A Safety, Tolerability and PK Study of DCC-2618 in Patients With Advanced Malignancies

Inclusion Criteria (Escalation and Expansion Phases)

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

   1. Male or female patients ≥18 years of age.

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

      1. 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.

      2. SM patients must have a confirmed diagnosis of advanced SM according to 2016
      World Health Organization (WHO) criteria for SM and must have documented KIT
      mutant disease. Patients with imatinib-sensitive KIT mutations must have
      progressed on or were intolerant to a tyrosine kinase inhibitor. Patients with
      advanced SM must present with at least 1 eligible C-Finding (organ damage) per
      2013 International Working Group-Myeloproliferative Neoplasms Research and
      Treatment (IWG-MRT) & European Competence Network on Mastocytosis consensus
      response criteria; please see below for MCL exception.

   Advanced SM includes:

   i. Aggressive SM (ASM)

   ii. SM with associated hematologic neoplasm (SM-AHN), wherein the AHN does not require
   immediate alternative therapy. AHNs that are eligible include: low grade
   myelodysplastic syndrome (MDS) with a high SM burden who require treatment for SM
   only, myeloproliferative neoplasms (MPN), MDS/MPN, unclassifiable MDS, and HES/CEL.

   iii. MCL

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

   iv. Symptomatic SSM

   • 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.

   v. Patients with hematologic malignancies featuring clonal expansion of eosinophils
   driven by genomic alterations of KIT or PDGFRA (eg, HES or CEL) 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.

   Other solid tumor patients that have alterations in genes encoding kinases that are
   targets of DCC-2618. This includes:

      - Melanoma

      - Soft tissue sarcoma patients (including but not limited to: malignant peripheral
      nerve sheath tumors (MPNST), desmoplastic small round cell tumors (DSRCT), and
      dermatofibrosarcoma protuberans tumors (DFSP)

      - Other solid tumor patients (non-melanoma, non-STS; specifically germ-cell,
      penile, and non-small cell lung carcinoma)

      - Renal impairment cohort

   3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤2.

   4. Adequate organ function and bone marrow function.

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 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.

      2. SM-AHN patients diagnosed with:

   i. SM with MDS who require treatment for MDS. ii. Patients requiring immediate
   treatment for AHN.

   c. Patients with leukemias, with the exception of MCL and CEL, that have progressed
   after imatinib.

   d. Eosinophilic myeloproliferative neoplasm patients: i. Lacking a mutation that is a
   known target of DCC-2618.

   3. Prior or concurrent malignancy whose natural history or treatment have the potential
   to interfere with the safety or efficacy assessment of DCC-2618. Patients receiving
   adjuvant cancer treatment are not eligible if those medications are potentially active
   against GIST or excluded per protocol.

   4. 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.

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

   6. 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.

   7. 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.

   8. Left ventricular ejection fraction (LVEF) <50% or below the lower limit of normal
   (whichever is higher).

   9. 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.

10. Any other clinically significant comorbidities.

11. Illnesses that could affect oral absorption.

12. Known human immunodeficiency virus or active hepatitis C infection only if the patient
   is taking per protocol prohibited medications, active hepatitis B, or active hepatitis
   C infection.

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

14. Known allergy or hypersensitivity to any component of the investigational drug
   product. Patients with history of Stevens-Johnson syndrome on a prior tyrosine kinase
   inhibitor (TKI) are excluded.