Dose Escalation Study of ARQ 621 in Adult Patients With Metastatic Solid Tumors and Hematologic Malignancies

Inclusion Criteria:

• Signed written informed consent must be obtained and documented according to International Conference on Harmonisation (ICH)- Good Clinical Practice (GCP), the local regulatory requirements, and permission to use private health information in accordance with the Health Insurance Portability and Accountability Act (HIPPA) prior to study-specific screening procedures
• A histologically or cytologically confirmed metastatic solid tumor or refractory/relapsed hematologic malignancy
• Have a life expectancy of at least 12 weeks
• ≥18 years of age

• Measurable disease as defined by:

  • Solid Tumors: Response Evaluation Criteria in Solid Tumors

  • Multiple Myeloma (MM): International Uniform Response Criteria, at least one of the following:

    • Monoclonal protein in the plasma of ≥0.5 g/dL
    • Monoclonal protein in the urine of ≥0.2 g/24 hr urine collection
    • Serum immunoglobulin free light chain (FLC) ≥100 mg/L (10 mg/dL) and abnormal serum immunoglobulin kappa to lambda FLC ratio

  • Malignant Lymphoma (ML): International Working Group Response Criteria

    • At least one site of disease ≥2 cm in longest diameter (a lesion ≥1 cm can be considered if PET positive)

  • Chronic Lymphocytic Leukemia (CLL): NCI Working Group Guidelines

    • Lymphocytosis (5 x 10^9 /L) with B-cell marker (CD19, CD20,CD23) + CD5
    • High-risk characteristics (hemoglobin <10g/dL OR platelets <100 x 10^9 /L)
  • Acute Myelogenous Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL): only patients with bone marrow or peripheral blast count of ≥20%
  • Acute Promyelocytic Leukemia (APML): patients must be refractory to all-trans retinoic acid (ATRA) and arsenic trioxide
  • Chronic Myelogenous Leukemia (CML): patients in blast crisis (bone marrow or peripheral blast count ≥20%) may be included if refractory to prior therapy and to any therapy the investigators deems of higher priority (for example, BCR-ABL inhibitors such as imatinib mesylate [Gleevec], nilotinib [Tasigna], or dasatinib [Sprycel])
• ECOG performance status ≤2
• Male or female patients of child-producing potential must agree to use contraception or avoidance of pregnancy measures during the study and for 30 days after the last ARQ 621 dose
• Females of childbearing potential must have a negative serum pregnancy test
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × upper limit of normal (ULN) or ≤5.0 × ULN with metastatic liver disease
• Hemoglobin (Hgb) ≥10 g/dL (except in cases considered related to hematologic malignancy)
• Total bilirubin ≤1.5 × ULN
• Creatinine ≤1.5 x ULN (≤2.0 x ULN in cases considered related to multiple myeloma)
• Absolute neutrophil count ≥1.5 x 10^9/L (except in cases considered related to hematologic malignancy)
• Platelets ≥100 x 10^9/L (except in cases considered related to hematologic malignancy)
• Patients with hematologic malignancies who have progressed following at least two prior treatment regimens

Exclusion Criteria:

• Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within four weeks of the first dose

  • In cases of hematologic malignancies, 4-week recovery from prior anticancer treatment is not required, however the patient must recover from prior treatment-related non-hematological toxicities to grade 2 or less
  • When required for supportive care corticosteroids or hydroxyurea may be used
• Surgery within four weeks prior to the first dose

• Known untreated brain metastases or leptomeningeal disease

  • Patients with solid tumors who were treated for brain metastases and who have shown stable disease for at least 8 weeks prior to enrollment will be allowed
• Pregnant or breastfeeding
• Uncontrolled concurrent illness including, but not limited to ongoing or active symptomatic infection requiring systemic therapy, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements
• Patients having a history of Thrombotic thrombocytopenic purpura (TTP) or Hemolytic-uremic syndrome (HUS) or HUS spectrum will be excluded from the study