A Phase 1b Open-Label Study to Evaluate the Safety and Tolerability of Eganelisib as Monotherapy and in Combination with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia
ESTADO CLÍNICO
Reclutando
FASE/S DEL ENSAYO
Fase I-II
PATOLOGÍA
Leucemia linfática crónica y otros SLPC, Leucemia mieloide aguda, Síndromes mielodisplásicos, Linfoma, Leucemia
FECHA DE APERTURA
Abril, 2025
FECHA DE CIERRE
,
CRITERIOS DE INCLUSIÓN
Provision of written informed consent.
Male patients and female patients/women of childbearing potential (WCBP) must agree to use an effective method of contraception per institutional standard for the study duration and for 30 days after the last dose of eganelisib and 6 months after the last dose of cytarabine.
WCBP must have a negative serum beta human chorionic gonadotropin ( HCG) test measured within 7 days prior to the first dose of eganelisib and consent to ongoing pregnancy testing during the study.
Willingness to practice adequate sun protection (use of sunscreen or sun-protective clothing, limitation of sun and artificial ultraviolet [UV] exposure) for the study duration and for 30 days after the last dose of eganelisib.
Pathological diagnosis of either - AML according to WHO 2022 revised criteria (Khoury et al., 2022) per the local pathology report and with 10% bone marrow blasts. Acute promyelocytic leukemia is excluded but secondary AML (including treated secondary AML, i.e., treatment included a hypomethylating agent [HMA] based therapy for MDS but transformed into AML) and treatment-related AML can be included. - Higher-risk (IPSS-R Intermediate, High or Very High Risk at time of study entry) myelodysplastic syndromes (HR-MDS) according to WHO 2022 revised criteria per the local pathology report and with 10% bone marrow blasts.
Relapsed/refractory disease. Patients must not be eligible for, or must have exhausted, other therapies known to be effective for treatment of their disease. - Hydroxyurea administered for white blood cell (WBC)/blast control will not be considered a prior line of therapy. - Treatments with erythroid-stimulating agents (eg, EPO, luspatercept, lenalidomide) will not be considered a prior line of therapy.
Male or female patients age 18 years.
Eastern Cooperative Oncology Group performance status (ECOG PS) 2.
Adequate hepatic function measured within 7 days prior to the first dose of eganelisib: - Total serum bilirubin 1.5 × institutional upper limit of normal (ULN) or 3 × ULN in case of Gilberts disease. -AST and ALT 2.5 × ULN.
Adequate renal function measured within 7 days prior to the first dose of eganelisib: Measured or calculated creatinine clearance (CrCl) 30 mL/min (calculation by Cockcroft-Gault formula).
Acceptable coagulation profile, measured within 7 days prior to the first dose of eganelisib: - Prothrombin time (PT) or International Normalized Ratio (INR) 1.5 × ULN. - Activated partial thromboplastin time (aPTT) 1.5 × ULN.
Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures, including to undergo a pre-treatment and subsequent on treatment bone marrow examinations.
Male patients and female patients/women of childbearing potential (WCBP) must agree to use an effective method of contraception per institutional standard for the study duration and for 30 days after the last dose of eganelisib and 6 months after the last dose of cytarabine.
WCBP must have a negative serum beta human chorionic gonadotropin ( HCG) test measured within 7 days prior to the first dose of eganelisib and consent to ongoing pregnancy testing during the study.
Willingness to practice adequate sun protection (use of sunscreen or sun-protective clothing, limitation of sun and artificial ultraviolet [UV] exposure) for the study duration and for 30 days after the last dose of eganelisib.
Pathological diagnosis of either - AML according to WHO 2022 revised criteria (Khoury et al., 2022) per the local pathology report and with 10% bone marrow blasts. Acute promyelocytic leukemia is excluded but secondary AML (including treated secondary AML, i.e., treatment included a hypomethylating agent [HMA] based therapy for MDS but transformed into AML) and treatment-related AML can be included. - Higher-risk (IPSS-R Intermediate, High or Very High Risk at time of study entry) myelodysplastic syndromes (HR-MDS) according to WHO 2022 revised criteria per the local pathology report and with 10% bone marrow blasts.
Relapsed/refractory disease. Patients must not be eligible for, or must have exhausted, other therapies known to be effective for treatment of their disease. - Hydroxyurea administered for white blood cell (WBC)/blast control will not be considered a prior line of therapy. - Treatments with erythroid-stimulating agents (eg, EPO, luspatercept, lenalidomide) will not be considered a prior line of therapy.
Male or female patients age 18 years.
Eastern Cooperative Oncology Group performance status (ECOG PS) 2.
Adequate hepatic function measured within 7 days prior to the first dose of eganelisib: - Total serum bilirubin 1.5 × institutional upper limit of normal (ULN) or 3 × ULN in case of Gilberts disease. -AST and ALT 2.5 × ULN.
Adequate renal function measured within 7 days prior to the first dose of eganelisib: Measured or calculated creatinine clearance (CrCl) 30 mL/min (calculation by Cockcroft-Gault formula).
Acceptable coagulation profile, measured within 7 days prior to the first dose of eganelisib: - Prothrombin time (PT) or International Normalized Ratio (INR) 1.5 × ULN. - Activated partial thromboplastin time (aPTT) 1.5 × ULN.
Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures, including to undergo a pre-treatment and subsequent on treatment bone marrow examinations.
