Clinical Trial Details
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NCT02571036 : A Safety, Tolerability and PK Study of DCC-2618 in Patients With Advanced Malignancies
PhasePhase 1
AgesMin: 18 Years Max: N/A
Eligibility
Inclusion Criteria (Escalation and Expansion Phases)

Patients must meet the following criteria to be eligible to enroll in the study:

1. Patients must have histologically confirmed solid tumors or hematologic malignancies.
Eligible patients include the following:

a) GIST patients must have a KIT and PDGFRA mutation and must have progressed on or
had an intolerability to at least 1 line of systemic anticancer therapy: i. Patients
with a pre-existing resistance mutation to an approved line of therapy are eligible.
For example, imatinib resistant mutations including KIT Exon 17 and PDGFRA D842V.

b) SM patients must have a confirmed diagnosis (confirmed by a central independent
pathologist) of advanced SM according to 2016 World Health Organization (WHO) criteria
for SM and must have documented KIT mutant disease. SM patients must also have a
normal karyotype.

Advanced SM includes: ASM, SM-AHN, wherein the AHN does not require immediate
alternative therapy, such as acute myeloid leukemia. AHNs that are eligible include:
low grade myelodysplastic syndrome (MDS) with a high SM burden who require treatment
for SM only, myeloproliferative neoplasms (MPNs), MDS/MPN, and HES/CEL], and MCL i.
Patients with advanced SM must present with at least 1 eligible C-Finding (organ
damage) as outlined in Table 3 of the 2013 International Working
Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European
Competence Network on Mastocytosis (ECNM) consensus response criteria (Appendix 10.5);
please see below for MCL exception) (#iii).

ii. Patients with imatinib-sensitive KIT mutations must have progressed on or were
intolerant to a tryosine kinase inhibitor.

iii. Patients with histopathologically-confirmed MCL without a C-finding are eligible.

iv. Patients with symptomatic SSM are eligible. By definition, SSM patients must have
at least 2 B-findings, and clinically significant symptom burden (eg, flushing,
diarrhea, etc.) despite maximal treatment with approved agents to treat mediator
symptoms, such as antihistamines and cromolyn sodium. Patients must have a normal
karyotype.

v. Patients with hematologic malignancies featuring clonal expansion of eosinophils
driven by genomic alterations of KIT or PDGFR (eg, HES or CEL) must have a diagnosis
confirmed by a central independent pathologist and are eligible if they have
progressed on or are intolerant of imatinib therapy. Patients with de novo imatinib
resistant mutations, such as but not limited to KIT D816V or PDGFRA D842V, are
eligible without prior imatinib therapy.

c) Malignant glioma patients with genomic alterations potentially conferring
sensitivity to DCC-2618 including, but not limited to, amplification and/or mutations
of PDGFRA and/or KIT.

i. Patients must not require use of enzyme-inducing antiepileptic drugs. ii. Patients
that require steroids must be on a stable dose for 2 weeks prior to the first dose of
study drug.

d) Other solid tumor patients that have alterations in genes encoding kinases that are
targets of DCC-2618. This includes KIT, PDGFR (A or B), TIE2, CSF1R, and VEGFR2.
Patients must have received approved treatments known to provide clinical benefit
prior to study entry.

e) If signs or symptoms suggest CNS metastases, a brain MRI must be performed to
confirm absence of CNS disease within 1 week prior to receiving study drug.

2. Patients with known CNS metastases may participate provided that:

1. they are stable (ie, without evidence of progression by magnetic resonance
imaging [MRI]) for at least 4 weeks prior to the first dose study drug (patients
with active disease may be eligible following discussion between the Investigator
and the Sponsor),

2. all neurologic symptoms have been stable for 2 weeks prior to the first dose of
study drug,

3. patients must not require use of enzyme-inducing antiepileptic drugs,

4. patients that require steroids must be on a stable dose for 2 weeks prior to the
first dose of study drug.

3. Patients with solid tumors (with the exception of glial tumors and tumors that are
anatomically inaccessible) must have an archival tumor biopsy sample as long as no
anticancer therapy was administered since the sample was collected; otherwise, a
current biopsy is required. In the case of glial tumors and anatomically inaccessible
tumors, the most recent archival tissue is required.

4. Male or female patients =18 years of age.

5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of =2.

6. Female patients of childbearing potential must have a negative serum beta-human
chorionic gonadotropin (ß-hCG) pregnancy test within 28 days prior to the start of
study drug. For clinical sites in the UK, pregnancy testing must occur within 7 days
prior to the start of study drug.

7. Patients of reproductive potential must agree to follow the contraception requirements
outlined in Section 6.8.11.

8. The patient is capable of understanding and complying with the protocol and has signed
the informed consent document. A signed informed consent form must be obtained before
any study-specific procedures are performed. Standard procedures performed as part of
the practice of medicine prior to consent (eg, imaging, physical exam) can be used to
determine eligibility if completed within 28 days prior to the initial dose of study
drug.

9. Patients with solid tumors must have at least 1 measurable lesion according to RECIST
Version 1.1 (non-nodal lesions must be =1.0 cm in the long axis or =double the slice
thickness in the long axis; nodal lesions must be =1.5 cm in the short axis) or
Response Assessment in Neuro-Oncology Criteria (RANO).

a) A non-brain lesion in a previously irradiated area is eligible to be considered as
measurable disease as long as there is objective evidence of progression of the lesion
before study enrollment.

