

Gastrointestinal Stromal Tumors
Gastrointestinal stromal tumors are driven by activating mutations in KIT
(approximately 80%) or the related PDGFRα (approximately 10%) receptor tyrosine
kinases. In GIST patients at presentation, primary mutations in KIT gene are
usually found in exon 9 or 11. Primary mutations in exon 11 disrupt the
auto-inhibited form of the kinase, and those in exon 9 increase receptor
dimerization. Both of these mechanisms cause ligand-independent receptor
activation, which leads to uncontrolled cell growth and transformation.
Multiple KIT targeted therapies have been approved for the treatment of GIST,
but there are limitations to their therapeutic success.

Advanced Systemic Mastocytosis and Hypereosinophilic Syndromes
Aggressive SM and MCL are 2 subcategories of SM that in most adults (>80%) are
characterized by primary KIT mutations in exon 17.
Currently, imatinib is the only approved therapy for patients with ASM wt-KIT
or with unknown KIT mutational status.
None of the currently available KIT inhibitors, including imatinib, sunitinib,
and regorafenib, are able to meaningfully inhibit KIT D816V and no curative
therapy for ASM and MCL has become available to date. Treatment of advanced SM
remains one of the most challenging areas in clinical hematology. Therefore, a
therapeutic agent able to inhibit KIT D816V in these patients would address
this high unmet medical need.
Hypereosinophilic syndromes are myeloproliferative neoplasms with significant
unmet need.
While some of these disorders are quite sensitive to imatinib and it should be
prescribed for patients with fusions or mutations known to be associated with
sensitivity to this agent there are cases of resistance that still have unmet
need. In addition, rare patients who are intolerant of imatinib may benefit
from investigational PDGFR inhibitors such as DCC-2618.

Malignant Gliomas
Gliomas depend on PDGF-PDGFR pathway signaling. Starting early in brain
development, the genesis of oligodendroglial precursors is dependent on
PDGF-PDGFRA signaling.
This normal embryonic signaling is co-opted by tumors including malignant
gliomas. Most GBMs have high expression of PDGFRA. A subset of GBMs exhibit
high amplification of the PDGFRA locus, sometimes including the adjacent KIT
gene. One such co-amplified GBM has shown an excellent response that is ongoing
at 14 months in a patient on the starting dose of DCC-2618. Hence additional
patients with malignant gliomas with genomic alterations including
amplification and/or mutation of PDGFRA and KIT will be recruited.

Other Solid Tumors
Activating mutations in the receptor tyrosine kinase KIT have been identified
in multiple cancer types such as melanoma and testicular seminomas. In
addition, aberrant wild-type KIT overexpression is found in melanoma, gliomas,
and neuroendocrine tumors . Thus, rare KIT genomic alterations are found in a
variety of solid tumors in addition to GIST and malignant gliomas and may
benefit from DCC-2618.

In summary, DCC-2618, a novel tyrosine kinase switch pocket inhibitor, could be
of high therapeutic value in the treatment of patients with advanced
malignancies harboring activated KIT/PDGFRα mutations and those refractory to
existing treatments.

Escalation Phase

Primary Objectives
The primary objectives of this study are to:
• Determine the safety and tolerability of oral DCC-2618
• Determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D)
of oral DCC-261

Secondary Objectives
The secondary objectives of this study are to:
• Determine the PK profile of oral DCC-2618
• Document preliminary evidence of DCC-2618 antitumor activity in patients with
advanced malignancies
• Assess the effect of food on the PK profile of oral DCC-2618

Exploratory Objectives
The exploratory objectives of this study are to:
• Investigate the effects of DCC-2618 on selected PD parameters
•To assess polymorphic variations in genes encoding drug metabolic enzymes
and/or transporters involved in metabolism and disposition of DCC-2618 and
DP-5439 and/or genes that may potentially be associated with clinical response
and/or study drug-related toxicity
• Determine allele fraction of KIT and PDGFRA mutations in plasma cell-free DNA
(cfDNA) and compare it with mutation allele fraction in GIST tumor tissue and
their association with prior treatment and study drug response
• Assess metabolic tumor response by 18F-fluorodeoxyglucose positron emission
tomography (FDG-PET) by European Organisation for Research and Treatment of
Cancer (EORTC) criteria in selected GIST patients.

