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

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

The study is designed as an open-label, prospective, single arm, multicenter study of everolimus in histologically confirmed, neuroendocrine carcinoma G3 /neuroendocrine tumor G3 after failure of first-line platin-based chemotherapy (open-label pilot study).

The aim of this study is to provide a second line therapy to patients with any type of platinum based first line chemotherapy, to gather data on disease control rate and progression free survival.

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:

1. Signed written informed consent

2. Male or female ≥ 18 years of age

3. 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

4. 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)

5. Measurable disease according to RECIST 1.1

6. Performance Status according to Eastern Cooperative Oncology Group (ECOG) status 0 - 2 (Karnofsky Performance status ≥ 80%)

7. Women of child-bearing potential must have a negative pregnancy test

8. 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:

1. Known or suspected allergy or hypersensitivity reaction to any of the components of study treatment or their excipients.

2. Previous therapy with mTOR inhibitor

3. 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

4. History of other malignant tumors within the last 5 years, except basal cell carcinoma or curatively excised cervical carcinoma in situ

5. Known brain metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids

6. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment

7. 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

8. Known active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or HIV infection

9. Serious concomitant disease or medical condition that in the judgment of the investigator renders the patient at high risk from treatment complication

10. Any systemic disease requiring oral intake of corticosteroids (except for replacement therapy of corticosteroids - hydrocortisone in case of adrenal or pituitary insufficiency)

11. Hearing loss ≥ Grade 3 (CTCAE v4.03)

12. Patient pregnant or breast feeding, or planning to become pregnant within 8 weeks after the end of treatment

13. 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.

14. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 28 days prior to treatment start

15. 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).

16. Known drug abuse/alcohol abuse

17. Peripheral polyneuropathy ≥ Grade 2 (CTCAE v4.03)

18. Active chronic inflammatory bowel disease

19. 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

20. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities. (AMG §40, Abs. 1 No. 4)

21. Affected persons who might be dependent on the sponsor or the investigator