A Multicenter Phase 1/2, Open-Label Study of DCC-3014 to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics in Patients with Advanced Tumors and Tenosynovial Giant Cell Tumor

A new compound named DCC 3014 is being developed by Deciphera Pharmaceuticals,
LLC, as an oral study drug for the treatment of advanced tumors and DTGCT. This
compound is a small molecule that blocks the activity of changes in specific
genes, specifically, CSF1R. Genes are the instructions that tell cells what to
do. In advanced tumor diseases and DTGCT there are change in the genes so that
the instructions are no longer correct. In laboratory studies DCC-3014 has
been shown to block genes that are giving incorrect instructions to the cell.
Subjects are being invited to take part in a research study of DCC 3014.

This study has been transitioned to CTIS with ID 2024-514933-39-00 check the CTIS register for the current data.

Primary Objectives:
• To assess the safety and tolerability of DCC 3014.
• To characterize the pharmacokinetic (PK) profile of DCC 3014.
• To determine the maximum tolerated dose (MTD) of DCC 3014.
• To determine the recommended Phase 2 dose (RP2D) of DCC 3014.
• To evaluate anti-tumorantitumor activity of DCC-3014 using Response
Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 in DTGCT (tenosynovial
giant cell tumor (TGCT; formerly known as pigmented villonodular synovitis
[PVNS] or giant cell tumor of the tendon sheath [GCT-TS]) (Expansion Cohort B A
only).
Secondary Objectives (DTGCTTGCT Expansion Cohort BA only):
• To evaluate antitumor activity of DCC-3014 using tumor volume score (TVS) and
modified RECIST (mRECIST).
• To assess the effects of DCC-3014 on range of motion (ROM) in DTGCT.).
• To assess the effects of DCC-3014 on physical function, worst pain, and worst
stiffness using patient reported outcome (PRO) measures.
Exploratory Objectives:
• To evaluate the preliminary evidence of DCC 3014 antitumor activity (in
malignant solid tumor (MST) patients enrolled in (Dose Escalation and Expansion
Cohort A)
• To evaluate the preliminary evidence of DCC-3014 antitumor activity in TGCT
patients (Dose Escalation and Expansion Cohort B)
• To assess the relationship between efficacy or safety and PK
• To assess the effects of DCC-3014 on ROM in DTGCT (patients enrolled in TGCT
(Dose Escalation and Expansion Cohort B)
• To assess the effects of DCC-3014 on symptomatic relief and functional
assessments using patient reported outcome (PRO) measures (DTGCT patients only
and those not covered as secondary endpoint above).Dose Escalation and
Expansion Cohorts A and B)
• To investigate the effects of DCC-3014 on select biomarkers in the tumor
microenvironment, and peripheral blood, and skin.
• To investigate the mechanism of serum enzyme level increases.
• To assess germline polymorphic variations in genes involved in the metabolism
or disposition of DCC-3014 or in relation to safety or efficacy.

