Study of DCC-3014 in Patients With Advanced Malignancies

Inclusion Criteria (Solid Tumor Patients):

1. Patients ≥18 years of age,

2. Must have progressed on all available therapies known to confer benefit for disease

3. Must have tissue source of tumor cells

4. Must have 1 measurable lesion according to RECIST Version 1.1

5. Must have objective evidence of progression of lesions that have been previously
irradiated

6. Must have ECOG performance status of 0-1

7. Bone Marrow Function: absolute neutrophil count (ANC) ≥1500/µL; hemoglobin ≥9 g/dL;
platelet count ≥75,000/µL

8. Hepatic Function: Total serum bilirubin ≤1.5 times the upper limit of normal (ULN;
except for patients with known Gilbert syndrome);); serum aspartate aminotransferase
(AST)/alanine aminotransferase (ALT), ≤32.5×ULN (≤5×ULN in the presence of hepatic
metastases)

9. Renal Function: Serum creatinine ≤1.5×ULN or creatinine clearance ≥50 mL/min based
either on urine collection or Cockcroft-Gault estimation

10. Coagulation Profile: Prothrombin time (PT) - international normalized ratio
(INR)/partial thromboplastin time (PTT) ≤1.5xULN5×ULN.

Inclusion Criteria (Hematologic Malignancies):

1. Patients ≥18 years of age, except for patients with ALL who can be ≥16 years of age

2. Morphologically documented relapsed/refractory myelodysplastic syndrome (MDS), acute
myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic lymphocytic
leukemia (CLL) as defined by World Health Organization (WHO) criteria

3. Patients with relapsed/refractory MDS, AML, ALL must have progressed on least 1 prior
therapy and cannot be a candidate for any available therapies in patients with a
rationale for known to confer clinical benefit

4. For patients with MDS, AML, ALL, or CLL, must have cells obtained either by bone
marrow biopsy or blood collection to use for biomarkers that may enrich for DCC-3014
response or provide PD information

5. For CLL, must have measurable disease per International Workshop on Chronic
Lymphocytic Leukemia (IWCLL) criteria (Hallek criteria) to allow evaluation of
response

6. May have primary phagocytic malignancies including histocytoses, including Erdheim
Chester Disease (as diagnosed in Diamond et al 2014) and Langerhans histiocytoses are
eligible if refractory to or unsuitable for other therapies.

7. ECOG PS of 0-2

8. Bone Marrow Function: ANC ≥1000/µL; hemoglobin ≥8 g/dL; platelet count ≥75,000/μL.

9. Hepatic Function: Total serum bilirubin <1.5×ULN; serum AST and ALT <2.5×ULN (≤5×ULN
in the presence of hepatic metastases).

10. Renal Function: Serum creatinine <2xULN1.5×ULN, or glomerular filtration rate >2050
mL/hr as calculated by CockgroftCockroft-Gault formula.

11. Serum potassium, magnesium and calcium (corrected for albumin) that are within
institutional normal limits or can be corrected with supplementation.

12. Total serum bilirubin <2xULN (except for patients with known Gilbert syndrome).

13. Serum AST and ALT <5xULN.

14. Coagulation Profile: Prothrombin time (PT) - international normalized ratio
(INR)/partial thromboplastin time (PTT) ≤1.5×ULN.

Exclusion Criteria (Solid Tumors):

1. Treatment with anticancer therapy, including investigational therapy, within 2 weeks
prior to the administration of study drug. For immediately prior therapies with a
half-life longer than 3 days, or if the half-life is not available, the interval must
be ≥28 days prior to the first administration of study drug.

2. Unresolved toxicity according to National Cancer Institute Common Terminology Criteria
for Adverse Events (NCI-CTCAE), Version 4.03 (ie, >Grade 1 or baseline) from previous
anticancer therapy, excluding alopecia.

3. The patient has known active CNS metastases. Patients with previously treated brain
metastases may participate provided that:

- They are stable (ie, without evidence of progression by magnetic resonance
imaging [MRI]) for ≥4 weeks prior to the first dose of study drug),

- All neurologic symptoms have returned to baseline, and

- Patients do not require continued steroid therapy or use of enzyme-inducing
antiepileptic drugs. Patients can be switched to a non-enzyme inducing
antiepileptic drug. If signs or symptoms suggest CNS metastases, a brain MRI must
be performed to confirm absence of detectable CNS disease within 2 weeks prior to
receiving study drug.

4. New York Heart Association class III or 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. Systemic arterial thrombotic or embolic events, such as cerebrovascular accident
(including ischemic attacks) or hemoptysis within 6 months prior to the start of study
drug.

6. Systemic venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial
events (eg, pulmonary embolism) within the 1 month prior to the start of study drug.
Patients with venous thrombotic events before the 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 (QTc) >450 ms or history of long QTc syndrome.

8. Left ventricular ejection fraction (LVEF) <50%.

9. Concurrent treatment with proton-pump inhibitor. Other medications that increase
gastric pH, ie, histamine H2 receptor antagonists and antacids may be taken provided
they are not administered within 2 hours before or after administration of study drug.

10. Major surgery within 2 weeks of the first dose of study drug; following major
surgeries >2 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, active hepatitis B, active hepatitis C, or active
mycobacterium tuberculosis infection.

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

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

16. Patients with known Gilbert's disease.

Exclusion Criteria (Hematologic Malignancies):

1. Concurrent active malignancy with expected survival of less than 1 year.

2. Graft versus host disease (GVHD) that is not well-controlled on a stable treatment
regimen for at least 3 weeks prior to initial dose of study drug.

3. Cancer-directed therapy within 2 weeks prior to starting treatment, with the exception
of hydroxyurea, which is allowed to control white blood cell count.

4. History of, or current, central nervous system involvement with MDS, AML, or CLL.

5. Systemic arterial thrombotic or embolic events, such as cerebrovascular accident
(including ischemic attacks) or hemoptysis within 2 months prior to the start of study
drug.

6. Systemic venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial
events (eg, pulmonary embolism) within the 1 month prior to the start of study drug.
Patients with venous thrombotic events before the start of study drug on stable
anticoagulation therapy are eligible.

7. Clinically significant coagulation disorder, such as disseminated intravascular
coagulation.

8. New York Heart Association class III or 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.

9. Baseline prolongation of the rate-corrected QT interval based on repeated
demonstration of QTc >450 ms or history of long QTc syndrome.

10. LVEF <50%.

11. Concurrent treatment with proton-pump inhibitor.

12. Major surgery within 2 weeks of the first dose of study drug; following major
surgeries >2 weeks prior to the first dose of study drug, all surgical wounds must be
healed and free of infection or dehiscence.

13. 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.

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

15. Known human immunodeficiency virus, active hepatitis B, active hepatitis C, active
cytomegalovirus (CMV), or active mycobacterium tuberculosis infection.

16. Active infection that is not well-controlled by antibacterial or antiviral therapy.

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

18. Known allergy or hypersensitivity to any component of the study drug.

19. Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype).

20. Unwillingness to receive infusion of blood products.

21. Patients with known Gilbert's disease.