Phase Ib: Estimate the MTD and the RP2D of the combination of AEB071 and MEK162 in patients with metastatic uveal melanoma. And to assess the preliminary anti-tumor activity of the combination of AEB071 and MEK162. To characterize the PK profiels of…
ID
Source
Brief title
Condition
- Ocular neoplasms
- Ocular neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1b: Incidence of Dose Limiting Toxicities during the first cycle
Phase II: Progression Free Survival (PFS)
Secondary outcome
Phase Ib/II: Adeverse events and serious adverse events, changes in laboratory
values, and electrocardiograms. Dose interruptions, reductions and dose
intensity.
Phase 1b/11: Disease control Rate (DCR: CR(complete resonse)+PR (partial
response) +SD (stable disease); Progression Free Survival (PFS); OS(overall
survival); ORR (Overall Response Rate)
Phase 1b: Concentration-time profiles of AEB071 and MEK162, PK parameters,
including but not limited to AUC0-8h, Ctrough, Cmax, Tmax, accumulation ratio
(Racc)
Background summary
No standard of care excist for patients with metastatic uveal melanoma and, due
to lack of available therapies, outcome for these patients is extremely poor.
AEB071 is able to attach to a protein called Protein Kinase C (PKC) and stop it
from working. PKC is involved in the regulation of healthy cells and if PKC
becomes too active it can cause tumor cell growth and help the tumor cells
survive. In uveal melanoma some genes are changed and these genes make proteins
that increase the activity of PKC. Giving AEB071 to patients is expected to
reduce the increased activity of PKC, but this is not guaranteed.
MEK162 is a type of medicine that works by stopping a protein called MEK from
working. This protein is one of a number of proteins working together in the
cell (together they are called a signaling pathway) to cause changes in the
cell. If the signaling pathway is too active it can cause certain types of
cancers. Although not directly causing uveal melanoma, the signaling pathway
may also be activated by PKC. Adding MEK162 may help reduce the activity of the
signaling pathway. The combination of the two medicines may slow or stop tumor
growth and may make tumors shrink, but this is not guaranteed. Animal studies
have shown that the combination of the two medicines leads to a greater
decrease in tumor growth than either drug given alone. The two drugs together
have not been tested before in patients with uveal melanoma and it is not known
whether they will be effective on the tumor or how effective they may be
The startdose of AEB071 is 400mg BID and of MEK162 30mg BID. Higher dosis could
be necessary to achieve anti-tumor activity. More details are found in
paragraph 1 and 2 of the protocol.
Study objective
Phase Ib: Estimate the MTD and the RP2D of the combination of AEB071 and MEK162
in patients with metastatic uveal melanoma. And to assess the preliminary
anti-tumor activity of the combination of AEB071 and MEK162. To characterize
the PK profiels of AEB071 and MEK162, as well as evaluate their active
metabolites
Phase II: Compare the preliminiary evidence for anti-tumor activity and
clinical benefit (measured as progression free survival) at the RP2D of AEB071
and MEK162 and at 45mg BID of single-agent MEK162. And to evaluate the
preliminiary anti-tumor activity at the RP2D for AEB071 and MEK162 and at 45 mg
BID of MEK162 alone.
For both phase 1b and phase II an objective is to further characterize the
safety and tolerability of the combination of AEB071 and MEK162, including
actue and chronic toxicities.
Study design
Phase Ib: Open label, multicenter, single arm, phase I dose finding part
(Bayesian) and escalation study
Phase II: Randomized open label, multicenter, two arms, phase II study
Intervention
Phase Ib: treatmet with AEB071 and MEK162
Phase II: treatment with AEB071 and MEK162 or with MEK162 only
Study burden and risks
Toxicities of the treatment with AEB071 and MEK162
Tumorbiopsies.
Exposure to radiation, CTscan (or X-ray, MRI or PETscan). Frequent visits and
blooddrawn.
See attachment C of the patientinformation for an overview of all the
procedures during the visits. The side effects are found in attachment D of the
patientinformation.
There is no guarentee that participation of this trial has direct benefit for
the patient. Obtained results could help devolpment in the future.
The burden on the patient is as expected in a phase Ib and II study.
Raapopseweg 1
Arnhem 6824DP
NL
Raapopseweg 1
Arnhem 6824DP
NL
Listed location countries
Age
Inclusion criteria
1. Male or female patients >=18 years of age
2. Uveal (ocular) melanoma with biopsy-confirmed metastatic disease
3. Consent to a new tumor biopsy at baseline, Cycle 1 Day 15 (C1D15), and at disease progression
4. The presence of measurable disease according RECIST v1.1
5. WHO performance status of <=1
Exclusion criteria
1. Any active metastatic CNS lesion
2. History of prior or current second malignancy (except adequately treated carcinoma of the cervix or localized basal cell carcinoma of the skin, or any other curatively treated malignancy that has not been treated or recurred in the past 3 years).
3. History or current evidence of retinal vein occlusion (RVO) in the contralateral eye, as assessed by ophthamologic examination at baseline or current risk factors for RVO.
4. Impaired cardiac function ro clinically significant cardiac disease; e.g. , LVEF < 50% as determined by MUGA scan or TTE
5. Serum creatinine of >1.5x ULN
6.Treatment with strong inducers or inhibitors (medications and herbal supplements) of cytochrome P450 3A4/5 (CYP3A4/5) or CYP3A4/5 substrates with a QT prolongation risk that cannot be discontinued at least 7 half lives (or if the half-life is unkonw, 14 days) prior to study drug treatment.
7.Prior exposure to a MEK or PKC inhibitor (i.e. patients treated in the Phase I will not be eligible for the Phase II)
Design
Recruitment
Medical products/devices used
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 | EUCTR2013-000281-11-NL |
| CCMO | NL43832.058.13 |
| Other | volgt |