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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 (EVINEC)

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ClinicalTrials.gov Identifier: NCT02113800
Recruitment Status : Recruiting
First Posted : April 15, 2014
Last Update Posted : March 6, 2019
Sponsor:
Collaborators:
Assign Data Management and Biostatistics GmbH
Novartis Pharmaceuticals
Information provided by (Responsible Party):
AIO-Studien-gGmbH

Tracking Information
First Submitted Date  ICMJE April 8, 2014
First Posted Date  ICMJE April 15, 2014
Last Update Posted Date March 6, 2019
Study Start Date  ICMJE August 2015
Estimated Primary Completion Date September 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 28, 2014)
Incidence of adverse events (AEs) [ Time Frame: approx. 18 month ]
Incidence of adverse events (AEs) overall and by severity, and serious adverse events (SAEs). Severity will be assessed using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) for Adverse Events, version 4.03 (CTCAEv4.03). To evaluate tolerability and safety of everolimus in second-line treatment of poorly differentiated neuroendocrine carcinoma / neuroendocrine carcinoma G3 according to WHO 2010 and neuroendocrine tumors G3.
Original Primary Outcome Measures  ICMJE
 (submitted: April 14, 2014)
Incidence of adverse events (AEs) [ Time Frame: approx. 12 month ]
Incidence of adverse events (AEs) overall and by severity, and serious adverse events (SAEs). Severity will be assessed using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) for Adverse Events, version 4.03 (CTCAEv4.03).
Change History Complete list of historical versions of study NCT02113800 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 28, 2014)
  • Progression free survival (PFS) [ Time Frame: approx. 18 month ]
    Progression free survival (PFS) as the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse as per local radiology assessment using Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)
  • Objective response rate (ORR) [ Time Frame: approx. 18 month ]
    Objective response rate defined as the rate of best overall response (CR+PR), determined by RECIST V 1.1.
  • Disease control rate (DCR) [ Time Frame: approx. 18 month ]
    Disease control rate defined as the rate of best overall response and stable disease (CR+PR+SD), determined by RECIST V 1.1.
  • Duration of response (DR) [ Time Frame: approx. 18 month ]
    Duration of response is defined as the time from onset of the first objective tumor response (CR/PR) to objective tumor progression or death from any cause.
  • Overall Survival (OS) [ Time Frame: approx. 18 month ]
    OS is defined as the time from date of randomization to the date of death from any cause. If a patient is not known to have died at the date of analysis cut-off, the OS will be censored at the last date of contact.
  • Quality of life [ Time Frame: approx. 18 month ]
    Quality of life (HRQoL) will be evaluated using the European Organisation for Research and Treatment of Cancer (EORTC), to assess the quality of life of cancer patients questionnaire (QLQ-C30)
  • chromogranin A & B [ Time Frame: approx. 12 month ]
    Percentage of patients showing normalization or a decrease of chromogranin A & B
  • Time to Progression (TTP) [ Time Frame: approx. 18 month ]
    Time to progression (TTP) is the time from date of start of treatment to the date of event defined as the first documented progression due to underlying cancer.
  • neuron-specific enolase [ Time Frame: approx. 12 month ]
    Percentage of patients showing normalization or a decrease of neuron-specific enolase
  • progastrin releasing peptide [ Time Frame: approx. 12 month ]
    Percentage of patients showing normalization or a decrease of progastrin releasing peptide.
  • Correlation mTOR pathway components in tumor tissue to tumor response [ Time Frame: approx. 18 month ]
    To explore expression of mTOR pathway components in tumor tissue (archive) in correlation to tumor response
Original Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2014)
  • Progression free survival (PFS) [ Time Frame: approx. 12 month ]
    Progression free survival (PFS) as the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse as per local radiology assessment using Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)
  • Objective response rate (ORR) [ Time Frame: approx. 12 month ]
    Objective response rate defined as the rate of best overall response (CR+PR), determined by RECIST V 1.1.
  • Disease control rate (DCR) [ Time Frame: approx. 12 month ]
    Disease control rate defined as the rate of best overall response and stable disease (CR+PR+SD), determined by RECIST V 1.1.
  • Duration of response (DR) [ Time Frame: approx. 12 month ]
    Duration of response is defined as the time from onset of the first objective tumor response (CR/PR) to objective tumor progression or death from any cause.
  • Overall Survival (OS) [ Time Frame: approx. 12 month ]
    OS is defined as the time from date of randomization to the date of death from any cause. If a patient is not known to have died at the date of analysis cut-off, the OS will be censored at the last date of contact.
  • Quality of life [ Time Frame: approx. 12 month ]
    Quality of life (HRQoL) will be evaluated using the EORTC QLQ-C30
  • chromogranin A & B [ Time Frame: approx. 12 month ]
    Percentage of patients showing normalization or a decrease of chromogranin A & B
  • Time to Progression (TTP) [ Time Frame: approx. 12 month ]
    Time to progression (TTP) is the time from date of start of treatment to the date of event defined as the first documented progression due to underlying cancer.
  • neuron-specific enolase [ Time Frame: approx. 12 month ]
    Percentage of patients showing normalization or a decrease of neuron-specific enolase
  • progastrin releasing peptide [ Time Frame: approx. 12 month ]
    Percentage of patients showing normalization or a decrease of progastrin releasing peptide.
  • Quality of life [ Time Frame: approx. 12 month ]
    Quality of life (HRQoL) will be evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Poorly Differentiated Malignant Neuroendocrine Carcinoma
  • Neuroendocrine Carcinoma, Grade 3
  • Neuroendocrine Carcinoma, Grade 1 [Well-differentiated Neuroendocrine Carcinoma] That Switched to G3
  • Neuroendocrine Carcinoma, Grade 2 [Moderately Differentiated Neuroendocrine Carcinoma] That Switched to G3
  • Neuroendocrine Tumor, Grade 3 and Disease Progression as Measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)
Intervention  ICMJE Drug: Everolimus (Afinitor®)
Formulation: 10 mg/day Route: oral (tablet)
Study Arms  ICMJE Experimental: Single Arm

Patients receive Everolimus orally, 10 mg/day.

The end of study will be performed when tumor progression has been observed for 28 patients. Patients who are still under treatment at that time may continue with chemotherapy at the discretion of the investigator, but will be excluded from the study.

Intervention: Drug: Everolimus (Afinitor®)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 14, 2014)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2019
Estimated Primary Completion Date September 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Katrin Krause, B.Sc. +49 30 8145 344 ext 32 Katrin.Krause@aio-studien-ggmbh.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02113800
Other Study ID Numbers  ICMJE AIO-NET-0112
CRAD001KDE55T ( Other Grant/Funding Number: Novartis )
2012-004550-28 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AIO-Studien-gGmbH
Study Sponsor  ICMJE AIO-Studien-gGmbH
Collaborators  ICMJE
  • Assign Data Management and Biostatistics GmbH
  • Novartis Pharmaceuticals
Investigators  ICMJE
Principal Investigator: Marianne Pavel, Prof. Dr. Charité-Universitätsmedizin
PRS Account AIO-Studien-gGmbH
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP