Phase II study of standard of care therapy azacitidine (AZA) combined with venetoclax (VEN) and Tagraxofusp (TAG) in patients with higher-Risk chronic myelomonocytic Leukemia (CMML): the PATROL Study
ESTADO CLÍNICO
Reclutando
FASE/S DEL ENSAYO
Fase II
PATOLOGÍA
Leucemia linfática crónica y otros SLPC, Neoplasias mieloproliferativas crónicas Philadelphia(-), Trasplante de progenitores hematopoyéticos, Leucemia mieloide crónica, Linfoma, Leucemia
CENTRO INVESTIGADOR
H.U. La Paz
INVESTIGADOR PRINCIPAL
Raquel de Paz Arias
FECHA DE APERTURA
Marzo, 2025
FECHA DE CIERRE
,
CRITERIOS DE INCLUSIÓN
1. Signed written informed consent
10. Women of childbearing potential and practicing a highly effective method of birth control according to the Clinical Trial Facilitation Coordination Group Recommendation (Version 1.1, 2020)3: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o oral o intravaginal o transdermal progestogen-only hormonal contraception associated with inhibition of ovulation: o oral o injectable o implantable intrauterine device (IUD) intrauterine hormone-releasing system (IUS) bilateral tubal occlusion vasectomised partner sexual abstinence For females, these requirements apply during the treatment period and for 6 months after the end of dosing.
11. A woman of childbearing potential must have a negative serum (-human chorionic gonadotropin [-hCG]) pregnancy test within one week of treatment initiation and agree to be tested (serum or urine) on day 1 of every cycle and at EOT
12. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a highly effective method of contraception) and all men must also not donate sperm. Highly effective methods of contraception include double-barrier contraception, total abstinence, vasectomization with confirmed azoospermia, female partner with an intrauterine device, etc.). For males, these requirements apply during the study treatment period and for 3 months after the end of dosing.
2. Male and female 18 years at date of signing informed consent
3. Must be able to adhere to the study visit schedule and other protocol requirements
4. CMML diagnosis according to WHO 2022 criteria
5. CPSS risk intermediate-2 or high2 (HR) CMML at study entry (WBC prior to HY used to compute CPSS at inclusion in HY-exposed patients, see below)
6. Patients who are eligible for and will receive azacitidine (AZA) as per standard of care.
7. Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale
8. Adequate organ function including the following: Liver: o Total bilirubin < 1.5 times upper limit of normal (ULN) (except moderate unconjugated hyperbilirubinemia due to intra medullary hemolysis or due to Gilbert syndrome), AND o Alanine transaminase (ALT) and aspartate transaminase (AST) < 2.5 times ULN Renal: Creatinine clearance >/= 45 mL/minute Cardiac o Left ventricular ejection fraction (LVEF) 50% by multigated acquisition scan (MUGA) or 2-dimensional (2-D) echocardiogram (ECHO) within 28 days prior to the start of therapy o No clinically significant abnormalities on a 12-lead electrocardiogram (ECG) Albumin: Serum albumin 3.2 g/dL (note: albumin infusions are not permitted in order to enable eligibility)
9. Availability of blood counts and transfusion events for previous 8 weeks
10. Women of childbearing potential and practicing a highly effective method of birth control according to the Clinical Trial Facilitation Coordination Group Recommendation (Version 1.1, 2020)3: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o oral o intravaginal o transdermal progestogen-only hormonal contraception associated with inhibition of ovulation: o oral o injectable o implantable intrauterine device (IUD) intrauterine hormone-releasing system (IUS) bilateral tubal occlusion vasectomised partner sexual abstinence For females, these requirements apply during the treatment period and for 6 months after the end of dosing.
