Relapsed/Refractory (R/R) FLT3+ Acute Myeloid Leukemia MedDRA version: 21.1 Level: LLT Classification code 10081514 Term: Acute myeloid leukemia refractory System Organ Class: 100000004864
Conditions
Interventions
Product Name: TL-895
Product Code: TL-895
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TL-895
CAS Number: 1415823-49-2
Current Sponsor code: TL-895
Other descriptive name: TL-895
Conce
Sponsors
Telios Pharma, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects in the Phase 1b and Phase 2 Dose Expansion must meet all the following criteria in order to be eligible for the study: 1.Adults =18 years of age. 2.Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 3.Documented primary TP53wt AML or TP53wt AML secondary to myelodysplastic syndrome (MDS), as defined by World Health Organization (WHO) criteria (Swerdlow 2016). 4.Subject is refractory to and/or relapsed after at least one prior therapy with no alternative therapeutic options likely to produce clinical benefit. Subjects must have received a FLT3 inhibitor (unless contraindicated), if FLT3 inhibitors are approved and available in the country in which the subject is to be treated. 5.Presence of the FLT3 activating mutation TKD or FLT3-ITD in bone marrow or peripheral blood detected by a test approved by the local health authority or, if not available, by a validated test. 6.Adequate renal function defined by an estimated creatinine clearance =30 mL/min by Cockcroft-Gault formula. 7.Adequate hepatic function within 28 days prior to the first dose of study treatment defined as: a.Total serum bilirubin within normal limits; if total bilirubin > upper limit of normal (ULN) then subjects are eligible if the direct bilirubin is = 2. 0 x ULN. b.Serum AST and/or ALT =2.5×ULN. 8.Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, male and female subjects must continue to use contraception for 3 months (+1 week) and 1 month (+1 week), respectively after the last dose of study drug. Effective birth control for males includes either vasectomy or use of condoms. Effective birth control for females includes (a) combined estrogen- and progestogen-containing hormonal contraception (oral, intravaginal, transdermal); (b) intrauterine device combined with a barrier method; (c) intrauterine hormone-releasing system combined with a barrier method; (d) bilateral tubal occlusion or ligation; (e) vasectomized partner; and (f) sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 29 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 29
Exclusion criteria
Exclusion criteria: Subjects in the Phase 1b and Phase 2 Dose Expansion who meet any of the following criteria will not be eligible for the study: 1.Acute promyelocytic leukemia (AML subtype M3). 2.Subjects with known active central nervous system involvement with AML. 3.Prior treatment with MDM2 antagonist therapies. 4.Prior treatment with a BTK inhibitor. 5.Chemotherapy, cytoreductive therapy, immune therapy, cytokine therapy or any investigational therapy within 14 days prior to first dose of study treatment. Subjects on hydroxyurea therapy may continue treatment until one day prior to the first dose of study drug. Subjects on FLT3 inhibitor therapy must discontinue treatment at least 2 days prior to first dose of study drug. 6.Active participation in other therapeutic clinical trials including supportive care trials. 7.Allogeneic stem cell transplant within 3 months; autologous stem cell transplant within 3 months or active graft-versus-host disease prior to first dose of study treatment. 8.Subjects who are eligible for an allogeneic hematopoietic stem cell transplantation (HSCT) per the opinion of the investigator and have a donor. Subjects who are HSCT eligible in the opinion of the investigator, but who refuse a transplant, are eligible for the study. 9.Subjects with a history of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study treatment 10.Known infection with human immunodeficiency virus. 11.Known active hepatitis B or C infection. 12.History of another malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated non-metastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection or superficial transitional cell bladder carcinoma. 13.Uncontrolled intercurrent illness including but not limited to clinically significant cardiac disease (New York Heart Class III or IV); symptomatic congestive heart failure, unstable angina pectoris, ventricular arrhythmia, or subjects with psychiatric illness/social situations that would limit compliance with study requirements; or subjects who have been committed to an institution by judicial or administrative authority. 14.Grade 2 or higher QTc prolongation >480 msec per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. 15.History of myocardial infarction within 3 months of first dose of study treatment 16.History of major organ transplant 17.Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of the first dose of study drug. 18.Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole); subjects receiving PPIs who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study provided the proton pump inhibitor is discontinued at least 5 days prior to first dose of study drug. 19.Phase 1b only: Subjects receiving medications, herbal supplements, or food known to be strong inhibitors of CYP3A within 7 days prior to the first dose of TL-895 20.Having history of difficulty swallowing, gastric or small bowel surgery with history of malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the KRT-2
