A Phase 1/2, Open-Label, Dose-Escalation, Dose-Expansion Study of Enzomenib (DSP 5336) in Adult Patients with Acute Leukemia and Other Selected Hematologic Malignancies, with and without Mixed Lineage Leukemia (MLL) rearrangement or Nucleophosmin 1 (NPM1) Mutation
ESTADO CLÍNICO
Reclutando
FASE/S DEL ENSAYO
Fase I-II
PATOLOGÍA
Leucemia mieloide aguda, Linfoma, Leucemia
CENTRO INVESTIGADOR
MD Anderson Cancer Center Madrid
INVESTIGADOR PRINCIPAL
Adolfo de la Fuente Burguera
FECHA DE APERTURA
Septiembre, 2023
FECHA DE CIERRE
,
CRITERIOS DE INCLUSIÓN
For patients in Phase 1: Have a confirmed diagnosis of refractory or relapsed AML, ALL, or acute leukemia of ambiguous lineage and whose disease has progressed after available standard therapies known to be active for their AML, ALL, or acute leukemia of ambiguous lineage. Participants must have a documented KMT2A (MLL) fusion or NPM1 mutation including those with coexisting FLT3 genomic alterations and/or IDH1/2 mutation.Participants who are candidates for stem cell transplantation must have been offered this therapeutic option
For all patients: Have an estimated life expectancy 3 months, based on the investigators assessment
For all patients: Females of childbearing potential must have a negative serum or urine pregnancy test.
For all patients: Must agree to use one highly effective contraception method or 2 acceptable methods of birth control (each partner to use one method) or use prevention of pregnancy measures (ie, sexual abstinence, when this is the usual and preferred lifestyle of the patient) during the study and for 6 months (for females and males alike) after the last dose of study drug, if the male or female patient is of child-producing potential
For all patients: Have bone marrow material suitable for genomic analysis (eg, MLLr or NPM1 mutations) of AML or ALL genetic alterations. Note: if a bone marrow material is insufficient, an alternative suitable tissue (eg, peripheral blood) must be provided.
For patients in Phase 2: Have a confirmed diagnosis of refractory or relapsed AML or ALL according to WHO 2022 classification, as determined by pathology review at the treating institution, and who have 5% blasts by morphologic assessment in the bone marrow. Patients must have received clinically applicable standard therapies with confirmed survival benefit. Patients must not have had prior exposure to a menin inhibitor
For patients in Phase 2: Have a documented KMT2A (MLL)-fusion or NPM1 mutation assessed at relapse or immediately prior to the determination of refractory status
For all patients: Be 18 years of age
For all patients: Have an Eastern Cooperative Oncology Group (ECOG) performance status 2.
For all patients: For DSP-5336 monotherapy, white blood cell (WBC) count must be below 30,000/L at the time of enrollment and prior to starting study treatment. (Hydroxyurea and steroid for cytoreduction purpose will be allowed prior to enrollment and during study treatment).
For all patients: Any prior treatment-related toxicities resolved to Grade 1 prior to enrollment, with the exception of Grade 2 alopecia or neuropathy
For all patients: Have adequate renal and hepatic function at Screening as determined by: a. Clearance of creatinine (CLcr) level 50 ml/min, assessed by the Cockcroft-Gault formula b. Total bilirubin 1.5 times the upper limit of normal (ULN) (or 2.0 times ULN for patients with known Gilberts syndrome) c. Aspartate aminotransferase (AST) 3.0 times ULN d. Alanine aminotransferase (ALT) 3.0 times ULN
For all patients: Be willing to attend study visits as required by the protocol
For all patients: Have an estimated life expectancy 3 months, based on the investigators assessment
For all patients: Females of childbearing potential must have a negative serum or urine pregnancy test.
For all patients: Must agree to use one highly effective contraception method or 2 acceptable methods of birth control (each partner to use one method) or use prevention of pregnancy measures (ie, sexual abstinence, when this is the usual and preferred lifestyle of the patient) during the study and for 6 months (for females and males alike) after the last dose of study drug, if the male or female patient is of child-producing potential
For all patients: Have bone marrow material suitable for genomic analysis (eg, MLLr or NPM1 mutations) of AML or ALL genetic alterations. Note: if a bone marrow material is insufficient, an alternative suitable tissue (eg, peripheral blood) must be provided.
