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Cabozantinib in Combination With Avelumab in Patients Refractory to Standard Chemotherapy With Advanced Neuroendocrine Neoplasias G3 (NEN G3)

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ClinicalTrials.gov Identifier: NCT05289856
Recruitment Status : Recruiting
First Posted : March 22, 2022
Last Update Posted : April 1, 2022
Sponsor:
Collaborators:
Ipsen
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Prof. Dr. Matthias M. Weber, Johannes Gutenberg University Mainz

Brief Summary:
The purpose of the CaboAveNEC trial is to investigate the clinical activity and safety of Cabozantinib in combination with avelumab in patients refractory to standard chemotherapy with advanced neuroendocrine neoplasias G3 (NEN G3).

Condition or disease Intervention/treatment Phase
Cancer Drug: combination of Avelumab and Cabozantinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Open-label, Multicenter Trial to Investigate the Clinical Activity and Safety of Cabozantinib in Combination With Avelumab in Patients Refractory to Standard Chemotherapy With Advanced Neuroendocrine Neoplasias G3 (NEN G3).
Actual Study Start Date : March 28, 2022
Estimated Primary Completion Date : March 1, 2025
Estimated Study Completion Date : December 1, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: combination of Avelumab and Cabozantinib
800 mg Avelumab every 2 weeks and 40 mg Cabozantinib daily
Drug: combination of Avelumab and Cabozantinib
Cabozantinib 40 mg daily PO in combination with Avelumab at a dose of 800 mg as a 1h intravenous (i.v.) infusion every two weeks (q2w) until disease progression (PD), unacceptable toxicity, or any criterion for treatment withdrawalis met, for a maximum of 12 months
Other Names:
  • Bavencio
  • Cabometyx




Primary Outcome Measures :
  1. Disease control rate (DCR: CR, PR, SD) [ Time Frame: 16 weeks ]
    Disease control rate (DCR: CR, PR, SD) according to iRECIST after 16 weeks from start of treatment until documented disease progression (PD)


Secondary Outcome Measures :
  1. Disease control rate (DCR: CR, PR, SD) [ Time Frame: week 8, week 24, week 48 ]
    Disease control rate (DCR: CR, PR, SD) according to iRECIST

  2. Objective response rate (ORR) [ Time Frame: week 8, week 16, week 24, week 48 ]
    Objective response rate (ORR) according to iRECIST

  3. Best overall response (BOR) [ Time Frame: week 8, week 16, week 24, week 48 ]
    Best overall response (BOR) according to iRECIST

  4. Duration of disease control (DDC) [ Time Frame: week 48 ]
    Duration of disease control (DDC) according to iRECIST

  5. Time to response (TTR) [ Time Frame: week 48 ]
    Time to response (TTR) according to iRECIST

  6. Progression-free survival time (PFS) [ Time Frame: week 48 ]
    Progression-free survival time (PFS) according to iRECIST

  7. Evaluation of tumor response according to RECIST1.1 [ Time Frame: week 8, week 16, week 24, week 48 ]
    Evaluation of tumor response according to RECIST1.1

  8. Overall survival (OS) [ Time Frame: week 48, week 96 ]
    Overall survival (OS)

  9. Quality of life (QoL) [ Time Frame: week 8, week 16, week 24, week 48 ]
    Quality of life (QoL) assessed by European Organisation for Research and Treatment of Cancer Quality of life questionnaire (EORTC QLQ-C30); Scale 0 - 100; higher levels indicate better quality of life

  10. Adverse events [ Time Frame: week 48 ]
    Number, severity, and duration of treatment-emergent AEs according to NCI-CTCAE v5.0

  11. Dose change of study drugs [ Time Frame: week 48 ]
    Dose change of study drugs

  12. Treatment interruption or termination [ Time Frame: week 48 ]
    Treatment interruption or termination of study drugs due to adverse events


Other Outcome Measures:
  1. Correlation of the primary and secondary endpoints with the differentiation of the NEN G3 [ Time Frame: week 8, week 16, week 24, week 48 ]
    Correlation of the primary and secondary endpoints with the differentiation of the NEN G3 (NET G3 vs NEC) and tumor immune microenvironment (e.g. PD-L1 expression, TIL)

  2. Comparison of the efficacy and tolerability of the combination treatment with Cabozantinib and Avelumab to the monotherapy with Avelumab [ Time Frame: week 8, week 16, week 24, week 48 ]
    Comparison of the efficacy and tolerability of the combination treatment with Cabozantinib and Avelumab to the monotherapy with Avelumab in the AveNEC trial (EudraCT No.: 2016-004373-40)

  3. Evaluation of tumor growth rate (TGR) [ Time Frame: week 8, week 16, week 24, week 48 ]
    Evaluation of tumor growth rate (TGR): TGR is the percentage change in tumour volume over one month



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years
  2. Histologically proven neuroendocrine neoplasia NEN G3 (WHO 2010/2019)
  3. One block or 20 slides (cut at 4 microns) of archival tumor tissue to perform central pathological review and biomarker assessment and for translational research
  4. No curative option available
  5. Progression within 9 months before study initiation and after at least one chemotherapy (platinum based chemotherapy or STZ/TEM/DTIC based chemotherapy)
  6. Presence of measurable disease as per RECIST1.1 criteria
  7. Adequate organ and bone barrow functionn:

