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

Multiple Myeloma Clinical Trial

— TG02-101  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01204164
• Other study ID #: TG02-101
• Status: Completed
• Phase: Phase 1
• First received: September 14, 2010
• Last updated: May 5, 2016
• Start date: August 2010
• Est. completion date: April 2016

Study information

• Verified date: May 2016
• Source: Tragara Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: April 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• ALL
• AML
• Blast Crisis
• MDS
• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• TG02 citrate
TG02 citrate capsules given orally.
• Carfilzomib
Carfilzomib per PI
• Dexamethasone
Dexamethasone (Oral or IV)

Locations

Country	Name	City	State
United States	Emory	Atlanta	Georgia
United States	Rush	Chicago	Illinois
United States	OSU	Columbus	Ohio
United States	RMCC	Denver	Colorado
United States	HUMC	Hackensack	New Jersey
United States	MDACC	Houston	Texas
United States	IU	Indianapolis	Indiana
United States	SCRI	Nashville	Tennessee
United States	Cornell	New York City	New York

Sponsors (1)

Lead Sponsor	Collaborator
Tragara Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Safety	Safety data will include vital signs, ECGs, PE findings, clinical laboratory parameters, ECOG PS, AEs/SAEs and concomitant medications.	28 days	Yes
Secondary	Pharmacokinetics of TG02	Plasma will be analyzed to determine TG02 concentration.	28 days	No
Secondary	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	No
Secondary	Overall Response Rate	Overall Response Rate is defined as the sum of patients with sCR, CR, VGPR and PR.	28 days	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Pharmacodynamics	Pharmacodynamic sampling may include whole blood and bone marrow at baseline and post-treatment for pathway determination if available.	28 days	No