Phase 1 Trial of MSC2490484A, an Inhibitor of a DNA-dependent Protein Kinase, in Combination With Radiotherapy

Inclusion Criteria:

- Phase Ia part: advanced solid tumors or metastases including lymphoma localized in the
head and neck region or thorax with an indication for fractionated palliative RT (Arm
A); or treatment-naïve SCCHN eligible for fractionated curatively intended RT with
concurrent cisplatin (Arm B)

- Phase Ib part: treatment-naïve Stage III A/B NSCLC not eligible for surgical resection
or concurrent chemoradiation (Arm A expansion cohort) or treatment-naïve SCCHN
eligible for fractionated curatively intended RT with concurrent cisplatin (Arm B
expansion cohort)

- cPoP study: any tumor with at least 2 (sub)cutaneous tumor/metastases at least 2 cm
apart which are RT naïve with an indication for high dose palliative RT

- Availability of archival tumor material, either as a block or slides (Phase Ia and
Ib). If no archival material is available then a fresh biopsy should be taken

- Willing to have tumor biopsies collected in cPoP

- Measurable or evaluable disease by RECIST v1.1 (not required for the cPoP study)

- Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2

- Life expectancy of ≥ 3 months (Phase Ia, Arm A) or ≥ 6 months (Phase Ia, Arm B and
Phase Ib)

- Female subjects of childbearing potential and male subjects with female partners of
childbearing potential must be willing to avoid pregnancy.

Exclusion Criteria:

- Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other
anticancer therapy or investigational medicinal product (IMP) within 28 days of first
trial drug intake for Phase Ia subjects, and any prior therapy for Phase Ib subjects.
For subjects with rapidly growing tumors localized in the head and neck region or
thorax where the treating physician cannot wait for 28 days, inclusion may take place
if there is no residual toxicity from previous treatment (maximum CTCAE Grade 1)

- Prior RT to the same region within 12 months (Phase Ia, Arm A; subjects with tumors
localized in the head and neck region or thorax) or at any time previously (Phase Ia,
Arm B; treatment-naïve subjects with SCCHN and Phase Ib; treatment-naïve subjects with
Stage III A/B NSCLC or SCCHN)

- Extensive prior RT on ≥30% of bone marrow reserve as judged by the investigator or
prior bone marrow/stem cell transplantation within 5 years before trial start.

- Poor vital organ functions defined as:

- Bone marrow impairment as evidenced by hemoglobin <10.0 g/dL, neutrophil count
<1.0 × 109/L, platelets <100 × 109/L

- Renal impairment as evidenced by serum creatinine >1.5 × upper limit of normal
(ULN)

- Liver function abnormality as defined by total bilirubin >1.5 × ULN or aspartate
aminotransferase (AST)/alanine aminotransferase (ALT) >2.5 × ULN (except for
subjects with liver involvement, who can have AST/ALT >5 × ULN)

- Abnormality in coagulation parameters. Received oral or parenteral anticoagulants
or thrombolytic agents within 10 days of the first dose of trial drug. Low dose
high molecular weight heparin is permitted if international normalized ratio is
within the normal range

- History of difficulty swallowing, malabsorption or other chronic gastrointestinal
disease or conditions that may hamper compliance and/or absorption of the IMP, use of
percutaneous endoscopic gastrostomy (PEG) tubes

- Significant cardiac conduction abnormalities, including a history of long QTc syndrome
and/or pacemaker, or impaired cardiovascular function such as New York Heart
Association classification score >2.

- Subjects currently receiving (or unable to stop using prior to receiving the first
dose of trial drug) medications or herbal supplements known to be potent inhibitors of
cytochrome P450 (CYP)3A or CYP2C19 (must stop at least 1 week prior), potent inducers
of CYP3A or CYP2C19 (must stop at least 3 weeks prior), or drugs mainly metabolized by
CYP3A with a narrow therapeutic index (must stop at least one day prior).

- Subjects currently receiving H2-blocker or proton pump inhibitors (or unable to stop
at least 5 days prior to the first treatment).

- If the planned radiation field includes any part of the esophagus and the subject has
symptoms of ongoing esophagitis, the subject is not eligible, unless an esophageal
endoscopy rules out the presence of esophagitis

- Subjects where more than 10% of the total esophagus volume receives more than 50% of
the prescribed RT dose

Main exclusion criteria for cPoP

- History of difficulty swallowing, malabsorption or other chronic gastrointestinal
disease or conditions that may hamper compliance and/or absorption of the IMP

- History of any other significant medical disease such as major gastric or small bowel
surgery, recent drainage of significant volumes of ascites or pleural effusion (as per
Investigator's judgement) or a psychiatric condition that might impair the subject's
well-being or preclude full participation in the trial

- Subjects currently receiving (or unable to stop using prior to receiving the first
dose of study drug) medications or herbal supplements known to be potent inhibitors of
CYP3A or CYP2C19 must stop at least 1 week prior to taking MSC2490484A. Subjects
receiving potent inducers of CYP3A or CYP2C19 must stop at least 3 weeks prior to
taking MSC2490484A. Those receiving drugs mainly metabolized by CYP3A with a narrow
therapeutic index as judged by the Investigator (and after optional consultation with
the Sponsor) must stop at least one day prior to taking MSC2490484A.