A Phase I Clinical Study of Safety, Tolerability, Pharmacokinetics, and Initial Efficacy of ETH-155008 Tablets in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Non-Hodgkin's Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- ETH-155008
- Conditions
- NHL, Adult
- Sponsor
- Shengke Pharmaceuticals (Jiangsu) Limited, China
- Enrollment
- 60
- Locations
- 2
- Primary Endpoint
- The RP2D(s) or the MTD of ETH-155008 in subjects with R/R AML and NHL
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This Trial is an open-label, multicenter trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ETH-155008 in subjects with AML and NHL who previously received standard treatment or are ineligible for standard treatment options.
Detailed Description
The primary objectives of this study are to evaluate the safety of ETH-155008 and to determine the recommended Phase 2 dose (RP2D) regimen or the maximum tolerated dose (MTD). Secondary objectives and endpoints will evaluate the pharmacokinetics(PK) and pharmacodynamics(PD) of ETH-155008 and preliminary clinical anti-tumor activity of ETH-155008 in subjects with R/R acute myeloid leukemia (AML) and Non-Hodgkin's lymphoma (NHL). This Trial is an open-label, multicenter trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ETH-155008 in subjects with R/R AML and NHL who previously received standard treatment or are ineligible for standard treatment options. The study will be conducted in 2 parts: dose escalation (Part 1) and cohort expansion (Part 2). In the dose escalation, ETH-155008 will be administrated orally, once daily (QD) for 28 days at 5 dose levels ranging from 20 mg to 100 mg in 28-day cycles. Dose-limiting toxicity (DLT) will be assessed during the first treatment cycle and the maximum tolerated dose (MTD) will be identified. Additional subjects will be treated in the dose expansion at the commended phase 2 dose (RP2D). During the study, safety will be monitored by the data review committee (DRC) at each dose escalation step and at regular intervals during cohort expansion. Continuous reassessment for DLTs will help minimize the potential risks associated with the study drug. Cumulative data from subsequent treatment cycles will also be monitored for late-onset toxicities.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Be at least 18 years of age and \< 80 years old.
- •Must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the trial and are willing to participate in the trial prior to any other trial-related assessments or procedures, and can communicated with investigators and are willing to comply with the protocol.
- •Has histologically or cytologically confirmed relapsed and/or refractory acute myelocytic leukemia(AML) or non-Hodgkin's lymphoma(NHL) with no available standard therapy or is not a candidate for available standard therapy, and for whom, in the opinion of the investigator, experimental therapy with ETH-155008 may be beneficial. In addition, the following disease-specific criteria outlined below must be met.
- •For all indolent NHL (Follicular Lymphoma\[FL\], Marginal Zone Lymphoma\[MZL\] and Waldenström Macroglobulinemia\[WM\]), previously treated with at least 2 prior lines of systemic therapy with at least 1 line being an anti-cluster of differentiation antigen 20(anti-CD20) antibody-containing combination regimen. For chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), prior treatment with at least 2 lines of systemic therapy, including Bruton's tyrosine kinase(BTK) inhibitors or B-cell lymphoma-2(BCL-2) inhibitors, is required.
- •For mantle cell lymphoma(MCL), prior treatment with at least 2 lines of systemic therapy (including a combination regimen of anti-CD20 antibodies and BTK inhibitors) and no other approved therapy considered more appropriate by the investigators.
- •For aggressive B-NHL (diffuse large B cell lymphoma\[DLBCL\], highly malignant B-cell lymphoma\[HGBCL\], and primary mediastinal large B-cell lymphoma\[PMBCL\]), patients who can tolerate intensive therapy or autologous hematopoietic stem cell transplantation are required to have received standard second-line therapy in the past but have failed or relapsed. If patients cannot tolerate intensive therapy or autologous hematopoietic stem cell transplantation, they must have received standard first-line therapy in the past, but therapy failed or relapsed.
- •For T-NHL, it is required to have been adequately treated with a systemic standard dose of drugs in the past without remission or recurrence.
