Phase 1 Study of TG02 Citrate in Patients With Advanced Hematological Malignancies

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