This is a multicenter, open-label Phase 1/2 study of DCC-3014 (vimseltinib) in
patients with advanced tumors and TGCT. There will be 2 distinct parts in this
study; Dose Escalation will enroll both MST and TGCT patients (Phase 1) and
Expansion will only enroll TGCT patients (Phase 2).
This study will enroll patients with solid tumors or manifestations of cancer
with known contribution of macrophages or phagocytes, ie, tumors known to have
expression of the receptor colony-stimulating factor 1 receptor (CSF1R) or its
ligands, colony-stimulating factor 1 (CSF1) or interleukin (IL)-34, confirmed
by the literature or prior testing. The prime example of such diseases is TGCT,
where aberrant over-production of CSF1 drives recruitment of macrophages
leading to local destruction of joints and anti-CSF1R therapy has demonstrated
clinical efficacy. Patients with any common carcinomas that have high
tumor-infiltrating macrophage content will be eligible for the study. In
addition, tumor-associated manifestations featuring macrophage pathophysiology
including bone metastases and ascites or effusions that typically contain
high levels of macrophages will be enrolled.
DCC-3014 will be administered to patients orally in 28-day cycles according to
assigned dose and regimen. Patients may remain on treatment until tumor
progression, occurrence of unacceptable toxicity, withdrawal of consent,
physician*s decision, or commercialization. Patients may continue receiving
treatment after tumor progression if agreed upon by the Investigator and
Sponsor, if there are no other treatments available. Additionally, treatment
may be extended by agreement between the Sponsor and Investigator for patients
who exhibit evidence of clinical benefit and tolerability to the drug, and who
adhere to the study procedures. Dose Escalation Phase:
Patients with solid tumors will receive the study drug, DCC-3014, at an
assigned dose level upon registration. The starting dose is 10 mg once daily
(QD), based on data from nonclinical toxicology and PK studies. Based on
clinical experience from Cohort 1 (10 mg QD), subsequent cohorts (Cohort 2 and
above) will include loading doses followed by maintenance doses.
Additional dosing schemes (eg, loading dosing period of 3 to 7 days or
modifications to maintenance dosing schedules) including QD dosing may be
explored based on PK, pharmacodynamic, and safety data as well as discussion
and agreement between the Sponsor and Investigators following safety and
PK/pharmacodynamic readouts.
Dose escalation of study drug will be based on a pharmacologically guided 3+3
study design in patients with MST and TGCT. A minimum of 3 patients will be
initially enrolled in each dose level cohort. If a patient experiences a
dose-limiting toxicity (DLT) during Cycle 1, then the cohort will be expanded
to 6 patients. If <=1 out of 6 patients (fewer than 33%) experience a DLT the
dose level may be escalated. If >=2 patients out of 3 to 6 patients (>=33%)
experience a DLT(s) during Cycle 1, Dose Escalation will end, and a lower dose
level cohort will be expanded for determination of the MTD. Decisions of dose
escalation and the dose level of the next cohort will be determined based on
evaluation of at least 3 patients completing Cycle 1 and in consultation
between the Sponsor and Investigators. A patient will be evaluable in the Dose
Escalation phase if the patient either experienced a DLT during Cycle 1 or
received >=80% of planned doses of study drug in Cycle 1, following review of
available safety, PK and pharmacodynamic. As of Cohort 4, no more than a 50%
increase in a total dose given in the first cycle will be allowed from the
previous cohort.
The MTD will be defined as the highest dose level at which no more than 1 of 6
DLT-evaluable patients (< 33%) experiences a DLT(s) in Cycle 1 during Dose
Escalation. The RP2D may be the MTD or a biologically active or maximally
feasible dose that is lower than the MTD. Different RP2Ds may be determined
for MST and TGCT patients. The determination of MTD will require treatment of
at least 6 patients at the same dose level whereas determination of RP2D will
be based on safety and tolerability of at least 3 patients if no more than 1
of 6 DLT-evaluable patients experiences a DLT(s) in Cycle 1 at a higher dose
level.
Each Dose Escalation cohort may enroll up to 6 additional patients for
evaluation of safety, efficacy, PK, and pharmacodynamic (up to 12 patients).
As of initiation of Dose Escalation Cohort 8, only TGCT patients will be
enrolled into the Escalation phase.
Expansion Phase (Cohorts A and B for TGCT patients):
The Expansion phase will be opened upon determination of RP2D from Dose
Escalation and may opened prior to the determination of MTD if further
exploration at higher doses is ongoing. Expansion consists of 2 cohorts to
further evaluate the safety, PK, pharmacodynamics, and preliminary efficacy of
DCC-3014 in patients with TGCT. Patients with MST will not be enrolled into
the Expansion phase.
Expansion Cohort A will enroll approximately 40 TGCT patients without prior
anti-CSF1 or anti-CSF1R treatment (with the exception of imatinib or
nilotinib) who will be treated at the RP2D. Intra-patient dose escalation will
be allowed following discussion between the Sponsor and the Investigator; the
dose level may be increased by 1 dose level at a time. If no clinical benefit
is observed in first 10 patients having completed at least one post-dose scan,
Expansion Cohort A will close.
Expansion Cohort B will enroll approximately 20 TGCT patients with prior
anti-CSF1 or anti-CSF1R therapy who will be treated at the RP2D; intra-patient
dose escalation will be allowed as described for Cohort A. If no clinical
benefit is observed in the first 10 patients having completed at least 1
post-dose scan, Expansion Cohort B will close.
If >=33% of patients experience an adverse event (AE) that meets the definition
of DLT during Cycle 1 in a given cohort, all patients will be reduced to a
lower dose determined by the Sponsor and Investigators. Patients subsequently
enrolled will be treated at the lower dose level.

N/A

Side Effects of DCC-3014
The study drug to be investigated may have side effects. You may experience
all, some, or no side effects, and the side effects may vary in severity. The
severity may be mild, moderate, severe, life threatening or fatal. Many side
effects may go away shortly after the drug is stopped, but in some cases, side
effects can last longer or be permanent. Also, there is always the risk of a
rare or previously unknown side effect occurring. If any of these side effects
occur, you must tell your study doctor who may give you other drugs to ease any
discomfort you experience.

This is the first study of DCC-3014 in humans, so the side effects are not well
established.

As of August 28, 2020, 60 patients including 37 patients with different types
of cancers and 23 patients with tenosynovial giant cell tumors have received
DCC-3014 in the Phase 1 escalation (part 1) study at various doses and dosing
schedules.

