A Single Arm, Open-label Multicenter Phase II Trial of Everolimus in Patients With Relapsed/Refractory Germ Cell Cancer
Patients with metastatic germ cell cancer and relapse after two or more courses of
cisplatin-based chemotherapy or after high-dose chemotherapy have a poor prognosis and few
treatment options. Everolimus is a derivative of rapamycin and acts as a signal transduction
inhibitor. Its target is mTOR (mammalian target of rapamycin), a key protein kinase
regulating cell growth, proliferation and survival. The mTOR pathway activity is modulated
by the PI3K1AKT pathway and is known to be deregulated in numerous human cancers, including
germ cell tumors. Everolimus is being investigated as an anticancer agent based on its
potential to act:
- Directly on tumor cells by inhibiting tumor cell growth and proliferation
- Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity
An open-label, single arm, non-randomized, single stage phase II study. Screening phase:
Baseline evaluations will be performed within 2 weeks before the first dose of study drug.
Treatment phase: All patients will receive everolimus until disease progression (by RECIST
or tumor markers) or unacceptable toxicity or study discontinuation for other reasons. A
treatment cycle consists of 3 weeks. Dose reductions and dose interruptions (for up to 2
weeks) are allowed for intolerable toxicity. Follow-up phase: All patients will be followed
Tumor Response and progression will be assessed using the RECIST criteria and assessments
with tumor markers. Tumor measurements by a CT scan or MRI will be performed at screening
within 2 weeks prior to the first dose of study drug. During the study period, the CT
scan/MRI will be performed every 6 weeks (± one week), and at the time of discontinuation of
study drug (within 2 weeks). The same type of scan (CT or MRI) used at screening must be
used for all subsequent follow-up assessments. A partial or a complete response warrants a
confirmation no sooner than 4 weeks and no later than 6 weeks after its observation.
Tumor markers (AFP, HCG) will be assessed every 3 weeks. A tumor marker reduction > 90%
without an increase in tumor size is considered a partial response. A tumor marker increase
> 25% without an increase in tumor size is considered progressive disease when confirmed 3
weeks after its observation.
The following retrospective pathological examinations of tumor samples will be performed in
those patients that gave additional informed consent:
- immunohistochemistry for the mismatch repair genes hMLH1, hMSH2, hMSH6, and PMS2, and
the cell signalling effectors pMAPK, pAKT, pS6K and PTEN.
- mutation analysis for PTEN, BRAF, p53, and examination of microsatellite instability
This information will be correlated with treatment response (CR, PR, SO or PD) at week
12 in an exploratory analysis.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Progression-free rate at 12 weeks
Percentage of patients that have not progressed after 12 weeks of treatment.
Martin H Fenner, MD
Hannover Medical School
Germany: Federal Institute for Drugs and Medical Devices