A Study of Volasertib Plus Induction Chemotherapy for Acute Myeloid Leukemia

A Phase I Study of Volasertib Combined With Standard Induction Chemotherapy for Previously Untreated Patients With Acute Myeloid Leukemia (VIAC)

This is a Phase I clinical trial to determine the maximum tolerated dose (MTD) of the polo-like kinase-1 inhibitor volasertib which can be safely combined with idarubicin plus cytarabine induction chemotherapy for previously untreated patients with acute myeloid leukemia. (AML).

Main inclusion criteria:

1. AML, any subtype except acute promyelocytic leukemia (APL)

2. At least one of the following features:

   i. Age 18-75 with adverse risk cytogenetics ii. Age 18-75 with antecedent myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD), or therapy-related AML iii. Age 60-75, regardless of risk category

3. No prior therapy for AML other than hydroxyurea

4. Judged by treating physician to be medically fit for induction chemotherapy

5. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2

6. Normal left ventricular ejection fraction

Subjects will receive induction chemotherapy consisting of idarubicin 12 mg/m2 on Days 1-3 plus cytarabine 200 mg/m2 (age 18-59) or 100 mg/m2 (age 60-75) as a continuous IV infusion x 7 days. Volasertib will be administered on day 4 in a dose-escalation schedule, using a standard 3+3 dose escalation design, over 3 dose levels. Once the MTD has been determined, an additional dose expansion cohort will be accrued.

Inclusion Criteria:

1. AML, any World Health Organization (WHO) subtype except APL, either de novo or secondary; extramedullary AML (i.e. granulocytic sarcoma) is permitted.

2. At least one of the following features:

   • Age 18-75 with adverse risk cytogenetics, including:

     • Complete or partial deletion of chromosome 5 or 7
     • Complex karyotype, defined as > 3 abnormalities, excluding t(15;17). t(8;21) or inv(16) or variant
     • 11q23 abnormality
     • Inv(3)(q21;q26) or variant
     • t(6;9)
     • abn(17p)

   • Age 18-75 with secondary AML, defined as arising from an antecedent myelodysplastic syndrome (MDS) or myeloproliferative disorder (MPD), or therapy-related AML

   • Age 60-75, regardless of risk category

3. No prior therapy for AML other than hydroxyurea (allowed for up to 28 days). Prior therapy for MDS, MPD or other malignancy is allowed.

4. Judged by treating physician to be medically fit for induction chemotherapy

5. ECOG performance status score 0-2.

6. Left ventricular ejection fraction (LVEF) within normal limits, by myocardial multigated scan (MUGA) or echocardiogram.

7. Signed and dated written informed consent prior to admission

Exclusion Criteria:

1. Prior anthracycline exposure equivalent to > 300 mg/m2 doxorubicin.
2. Prior chemotherapy or radiotherapy within previous four weeks except for hydroxyurea.
3. Prior treatment with volasertib or any other Polo-like kinase inhibitor
4. Known hypersensitivity to the trial drug
5. Serum creatinine > 1.5 times (1.5x) upper limit of normal (ULN) or creatinine clearance (CLcr) < 30 ml/min (estimated creatinine clearance by the Cockcroft-Gault (C-G) equation
6. Serum bilirubin > 1.5x ULN, or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x ULN
7. Persistence of clinically relevant therapy related toxicity from previous anti-cancer therapy
8. Active central nervous system leukemia (no lumbar puncture required; clinical judgement is sufficient)
9. Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial
10. Significant cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure (> New York Heart Association-II), serious cardiac arrhythmia, pericardial effusion)
11. QTcF prolongation > 470 ms or QT prolongation deemed clinically relevant by the investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the mean of the 3 ECGs taken at screening.
12. Other concurrent malignancy requiring active therapy (except hormonal therapy for prostate or breast cancer).
13. Severe uncontrolled infection. Controlled infection on antibiotics is permitted.
14. Active or chronic hepatitis C and/or B infection
15. Known HIV infection
16. Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study.
17. Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial and for at least six months after end of active therapy on study.
18. Pregnancy or breast feeding, female patients must have a negative pregnancy test prior to commencing study treatment.
19. Psychological, familial or sociological factors potentially hampering compliance with the study protocol and follow-up schedule
20. Known or suspected active alcohol or drug abuse