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

Phase 1 Dose-Escalation and Pharmacokinetic Study of TG02 Citrate in Patients With Advanced Hematological Malignancies

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

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma; AML; Blast Crisis; MDS; ALL
• Intervention / Treatment: Drug: TG02 citrate; Drug: Carfilzomib; Drug: Dexamethasone

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.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • RMCC
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • IU
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • HUMC
  • New York
    • New York City, New York, United States, 10021
      • Cornell
  • Ohio
    • Columbus, Ohio, United States, 43210
      • OSU
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • SCRI
  • Texas
    • Houston, Texas, United States, 77030
      • MDACC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TG02 in AL; Single agent TG02 citrate in acute leukemia patients	Drug: TG02 citrate; TG02 citrate capsules given orally.; Other Names: No other names.
Experimental: TG02 in MM; Single Agent TG02 citrate in multiple myeloma patients	Drug: TG02 citrate; TG02 citrate capsules given orally.; Other Names: No other names.
Experimental: TG02 + CFZ in MM; TG02 in combination with carfilzomib and dexamethasone in multiple myeloma patients	Drug: TG02 citrate; TG02 citrate capsules given orally.; Other Names: No other names.; Drug: Carfilzomib; Carfilzomib per PI; Other Names: Kyprolis
Experimental: TG02 + CFZ + DEX in CFZ refractory MM; TG02 in combination with carfilzomib and dexamethasone in carfilzomib refractory multiple myeloma patients	Drug: TG02 citrate; TG02 citrate capsules given orally.; Other Names: No other names.; Drug: Carfilzomib; Carfilzomib per PI; Other Names: Kyprolis; Drug: Dexamethasone; Dexamethasone (Oral or IV); Other Names: Ozurdex, Maxidex, Decadron, Baycadron

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety	Safety data will include vital signs, ECGs, PE findings, clinical laboratory parameters, ECOG PS, AEs/SAEs and concomitant medications.	28 days
Pharmacokinetics of TG02	Plasma will be analyzed to determine TG02 concentration.	28 days
Clinical Benefit Response	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).	28 days
Overall Response Rate	Overall Response Rate is defined as the sum of patients with sCR, CR, VGPR and PR.	28 days
Progression-Free Survival	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.	28 days
Overall Survival	Overall Survival is time to death, which is measured from the date of first study drug administration until the date of death.	28 days
Duration of Response	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.	28 days
Pharmacodynamics	Pharmacodynamic sampling may include whole blood and bone marrow at baseline and post-treatment for pathway determination if available.	28 days

Collaborators and Investigators

• Sponsor: Tragara Pharmaceuticals, Inc.
• Investigators: Study Director: T Parrott, Tragara Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: September 14, 2010
• First Submitted That Met QC Criteria: September 15, 2010
• First Posted (Estimate): September 17, 2010

Study Record Updates

• Last Update Posted (Estimate): May 6, 2016
• Last Update Submitted That Met QC Criteria: May 5, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Multiple Myeloma; AML; ALL; MDS; CML in blast crisis; Carfilzomib refractory
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplastic Processes; Neoplasms, Plasma Cell; Leukemia; Cell Transformation, Neoplastic; Carcinogenesis; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hematologic Neoplasms; Multiple Myeloma; Blast Crisis; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: TG02-101