10. Adequate organ function and bone marrow function as indicated by the following central
laboratory screening assessments performed within 14 days prior to the first dose of
study drug. Local laboratory values obtained after screening and prior to Cycle 1 Day
1 dosing that do not meet the criteria below must be discussed with the Sponsor:

1. Solid Tumor Patients: Bone Marrow Function: Absolute neutrophil count (ANC)
=1500/µL; hemoglobin =9 g/dL; platelet count =75,000/µL.

2. All Patients:

i. Hepatic Function: Serum direct bilirubin =1.5 times the upper limit of normal (ULN)
(=3 × ULN if this elevation is solely due to ASM/MCL); aspartate transaminase
(AST)/alanine transaminase (ALT), =3 × ULN (=5 × ULN in the presence of hepatic
metastases or if this elevation is solely due to ASM/MCL).

ii. Renal Function: Serum creatinine =2.0 × ULN or creatinine clearance =50 mL/min
based either on urine collection or Cockcroft Gault estimation.

iii. Coagulation Profile: Prothrombin time (PT) - international normalized ratio
(INR)/partial thromboplastin time (PTT) =1.5 × ULN. Patients on a stable, maintenance
regimen of anticoagulant therapy for at least 30 days prior to study drug
administration may have PT/INR measurements >1.5 × ULN if, in the opinion of the
Investigator, the patient is suitable for the study. An adequate rationale must be
provided to the Sponsor prior to enrollment.

c) SM patients with one or more inadequate organ function laboratory value may be
eligible if both the Investigator and Sponsor deem it to be disease-related and the
abnormality qualifies as a C-Finding (see Appendix 10.5).

11. Resolution of all toxicities from prior therapy to =Grade 1 (or baseline) within 1
week prior to the first dose of study drug (excluding alopecia and =Grade 3 clinically
asymptomatic lipase, amylase, and creatine phosphokinase laboratory abnormalities).

Exclusion Criteria (Escalation and Expansion Phases)

Patients meeting any of the following criteria will be excluded from the study:

1. GIST patients with wild type or unknown KIT or PDGFRA status.

2. Patients with SM or other hematologic malignancies will be excluded if the following
apply:

1. SM patients with wild type KIT mutational status.

2. SM patients with neutropenia accompanied by fever or infection, or
thrombocytopenia associated with clinically significant bleeding.

- Patients with an infection that is well controlled with antibiotics are
eligible if there is an immediate need for treatment

3. SM-AHN patients diagnosed with:

i. SM with MDS (SM-MDS) who require treatment for MDS. ii. Patients requiring
immediate treatment for AHN. d) Patients with leukemias, with the exception of MCL and
CEL, that have progressed after imatinib.

e) Eosinophilic myeloproliferative neoplasm patients: i. Lacking a mutation that is a
known target of DCC-2618. This includes, but is not limited to, fusions/mutations of
FGFR1, JAK2, and ABL.

3. Has a known additional malignancy that is progressing or required active treatment
within 3 years of the first dose of study treatment. Exceptions include basal cell
carcinoma of the skin, squamous cell carcinoma of the skin that has undergone
potentially curative therapy, or other in situ cancers.

4. Treatment with anticancer therapy, including investigational therapy, within 2 weeks
prior to the administration of study drug, with the exception of hydroxyurea that is
allowed to control white blood cell count. For prior therapies with a half-life longer
than 3 days, the interval must be at least 28 days prior to the first administration
of study drug.

5. New York Heart Association class III and IV heart disease, active ischemia or any
other uncontrolled cardiac condition such as angina pectoris, clinically significant
cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart
failure.

6. Arterial thrombotic or embolic events such as cerebrovascular accident (including
ischemic attacks) or hemoptysis within 6 months before start of study drug.

7. Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (eg,
pulmonary embolism) within the 3 months before start of study drug. Patients with
venous thrombotic events =3 months before start of study drug on stable
anticoagulation therapy are eligible.

8. Baseline prolongation of the rate-corrected QT interval based on repeated
demonstration of QT interval corrected by Fridericia's formula (QTcF) >450 ms in males
or >470 ms in females or history of long QT interval corrected (QTc) syndrome.

9. LVEF <50% or below the lower limit of normal (whichever is higher).

10. Major surgery within 4 weeks of the first dose of study drug; following major
surgeries >4 weeks prior to the first dose of study drug, all surgical wounds must be
healed and free of infection or dehiscence.

11. Any other clinically significant comorbidities, such as uncontrolled pulmonary
disease, active infection, or any other condition, which in the judgment of the
Investigator, could compromise compliance with the protocol, interfere with the
interpretation of study results, or predispose the patient to safety risks.

12. Malabsorption syndrome or other illness that could affect oral absorption.

13. Known human immunodeficiency virus or active hepatitis C infection only if the patient
is taking medications that are described in Section 5.8.2.2, active hepatitis B, or
active hepatitis C infection.

14. If female, the patient is pregnant or lactating.

15. Known allergy or hypersensitivity to any component of the investigational drug
product.
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