A Study in Leukemia Patients With Karonudib

Primary Objective Part I

• To determine the safety and tolerability of Karonudib in escalating doses for the treatment of patients with advanced relapsed/refractory Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL) , Diffuse Large B-Cell Lymphoma, Multiple Myeloma (MM) and high-risk Myelodysplastic Syndrome (MDS)AML, ALL, DLBCL, Burkitt´s lymphoma, multiple myeloma and high-risk MDS Primary Objective Part II
• To determine the safety and tolerability of Karonudib in combination with standard of care treatment, Idarubicinother anti-cancer agents for the treatment of patients with advanced progressive, relapsed/refractory AML, and high-risk MDS

Inclusion criteria

• Written informed consent.
• Age 18-75 years (may be extended to older if deemed fit).
• The patient has received standard of care treatments and has refractory or relapsed or progressive disease with no suitable standard of care options available.

For expansion cohort (Cohort V): Patients can only have received a maximum of 70% of anthracycline lifetime exposure to date of proposed dosing day.

Cohorts I-IV: AML, ALL, DLBCL, Burkitt lymphoma, multiple myeloma or high-risk MDS, according to the WHO 2016 criteria.

• Expansion cohort (Cohort V): Relapsed, Recurrent or Progressive AML or MDS according to the ELN 2017 criteriaWHO 2016 criteria.
• For expansion cohort (Cohort V): Patients can only have received a maximum of 70% of anthracycline lifetime exposure to date of proposed dosing day.
• The patient has received standard of care treatments and has refractory or relapsed disease with only experimental therapies as further treatment options.
• Life expectancy of at least 8 weeks (as per investigators clinical assessment).
• ECOG PFS 0-2
• Patients must have measurable disease by blood or bone marrow or imaging examination.
• Have a normal left ventricular ejection fraction (LVEF) based on institutional ranges.
• Adequate hepatic and renal function defined as:

• Total bilirubin < 3 x ULN (does not apply to patients with Gilberts Syndrome).
• AST and ALT ≤ 5 x ULN.
• The calculated GFR is at least 30 ml/min using Cockcroft-Gault method.
• Platelet count≥10 x 109/L. (Can be supported by platelet transfusion)
• Subject must be able to take oral medication.
• Negative pregnancy test according to CTFG guidance 2014 for females of child-producing potential.

Exclusion criteria

• Age less than 18 years.
• Less than 4 weeks since stopping previous systemic chemotherapy treatment with the exception of stable dose Hydroxyurea, Trophosphamide, oral Cyclophosphamide, ImID or Thioguanine which needs to be stopped 10 x t1/2 prior to Karonudib administration.
• Less than 1 week since stopping palliative radiotherapy.
• Less than 2 weeks after surgery except access surgical procedures.
• Less than 6 months since a clinically significant cardiovascular event such as myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke or TIA.
• Congestive heart failure NYHA class > II.
• History of arrhythmias or arrhythmias discovered during the screening period (apart from atrial fibrillation without ventricular tachycardia and premature extra beats).
• Patients requiring anti-arrhythmic drugs except for stable dose beta-blocking or calcium channel blocking agents.
• QTc interval >470 ms at baseline (Fridericia correction).
• Use of Fentanyl (must be stopped at least 1 week prior to initiation of Karonudib).
• Use of anti-oxidants vitamins and Acetylcysteine (must be stopped within 48 hours of starting treatment with Karonudib).
• Use of antidepressant medications which are substrate for CYP2D6 (must be stopped at least 3 weeks prior to starting treatment with Karonudib).
• Any severe acute or chronic medical condition that places the patient at increased risk or interferes with the interpretation of study results.
• Intracerebral engagement (patient with previously known engagement are eligible provided that there is no evidence of disease progression for a minimum of 8 weeks prior to inclusion.
• Known acute or chronic infection with hepatitis B or C except for DNA-negative hepatitis B with stable dose anti-viral agents.
• Known HIV infection.
• Pregnant or breast-feeding women.
• Patients with reproductive potential not implementing accepted and effective means of contraception.
• Participation in any other clinical trial with a pharmaceutical product within 5 x t½, or minimum 1 week, since last dosing of the IMP, whichever is the shorter.
• Acute promyelocytic leukemia (AML M3).
• Uncontrolled ongoing systemic or localized infection.
• Unable to comply with study procedures.
• Peripheral neurological toxicity CTCAE grade 2 or higher.