VENETOCLAX for Chronic myelomonocytic leukemia

Inclusion criteria

• {"criterion_text":"- 1. Signed written informed consent\n- 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: •\tcombined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: o\toral o\tintravaginal o\ttransdermal •\tprogestogen-only hormonal contraception associated with inhibition of ovulation: o\toral o\tinjectable o\timplantable •\tintrauterine device (IUD) •\tintrauterine hormone-releasing system (IUS) •\tbilateral tubal occlusion •\tvasectomised partner •\tsexual abstinence For females, these requirements apply during the treatment period and for 6 months after the end of dosing.\n- 11. A woman of childbearing potential must have a negative serum (β-human chorionic gonadotropin [β-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\n- 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.\n- 2. Male and female ≥ 18 years at date of signing informed consent\n- 3. Must be able to adhere to the study visit schedule and other protocol requirements\n- 4. CMML diagnosis according to WHO 2022 criteria\n- 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)\n- 6. Patients who are eligible for and will receive azacitidine (AZA) as per standard of care.\n- 7. Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale\n- 8. Adequate organ function including the following: •\tLiver: o\tTotal 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\tAlanine transaminase (ALT) and aspartate transaminase (AST) < 2.5 times ULN •\tRenal: Creatinine clearance >/= 45 mL/minute •\tCardiac o\tLeft 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\tNo clinically significant abnormalities on a 12-lead electrocardiogram (ECG) •\tAlbumin: Serum albumin ≥ 3.2 g/dL (note: albumin infusions are not permitted in order to enable eligibility)\n- 9. Availability of blood counts and transfusion events for previous 8 weeks"}

Exclusion criteria

• {"criterion_text":"- 1. CMML with t (5 ;12) or PDGFRB rearrangement that may be treated with imatinib\n- 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.\n- 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\n- 12. Patients with known CNS involvement\n- 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\n- 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\n- 15. The patient is receiving immunosuppressive therapy for any reason, with the exception of low-dose prednisone (≤ 10 mg/day) or equivalent\n- 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)\n- 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).\n- 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.\n- 19. The patient has known positive status for human immunodeficiency virus (HIV) or active or chronic Hepatitis B or Hepatitis C.\n- 2. Myeloproliferative / myelodysplastic neoplasm other than CMML\n- 20. Patient is unable to attend site visits as patient is in custody by order of an authority or a court of law\n- 21. Participation in another interventional clinical study within the last 3 months prior to signing the ICF or simultaneous participation in other clinical studies\n- 22. Previous assignment to treatment during this study\n- 23. Close affiliation with the investigator (e.g. a close relative) or persons working at the study site\n- 24. Patient is an employee of the sponsor or involved CRO\n- 25. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the patient’s safety\n- 3. Bone marrow or peripheral blood blasts (including promonocytes) ≥ 20%\n- 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\n- 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\n- 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\n- 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.\n- 8. Major surgery within 4 weeks prior to day 1 of C1 (excluding the placement of vascular access and other minor surgical procedures)\n- 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)"}

Primary endpoints

• {"endpoint_text":"- The primary outcome measure is the response rate defined as CR or mCR or PR after 3 cycles of treatment.","definition_or_measurement_approach":"Response rate defined as CR (complete response), mCR (marrow CR), or PR (partial response) assessed after 3 cycles of treatment."}
• {"endpoint_text":"- Response will be assessed according to Savona et al., 20151.","definition_or_measurement_approach":"Responses will be assessed using the criteria/methods described in Savona et al., 2015."}

Secondary endpoints

• {"endpoint_text":"- Adverse events (AEs) and serious adverse events (SAEs), clinical laboratory values, vital signs, ECG, and ECHO/MUGA parameters","definition_or_measurement_approach":"Safety assessed by recording AEs/SAEs, clinical labs, vital signs, ECG, and ECHO/MUGA parameters."}
• {"endpoint_text":"- Overall survival (OS), time to leukemia transformation (TLT), median duration of response until EOT","definition_or_measurement_approach":"Efficacy assessed by OS, TLT, and median duration of response up to end of treatment (EOT)."}
• {"endpoint_text":"- Proportion of patients achieving hematologic improvement after 3 cycles of treatment (IWG 2018/2023 criteria)","definition_or_measurement_approach":"Hematologic improvement measured per IWG 2018/2023 criteria after 3 cycles."}
• {"endpoint_text":"- Proportion of patients achieving transfusion independence after 3 cycles of treatment (IWG 2018/2023 criteria)","definition_or_measurement_approach":"Transfusion independence assessed per IWG 2018/2023 criteria after 3 cycles."}
• {"endpoint_text":"- Change of quality of life after 3 cycles and 12 cycles of treatment compared to baseline","definition_or_measurement_approach":"Quality of life change measured vs baseline after 3 and 12 cycles (instrument not specified here; protocol lists QLQ-C30 questionnaire in documents)."}

Germany

Earliest CTIS Part Ii Submission Date

30-01-2025

Latest Decision Or Authorization Date

19-01-2026

Processing Time Days

354

Number Of Sites

4

Number Of Participants

10

Italy

Earliest CTIS Part Ii Submission Date

11-03-2025

Latest Decision Or Authorization Date

13-05-2025

Processing Time Days

63

Number Of Sites

4

Number Of Participants

10

Spain

Earliest CTIS Part Ii Submission Date

11-02-2025

Latest Decision Or Authorization Date

21-05-2025

Processing Time Days

99

Number Of Sites

4

Number Of Participants

10

Primary sponsor

Full Name

GCP-Service International West GmbH

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Contract research organisations

Name

GCP-Service International Limited & Co. KG

Responsibilities

Sponsor/cro responsibilities as provided: codes 1,10,11,12,13,2,5,6,8,9

Third parties

• {"country":"Sweden","full_name":"Viedoc Technologies AB","duties_or_roles":"sponsorDuties codes: 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Spain","full_name":"Red De Apoyo A La Investigacion Clinica En Hematologia Y Hemoterapia S.L.","duties_or_roles":"sponsorDuties: code 1; code 15 (contracts with sites)","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Bremen Briteline GmbH","duties_or_roles":"sponsorDuties: code 15 (archiving)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"Universitaet Leipzig","duties_or_roles":"sponsorDuties: code 13","organisation_type":"Educational Institution"}
• {"country":"Germany","full_name":"Universitaet Leipzig","duties_or_roles":"sponsorDuties: code 4","organisation_type":"Educational Institution"}
• {"country":"Italy","full_name":"FISiM Fondazione Italiana Sindromi Mielodisplastiche Ets","duties_or_roles":"sponsorDuties: code 1; code 15 (contracts with sites)","organisation_type":"Patient organisation/association"}
• {"country":"Germany","full_name":"GCP-Service International Limited & Co. KG","duties_or_roles":"sponsorDuties codes: 1,10,11,12,13,2,5,6,8,9","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Activoris Medizintechnik GmbH","duties_or_roles":"sponsorDuties: code 14","organisation_type":"Pharmaceutical company"}

Co-sponsors

• Stemline Therapeutics, Inc.
• AbbVie Inc.