For patients in Phase 2: Have a confirmed diagnosis of refractory or relapsed AML or ALL according to WHO 2022 classification, as determined by pathology review at the treating institution, and who have 5% blasts by morphologic assessment in the bone marrow. Patients must have received clinically applicable standard therapies with confirmed survival benefit. Patients must not have had prior exposure to a menin inhibitor
For patients in Phase 2: Have a documented KMT2A (MLL)-fusion or NPM1 mutation assessed at relapse or immediately prior to the determination of refractory status
For all patients: Be 18 years of age
For all patients: Have an Eastern Cooperative Oncology Group (ECOG) performance status 2.
For all patients: For DSP-5336 monotherapy, white blood cell (WBC) count must be below 30,000/L at the time of enrollment and prior to starting study treatment. (Hydroxyurea and steroid for cytoreduction purpose will be allowed prior to enrollment and during study treatment).
For all patients: Any prior treatment-related toxicities resolved to Grade 1 prior to enrollment, with the exception of Grade 2 alopecia or neuropathy
For all patients: Have adequate renal and hepatic function at Screening as determined by: a. Clearance of creatinine (CLcr) level 50 ml/min, assessed by the Cockcroft-Gault formula b. Total bilirubin 1.5 times the upper limit of normal (ULN) (or 2.0 times ULN for patients with known Gilberts syndrome) c. Aspartate aminotransferase (AST) 3.0 times ULN d. Alanine aminotransferase (ALT) 3.0 times ULN
For all patients: Be willing to attend study visits as required by the protocol
CRITERIOS DE EXCLUSIÓN
Have a histologic diagnosis of acute promyelocytic leukemia
Have a cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient to receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent/assent process, protocol, or protocol-required visits and procedures
Have a history of Grade 2 drug-induced interstitial lung disease or Grade 2 non-infectious pneumonitis within 6 months of starting study treatment.
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336.
Receive concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5. Other antifungals that are used as standard of care to prevent or treat infections are permitted Note: If a patient is on one of the excluded azole class antifungals and can be switched to a permitted azole 7 or more days prior to study, that patient could be allowed on study (Arm B).
Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of a hepatitis B surface antigen, all being indicative of active infection.
In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results; these conditions include, but are not limited to: clinically significant non-healing or healing wounds; concurrent congestive heart failure (New York Heart Association Functional Classification Class III or IV; see Section 21.7); concurrent unstable angina; concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation); recent (within the prior 6 months) myocardial infarction; acute coronary syndrome within the previous 6 months; significant pulmonary disease (shortness of breath at rest or on mild exertion), eg, due to concurrent severe obstructive pulmonary disease, concurrent hypertension not controlled with concomitant medication, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 6 months.
Have a history of Torsades de Pointes
Have abnormal ECGs at screening that are clinically significant, such as QTc >480 with QTc corrected according to Fridericias formula [QTcF]).
Are pregnant or breastfeeding or planning to become pregnant Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug. .
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336.
Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP 5336, or receiving immunosuppressive therapy post-HSCT at the time of Screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD.
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336
Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
Had major surgery within 28 days prior to the first dose of DSP-5336
Have active central nervous system leukemia (prophylactic intrathecal chemotherapy is allowed).
Have any history or complication of interstitial lung disease (for sites in Japan only) and, for clinical sites operating under the European Medicines Agencies, a history of Grade 2 drug-induced interstitial lung disease or Grade 2 non-infectious pneumonitis within 6 months of starting study treatment
Have a known intolerance or hypersensitivity reaction to components of any of the investigational medicinal products
Have a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336 .
Received systemic calcineurin inhibitors within 42 weeks prior to the first dose of DSP 5336.
Have an active and uncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy
Have known severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication
Have a cognitive, psychologic, or psychosocial impediment that would impair the ability of the patient to receive therapy according to the protocol, or adversely affect the ability of the patient to comply with the informed consent/assent process, protocol, or protocol-required visits and procedures
Have a history of Grade 2 drug-induced interstitial lung disease or Grade 2 non-infectious pneumonitis within 6 months of starting study treatment.