- •For AML, relapsed/refractory AML diagnosed according to the World Health Organization (WHO) classification in 2016, for which no standard treatment is available or for which standard treatment is not tolerated; According to Chinese Guidelines for the Diagnosis and Treatment of Relapsed and Refractory acute myeloid Leukemia (2021 Edition), the definition of relapsed and refractory is as follows:
- •Recurrent AML: recurrence of leukemia cells in peripheral blood or original cells in bone marrow ≥ 5% after CR (except for other reasons such as bone marrow regeneration after consolidation chemotherapy) or extramedullary leukemia cell infiltration.
- •Refractory AML: initial patients who failed to respond to 2 courses of treatment with standard protocols; Patients with CR relapse within 12 months after consolidation and intensive treatment; Patients who relapse after 12 months but fail to respond to conventional chemotherapy; Patients with two or more relapses; Extramedullary leukemia persists.
Exclusion Criteria
- •Acute promyelocytic leukemia, acute mixed phenotypic leukemia, acute myeloid leukemia with Philadelphia chromosome (Ph chromosome) positive.
- •AML with myeloid sarcoma.
- •The central nervous system (CNS) is known to be involved.
- •Previous solid organ transplantation.
- •Previously received allogeneic hematopoietic stem cell transplantation.
- •The patient received autologous hematopoietic stem cell transplantation (HSCT) within 3 months prior to initial administration of ETH-
- •Have an active autoimmune disease within the past 2 years that requires treatment with systemic immunosuppressive drugs (i.e., long-term corticosteroids, methotrexate, or tacrolimus).
- •Toxicities from previous anti-cancer therapies have not resolved to baseline levels or to Grade 1 or less except for alopecia and peripheral neuropathy.
- •Has known past or current malignancy other than inclusion diagnosis, except for:
- •Cervical carcinoma of Stage ⅠB or less.
Arms & Interventions
ETH-155008
Dose level: 20mg/day, 40mg/day, 60mg/day, 80mg/day, 100mg/day. Each dose level will recruit 1-6 subjects, taking ETH-155008 tablets once daily. Intervention: Drug: ETH-155008
Intervention: ETH-155008
Outcomes
Primary Outcomes
The RP2D(s) or the MTD of ETH-155008 in subjects with R/R AML and NHL
Time Frame: At the end of Cycle 1 (each cycle is 28 days)
The RP2D is the maximum tolerated dose (MTD) or less.
Incidence and severity of adverse events
Time Frame: At the end of Cycle 1 (each cycle is 28 days)
Determine the safety of ETH-155008 in subjects with R/R AML and NHL
Dose Limiting Toxicity (DLTs)
Time Frame: At the end of Cycle 1 (each cycle is 28 days)
Incidence of DLTs in the first treatment cycle of ETH-155008
Secondary Outcomes
- PK parameter of ETH-155008: AUC(At the end of Cycle 1 (each cycle is 28 days))
- Disease evaluation of efficacy of ETH-155008: ORR(12 months post first dosing)
- Disease evaluation of efficacy of ETH-155008: DCR(12 months post first dosing)
- Assess the PD of ETH-155008: Inhibition of CDK4/6 kinase(2 months post first dosing)
- PK parameter of ETH-155008: Tmax(At the end of Cycle 1 (each cycle is 28 days))
- Disease evaluation of efficacy of ETH-155008: DOR(12 months post first dosing)
- Assess the PD of ETH-155008: Inhibition of Pim kinase(2 months post first dosing)
- PK parameter of ETH-155008: Cmax(At the end of Cycle 1 (each cycle is 28 days))
- Disease evaluation of efficacy of ETH-155008: PR(12 months post first dosing)
- Assess the PD of ETH-155008: Inhibition of FLT3 kinase(2 months post first dosing)
- Disease evaluation of efficacy of ETH-155008: CR(12 months post first dosing)
- Disease evaluation of efficacy of ETH-155008: TTR(12 months post first dosing)