11. A woman of childbearing potential must have a negative serum (-human chorionic gonadotropin [-hCG]) pregnancy test within one week of treatment initiation and agree to be tested (serum or urine) on day 1 of every cycle and at EOT
12. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a highly effective method of contraception) and all men must also not donate sperm. Highly effective methods of contraception include double-barrier contraception, total abstinence, vasectomization with confirmed azoospermia, female partner with an intrauterine device, etc.). For males, these requirements apply during the study treatment period and for 3 months after the end of dosing.
2. Male and female 18 years at date of signing informed consent
3. Must be able to adhere to the study visit schedule and other protocol requirements
4. CMML diagnosis according to WHO 2022 criteria
5. CPSS risk intermediate-2 or high2 (HR) CMML at study entry (WBC prior to HY used to compute CPSS at inclusion in HY-exposed patients, see below)
6. Patients who are eligible for and will receive azacitidine (AZA) as per standard of care.
7. Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale
8. Adequate organ function including the following: Liver: o Total bilirubin < 1.5 times upper limit of normal (ULN) (except moderate unconjugated hyperbilirubinemia due to intra medullary hemolysis or due to Gilbert syndrome), AND o Alanine transaminase (ALT) and aspartate transaminase (AST) < 2.5 times ULN Renal: Creatinine clearance >/= 45 mL/minute Cardiac o Left ventricular ejection fraction (LVEF) 50% by multigated acquisition scan (MUGA) or 2-dimensional (2-D) echocardiogram (ECHO) within 28 days prior to the start of therapy o No clinically significant abnormalities on a 12-lead electrocardiogram (ECG) Albumin: Serum albumin 3.2 g/dL (note: albumin infusions are not permitted in order to enable eligibility)
9. Availability of blood counts and transfusion events for previous 8 weeks
CRITERIOS DE EXCLUSIÓN
1. CMML with t (5 ;12) or PDGFRB rearrangement that may be treated with imatinib
10. Serious concomitant systemic disorder, including active bacterial, fungal, psychiatric illness, or viral infection that in the opinion of the investigator, would compromise the safety of the patient and/or his/her ability to complete the study.
11. Medical condition requiring therapies with CYP3A inducing activity. All CYP3A inducers should be discontinued 7 days prior to the first dose of study drug
12. Patients with known CNS involvement
13. Females who are pregnant or are currently breastfeeding or planning to become pregnant while enrolled in this study or within 6 months after the end of dosing
14. Patient is a man who plans to father a child while enrolled in this study or within 3 months after the end of dosing
15. The patient is receiving immunosuppressive therapy for any reason, with the exception of low-dose prednisone ( 10 mg/day) or equivalent
16. The patient has persistent clinically significant toxicities Grade 2 from previous therapies, including cytotoxic chemotherapy, targeted therapies, biological therapies, or immunotherapies, not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue)
17. The patient has clinically significant cardiovascular disease (e.g. uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
18. The patient has uncontrolled, clinically significant pulmonary disease (e.g. chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.
19. The patient has known positive status for human immunodeficiency virus (HIV) or active or chronic Hepatitis B or Hepatitis C.
2. Myeloproliferative / myelodysplastic neoplasm other than CMML
20. Patient is unable to attend site visits as patient is in custody by order of an authority or a court of law
21. Participation in another interventional clinical study within the last 3 months prior to signing the ICF or simultaneous participation in other clinical studies
22. Previous assignment to treatment during this study
23. Close affiliation with the investigator (e.g. a close relative) or persons working at the study site
24. Patient is an employee of the sponsor or involved CRO
25. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the patients safety
3. Bone marrow or peripheral blood blasts (including promonocytes) 20%
4. Patients with unavailable CPSS at inclusion (WBC prior to HY used to compute CPSS at inclusion in HY-exposed patients) or with a CPSS low or intermediate-1 at study entry
5. Patient has received an experimental or investigational drug or used an invasive investigational medical device within 14 days prior to day 1 of C1
6. Prior treatment with TAG, VEN and/or HMA treatment, including AZA/CC-486, decitabine (DEC), SGI-110, AST7227. Prior treatment with Erythropoiesis Stimulating Agents (ESA) or hydroxyurea (HY) is acceptable, with a > 15 days washout from ESAs and > 3 days washout from HY
7. Patients who previously received an allogeneic stem cell transplantation (HSCT) for CMML or an antecedent hematological malignancy. Those never transplanted but eligible for HSCT are eligible for the trial.
8. Major surgery within 4 weeks prior to day 1 of C1 (excluding the placement of vascular access and other minor surgical procedures)
9. Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, asymptomatic prostatic cancer not requiring treatment, or other tumors if not active during the last 2 years)
10. Serious concomitant systemic disorder, including active bacterial, fungal, psychiatric illness, or viral infection that in the opinion of the investigator, would compromise the safety of the patient and/or his/her ability to complete the study.
11. Medical condition requiring therapies with CYP3A inducing activity. All CYP3A inducers should be discontinued 7 days prior to the first dose of study drug
12. Patients with known CNS involvement
13. Females who are pregnant or are currently breastfeeding or planning to become pregnant while enrolled in this study or within 6 months after the end of dosing
14. Patient is a man who plans to father a child while enrolled in this study or within 3 months after the end of dosing
15. The patient is receiving immunosuppressive therapy for any reason, with the exception of low-dose prednisone ( 10 mg/day) or equivalent
16. The patient has persistent clinically significant toxicities Grade 2 from previous therapies, including cytotoxic chemotherapy, targeted therapies, biological therapies, or immunotherapies, not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue)
17. The patient has clinically significant cardiovascular disease (e.g. uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
18. The patient has uncontrolled, clinically significant pulmonary disease (e.g. chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.
19. The patient has known positive status for human immunodeficiency virus (HIV) or active or chronic Hepatitis B or Hepatitis C.
2. Myeloproliferative / myelodysplastic neoplasm other than CMML
20. Patient is unable to attend site visits as patient is in custody by order of an authority or a court of law
21. Participation in another interventional clinical study within the last 3 months prior to signing the ICF or simultaneous participation in other clinical studies
22. Previous assignment to treatment during this study
23. Close affiliation with the investigator (e.g. a close relative) or persons working at the study site
24. Patient is an employee of the sponsor or involved CRO
25. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the patients safety
3. Bone marrow or peripheral blood blasts (including promonocytes) 20%
4. Patients with unavailable CPSS at inclusion (WBC prior to HY used to compute CPSS at inclusion in HY-exposed patients) or with a CPSS low or intermediate-1 at study entry
5. Patient has received an experimental or investigational drug or used an invasive investigational medical device within 14 days prior to day 1 of C1
6. Prior treatment with TAG, VEN and/or HMA treatment, including AZA/CC-486, decitabine (DEC), SGI-110, AST7227. Prior treatment with Erythropoiesis Stimulating Agents (ESA) or hydroxyurea (HY) is acceptable, with a > 15 days washout from ESAs and > 3 days washout from HY
7. Patients who previously received an allogeneic stem cell transplantation (HSCT) for CMML or an antecedent hematological malignancy. Those never transplanted but eligible for HSCT are eligible for the trial.
8. Major surgery within 4 weeks prior to day 1 of C1 (excluding the placement of vascular access and other minor surgical procedures)
9. Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, asymptomatic prostatic cancer not requiring treatment, or other tumors if not active during the last 2 years)
DESCRIPCIÓN
Main objective is the primary objective of the trial is to generate data on the efficacy by CR, mCR, or PR of the combination of the SOC agent AZA combined with venetoclax (VEN) and tagraxofusp (TAG) in the studied patient population in a descriptive manner and by statistical analysis.
PALABRAS CLAVE
chronic leukemia, chronic myelomonocytic leukemia (cmml), donor lymphocyte infusion, leucemia linfocítica crónica (llc / cll), leukemia
