ALL, AML, Blast Crisis, MDS, Multiple Myeloma
Conditions
Keywords
AML, ALL, MDS, CML in blast crisis, Multiple Myeloma, Carfilzomib refractory
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.
Interventions
DRUGTG02 citrate
TG02 citrate capsules given orally.
DRUGCarfilzomib
Carfilzomib per PI
DRUGDexamethasone
Dexamethasone (Oral or IV)
Sponsors
Tragara Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Safety | 28 days | Safety data will include vital signs, ECGs, PE findings, clinical laboratory parameters, ECOG PS, AEs/SAEs and concomitant medications. |
| 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. |
| 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. |
Countries
United States
Outcome results
None listed