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336.
Receive concurrent sensitive substrates with a narrow safety window or strong inhibitors or inducers of CYP3A4/5. Other antifungals that are used as standard of care to prevent or treat infections are permitted Note: If a patient is on one of the excluded azole class antifungals and can be switched to a permitted azole 7 or more days prior to study, that patient could be allowed on study (Arm B).
Have a known detectable viral load for human immunodeficiency virus or hepatitis C, or evidence of a hepatitis B surface antigen, all being indicative of active infection.
In the opinion of the treating investigator, have any concurrent conditions that could pose an undue medical hazard or interfere with interpretation of study results; these conditions include, but are not limited to: clinically significant non-healing or healing wounds; concurrent congestive heart failure (New York Heart Association Functional Classification Class III or IV; see Section 21.7); concurrent unstable angina; concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation); recent (within the prior 6 months) myocardial infarction; acute coronary syndrome within the previous 6 months; significant pulmonary disease (shortness of breath at rest or on mild exertion), eg, due to concurrent severe obstructive pulmonary disease, concurrent hypertension not controlled with concomitant medication, or diabetes mellitus with more than 2 episodes of ketoacidosis in the prior 6 months.
Have a history of Torsades de Pointes
Have abnormal ECGs at screening that are clinically significant, such as QTc >480 with QTc corrected according to Fridericias formula [QTcF]).
Are pregnant or breastfeeding or planning to become pregnant Note: Patients who are breastfeeding may be enrolled if they interrupt breastfeeding prior to the first dose of any study drugs and do not feed the baby with breast milk expressed after receiving the first dose of any study drugs. Breastfeeding should not be resumed for at least 6 months after the last dose of study drug. .
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336
Underwent HSCT or chimeric antigen receptor cell (CAR-T) therapy or other modified T-cell therapy within 60 days prior to the first dose of DSP-5336.
Received a donor lymphocyte infusion within 28 days prior to the first dose of DSP 5336, or receiving immunosuppressive therapy post-HSCT at the time of Screening, or with clinically active GVHD or GVHD requiring active medical intervention other than the use of topical steroids for ongoing cutaneous GVHD.
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336
Received systemic calcineurin inhibitors within 2 weeks prior to the first dose of DSP 5336
Had major surgery within 28 days prior to the first dose of DSP-5336
Have active central nervous system leukemia (prophylactic intrathecal chemotherapy is allowed).
Have any history or complication of interstitial lung disease (for sites in Japan only) and, for clinical sites operating under the European Medicines Agencies, a history of Grade 2 drug-induced interstitial lung disease or Grade 2 non-infectious pneumonitis within 6 months of starting study treatment
Have a known intolerance or hypersensitivity reaction to components of any of the investigational medicinal products
Have a left ventricular ejection fraction (LVEF) <50%, as determined by ECHO
Received antineoplastic agents (except hormonal therapies as adjuvant maintenance for breast or prostate cancers if a patient is taking before starting study treatment, and hydroxyurea given for controlling blast cells) or other investigational treatment within 14 days or 5 half-lives, whichever is shortest, prior to the first dose of DSP-5336 .
Received systemic calcineurin inhibitors within 42 weeks prior to the first dose of DSP 5336.
Have an active and uncontrolled, bacterial, viral, or fungal infection requiring parenteral therapy
Have known severe dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally, including the inability to swallow oral medication
DESCRIPCIÓN
Phase 1: To assess the safety and tolerability of DSP-5336 monotherapy in patients with relapsed or refractory AML, ALL, or acute leukemia of ambiguous lineage. To determine the recommended Phase 2 dose (RP2D) of DSP-5336 based on the lowest dose of DSP-5336 that provides the maximum biologic and clinical effect, or the maximum tolerated dose (MTD), whichever is lower Phase 2: To evaluate the clinical activity of DSP-5336 monotherapy in patients with relapsed/refractory acute leukemia with an MLLr or patients with relapsed/refractory AML with an NPM1m
PALABRAS CLAVE
leukemia, npm1
