Precision therapy versus standard therapy in Acute Myeloid Leukaemia and Myelodysplastic syndrome in elderly (PALM) – a phase II randomized clinical trial

Prior treatment

• Current concomitant chemotherapy, radiation therapy, or immunotherapy for other malignancies; other than hydroxyurea.
• Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load within 3 months. (Hepatitis B or C testing is not required). Subjects with serologic evidence of prior vaccination to HBV [ie. HBs Ag-, and anti-HBs+] may participate.
• AML with favourable cytogenetic or genetic changes in patients who are fit for intensive chemotherapy. Favourable genetics are: t(8;21)(q22;q22.1); RUNX1-RUNX1T1; inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11; mutated NPM1 without FLT3-ITD or with FLT3-ITDlow†; Biallelic mutated CEBPA.
• Patients who previously were included in the Palm-study.
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.)

Other illness

• Subject is known to be positive for HIV (HIV testing is not required).
• Subject has a malabsorption syndrome or other condition that precludes enteral route of administration.
• Cardiac dysfunction as defined by: a. Unstable angina or b. New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or angina pain or c. Unstable cardiac arrhythmias
• Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance with the study protocol and follow-up schedule.
• Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.

Other

• Acute promyelocytic leukemia.
• Patients who do not understand the Written Informed Consent (e.g., language problems)
• Patients where it is not possible to get bone-marrow for NGS, i.e., “dry tap”.
• Blast crisis of chronic myeloid leukemia.

• Patients with: a. a newly or recurrent/refractory diagnosis of AML and related precursor neoplasms according to WHO 2016 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease and therapy-related AML ), or b. acute leukemias of ambiguous lineage according to WHO 2016 or c. a newly or recurrent diagnosis of myelodysplastic syndrome (MDS) with IPSS-R > 4.5.1 or d. a newly or recurrent diagnosis of chronic myelomonocytic leukemia with 10-19% blasts or blast equivalents in the bone-marrow (CMML-2).
• Patients 60 years and older.
• Patients must NOT be eligible for intensive chemotherapy or allogeneic stem cell therapy
• WBC ≤ 30 x109/L (prior hydroxyurea allowed for a maximum of 14 days, stopped before start of treatment)
• Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values: a. Serum creatinine ≤ 2.5 mg/dL (≤ 221.7 μmol/L), unless considered AML-related b. Serum bilirubin ≤ 2.5 x upper limit of normal (ULN), unless considered AML-related or due to Gilbert’s syndrome c. Alanine transaminase (ALT) ≤ 2.5 x ULN, unless considered AML-related
• WHO performance status 0, 1 or 2 for subjects ≥ 75 years of age OR 0 to 3 for subjects ≥ 60 to 74 years of age.
• Signed Informed Consent
• Male Subjects Only: Male subjects who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice contraception with condom. Male subjects must agree to refrain from sperm donation from initial study drug administration until at least 90 days after the last dose of study drug. If the patient is randomized to a targeted drug where the SPC recommends contraception more than 90 days after last dose, the SPC recommendation should be followed.