| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory (R/R) FLT3+ Acute Myeloid Leukemia |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with Acute Myeloid Leukemia |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10081514 |
| E.1.2 | Term | Acute myeloid leukemia refractory |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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
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| E.2.2 | Secondary objectives of the trial |
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
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 who are able to provide informed consent.
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 (Arber 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 within 7 days (Phase 1b) or 28 days (Phase 2) prior to the first dose of study treatment defined as an estimated creatinine clearance ≥30 mL/min by Cockcroft-Gault formula.
7.Adequate hepatic function within 7 days (Phase 1b) or 28 days (Phase 2) prior to the first dose of study treatment defined as:
a.Total serum bilirubin ≤ 2.0 x ULN. Subjects with known Gilbert’s syndrome or disease-related hemolysis must have a total bilirubin ≤3.0 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 a highly effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for 1 month and 1 week and male subjects must continue to use a highly effective method of contraception for 3 months and 1 week. A woman is considered of childbearing potential (ie, fertile, following menarche and until becoming post menopausal) unless permanently sterile. |
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| E.4 | Principal 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 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 3 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-232 or TL-895 treatment.
21.Major surgery or planned major surgery within 28 days prior to first dose of study treatment.
22.Subjects with clinically significant active infection requiring parenteral therapy.
23.Pregnant or breast feeding.
24.Medical condition, serious intercurrent illness, or other circumstance that, in the Investigator's judgment, could jeopardize the candidate's safety as a study subject, or that could interfere with study objectives, including known hypersensitivity to or contraindications to the study drugs or their excipients, or to required prophylaxis. |
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| E.5 End points |
| E.5.1 | 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 <5% of blasts by morphology in the bone marrow, no evidence of disease (blasts in blood by flow cytometry) and at least partial recovery of peripheral blood counts (platelets >50,000/µl and ANC >500/µl).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase Ib=C1D1 to C2D1
Phase 2=Until progression |
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| E.5.2 | 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-α, IFN-γ, 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 aspirate and/or 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 and/or biopsy 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 treatment dose to death due to any cause
-The proportion of subjects who transition to allogeneic transplant
-Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, AEs, SAEs, ECGs, and vital signs
-TL-895, KRT-232, KRT-232 acyl glucuronide metabolite (M1), plasma concentrations monitored using sparse sampling.
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 CRP, AAG, IL-1b, IL-2, IL-6, IL-8, IL-10, TNF-α, IFN-γ, 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 (US sites only)
•Evaluations of BTK/BMX target engagement in bone marrow aspirates (US sites only)
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| as per Appendix 1 Schedule of Assessments in the study protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| phase Ib (dose escalation, to determine the MTD/MAD and RP2D) |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Korea, Republic of |
| United States |
| Austria |
| France |
| Spain |
| Germany |
| Italy |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will be considered complete 2 years after the last subject is enrolled, at which time subjects will be evaluated for eligibility for a rollover study that allows long-term follow-up |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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