Olaparib as Salvage Treatment for Cisplatin-resistant Germ Cell Tumor

This is a proof-of principle open-label, single-arm, two-stage phase II trial of olaparib 300 mg twice daily in patients with relapsed/refractory metastatic germ cell cancer. The study will recruit 10 patients, if no response is seen the study is terminated. If one or more responses are observed, further 19 patients (for a total of 29 patients) will be enrolled. If 4 or more of the first 29 evaluable patients have achieved objective response, further studies in patients with metastatic germ cell cancer are warranted.

The main inclusion criteria are:

• Patient with metastatic gonadal GCT or extragonadal GCT originating from retroperitoneum or mediastinum.
• Disease progression during cisplatin-based chemotherapy or disease progression or relapse after high-dose chemotherapy or disease progression or relapse after at least 2 different cisplatin-based regimens
• At least one measurable lesion that can be accurately assessed by CT/MRI/plain x-ray) at baseline and follow up visits.

The study will be analyzed on an intent-to-treat basis. Secondary parameters will be analyzed exploratively for the intent-to-treat population.

Correlations between with biomarkers (PAR, poly adenosine diphosphate-ribose polymerase (PARP-1), PTEN, XPA, ERCC1-3, XPF, FanD2, γ-H2AX) expression in paraffin-embedded tumor samples and clinical outcome will be performed in an exploratory intent. Plasma samples will be collected at baseline and at response/progression for possible retrospective biomarkers study.

Inclusion criteria

• Patients ≥ 18 years old
• Histologically verified metastatic gonadal GCT or extragonadal GCT originating from retroperitoneum or mediastinum.
• Disease progression during cisplatin-based chemotherapy or disease progression or relapse after high-dose chemotherapy or disease progression or relapse after at least 2 different cisplatin-based regimens
• patients who progressed during cisplatin-based therapy and who are not eligible for high-dose chemotherapy
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0-2
• Life expectancy ≥3 months
• At baseline adequate function of liver, kidneys and bone marrow

• Neutrophils ≥ 1500 /mm3;
• Hemoglobin ≥ 9.0 g/dL;
• Platelets ≥ 80 x109/L;
• Creatinine ≤ 1.5x upper limit of normal (ULN) In case of liver metastases increased levels of the following three parameters is acceptable:
• Bilirubin ≤ 1.5 x ULN
• serum glutamate oxaloacetate transaminase (SGOT (AST) ≤2.5 x ULN
• serum glutamate pyruvate transaminase (SGPT (ALT) < 2.5 x ULN;
• Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to International Conference on Harmonization Good Clinical Practice (ICH GCP), and national/local regulations.Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
• At least one measurable lesion that can be accurately assessed by CT/MRI/plain x-ray) at baseline and follow up visits.

Exclusion criteria

• Systemic antitumor treatment within 21 days before study entry
• Simultaneous radiotherapy to the only target lesion
• Patients with resting ECG with QTc > 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome. If ECG demonstrates QTc >470 msec, patient will be eligible only if repeat ECG demonstrates QTc ≤470 msec
• Patients who have experienced a seizure or seizures within 6 months of study treatment or who are currently being treated with cytochrome P450 enzyme inducing anti-epileptic drugs for seizures.
• Patients with uncontrolled brain metastases.
• Patients receiving prohibited classes of inhibitors of CYP3A4 (see section 6.5.1).
• Patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Patients with any acute toxicities due to previous cancer treatment that have not resolved to a Common Toxicity Criteria for Adverse Effects (NCI-CTCAE v 4.03) grade 0 or 1 with the exception of chemotherapy induced alopecia and grade 2 peripheral neuropathy.
• Patients affected by myelodysplastic syndrome or acute myeloid leukemia
• Known to be serologically positive for HIV and receiving antiretroviral therapy
• Known seropositive for active viral infection with hepatitis B virus (HBV) (patients who are HBsAg negative, anti-HBs positive and/or hepatitis B core antigen (Anti-HBc) positive, but viral DNA negative are eligible)
• Known seropositive for active infection with hepatitis C virus (HCV)
• Patients unwilling or unable to comply with the protocol
• Patients with unstable angina pectoris, myocardial infarction ≤ 6 months prior to first study treatment, congestive heart failure New York Heart Association (NYHA) III-IV or serious uncontrolled cardiac arrhythmias
• Patients with an active or uncontrolled infection
• Patients who have a history of another primary malignancy and are off treatment for ≤ 3 years, with the exception of non-melanoma skin cancer
• Patients who have undergone major surgery within 4 weeks prior to starting study drug (e.g. intra-thoracic, intra-abdominal, or intra-pelvic) or significant traumatic injury, or who have not recovered from the side effects of any of the above within 6 weeks
• Patients who have participated in another interventional clinical trial within 30 days before study entry
• Other serious medical conditions that could impair the ability of the patient to participate in the study
• Active infection requiring systemic antibiotic-, anti-viral-, or anti-fungal medication
• Active cancer (other than GCT) including prior malignancy from which the patient has been disease-free for ≤3 years (except superficial basal cell skin cancer)
• Patients with a known hypersensitivity to the combination/comparator agent
• Patients with uncontrolled seizures.