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1b: Primary: To determine the MTD/MAD and RP2D of TL-895 in combination with KRT-232 To determine the safety and tolerability of TL-895 in combination with KRT-232 Phase II: Primary: To determine the rates of complete remission and complete remission with partial hematologic recovery ;Secondary Objective: Phase Ib: Secondary: To characterize the PK profile of TL 895 and KRT-232 Exploratory: To evaluate the effect of TL-895 in combination with KRT-232 relative to select PD, PK, or disease markers and markers of resistance Phase II: Secondary: To determine the overall response rate To determine the duration of Complete Remission/Complete Remission with partial hematologic recovery response (Duration of Response) To determine progression-free survival To determine Overall Survival To determine the proportion of subjects who transition to allogeneic stem cell transplant To determine the safety and tolerability of TL-895 in combination with KRT-232 To monitor the PK of TL-895 and KRT-232 Exploratory: To evaluate the efficacy and safety of TL-895 in combination with KRT 232 relative to select PK, PD, or disease markers, and markers of resistance ;Primary end point(s): Phase Ib: Endpoints for primary objectives: -Dose Limiting Toxicities will be used to establish the MTD/MAD of TL-895 in combination with KRT-232. The Safety Review Committee (SRC) will determine the RP2D based on safety data of the combination of TL 895 and KRT-232. -Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, AEs, serious AEs (SAEs), ECGs, and vital signs. Phase II: Endpoints for primary objectives: -The proportion of subjects who achieved CR or CRh as their best response based on the Modified 2017 European LeukemiaNet (ELN) Response Criteria. CRh is defined as 50,000/µl and ANC >500/µl). ;Timepoint(s) of evaluation of this end point: Phase Ib=C1D1 to C2D1 Phase 2=Until progression | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase Ib: Endpoints for secondary objectives: TL-895, KRT-232, and KRT-232 acyl glucuronide metabolite (M1) PK parameters, including but not limited to: •Cmax •AUC •Time of maximum plasma concentration (Tmax) Endpoints for exploratory objectives: Biomarkers including but not limited to: •TP53 mutation status •AML related genes •Functional and mechanistic markers of BMX/BTK •Characterization of peripheral blood blasts •Serum/plasma cytokine/chemokine panel, including but not limited to c-reactive protein (CRP), alpha-1-acid glycoprotein (AAG), IL-1b, IL-2, IL-6, IL-8, IL 10, TNF-a, IFN-?, IL12p70 and SDF-1 •p53-related gene expression panel, including: p21 (CDKN1A), MDM2, PUMA (BBC3), MIC-1 (GDF15), PIG3(TP53I3), DR5 (TNFRSF10B), GADD45, PCNA, MDMX (MDM4) •MIC-1 protein in serum •BTK/BMX target occupancy in peripheral blood leukocytes •Functional assays in cultured peripheral blasts (United States [US] sites only) •Evaluations of BTK/BMX target engagement in bone marrow aspirates (US sites only) Phase II: Endpoints for secondary objectives: -The proportion of subjects who achieve PR or better -Median Duration of Response (Kaplan-Meier estimate) defined as the time from first observation of Complete Remission/Complete Remission with partial hematologic recovery to relapse or death from any cause, whichever occurs first. Subjects with morphologic leukemia-free state by bone marrow biopsy performed earlier in the course of therapy who convert to Complete Remission or complete remission with partial hematologic recovery do not require a separate bone marrow aspirate at the time of Complete Remission or complete remission with partial hematologic recovery to document this. -Median Progression-free Survival (Kaplan- Meier estimate) defined as the time from the first treatment dose to disease progression, relapse or death from any cause, whichever occurs first. -Median Overall Survival (Kaplan-Meier estimate) defined as the time from the first tre | — |
Countries
Australia, Austria, France, Germany, Italy, Korea, Republic of, Spain, United States
Contacts
Public ContactRegulatory Affairs
Telios Pharma, Inc.
Outcome results
None listed