CRITERIOS DE EXCLUSIÓN
Any of the following within the specified time frame: -Prior systemic cancer therapy is allowed regardless of the stop date, but the patient must have recovered to eligibility levels from prior toxicity. --> Hydroxyurea is allowed for patients with rapidly proliferative disease for peripheral blast control, up to Cycle 1 Day 7. - Major surgery within 28 days prior to Cycle 1 Day 1. - Autologous or allogeneic stem cell transplant within 6 months prior to Cycle 1 Day 1. - Receiving immunosuppressants (eg, cyclosporin or calcineurin inhibitors) or systemic steroids (except for steroid use as cortisol replacement therapy in documented adrenal insufficiency or low-dose steroids with a maximum of an equivalent of 10 mg prednisone/day) within 28 days prior to Cycle 1 Day 1. - Active fungal disease or uncontrolled infection of any kind; patients receiving antibiotic, antifungal or antiviral treatment must be afebrile and hemodynamically stable for >72 hours prior to treatment. - Active graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, or chronic GVHD requiring systemic steroid administration. - Current use (including within 5 half-lives) of an investigational agent.
History or current evidence of any acute or chronic condition, therapy, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or might confound the results of the trial, interfere with participation for the full duration of the trial, or render trial participation not compatible with the patients best interest, in the opinion of the Investigator.
Administration of any of the following within 14 days prior to the first dose of eganelisib and for the study duration: - Moderate or strong inhibitors or inducers of CYP2C8 and CYP3A4, including grapefruit, grapefruit juice, Seville oranges, St. Johns wort and herbal supplements, except for antibiotics, antifungals, or antivirals that are moderate or strong inhibitors of CYP3A if they cannot be avoided. - P-glycoprotein (P-gp) inhibitors, except for antibiotics, antifungals, or antivirals if they cannot be avoided. - Breast cancer resistance protein (BCRP) inhibitors.
Administration of any of the following as of Cycle 1 Day 1 and for the study duration: - P-gp substrates with a narrow therapeutic index. - Warfarin, phenytoin, or other CYP2C8 or CYP2C9 substrates with a narrow therapeutic index.
Corrected QT with Fridericias method (QTcF) interval on screening electrocardiogram (ECG) 450 msec for males and 470 msec for females, except for patients with atrioventricular pacemakers or other conditions (eg, right bundle branch block) that render the QT measurement invalid.
WBC count >25 × 10^9/L measured within 7 days prior to the first dose of eganelisib (hydroxyurea is permitted to decrease the WBC count).
Presence of a clinically significant non-hematologic toxicity of prior therapy that has not resolved to Grade 1 or Baseline, whichever is worst, as determined by NCI CTCAE, except alopecia or skin pigmentation. Fatigue and neuropathy must have resolved to Grade 2.
History of another primary malignancy that is currently clinically significant or currently requires active intervention.
Known hypersensitivity to any excipient in the study drugs.
Pregnant or lactating female.
Known central nervous system (CNS) leukemia.
Known isolated extramedullary disease.
Significant gastrointestinal abnormalities, including requirement for IV alimentation, active peptic ulcer, chronic diarrhea or vomiting considered to be clinically significant in the judgment of the Investigator, or malabsorption syndrome or prior surgical procedures affecting drug absorption (eg, gastric bypass surgery, gastrectomy).
History or current evidence of any acute or chronic condition, therapy, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or might confound the results of the trial, interfere with participation for the full duration of the trial, or render trial participation not compatible with the patients best interest, in the opinion of the Investigator.
Administration of any of the following within 14 days prior to the first dose of eganelisib and for the study duration: - Moderate or strong inhibitors or inducers of CYP2C8 and CYP3A4, including grapefruit, grapefruit juice, Seville oranges, St. Johns wort and herbal supplements, except for antibiotics, antifungals, or antivirals that are moderate or strong inhibitors of CYP3A if they cannot be avoided. - P-glycoprotein (P-gp) inhibitors, except for antibiotics, antifungals, or antivirals if they cannot be avoided. - Breast cancer resistance protein (BCRP) inhibitors.
Administration of any of the following as of Cycle 1 Day 1 and for the study duration: - P-gp substrates with a narrow therapeutic index. - Warfarin, phenytoin, or other CYP2C8 or CYP2C9 substrates with a narrow therapeutic index.
Corrected QT with Fridericias method (QTcF) interval on screening electrocardiogram (ECG) 450 msec for males and 470 msec for females, except for patients with atrioventricular pacemakers or other conditions (eg, right bundle branch block) that render the QT measurement invalid.
WBC count >25 × 10^9/L measured within 7 days prior to the first dose of eganelisib (hydroxyurea is permitted to decrease the WBC count).
Presence of a clinically significant non-hematologic toxicity of prior therapy that has not resolved to Grade 1 or Baseline, whichever is worst, as determined by NCI CTCAE, except alopecia or skin pigmentation. Fatigue and neuropathy must have resolved to Grade 2.
History of another primary malignancy that is currently clinically significant or currently requires active intervention.
Known hypersensitivity to any excipient in the study drugs.
Pregnant or lactating female.
Known central nervous system (CNS) leukemia.
Known isolated extramedullary disease.
Significant gastrointestinal abnormalities, including requirement for IV alimentation, active peptic ulcer, chronic diarrhea or vomiting considered to be clinically significant in the judgment of the Investigator, or malabsorption syndrome or prior surgical procedures affecting drug absorption (eg, gastric bypass surgery, gastrectomy).
DESCRIPCIÓN
Part 1 Monotherapy and Combination Dose Escalation (DE): Assess the safety and tolerability of eganelisib administered as monotherapy and in combination with cytarabine Determine the recommended dose for expansion (RDE) of eganelisib as monotherapy and in combination with cytarabine Part 2 Dose Optimization (OPT): Evaluate preliminary clinical activity of eganelisib administered as monotherapy and in combination with cytarabine
PALABRAS CLAVE
acute myeloid leukemia, aml, leucemia linfocítica crónica (llc / cll), leukemia, mds, myelodysplastic syndrome, refractory aml, relapsed aml
