Phase 1 Study of TG02 Citrate in Patients With Advanced Hematological Malignancies (TG02-101)

Part 1 Inclusion Criteria:

• Relapsed AML, ALL, CML in blast crisis, or MDS
• 65+ yrs with AML not eligible for standard frontline chemo
• Interval from prior treatment to time of study drug at least 5 half-lives for cytotoxic/ noncytotoxic agents.
• Persistent clinically significant toxicities from prior chemo ≤ Grd 1
• ECOG PS 0-2

• Lab values:

  • Cr ≤ 2X ULN
  • ALT and/or AST ≤2.5 X ULN
  • Total bilirubin ≤1.5 X ULN unless considered due to Gilbert's syndrome
• Negative pregnancy test
• Can take oral med

Part 2 Inclusion Criteria:

• Relapsed multiple myeloma. At least ≥1 line of therapy and progressed after ≥1 prior therapy

• Measurable disease defined as at least one of the following:

  • Serum M ≥500 mg/dL
  • Urine M ≥200 mg per 24hr
  • Involved FLC ≥10 mg/dL and abnormal FLC ratio in serum (<0.26 or >1.65)
  • Measurable soft tissue plasmacytoma
• Persistent clinically significant toxicities from prior chemo ≤ Grd 1
• ECOG PS 0-2

• Lab values:

  • ANC of >1000/mm3
  • Platelets ≥50,000/mm3
  • Cr ≤2X the ULN
  • ALT and/or AST ≤2.5X ULN
  • Total bilirubin ≤1.5X ULN, unless considered due to Gilbert's syndrome
• Negative pregnancy test
• Can take oral med

Part 3 Inclusion Criteria:

• Measurable disease defined as at least one of the following:

  • Serum M ≥500 mg/dL
  • Urine M protein ≥200 mg per 24hr
  • Involved FLC level ≥10 mg/dL and abnormal FLC ratio in serum (<0.26 or >1.65)

• Meet at least one of the criteria below:

  • a. ≥2 prior therapies including proteasome inhibitor and immunomodulatory agent (IMiD)
  • b. ≥1 prior therapy and one of the following abnormalities: 17p del, p53, 1q amp, 1p del, t(4;14)
• Interval from prior treatment to time of study drug at least 5 half-lives or 3 wks, which ever is shorter, for noncytotoxic agents
• Persistent clinically significant toxicities from prior chemo ≤ Grd 1 or Grd 2 neuropathy without pain
• ECOG PS 0-2

• Lab values:

  • ANC of >1000/mm3 independent of G-CSF
  • Platelets ≥50,000/mm3 independent of transfusion
  • MDRD calculated or measured CrCl of ≥30 mL/min
  • ALT and/or AST ≤3X ULN
  • Total bilirubin ≤2X ULN, unless considered due to Gilbert's syndrome
• Negative pregnancy test
• Can take oral med

Part 4 Inclusion Criteria:

• Measurable disease defined as at least one of the following:

  • Serum M ≥500 mg/dL
  • Urine M protein ≥200 mg per 24hr
  • Involved FLC level ≥10 mg/dL and an abnormal FLC ratio in serum (<0.26 or >1.65)

• Received prior therapies including:

  • a. bortezomib
  • b. an IMiD
  • c. carfilzomib. Demonstrated disease progression on or within 60d of completion of carfilzomib therapy
• Interval from prior treatment to time of study drug at least 5 half-lives or 3 wks, which ever is shorter, for noncytotoxic agents.
• Persistent clinically significant toxicities from prior chemo ≤ Grd 1, or Grd 2 neuropathy without pain.
• ECOG PS 0-2

• Lab values:

  • ANC of >1000/mm3 independent of G-CSF
  • Platelets ≥50,000/mm3 independent of transfusion
  • MDRD calculated or measured CrCl of ≥30 mL/min
  • ALT and/or AST ≤3X ULN
  • Total bilirubin ≤2X ULN, unless considered due to Gilbert's syndrome
• Negative pregnancy test
• Can take oral med

Parts 1 and 2 Exclusion Criteria:

• Previous allogenic hematopoietic transplant within 90 d
• Concurrent severe or uncontrolled medical disease that would compromise the safety or compromise the ability of the patient to complete the study
• Prolonged QTC interval >450ms
• Symptomatic CNS metastases
• Known HIV or AIDS
• Actively treated for a second malignancy
• Pregnant or nursing women

Part 3 Exclusion Criteria:

• Multiple myeloma of IgM subtype, POEMS, plasma cell leukemia
• Corticosteroids discontinued ≥7 days of initiating therapy
• Previous chemo within 2 wks
• Hx of ventricular arrhythmia or symptomatic conduction abnormality within 12m
• CHF, symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, myocardial infarction within 6m
• Prolonged QTc interval (males >450ms, females >470ms)
• Previous allogeneic hematopoietic transplant within 90 days of study enrollment, Active GVHD requiring treatment.
• Concurrent severe or uncontrolled medical disease that would compromise the safety or compromise the ability of the patient to complete the study
• Symptomatic CNS metastases
• Known HIV or AIDS
• Prior or 2nd malignancy, except non-melanoma skin cancer, completely resected cervical or prostate cancer (with PSA of less than or equal to 0.1 ng/ml), or other cancer for which the subject has received curative therapy at least 3 yrs prior to study entry
• Treatment-related MDS
• Significant neuropathy (Grd 3-4 or Grd 2 with pain) at the time of 1st dose
• Primary AL amyloidosis
• Pleural effusions requiring thoracentesis or ascites requiring paracentesis
• Pregnant or nursing women

Part 4 Exclusion Criteria:

• Multiple myeloma of IgM subtype, POEMS, plasma cell leukemia
• Previous chemo within 2 wks
• Hx ventricular arrhythmia or symptomatic conduction abnormality within 12m
• CHF, symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, and myocardial infarction within 6m
• Prolonged QTc interval (males >450ms, females >470ms)
• Previous allogeneic hematopoietic transplant within 90 days. Active GVHD requiring treatment
• Concurrent severe or uncontrolled medical disease that would compromise the safety or compromise the ability of the patient to complete study
• Symptomatic CNS metastases
• Known HIV or AIDS
• Prior or 2nd malignancy, except non-melanoma skin cancer, completely resected cervical or prostate cancer (with PSA of less than or equal to 0.1 ng/ml), or other cancer for which the subject has received curative therapy at least 3 yrs prior to study entry
• Treatment-related MDS
• Significant neuropathy (Grd 3-4 or Grd 2 with pain) at the time of 1st dose
• Primary AL amyloidosis
• Pleural effusions requiring thoracentesis or ascites requiring paracentesis
• Pregnant or nursing women