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A Phase 1b Dose Escalation Study Evaluating the Safety and Pharmacokinetics of Venetoclax in Combination with Azacitidine in Subjects with Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)

Status: Active (Recruitment Closed)

Purpose / Objectives

Primary Outcome

- Assess the safety Profile and pharmacokinetics (PK) of venetoclax with combination with azacitidine

- Determine the recommended Phase 2 dose (RPTD) and dosing schedule of venetoclax in combination with azacitine

Secondary Outcomes

The secondary objectives of the study are to assess preliminary efficacy data on:

- the Overall Response rate (ORR = sum of the rates of complete Remission (CR) + partial Remission (PR)

- Rate of CR

- Rate of hematologic improvement (HI; erythroid / platelet / neutrophil responses)

- Rate of red blood cell ( RBC) Transfusion independence

- Rate of platelet (PLT) Transfusion independence

- Rate of cytogenetiv response

- Rate of bone marrow blast response

- Time to transformation to acute myeloid leukemia (AML)

- Duration of Response (DOR)

- Overall survival (OS)

- Progression-free survival (PFS)

- Time to next MDS Treatment (TTNT)

- Event-free survival (EFS)


Exploratory objectives and outcome measures of the study may include:

- Translational biomarkers

- Patient-Reported Outcome (PRO) measures as assessed by:

-  PRO Measurement Information System (PROMIS) Fatiuge Short Form (SF) 7a

-  PROMIS Physical Function SF 10a

-  European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30)

-  EuroQoL EQ-5D-5L





Myelodysplastic Syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders with significant morbidity and high mortality. These syndromes are characterized by ineffective hematopoiesis that manifest clinically as cytopenias and a variable rate of transformation to acute myeloid leukemia (AML). The median age of patients at diagnosis is reported to be between 65 – 70 years. About15% of MDS cases occur after chemotherapy or radiotherapy and are referred to as treatment-related MDS (t-MDS). Myelodysplastic syndromes are classified by the International Prognostic Scoring System (IPSS) into low-, intermediate-1, intermediate-2, and high-risk groups based on the percentage of bone marrow blasts, number of lineages with cytopenias, and bone marrow cytogenetics. According to the IPSS, MDS patients are grouped into two major risk groups, low risk and higher risk (HR, IPSS overall score > 1.5).Approximately half (45%) of MDS patients present with higher-risk MDS3-5 and have a median survival less than one year with best supportive care.

Patient attributes


Treatment-naïve higher-risk myelodysplastic syndromes



Inclusion criteria

A subject will be eligible for study participation if he/she meets the following criteria within 28 days prior to the first day of study drug administration.

  • Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

  • Subject must have documented diagnosis of previously untreated de novo MDS with:

    • International Prognostic Scoring System (IPSS) risk categories Int-2 or High (IPSS overall score ≥ 1.5)


    • Presence of ≥ 5% and < 20% bone marrow blasts per bone marrow biopsy/aspirate at screening

  • Subject must have an Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.

  • Subject is not a candidate to undergo intensive chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT).

  • Subject must meet the following laboratory parameters, per laboratory reference range:

    • White blood cell (WBC) count ≤ 10,000/μL

      Note: Treatment with hydroxyurea is permitted to lower the WBC to reach this inclusion criterion. The WBC should be determined ≥ 24 hours after the last dose of hydroxyurea. The last dose of hydroxyurea should not be administered ≤ 3 days prior to the first dose of azacitidine.

    • Serum alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN)

    • Serum aspartate aminotransferase (AST) ≤ 2.5 × ULN

    • Serum total bilirubin ≤ 2.0 × ULN

      Note: Subjects with Gilbert's Syndrome may have a bilirubin concentration of > 2.0 × ULN per discussion between the investigator and AbbVie Therapeutic Area Medical Director (TA MD)

    • Creatinine clearance ≥ 30 mL/min

  • Female subject of childbearing potential must practice at least one protocol specified method of birth control (Section 5.2.4), starting on Study Day 1 through at least 30 days after the last dose of venetoclax or 3 months after the last dose of azacitidine.

Not being of childbearing potential is defined as:

    • Age > 55 years with no menses for 12 or more months without an alternative medical cause, or

    • Age ≤ 55 years with no menses for 12 or more months without an alternative medical cause AND an FSH level > 40 IU/L, or

    • Permanent surgical sterility (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)

  • Female subjects of childbearing potential must have negative results for pregnancy test performed:

    • At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and

    • Prior to dosing with urine sample obtained on Cycle 1 Day 1, if it has been > 7 days since obtaining the serum pregnancy test results.

    • Female subjects who are not of childbearing potential at Screening do not require pregnancy testing.

  • Male subjects must agree from first dose of study drug(s) through at least 30 days after the last dose of venetoclax or 3 months after the last dose of azacitidine to practice the protocol specified contraception


Exclusion criteria

A subject will not be eligible for study participation if he/she meets any of the following criteria:

  • Subject has received prior therapy for MDS.