    1. Hematologic: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused)
    2. Hepatic: total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤ 2.5 × ULN or AST and ALT levels ≤ 5 × ULN for subjects with documented metastatic disease to the liver)
    3. Renal: estimated creatinine clearance ≥ 60 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
  8. Pregnancy and contraception:

    1. Pregnancy test: Negative serum or urine pregnancy test at screening for women of childbearing potential.
    2. Contraception: Women of child-bearing potential (WOCBP) and men who are able to father a child, willing to be abstinent or use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly beginning at informed consent, for the duration of study participation and for at least 30 days for female and 90 days for male patients after last dose of avelumab and at least for 4 months after last dose of cabozantinib
  9. ECOG Performance Status 0 - 1
  10. Life expectancy of at least 12 weeks according to the assessment of the investigator
  11. Written informed consent: Signed and dated informed consent of the subject must be available before start of any specific trial procedures
  12. Ability of subject to understand nature, importance and individual consequences of clinical trial.

Exclusion Criteria:

  1. Merkel Cell carcinoma (MCC) or small cell lung cancer (SCLC)
  2. Typical or Atypical Carcinoid of the lung with a Ki67 < 20%
  3. Prior therapy with any TKI or immune therapy
  4. Neuroendocrine neoplasias that are potentially curable by surgery
  5. Major surgery within 4 weeks before first dose of study medication. Complete wound healing must be observed at least 10 days prior to enrollment.
  6. Patients who are at increased risk for severe haemorrhage
  7. TACE, TAE, SIRT or PRRT within 8 weeks before first dose of study medication
  8. Patients pretreated with Interferon as last treatment line prior to study entry
  9. Concurrent anticancer treatment after start of trial treatment (e.g., cyto¬reductive therapy, TKI therapy, mTOR inhibitor therapy, radiotherapy [with the exception of palliative radiotherapy], immune therapy, or cytokine therapy except for erythropoietin or use of any investigational drug).
  10. Concurrent treatment with strong inducers of cytochrome P450 3A4 (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's wort) and strong inhibitors of cytochrome P450 3A4 (eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir), warfarin (due to its high protein bound)
  11. Immunosuppressants: Current use of immunosuppressive medication, EXCEPT for the following:

    1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
    2. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  12. Prior organ transplantation, including allogeneic stem cell transplantation
  13. Active infection requiring systemic therapy
  14. HIV/AIDS: Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
  15. Hepatitis: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
  16. Active SARS-CoV-2 infection (detected via positive PCR test)
  17. Autoimmune disease: Severe active autoimmune disease that requires immunomodulatory therapy. Patients with diabetes type I, vitiligo, psoriasis, autoimmune thyroid disease not requiring immunosuppressive treatment are eligible.
  18. Persisting toxicity related to prior therapy (NCI CTCAE v.5.0 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable
  19. Pregnancy or lactation
  20. Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
  21. Vaccination: Vaccination within 4 weeks before the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines.
  22. Hypersensitivity to study drugs: Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3) and lactose contained in cabozantinib tablets
  23. Cardiovascular disease: Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), uncontrolled arterial hypertension or serious cardiac arrhythmia requiring medication.
  24. Clinical significant hematemesis or hemoptysis
  25. Medical or psychological conditions that would jeopardise an adequate and orderly completion of the trial
  26. Patients, who are legally institutionalized.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05289856


Contacts
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Contact: Matthias M Weber, MD 00496131 ext 177260 mmweber@unimedizin-mainz.de
Contact: Christian Fottner, MD 00496131 ext 175352 christian.fottner@unimedizin-mainz.de

Locations
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Germany
Nationales Centrum für Tumorerkrankungen, Universitätsklinikum Heidelberg Not yet recruiting
Heidelberg, Germany, 69120
Contact: Leonidas A Apostolidis, MD    00496221 ext 56 5982    Leonidas.Apostolidis@med.uni-heidelberg.de   
Contact: Christine B Grün, MD    00496221 ext 56 5982    barbara.gruen@med.uni-heidelberg.de   
I. Medizinische Klinik und Poliklinik, Endokrinologie und Stoffwechselerkrankungen, Universitätsmedizin Mainz Recruiting
Mainz, Germany, 55131
Contact: Matthias M Weber, MD    00496131 ext 177260    mmweber@uni.mainz.de   
Contact: Christian M Fottner, MD    00496131 ext 175352    christina.fottner@unimedizin-mainz.de   
Sponsors and Collaborators
Johannes Gutenberg University Mainz
Ipsen
Merck Sharp & Dohme LLC
Investigators
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Principal Investigator: Matthias M Weber, MD Universitätsmedizin der Johannes Gutenberg-Universität Mainz, I. Medizinische Klinik und Poliklinik, Abteilung Endokrinologie und Stoffwechselkrankheiten, D-55131 Mainz, Germany
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Responsible Party: Prof. Dr. Matthias M. Weber, Professor, Johannes Gutenberg University Mainz
ClinicalTrials.gov Identifier: NCT05289856    
Other Study ID Numbers: CaboAveNEC
2021-000986-34 ( EudraCT Number )
First Posted: March 22, 2022    Key Record Dates
Last Update Posted: April 1, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Prof. Dr. Matthias M. Weber, Johannes Gutenberg University Mainz:
neuroendocrine neoplasias (NEN)
NET G3
NEC G3
avelumab
cabozantinib
Additional relevant MeSH terms:
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Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Avelumab
Antineoplastic Agents, Immunological
Antineoplastic Agents