Very common side effects reported in at least 6 patients (10%) are listed
below. These side effects were reported as related to DCC-3014:
• Periorbital oedema (Swelling around the eyes due to accumulation of fluid)
(28%)
• Increased levels of an enzyme produced by the liver in blood, which in rare
cases, may indicate liver injury (23%)
• Fatigue (23%)
• Increased levels of an enzyme produced by the heart or muscle in blood, which
may indicate muscle injury/inflammation, rarely heart injury (22%)
• An increase in enzymes produced by the pancreas in the blood which may
indicate pancreatic injury or inflammation (17%)
• Diarrhea (12%)
• Nausea (12%)
• Face edema (Swelling of the face due to accumulation of fluid) (12%)
• Itching (12%)

Side effects reported in more than 3 patients (5%) but less than 6 patients
(10%):
• Peripheral Edema (swelling of the arms and/or legs due to accumulation of
fluid) (8%)
• Rash (8%)
• Muscle pain or muscle aches (7%)
• Abdominal pain (5%)
• Headache (5%)
• Vomiting (5%)

As of August 28, 2020, 14 patients (23%) died during the study. All
deaths were considered not related to DCC-3014. Most of the deaths were a
result of progressive disease in patients with disease progression. There were
no deaths reported in patients with tenosynovial giant cell tumor.
Possible Drug Interactions: DCC-3014 may interfere with other drugs that you
are taking. Likewise, other drugs may interfere with DCC-3014. Allergic
reactions may occur. For this reason, it is important that you tell your study
doctor about any other medications that you are taking, prior to and during the
study. Your study doctor may monitor certain medications you take more
closely. Your study doctor will tell you about medications that you should
avoid taking during this study.
Phototoxicity Precaution: You should avoid strong sunlight, sunlamps, and other
sources of ultraviolet radiation (a type of light) for the duration of the
study. For prevention of phototoxicity, use of the following are recommended:
sunscreen with sun protection factor of 30 or higher, hypoallergenic
moisturizing creams or ointments for dry skin, and gentle skincare with
fragrance-free soaps and detergents.
Allergic Reactions
As with taking any drug, there is a risk of allergic reaction. If you have a
very serious allergic reaction, you may be at risk of death. Some symptoms of
allergic reactions include an itchy rash (hives) or swelling of the throat
making it difficult to breathe.
Please seek treatment immediately and tell the study doctor and study staff if
you have any of these symptoms, or any other side effects, during the study.
Tests
Blood Sampling
Blood collections may cause injection site swelling and/or pain, dizziness,
lightheadedness, bleeding or bruising. You 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).
Fasting may cause your blood sugar to drop. You may feel tired, hungry, and/or
nauseous. If you have diabetes, it is important to talk to your doctor about
managing your blood sugar while fasting.
The total volume to be collected will depend on how long you will participate
in the study. Cycle 1 should be 80 mL and approximatively 60ml during Cycle 2
and cycle 3 and then approximatively 56 mL for the subsequent visits (once a
month for 2 years). This may be more if you are required to attend any
unscheduled visits. However, this amount should not cause any problems in
adults. In comparison: at the blood bank, 500 mL of blood is collected at one
time.

Electrocardiogram
Skin irritation from the ECG electrode pads or pain when removing the pads are
possible side effects.
Skin punch Biopsy (removing a tiny sample of skin tissue close to the affected
joint)
You will receive anesthesia to numb the area where the biopsy will be taken.
Once anesthesia wears off, you 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.
Tumor Biopsy:
Risks associated with biopsy of your tumor may include bleeding, pain, and
infection. You will receive anesthesia to numb the area where the biopsy will
be taken. Once anesthesia wears off, you 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.
MRI Scan
MRI scanners use a large magnet and radio waves to take pictures of your body.
The scanning takes about 30 to 60 minutes. The effects of the magnetic fields
in an MRI scanner have been widely studied. There are no known risks from
being exposed to the magnetic fields. Before an MRI scan, you will be asked a
series of questions by the MRI staff to be sure that you do not have any
medical reasons that stop you from having an MRI. You should not have an MRI
if you have a pacemaker, metallic cardiac valve(s), or certain types of
metallic aneurysm clips. You should not have an MRI if you have implanted
electronic infusion pumps or other metallic pieces in your body.
You will lie flat on a table that will move into a horizontal tube that is
within a large magnet. You may feel *closed in* from being in the small space
and you will hear loud banging sounds while having the MRI scan. For some MRI
scans, you may get an MRI contrast material. This contrast material is
injected into your vein. You will not get the MRI contrast material if you
have abnormal kidney function. It is uncommon, but you may feel warmth or pain
in the area where the needle was inserted. You may also experience nausea,
vomiting, or a headache. Serious allergic reactions that may be life
threatening are very rare.
The study drug may also cause adverse effects that are unknown and unexpected.