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

Sponsor

Tragara Pharmaceuticals, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT01204164

Collaborator

(none)

120

Enrollment

Locations

Arms

Duration (Months)

13.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
AML ALL Blast Crisis MDS Multiple Myeloma	Drug: TG02 citrate Drug: Carfilzomib Drug: Dexamethasone	Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2010

Actual Primary Completion Date :

Mar 1, 2016

Actual Study Completion Date :

Apr 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Maximum Tolerated Dose [28 days]
Maximum Tolerated Dose refers to the highest dose of TG02 administered that will produce the desired effect without unacceptable toxicity.

Secondary Outcome Measures

Safety [28 days]
Safety data will include vital signs, ECGs, PE findings, clinical laboratory parameters, ECOG PS, AEs/SAEs and concomitant medications.
Pharmacokinetics of TG02 [28 days]
Plasma will be analyzed to determine TG02 concentration.
Clinical Benefit Response [28 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 Rate [28 days]
Overall Response Rate is defined as the sum of patients with sCR, CR, VGPR and PR.
Progression-Free Survival [28 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 Survival [28 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 Response [28 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.
Pharmacodynamics [28 days]
Pharmacodynamic sampling may include whole blood and bone marrow at baseline and post-treatment for pathway determination if available.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:
1. ≥2 prior therapies including proteasome inhibitor and immunomodulatory agent (IMiD)
1. ≥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:
1. bortezomib
1. an IMiD
1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	RMCC	Denver	Colorado	United States	80218
2	Emory	Atlanta	Georgia	United States	30322
3	Rush	Chicago	Illinois	United States	60612
4	IU	Indianapolis	Indiana	United States	46202
5	HUMC	Hackensack	New Jersey	United States	07601
6	Cornell	New York City	New York	United States	10021
7	OSU	Columbus	Ohio	United States	43210
8	SCRI	Nashville	Tennessee	United States	37203
9	MDACC	Houston	Texas	United States	77030