Expansion Phase

The primary objectives are to:
• Further evaluate the safety and tolerability of oral DCC-2618
• Determine the antitumor activity of DCC-2618 in all diseases under study
The secondary objectives are to:
• Determine the PK, including population PK, profile of oral DCC-2618
• Evaluate the safety and tolerability of the RP2D of oral DCC-2618 in a cohort
of patients with moderate to severe renal impairment
• Determine allele fraction of KIT and PDGFRA mutations in plasma cfDNA and
compare it with mutation allele fraction in GIST tumor tissue and their
association with prior treatment and study drug response
The exploratory objectives are to:
• To characterize the PK of parent drug DCC-2618 and its metabolite, DP-5439
• To explore the relationship between total drug (DCC-2618 + DP-5439) exposure
and potential safety, PD (PK/PD relationships), and total drug exposure and
clinical endpoints, analyzed separately for each cohort and in all patients
receiving at least RP2D
• To assess polymorphic variations in genes encoding drug metabolic enzymes
and/or transporters involved in metabolism and disposition of DCC 2618 and DP
5439 and/or in genes that may potentially be associated with clinical response
and/or study drug-related toxicity
• Investigate the effects of DCC-2618 on selected PD parameters
• Assess the effects of DCC-2618 using patient reported outcome (PRO) measures
to support the selection of future dosing regimen(s).

This is an open-label Phase 1 study. The study will start with an Escalation
Phase evaluating increasing doses of single agent DCC-2618 administered in
repeated 28-day cycles in patients with advanced malignancies with a molecular
rationale for activity. The Escalation Phase will be followed by an Expansion
Phase testing for further safety, PK PD and evidence of antitumor activity
across a variety of tumors with evidence of alterations in genes that are
targets of DCC-2618.

Escalation Phase:
Sequentially increasing dose levels of oral DCC-2618 dosed once daily (QD) or
twice daily (BID) in repeated 28-day cycles will be evaluated for safety based
on pharmacologically guided 3+3 escalation rules until an MTD has been
identified or a recommended expansion dose/regimen(s) is declared (ie, RP2D).
During the Escalation Phase of the study, the effect of food on DCC-2618 PK and
safety was assessed at the baseline visit (Day -7).
As of Amendment 3, the food effect objective was discontinued because
sufficient information is available on the effect of a high-fat meal on PK. The
food effect objective will not apply to the Expansion Phase of the study.

Dose escalation will follow a pharmacologically guided 3+3 design outlined in
Table 5. A minimum of 3 patients will be enrolled in each dose level cohort.
The occurrence of 1 DLT during Cycle 1 will trigger a cohort to expand to 6
patients, for additional safety testing if further dose escalation is planned.
If 1 or more additional DLT(s) occur in the expanded cohort, the DLT dose level
will be declared, dose escalation will end, and an MTD will be determined. Once
a dose level has been declared safe, the dose level of the next cohort will be
determined in consultation with the investigators based on:
1.) safety data from all enrolled patients, and
2.) supplemental PK data from at least 3 patients in the current cohort who
have completed the Cycle 1 Day 15 visit.
If a dose level is declared safe (ie, 0 DLTs in 3 patients or 1 DLT in 6
patients), then the cohort may be expanded to an additional 6 patients to
further investigate PK, PD, tolerability, and antitumor activity. AEs occurring
in such additional patients that meet the definition of a DLT will not count as
DLT but will be considered for the overall safety assessment of a given dose
level.
Once the DLT dose level is reached, an MTD may be determined to be a previously
confirmed safe dose level (assessed in >=6 patients) or it may result from
assessment of additional lower, intermediate dose levels above the last
previous safe dose level. An MTD will be defined as the highest dose level
immediately below the DLT dose level.
Patients may escalate, after the completion of Cycle 2, to a higher daily dose
that has subsequently been found to be safe and tolerable (eg, intra-patient
dose escalate).

