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

Phase 1
Completed
Conditions
Blast Crisis
AML
Multiple Myeloma
ALL
MDS
Interventions
Drug: TG02 citrate
Drug: Carfilzomib
Drug: Dexamethasone
Registration Number
NCT01204164
Lead Sponsor
Tragara Pharmaceuticals, Inc.
Brief Summary

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.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
120
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

Read More
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
Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
TG02 in MMTG02 citrateSingle Agent TG02 citrate in multiple myeloma patients
TG02 in ALTG02 citrateSingle agent TG02 citrate in acute leukemia patients
TG02 + CFZ in MMCarfilzomibTG02 in combination with carfilzomib and dexamethasone in multiple myeloma patients
TG02 + CFZ + DEX in CFZ refractory MMTG02 citrateTG02 in combination with carfilzomib and dexamethasone in carfilzomib refractory multiple myeloma patients
TG02 + CFZ in MMTG02 citrateTG02 in combination with carfilzomib and dexamethasone in multiple myeloma patients
TG02 + CFZ + DEX in CFZ refractory MMDexamethasoneTG02 in combination with carfilzomib and dexamethasone in carfilzomib refractory multiple myeloma patients
TG02 + CFZ + DEX in CFZ refractory MMCarfilzomibTG02 in combination with carfilzomib and dexamethasone in carfilzomib refractory multiple myeloma patients
Primary Outcome Measures
NameTimeMethod
Maximum Tolerated Dose28 days

Maximum Tolerated Dose refers to the highest dose of TG02 administered that will produce the desired effect without unacceptable toxicity.

Secondary Outcome Measures
NameTimeMethod
Safety28 days

Safety data will include vital signs, ECGs, PE findings, clinical laboratory parameters, ECOG PS, AEs/SAEs and concomitant medications.

Pharmacokinetics of TG0228 days

Plasma will be analyzed to determine TG02 concentration.

Clinical Benefit Response28 days

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).

Overall Response Rate28 days

Overall Response Rate is defined as the sum of patients with sCR, CR, VGPR and PR.

Progression-Free Survival28 days

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.

Overall Survival28 days

Overall Survival is time to death, which is measured from the date of first study drug administration until the date of death.

Duration of Response28 days

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.

Pharmacodynamics28 days

Pharmacodynamic sampling may include whole blood and bone marrow at baseline and post-treatment for pathway determination if available.

Trial Locations

Locations (9)

MDACC

🇺🇸

Houston, Texas, United States

RMCC

🇺🇸

Denver, Colorado, United States

Cornell

🇺🇸

New York City, New York, United States

Rush

🇺🇸

Chicago, Illinois, United States

HUMC

🇺🇸

Hackensack, New Jersey, United States

OSU

🇺🇸

Columbus, Ohio, United States

Emory

🇺🇸

Atlanta, Georgia, United States

SCRI

🇺🇸

Nashville, Tennessee, United States

IU

🇺🇸

Indianapolis, Indiana, United States

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