Clinical Phase I Study Investigating MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Advanced Solid Tumors or Chronic Lymphocytic Leukemia
Clinical Phase I Study Investigating MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Advanced Solid Tumors or Chronic Lymphocytic Leukemia
MSC2490484A is an investigational drug that is being evaluated for the treatment of subjects
 with advanced solid tumors or chronic lymphocytic leukemia (CLL) that likely differs from
 other cancers in how it repairs damaged DNA (genetic material). This is a first-in-man Phase
 I study, which means that it is the first time the study drug is being used in humans. The
 main purpose is to determine the highest dose that does not cause unacceptable side effects.
 The second is to determine the appropriate dose to use in future research for subjects with
 cancer. Othergoals of the study are to learn about the drug's safety and side effects, how it
 affects the tumor, and how the body processes the drug.
This is a Phase I, first-in-human, open-label, dose escalation, and dose expansion trial
 designed to explore the safety, tolerability, PK and PD profiles, and clinical activity of
 MSC2490484A administered daily as a single agent to subjects with advanced solid tumors or
 CLL likely to have alterations in DNA repair mechanisms.

 Dose Escalation : Subjects will receive MSC2490484A continuously at the starting dose of 100
 mg once daily. Sequential treatment cohorts will receive ascending doses of MSC2490484A once
 daily or twice daily (if determined to be appropriate by the Safety Monitoring Committee
 [SMC]) following a standard "3+3" design. The SMC will make dose escalation decisions based
 on review of available safety, tolerability, Pharmacokinetic (PK), and Pharmacodynamic (PD)
 data. Once the maximum tolerated dose (MTD) has been established, an Recommended Phase II
 Dose (RP2D) will be defined by the SMC, either at the MTD level or another dose level,
 depending on the available data on safety, efficacy, PK, and PD observed in the trial. The
 SMC may decide to stop dose escalation at any time during the trial.

 Up to 12 subjects will be enrolled at the RP2D/Optimal biologic dose (OBD) to confirm safety
 and tolerability and explore the PK and PD profile of MSC2490484A.

 Expansion cohorts: Once subjects have been evaluated at the RP2D, additional subjects will be
 enrolled into 2 or more expansion cohorts (20 evaluable subjects per expansion cohort) to
 evaluate clinical efficacy in tumors likely to have alterations in the DNA repair mechanism
 (eg, CLL and other tumor types). Subjects are evaluable for efficacy if they have received at
 least 1 dose of study drug and have radiographic baseline. Subjects who are not evaluable for
 efficacy will be replaced.
Inclusion Criteria:

 -  Advanced solid tumors likely to have alterations in DNA repair mechanisms, such as the
 BRCA and ATM pathways, or CLL, with no other standard surgical, radiation, or systemic
 anticancer therapies available. Subjects with CLL will be enrolled in 1 of the RP2D
 expansion cohorts only

 -  Tumor accessible for biopsies and agree to pretreatment tumor biopsy

 -  Measurable or evaluable disease in accordance with RECIST v 1.1 for solid tumors or
 Cheson´s criteria for CLL

 -  Male or female subjects at least 18 years of age who sign written informed consent.

 -  Other protocol-defined criteria could apply

 Exclusion Criteria:

 -  Eastern Cooperative Oncology Group performance status > 1

 -  Prior treatment with chemotherapy, immunotherapy, hormonal therapy, with the exception
 of luteinizing hormone releasing hormone (LHRH) analogs, biologic therapy, any other
 anticancer therapy, or any other investigational agent within 28 days of the first
 dose of MSC2490484A (6 weeks for nitrosoureas or mitomycin C)

 -  Extensive prior radiotherapy on more than 30% of bone marrow reserves or prior bone
 marrow/stem cell transplantation within 5 years of study start. The extent of previous
 radiotherapy to the bone marrow will be determined by the investigator.

 -  Receiving medications or herbal supplements that are known to be potent inhibitors of
 cytochrome P450 3A4 or inducers of cytochrome P450 3A4.

 -  Not recovered from toxicity due to prior therapy to baseline or an AE CTCAE Grade of 1
 or less (except alopecia)

 -  Poor vital organ function as defined in the protocol

 -  Significant cardiac conduction abnormalities as defined in the protocol

 -  Central nervous system metastases unless previously radiotherapy treated, stable by
 computerized tomography (CT) scan for at least 3 months without evidence of cerebral
 edema, and no requirements for corticosteroids or anticonvulsants

 -  Other protocol-defined criteria could apply