Clinical Trials /

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

NCT01204164

Description:

This is a multicenter, open-label, dose escalation Phase 1 study.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Acute Myeloid Leukemia
  • Multiple Myeloma
  • Myelodysplastic Syndromes
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase 1 Study of TG02 Citrate in Patients With Advanced Hematological Malignancies
  • Official Title: Phase 1 Dose-Escalation and Pharmacokinetic Study of TG02 Citrate in Patients With Advanced Hematological Malignancies

Clinical Trial IDs

  • ORG STUDY ID: TG02-101
  • NCT ID: NCT01204164

Conditions

  • AML
  • ALL
  • Blast Crisis
  • MDS
  • Multiple Myeloma

Interventions

DrugSynonymsArms
TG02 citrateNo other names.TG02 in AL
CarfilzomibKyprolisTG02 + CFZ in MM
DexamethasoneOzurdex, Maxidex, Decadron, BaycadronTG02 + CFZ + DEX in CFZ refractory MM

Purpose

This is a multicenter, open-label, dose escalation Phase 1 study.

Detailed Description

      This is a multicenter, open-label, dose escalation, Phase 1/1b study.

      For Parts 1, 2, and 3 of the study, the primary objective is to determine the highest dose of
      TG02 citrate that can safely be given to patients with different types of hematological
      malignancy.

      For Part 4, the primary objective is to evaluate the safety and tolerability of once-weekly
      dosing at the maximum-tolerated dose/ Recommended Phase 2 Dose of TG02 in combination with
      carfilzomib.

      This study consists of four parts:

        -  Part 1: single agent TG02 in acute leukemia patients

        -  Part 2: single agent TG02 in multiple myeloma patients

        -  Part 3: TG02 in combination with carfilzomib in multiple myeloma patients

        -  Part 4: TG02 in combination with carfilzomib in carfilzomib refractory multiple myeloma
           patients.
    

Trial Arms

NameTypeDescriptionInterventions
TG02 in ALExperimentalSingle agent TG02 citrate in acute leukemia patients
  • TG02 citrate
TG02 in MMExperimentalSingle Agent TG02 citrate in multiple myeloma patients
  • TG02 citrate
TG02 + CFZ in MMExperimentalTG02 in combination with carfilzomib and dexamethasone in multiple myeloma patients
  • TG02 citrate
  • Carfilzomib
TG02 + CFZ + DEX in CFZ refractory MMExperimentalTG02 in combination with carfilzomib and dexamethasone in carfilzomib refractory multiple myeloma patients
  • TG02 citrate
  • Carfilzomib
  • Dexamethasone

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:28 days
Safety Issue:
Description:Maximum Tolerated Dose refers to the highest dose of TG02 administered that will produce the desired effect without unacceptable toxicity.

Secondary Outcome Measures

Measure:Safety
Time Frame:28 days
Safety Issue:
Description:Safety data will include vital signs, ECGs, PE findings, clinical laboratory parameters, ECOG PS, AEs/SAEs and concomitant medications.
Measure:Pharmacokinetics of TG02
Time Frame:28 days
Safety Issue:
Description:Plasma will be analyzed to determine TG02 concentration.
Measure:Clinical Benefit Response
Time Frame:28 days
Safety Issue:
Description:Clinical Benefit Response is defined as the sum of all response categories for Overall Response Rate (ORR is defined as the sum of patients with sCR, CR, VGPR and PR) plus minimal response (MR).
Measure:Overall Response Rate
Time Frame:28 days
Safety Issue:
Description:Overall Response Rate is defined as the sum of patients with sCR, CR, VGPR and PR.
Measure:Progression-Free Survival
Time Frame:28 days
Safety Issue:
Description:Progression-Free Survival is the time to disease progression or death, which is measured from the date of first study drug administration until the first date that recurrent or progressive disease is objectively documented or the date of death.
Measure:Overall Survival
Time Frame:28 days
Safety Issue:
Description:Overall Survival is time to death, which is measured from the date of first study drug administration until the date of death.
Measure:Duration of Response
Time Frame:28 days
Safety Issue:
Description:Duration of Response is the duration from first observation of response to the first documentation of disease progression, with deaths from causes other than disease progression censored. For the purposes of the calculation of the DOR, the date at which the response status was first observed rather than the date of confirmation is used as the start date.
Measure:Pharmacodynamics
Time Frame:28 days
Safety Issue:
Description:Pharmacodynamic sampling may include whole blood and bone marrow at baseline and post-treatment for pathway determination if available.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Tragara Pharmaceuticals, Inc.

Trial Keywords

  • AML
  • ALL
  • MDS
  • CML in blast crisis
  • Multiple Myeloma
  • Carfilzomib refractory

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