cancer NSCLC solid tumors
Conditions
Interventions
The trial duration is expected to be 15 30 months for Phase Ia completion
(determination of MTD/RP2D) and 12 months for Phase Ib completion (evaluation
of efficacy up to 12 months after RT). The tri
Sponsors
Merck KGaA
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
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 * Phase Ib part: treatment-naïve Stage III A/B NSCLC not eligible for concurrent chemoradiation RT * 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) *1 * Life expectancy of *3 months (Phase Ia Arm A) or *6 months (Phase Ib) * Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy.
Exclusion criteria
Exclusion criteria: Main exclusion criteria for Phase Ia and Phase Ib: * Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other anticancer therapy or 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 Ib; treatment-naïve subjects with Stage III A/B NSCLC) * 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: o Bone marrow impairment as evidenced by hemoglobin 1.5 × upper limit of normal (ULN) o 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) * History of difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the IMP, current 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 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. * Subjects currently receiving H2-blocker or proton pump inhibitors (or unable to stop at least 5 days prior to the first treatment).;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 M3814. Subjects receiving potent inducers of CYP3A or CYP2C19 must stop at least 3 weeks prior to taking M3814. Those receiving drugs mainly metabolized by CYP3A with a n
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1)Phase Ia (Arm A): Occurence of dose limiting toxicities (DLTs) up to 5 weeks after the first dose of study drug M3814 in combination with palliative fractionated RT. 2) Phase 1b (Arm A) first 3 subjects: Occurence of DLT up to 12 weeks after the first dose of M3814 in combination with curatively intended fractionated RT. 3) Phase Ib: Safety and tolerability as follows: Occurence of treatment-emergent adverse events (TEAEs) severity graded according to National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v4.03). 4) Results of laboratory tests, vital signs, ECGs | — |
Secondary
| Measure | Time frame |
|---|---|
| Safety endpoints: 1) Occurence of TEAEs (severity graded according to the NCI CTCAE v4.03) 2) Results of laboratory tests, vital signs, ECGs Efficacy parameters: 3) Best overall response based on tumor evaluations made by Investigator in accordance with RECIST (Response evaluation criteria in solid tumors) v1.1 4) Tumor size measurement based on Investigator assessment in accordance with RECIST v1.1 5) PFS time defined as time from the first dose of trial treatment to progressive disease (per RECIST v1.1) based on the Investigator assessment or death from any cause, and local/local regional tumor control (Phase 1b Arm B expansion cohort) 6) OS time defined as time from the first dose of trial treatment to the date of death from any cause Pharmacokinetic endpoints: Plasma PK parameters of MSC2490484A for Phase Ia part: 7) Pharmacokinetics Profile of MSC2490484A in Plasma on Day 1 (Cmax, tmax, AUC (0-t) and AUC (0-infinity), t1/2, CL/f and Vz/f) 8) Pharmacokinetics Profile of MSC2490484A in Plasma on Day 10 (Cmax, tmax, AUC (0-tau), AUC (0-infinity), t1/2, CLss/f, Vss/f, Racc [AUC] and Racc [Cmax]) Pharmacokinetic endpoints-tablets: Plasma PK parametersof M3814 for Phase Ia part 9) Pharmacokinetics Profile of MSC2490484A in Plasma van Dag 1 (Cmax, tmax, AUC (0-t) en AUC (0-oneindig), t1/2, CL/f and Vz/f) 10) Pharmacokinetics Profile of MSC2490484A in Plasma van Dag 6 (Cmax, tmax, AUC0-t, AUC0-oneindig, t1/2, CL/f and Vz/f) 11) Pharmacokinetics Profile of MSC2490484A in Plasma van Dag 10 (Cmax, tmax, AUC (0-tau), AUC (0-oneindig), t1/2, CLss/f, Vss/f, Racc [AUC] en Racc [Cmax]) | — |
Countries
Netherlands
Outcome results
None listed