Cabozantinib in combination with Avelumab in patients refractory to standard chemotherapy with advanced neuroendocrine neoplasias G3 (NEN G3)

2024-513518-37-00 Protocol CaboAveNEC Therapeutic exploratory (Phase II) Ended

Start 15 Mar 2022 · End 3 Jan 2025 · Status Ended · 1 EU/EEA countries · 2 sites · Protocol CaboAveNEC

Overview

Sponsor-declared trial summary

Phase Therapeutic exploratory (Phase II)
Status Ended
Participants planned 30
Countries 1
Sites 2

Advanced neuroendocrine neoplasias G3 (NEN G3) (excluding SCLC and Merkel cell carcinomas)

Primary study objective is to assess the clinical activity of the combination therapy of Cabozantinib with Avelumab in comparison to monotherapy with avelumab in the AveNEC trial (EudraCT No.: 2016-004373-40) in patients with progressive Neuroendocrine Neoplasias G3 (NEN G3) after standard chemotherapy. The primary end…

Key facts

Sponsor
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
Participant type
Patients
Age range
18-64 years, 65+ years
Gender
Male and Female
Therapeutic area
Diseases [C] - Neoplasms [C04]
Trial duration
15 Mar 2022 → 3 Jan 2025
Decision date (initial)
2024-06-26
Transition trial
Yes
Low-intervention
No
Rare-disease indication
No
Vulnerable population
Yes
Funding sources
Merck KGaA, Germany · Ipsen Pharma GmbH, Germany

External identifiers

EU CT number
2024-513518-37-00
EudraCT number
2021-000986-34
ClinicalTrials.gov
NCT05289856

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Primary study objective is to assess the clinical activity of the combination therapy of Cabozantinib with Avelumab in comparison to monotherapy with avelumab in the AveNEC trial (EudraCT No.: 2016-004373-40) in patients with progressive Neuroendocrine Neoplasias G3 (NEN G3) after standard chemotherapy. The primary end point is the disease control rate (DCR) according to iRECIST after 16 weeks from start of treatment until documented disease progression (PD). The tumor assessment is done every 8 weeks for the first 6 month and every 12 weeks thereafter.

Secondary objectives 9

  1. Objective response rate (ORR)
  2. Duration of disease control (DDC)
  3. Best overall response (BOR)
  4. Progression-free survival time (PFS)
  5. Overall survival (OS)
  6. Quality of life (QoL)
  7. Safety and tolerability
  8. Correlation of subclassification of the NEN G3 (NET G3 vs NEC) and tumor immune microenvironment (e.g. PD-L1 expression, tumor infiltrating lymphocytes (TIL)) with tumor response and (when tumor tissue on/after treatment is available) effect of treatment on tumor microenvironment
  9. Comparison of the efficacy and tolerability of the combination of Cabozantinib and Avelumab to the monotherapy with avelumab in the AveNEC trial (EudraCT No.: 2016-004373-40) and evaluation of tumor growth rate (TGR)

Conditions and MedDRA coding

Advanced neuroendocrine neoplasias G3 (NEN G3) (excluding SCLC and Merkel cell carcinomas)

VersionLevelCodeTermSystem organ class
20.0 PT 10057270 Neuroendocrine carcinoma 100000004864

Study design 1 period

#TitleAllocationBlindingRoles blindedArms
1 Period 1
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 withdrawal is met, for a maximum of 12 months
 Not Applicable None Single arm: 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 withdrawal is met, for a maximum of 12 months

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

  1. Age ≥ 18 years
  2. Histologically proven neuroendocrine neoplasia NEN G3 (WHO 2010/2019)
  3. One block or 20 slides (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 after at least one chemotherapy (platinum based or STZ/TEM/DTIC based chemotherapy)
  6. Presence of measurable disease as per RECIST1.1 criteria
  7. Adequate organ and bone marrow function
  8. ECOG Performance Status 0 - 1
  9. Written informed consent

Exclusion criteria 15

  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 tumors 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
  10. Active infection requiring systemic therapy including, HIV/AIDS, HBV, HCV, Covid 19
  11. Severe active autoimmune disease that requires immunomodulatory therapy
  12. Uncontrolled hypertension
  13. Congestive heart failure or symptomatic coronary artery disease
  14. Pregnancy or lactation
  15. Vaccination within 4 weeks before the first dose of avelumab and while on trial