    Note: Prior supportive care in form of transfusions or growth factors, etc., is not considered prior therapy.

    Supportive care should be discontinued ≥ 14 days prior to the first dose of study drug.

    Subjects may continue oral corticosteroids for management of conditions other than MDS (e.g., asthma, rheumatoid arthritis) at a stable daily dose equivalent to ≤ 10 mg prednisone during screening and study participation.


  • Subject has received prior therapy with a BH3 mimetic

  • Subject has a diagnosis other than previously untreated de novo MDS with IPSS risk categories Int-2 or High, including:

    • MDS with IPSS risk categories Low or Int-1 (overall IPSS score < 1.5)

    • Therapy-related MDS (t-MDS)

    • MDS evolving from a pre-existing myeloproliferative neoplasm (MPN)

    • MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN.

  • Subject received allogeneic HSCT or solid organ transplantation.

  • Subject has a history of an active malignancy within the past 2 years prior to study entry, with the exception of:

    • Adequately treated in situ carcinoma of the cervix uteri

    • Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin

    • Asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy

  • Subject has a known positive test for human immunodeficiency virus (HIV).

    Note: HIV testing is not required at Screening.

    • Subject has chronic active hepatitis B (HBV) or hepatitis C (HCV) requiring treatment.

  • Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

    • Ongoing systemic infection (viral, bacterial, or fungal)

    • Acute pneumonia

    • Febrile neutropenia

  • Subject has received any of the following within 7 days prior to the first dose of study drug:

    • Strong or moderate CYP3A inhibitors

    • Strong or moderate CYP3A inducers

  • Subject has consumed one or more of the following within 3 days prior to the first dose of study drug:

    • Grapefruit or grapefruit products

    • Seville oranges (including marmalade containing Seville oranges)

    • Star fruit (carambola)

  • Subject has a malabsorption syndrome or other condition that precludes an enteral route of administration.

  • Subject has history of a cardiovascular, endocrinologic, hepatic, immunologic metabolic, neurologic, psychiatric, pulmonary, renal disease, or any other condition that in the opinion of the investigator would adversely affect his/her participation in this study or interpretation of study results.

    Note: For subjects who have required an intervention for any above diseases within the past 6 months a discussion between the investigator and the AbbVie TA MD must take place prior to any decision to enroll the patient with the agreement of the AbbVie TA MD.

  • Subject is concurrently participating in another therapeutic clinical trial.

  • Subject is pregnant or breast-feeding.



Trial design

  • Phase I
  • Multicenter
  • Prospective
  • Cohort
  • Open Label


This open-label, Phase 1b dose-escalation study evaluates the safety and pharmacokinetics of venetoclax in combination with azacitidine in subjects with treatment-naïve HR MDS. The initial dose-escalation portion will be followed by an expansion safety cohort.

The dose escalation portion will enroll approximately 18 – 24 subjects with dose escalation guided by a Bayesian optimal interval (BOIN) design. Dose limiting toxicities (DLT) will be assessed during each dose-escalation cohort in order to define the maximum tolerated dose (MTD). For this study, the DLT observation period is defined as the first treatment cycle (Cycle 1). Adverse events occurring after the DLT observation period will also be reviewed and may be taken into consideration for dose escalation decisions. Pharmacokinetic data will be collected during the DLT observation period of the dose escalation portion. The MTD will guide the determination of the preliminary RPTD.

Pharmacokinetic samples and exploratory biomarkers (such as cytogenetics, molecular markers, and/or characterization of Bcl-2 and associated proteins) that may be predictive of venetoclax activity will be assessed throughout the trial. In addition exploratory analysis of minimal identifiable disease (MID) may be performed to evaluate depth of clinical response and whether MID correlates with other outcome measures. Pharmacogenetic (PG) samples will be collected and stored for future analysis.



Documents (password protected)

Responsibilities in overall trial

Abbvie Deutschland GmbH & Co.KG

National Coordinating Investigator

Prof. Dr. med. Katharina Götze

Study Sites

Klinik I für Innere Medizin

Study office

  • Klinisches Studienzentrum der Klinik I für Innere Medizin Köln


Active (Recruitment Closed)

Principal Investigator

Prof. Dr. med. Karl-Anton Kreuzer

Deputy of Principal Investigator

  • Dr. med. Christian Maurer


  • Dr. med. Janine Böll, geb. Schwamb
  • Dr. med. Birgit Cremer
  • Dr.med. Vangica Galkin geb.Ristovska
  • Valeska Möntenich
  • Prof. Dr. med. Christian Pallasch
  • Dr. med. Armin Tuchscherer
  • Univ.-Prof. Dr. med. Dr. rer.-nat. Roland Ullrich
  • PD Dr. med. Thomas Zander
  • Johanna Prinz
  • Dr. med. Nadine Kutsch

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