The primary objective of the trial is as follows:To determine the maximum tolerated dose (MTD) and/or the recommended Phase II dose (RP2D) of MSC2490484A.
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Number of Dose Limiting Toxicities (DLTs) occurring in Cycle 1
Secondary outcome
1) Pharmacokinetics profile in plasma (Cmax, tmax, Cmin, Cavg, fluctuation
indices (peak-to-trough fluctuation and swing), AUC0-24, AUC0-12,
AUC0-t, AUC0-*, AUC*, t1/2, *z, CL/f, Vz/f, Vss/f, Racc(AUC), and Racc(Cmax)
2)Best overall response rate
3) Clinical benefit rate defined as the proportion of subjects with Complete
Response, Partial Response, or stable disease at Week 12
4) Progression-free survival time (PFS)
Background summary
Most cancer treatments work by damaging the DNA in the cancer cells, but
sometimes those cells can repair themselves. When this happens, the cancer
treatment is not as effective, and the condition might not improve and could
even get worse. In Chronic Lymphocytic Leukemia (CLL), the cancer cells have a
large amount of a protein (DNA-dependent protein kinase, DNA-PK) that helps
repair those damaged cells. The study drug is a DNA PK inhibitor, which means
it is designed to block that protein. In some solid tumors, there are
particular genes (like the Ataxia telangiectasia mutated (ATM) and Breast
cancer early onset (BRCA) genes) with certain changes that make it harder to
repair their DNA. The study drug may also affect these tumors to further
decrease these malignant cells* ability to repair themselves.
Study objective
The primary objective of the trial is as follows:
To determine the maximum tolerated dose (MTD) and/or the recommended Phase II
dose (RP2D) of MSC2490484A.
Study design
This is a Phase I, first-in-human, open-label, dose escalation, and dose
expansion trial designed to explore the safety, tolerability, pharmacokinetic
(PK) and pharmacodynamic (PD) profiles, and clinical activity of MSC2490484A
administered daily as a single agent to subjects with advanced solid tumors
likely to have alterations in the tumor*s DNA repair mechanisms or Chronic
Lymphocytic Leukemia (CLL).
Dose Escalation.
Subjects will receive MSC2490484A continuously in 21-day cycles at the starting
dose of 100 mg once daily. The once daily administrations will also be supplied
to the second cohort (currently scheduled at 200 mg). Subsequent treatment
cohorts are planned to receive ascending doses of MSC2490484A twice daily
following a standard *3+3* design. The SMC (Safety Monitoring Committee) will
make dose escalation decisions based on review of all available safety,
tolerability, PK, and PD data. Staggered enrolment is planned for the first
cohort and will be maintained for subsequent cohorts if deemed necessary by the
SMC. Once the maximum tolerated dose (MTD) has been established, a 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 or to
revert to once daily dosing at any time during the trial. Up to 12 subjects
will be enrolled at the recommended Phase II dose/Optimal biological dose to
confirm safety and tolerability and explore the PK and PD profile of
MSC2490484A.
Expansion cohorts.
Once subjects have been evaluated at the recommended Phase II dose (RP2D) in
the first part of the study, relevant available data, assessment of
benefit/risk and rationale for opening the second part of the trial will be
submitted to the Health Authorities for approval. After Health Authorities
approval is received, 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.
Intervention
MSC2490484A is administered orally in a continuous dosing regimen over 21-day
cycles in the dose escalation and dose expansion cohorts. Patients can continue
on MSC2490484A until they withdraw consent, or experience unacceptable toxicity
or disease progression.
Study burden and risks
Text taken from the subject information form:
Side Effects
We do not have clinical experience (studies done in humans) with this drug.
This study will be the first time that MSC2490484A, the study drug, is tested
in humans, so the side effects are unknown. Based on studies done in animals
with MSC2490484A, the study drug, may cause the following adverse events:
* Increased risk of bleeding (as bleeding time is increased and platelet
aggregation is inhibited)
* Inflammation of mucosa of the digestive system (mouth, esophagus, or
intestine)
* Increase in liver enzymes
* Increase in white blood cell count
* Decreased lymphocytes (types of blood cells that fight infections), which
might increase the risk of infections
* Bleeding in the ovaries, reduced amounts of spermatids, and a temporary
impairment of the testis epithelium
In animal studies, most of these side effects disappeared after the study drug
was stopped.
Frankfurter Strasse 250
Darmstadt 64293
DE
Frankfurter Strasse 250
Darmstadt 64293
DE
Listed location countries
Age
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;*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.
Exclusion criteria
1. Eastern Cooperative Oncology Group performance status > 1;2. Received:
a. Chemotherapy, immunotherapy, hormonal therapy with the exception
of luteinizing hormone releasing hormone (LHRH) analogs, biologic
therapy, or any other anticancer therapy within 28 days prior to the first
dose of IMP administration (6 weeks for nitrosoureas or mitomycin C)
b. Any investigational agent within 28 days prior to the first dose of IMP
administration
c. Extensive prior radiotherapy on more than 30% of bone marrow
reserves or prior bone marrow/stem cell transplantation within 5 years
before study start. The extent of previous radiotherapy to the bone
marrow will be determined by the investigator
3. 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 CYP3A 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)
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-003099-22-NL |
| CCMO | NL50204.056.14 |