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 12

  1. Disease control rate (DCR) at week 8, week 24, week 48
  2. Objective response rate (ORR)
  3. Best overall response (BOR)
  4. Duration of disease control (DDC)
  5. Time to response (TTR)
  6. Progression-free survival time (PFS)
  7. Evaluation of tumor response according to RECIST 1.1
  8. Overall survival (OS)
  9. Quality of life (QoL) assessed by EORTC QLQ-C30
  10. Number, severity, and duration of treatment-emergent AEs according to NCI-CTCAE v5.0
  11. Dose reduction of study drugs
  12. Treatment interruption or termination of study drugs due to adverse events

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Avelumab

PRD9599441 · Product

Active substance
Avelumab
Pharmaceutical form
SOLUTION FOR INFUSION
Route of administration
INTRAVENOUS USE
Max daily dose
800 mg milligram(s)
Max total dose
19200 mg milligram(s)
Max treatment duration
12 Month(s)
Authorisation status
Not Authorised
MA holder
MERCK HEALTHCARE KGAA
Paediatric formulation
No
Orphan designation
No

CABOMETYX 20 mg film-coated tablets

PRD4381882 · Product

Active substance
Cabozantinib
Substance synonyms
XL-184, Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide
Pharmaceutical form
FILM-COATED TABLET
Route of administration
ORAL USE
Max daily dose
20 mg milligram(s)
Max total dose
7300 mg milligram(s)
Max treatment duration
12 Month(s)
Authorisation status
Authorised
ATC code
L01EX07 — -
Marketing authorisation
EU/1/16/1136/002
MA holder
IPSEN PHARMA
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
Yes
Modification description
additional label

CABOMETYX 40 mg film-coated tablets

PRD4382703 · Product

Active substance
Cabozantinib
Substance synonyms
XL-184, Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide
Pharmaceutical form
FILM-COATED TABLET
Route of administration
ORAL USE
Max daily dose
40 mg milligram(s)
Max total dose
14600 mg milligram(s)
Max treatment duration
12 Month(s)
Authorisation status
Authorised
ATC code
L01EX07 — -
Marketing authorisation
EU/1/16/1136/004
MA holder
IPSEN PHARMA
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
Yes
Modification description
additional label

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR

6 Total trials 2 Recruiting 4 Ended
Academic / Non-commercial
Sponsor organisation
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
Address
Langenbeckstrasse 1, Oberstadt Oberstadt
City
Mainz
Postcode
55131
Country
Germany

Scientific contact point

Organisation
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
Contact name
Sponsor contact point clinical trials

Public contact point

Organisation
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
Contact name
Sponsor contact point clinical trials

Locations

1 EU/EEA country · 2 investigational sites

By country

CountryMS statusPlanned subjectsSites
Germany Ended 30 2
Rest of world — 0 —

Investigational sites

Germany

2 sites · Ended
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
I. Medizinische Klinik, Abteilung für Endokrinologie, Langenbeckstrasse 1, Oberstadt, Mainz
Universitaetsklinikum Heidelberg AöR
Nationales Centrum für Tumorerkrankungen, Im Neuenheimer Feld 460, Neuenheim, Heidelberg

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Country Trial startTrial end Recruitment startRecruitment end Early termination
Germany 2022-03-15 2025-01-03 2022-03-21 2023-10-11

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

TitleSubmission dateStatusType
ICH-E3 CTR Annex IV_Report Synopsis_CaboAveNEC_2025-12-19_final
SUM-112429
 2025-12-19T17:05:45 Submitted Summary of Results

Layperson summary Annex V

TitleSubmission dateStatusType
lay summary_CaboAveNEC_2025-12-19_final 2025-12-19T17:04:19 Submitted Laypersons Summary of Results

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

TypeTitleVersion
Laypersons summary of results (for publication) lay summary_CaboAveNEC_2025-12-19_final 1
Summary of results (for publication) ICH-E3 CTR Annex IV_Report Synopsis_CaboAveNEC_2025-12-19_final 1

Application history

1 submissions — initial application plus substantial / non-substantial modifications

#TypeCodeSubmittedReference MSConclusionDecision date
1 INITIAL IN 2024-06-11 Germany Acceptable
2024-06-26
 2024-06-26

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