Expansion Phase:
In the Expansion Phase, additional patients will be enrolled in disease
specific cohorts for KIT or PDGFRA mutant GIST, SM and other hematologic
malignancies, malignant gliomas, and other solid tumors (See Section 3.4.2 for
further details).
Patients with GIST and other solid tumors will start DCC-2618 at the RP2D (150
mg QD) in the Expansion Phase to further evaluate the safety, tolerability, and
preliminary evidence of antitumor response. Preliminary PK analysis from three
SM patients showed apparently lower exposure than GIST patients. To ensure
sufficient drug exposure, 150 mg BID was selected for patients with SM and
other hematologic malignancies. A dose of 150 mg BID has been administered to
66 patients to date with acceptable safety. Patients with SM or other
hematologic malignancies who are currently receiving DCC-2618 at a dose of 150
mg QD may be dose escalated to 150 mg BID at any time.
In addition to antitumor activity, population PK, PD analysis, and PRO measures
may be used to support RP2D confirmation.
Patients with GIST or other solid tumors enrolled in the Expansion
Phase who have disease progression by the appropriate indication response
criteria (see Appendices 10.2, 10.3, 10.7) may escalate to 150 mg BID after the
completion of Cycle 2. See Section 5.2.6.1 for further details on intra patient
dose escalation in the Expansion Phase. SM patients who were originally
enrolled and dosed at 150 mg QD may be dose escalated to 150 mg BID at any
time. Patients with SM and other hematologic malignancies receiving doses of
DCC-2618 at a dose of 150 mg BID will not be dose escalated following PD.
The safety and tolerability of DCC-2618 will be evaluated in Cohort 10 -
patients with renal impairment (Section 4.2.1). Patients will be dosed at the
RP2D, a total of up to 10 patients will be enrolled and evaluated. PK samples
will be collected for all patients in this cohort (Section 6.3). Patients who
do not have sufficient PK data, may be replaced. Patients with severe renal
impairment who do not complete cycle 1 of treatment due to reasons that are not
study-drug related such as early disease progression may be replaced. Patients
with severe renal impairment who discontinue due to AEs related to DCC-2618
will not be replaced in the study.


Escalation and Expansion Phases:
In addition to safety and assessment of antitumor activity, the PK profile and
PD effects of DCC-2618 will be assessed. PD biomarkers from plasma and whole
blood will be assessed throughout the study. PD and evidence of treatment
response may be investigated in a biopsy containing tumor or mastocytosis cells
when available. A single blood sample will be obtained for pharmacogenomics
research. FDG-PET scans will be used to assess metabolic activity by EORTC
criteria in subsets of patients whose disease can be appropriately assessed
with this testing (eg, GIST). As of Amendment 3, the Sponsor no longer requests
PET scans in the Escalation Phase because sufficient data are available to
estimate the metabolic response rate in KIT mutant GIST. In the Expansion
Phase, PET scans will be performed for GIST patients that progress and dose
escalate (ie, intra-patient dose escalation).

The study will be conducted from the third quarter of 2015 to approximately the
second quarter of 2019.

The current study is a first-in-human (FIH) study with DCC-2618. The study will
consist of an Escalation Phase assessing increasing doses of single agent
DCC-2618 in patients with advanced malignancies, followed by an Expansion Phase
testing for safety and preliminary evidence of antitumor activity in select
tumors. Patients in Netherlands will only be enrolled in the Expansion Phase of
the study.

Expansion Phase only:
In the Expansion Phase, additional patients will be enrolled in disease
specific cohorts for KIT or PDGFRA mutant GIST, SM and other hematologic
malignancies, malignant gliomas, and other solid tumors.
Patients will start DCC-2618 at the preliminary RP2D in the Expansion Phase to
further evaluate the safety, tolerability, and preliminary evidence of
antitumor response. In addition to antitumor activity, population PK, PD
analysis, and PRO measures may be used to support RP2D confirmation.
Patients who have disease progression by the appropriate indication response
criteria in the Expansion Phase may escalate to a higher daily dose after the
completion of Cycle 2. See Section 5.2.6.1 for further details on intra patient
dose escalation in the Expansion Phase.

In the Expansion Phase, Patients with GIST and other solid tumors will start
DCC-2618 at the RP2D (150 mg QD) in the Expansion Phase to further evaluate the
safety, tolerability, and preliminary evidence of antitumor response.
Preliminary PK analysis from three SM patients showed apparently lower exposure
than GIST patients. To ensure sufficient drug exposure, 150 mg BID was selected
for patients with SM and other hematologic malignancies. A dose of 150 mg BID
has been administered to 66 patients to date with acceptable safety. Patients
with SM or other hematologic malignancies who are currently receiving DCC-2618
at a dose of 150 mg QD may be dose escalated to 150 mg BID at any time.
In addition to antitumor activity, population PK, PD analysis, and PRO measures
may be used to support RP2D confirmation.
Patients with GIST or other solid tumors enrolled in the Expansion
Phase who have disease progression by the appropriate indication response
criteria (see Appendices 10.2, 10.3, 10.7) may escalate to 150 mg BID after the
completion of Cycle 2. See Section 5.2.6.1 for further details on intra patient
dose escalation in the Expansion Phase. SM patients who were originally
enrolled and dosed at 150 mg QD may be dose escalated to 150 mg BID at any
time. Patients with SM and other hematologic malignancies receiving doses of
DCC-2618 at a dose of 150 mg BID will not be dose escalated following PD.
The safety and tolerability of DCC-2618 will be evaluated in Cohort 10 -
patients with renal impairment (Section 4.2.1). Patients will be dosed at the
RP2D, a total of up to 10 patients will be enrolled and evaluated. PK samples
will be collected for all patients in this cohort (Section 6.3). Patients who
do not have sufficient PK data, may be replaced. Patients with severe renal
impairment who do not complete cycle 1 of treatment due to reasons that are not
study-drug related such as early disease progression may be replaced. Patients
with severe renal impairment who discontinue due to AEs related to DCC-2618
will not be replaced in the study.





