Safety and Tolerability of Everolimus as Second-line Treatment in Poorly Differentiated Neuroendocrine Carcinoma / Neuroendocrine Carcinoma G3 (WHO 2010) and Neuroendocrine Tumor G3 - an Investigator Initiated Phase II Study

As more efficient drugs are urgently needed for the treatment of neuroendocrine tumors the investigator evaluated phosphorylated Mammalian target of rapamycin (mTOR) and effectors in a series of NEC G3 at the Charité Center. Everolimus showed antiproliferative effects in bronchial NET.

In a second approach the data of this study should be the basis to generate another study to further explore everolimus as maintenance therapy in NEC G3/ NET G3.

Inclusion criteria

• Signed written informed consent
• Male or female ≥ 18 years of age
• Patients with poorly differentiated neuroendocrine carcinoma, neuroendocrine carcinoma G3 (NEC - G3 according to WHO 2010) or well or moderately differentiated neuroendocrine carcinoma (NET - G1 / G2) that switched to G3 (confirmed by histology) or neuroendocrine tumor G3 (NET G3) and disease progression as measured by RECIST 1.1
• Progression during or after treatment with first-line platinbased chemotherapy. In NET G3 that switched from NET G2 the line of therapy is determined from the time of revised histology (confirming a G3 NEN)
• Measurable disease according to RECIST 1.1
• Performance Status according to Eastern Cooperative Oncology Group (ECOG) status 0 - 2 (Karnofsky Performance status ≥ 80%)
• Women of child-bearing potential must have a negative pregnancy test
• Laboratory requirements:

• Hematology

• Absolute neutrophil count ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 10^9/L
• Leukocyte count ≥ 3.0 x 10^9/L
• Hemoglobin ≥ 9 g/dL or 5.59 mmol/L
• Hepatic Function

• Total bilirubin ≤ 1.5 time the upper limit normal (ULN)
• Aspartate Aminotransferase (AST) ≤ 3 x ULN in absence of liver metastases, or ≤ 5 x ULN in presence of liver metastases
• Alanine Aminotransferase (ALT) ≤ 3 x ULN in absence of liver metastases, or ≤ 5 x ULN in presence of liver metastases
• Renal Function

• Creatinine clearance ≥ 50 mL/min according to cockroft-Gault formula
• Metabolic Function

• Magnesium ≥ lower limit of normal
• Calcium ≥ lower limit of normal
• Others:

• CRP (PCT if CRP is elevated to exclude infection)
• negative urinary screening test for leukocytes and nitrite (U - stix) to exclude urinary tract infection

Exclusion criteria

• Known or suspected allergy or hypersensitivity reaction to any of the components of study treatment or their excipients.
• Previous therapy with mTOR inhibitor
• Radiotherapy :

• Concurrent radiotherapy involving target lesions used for this study.
• Concurrent palliative radiation (but radiation for non-target lesions is allowed if other target lesions are available outside the involved field)
• previous pre-operative or post-operative radiotherapy within 3 months before study treatment
• History of other malignant tumors within the last 5 years, except basal cell carcinoma or curatively excised cervical carcinoma in situ
• Known brain metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids
• Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment
• Inadequate pulmonary function according to the Investigator's judgment, history of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan
• Known active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or HIV infection
• Serious concomitant disease or medical condition that in the judgment of the investigator renders the patient at high risk from treatment complication
• Any systemic disease requiring oral intake of corticosteroids (except for replacement therapy of corticosteroids - hydrocortisone in case of adrenal or pituitary insufficiency)
• Hearing loss ≥ Grade 3 (CTCAE v4.03)
• Patient pregnant or breast feeding, or planning to become pregnant within 8 weeks after the end of treatment
• Patient (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 8 weeks (male or female) after the end of treatment.
• Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 28 days prior to treatment start
• Concurrent treatment with inhibitors (e.g. itraconazole, ketoconazole) and inducers (e.g. phenytoin, rifampicin) of Cytochrome P450 3A4 (CYP3A4) and / or the multidrug efflux pump P-glycoprotein (PgP).
• Known drug abuse/alcohol abuse
• Peripheral polyneuropathy ≥ Grade 2 (CTCAE v4.03)
• Active chronic inflammatory bowel disease
• Any condition which might interfere with study objectives (e.g. infections) or would limit the patient's ability to complete the study in the opinion of the investigator
• Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities. (AMG §40, Abs. 1 No. 4)
• Affected persons who might be dependent on the sponsor or the investigator