The Expansion Phase will consist of a screening period that will be conducted
within 28 days prior to first dose of study drug, a baseline visit, a treatment
period of 28-day cycles, an intra-patient dose escalation (if applicable for
some patients), a final study visit, and a follow-up safety visit within 30
days after the last dose of study drug.

Patients will be eligible to receive study drug for as long as the patient is
showing clinical benefit as evidenced by disease response for as long as
DCC-2618 is being developed to support the indication and continuation of
treatment does not conflict with the Sponsor*s right to terminate the study as
detailed in Section 3.5. The study will end following the last patient last
visit.

Your disease may not improve or may worsen during your participation in this
study. While you are taking the study drug, you may have side effects. You may
experience all, some, or no side effects, and the side effects may vary in
severity. 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 studies in humans and not all the
side effects are known. There is a risk of a rare or previously unknown side
effect occurring. You must tell your study doctor if you experience any side
effects as soon as they occur, even if you think they are not caused by the
study drug. The study doctor may give you other drugs to ease any discomfort
you experience.
As of August 2018, 227 patients with different types of cancer have received
DCC-2618 in the Phase 1 study. The following 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 in 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 reported 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.

One patient treated with DCC-2618 was diagnosed with diastolic dysfunction,
which is a condition where the heart has trouble relaxing between beats.

As of August 2018, 27 patients died during the study with most (22 patients)
having died due to disease progression. One patient died due to an infection of
the bile duct and one died due to heart attack; neither event was considered
related to study treatment. Three patients died due to unknown reasons.
Although no deaths were considered related to study treatment prior to August
2018, one patient was reported to have died of a heart attack in December 2018
that was possibly related to study treatment.

Skin Side Effects Observed 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) was found. 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 skin lesions (actinic
keratosis and keratoacanthoma) reported in 13 patients.


Possible Drug Interactions: DCC-2618 may interfere with, other drugs that you
are taking, and other drugs may interfere with DCC-2618.

Blood Draws: Blood draws may cause pain, bleeding, and/or bruising. Patients
may faint and/or develop an infection with redness and irritation of the vein
at the site where blood is drawn. Frequent blood collection may cause anemia
(low red blood cell count), which may create a need for blood transfusions.

Tumor Biopsy, Bone Marrow Biopsy and Bone Marrow Aspirate: Risks associated
with biopsy of tumor or bone marrow biopsy and aspirate include bleeding, pain,
and infection. Patients will receive anesthesia to numb the area where the
biopsy will be taken. Once anesthesia wears off, they may feel pain that can
last for several days. Risks associated with localized anesthesia include pain
during administration, prolonged numbness, infection, or a reaction to the
anesthesia.

Magnetic Resonance Imaging (MRI): An MRI scan is painless and will not expose
patients to any radiation. Some patient may feel frightened of enclosed spaces
when they have an MRI scan, as the space inside the machine is cramped. Some
people are also frightened by the noise the machines can make.


Radiation Risks Associated with FDG-PET Scans (GIST Patients Who Dose Escalate
Only): GIST patients who escalate to a higher dose will be exposed to radiation
from two FDG-PET scans. The total amount of radiation exposed to in this study
is [XX] mSv (to compare: the background radiation in the Netherlands is ~2.5
mSv per year). From participating in this study, the maximum amount of
additional radiation your body will be exposed to in one year is less than what
a person performing imaging scans can receive in one year. There is thought to
be an increased long term risk of cancer associated with radiation. However,
this risk is small. The patient will be advised not to participate in another
scientific study involving exposure to radiation in the near future. Previous
studies have shown the more common side effects associated with FDG-PET
scanning to be: mild and brief discomfort with placement of the intravenous
line in your forearm; slight risk of infection; possible bruising, bleeding or
swelling; claustrophobia and anxiety.

Reproductive risks: The effects of DCC-2618 on the unborn child or nursing
children are unknown, It is not known if DCC-2618 could affect male sperm.


There is a potential risk of photoirritation/phototoxicity.