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Avelumab

Antineoplastic Agents, Immunological

Avelumab will be administered as intravenous infusion at 10 mg/kg once every two weeks until documented disease progression (PD), unacceptable toxicity, or any criterion for treatment withdrawal are met.

Matthias M Weber, MD

The purpose of the AveNEC trial is to investigate the clinical activity and safety of avelumab in patients with NEC G3 (WHO 2010), including "NET G3" who are progressive after first line chemotherapy.

According to the WHO classification of 2010, Neuroendocrine neoplasms (NEN) are divided into well to moderately differentiated neuroendocrine tumors (NET), which are graded depending on their proliferation status into NET G1 (Ki67 index \< 2%) and NET G2 (Ki67 2-20%), and into the poorly differentiated high grade neuroendocrine Carcinomas (NEC G3, ki67 \> 20%), which - depending on their morphology - are subdivided into small cell as well as large cell NECs. The vast majority (60-90%) of patients with high grade NEC are metastasized at the time of diagnosis with distant metastases present in approximately two third of the patients.

G3 neuroendocrine neoplasia according to the WHO classification of 2010 are not a homogenous entity. Based on clinical and morphological criteria a differentiated subgroup with a Ki67 in the lower proliferative range (usually between 20-55%) which is unofficially termed "NET G3", can be subdivided from the more aggressive and undifferentiated "classical" NEC G3.

The prognosis of patients with metastatic NEC G3 is poor, and median overall survival has been reported to be 5 months with a 2-year survival rate of 11 % in the SEER data base for gastrointestinal NEC. In two large series of GEP-NEC, median survival was 12-19 months for patients with best available therapy (mainly platinum based chemotherapy) and as short as 1 month for those receiving only best supportive therapy. In contrast to the "classical" NEC G3 with a poorly differentiated morphology and a Ki 67 \> 55%, NET G3 typically do not respond as well to a platinum based chemotherapy but a have a somewhat better prognosis with a 4-months longer median survival as compared to classical NEC G3. Therefore, according to current guidelines other treatment options like temozolomide based chemotherapy may be considered as a first line therapy in patients with differentiated "NET G3" .

There is a strong and unmet medical need for a novel and effective second line treatment option for these highly aggressive and rapidly progressing tumors. Considering the lack of any other established therapeutic option and the very limited efficacy of alternative second or third line chemotherapy in patients with NEC G3 (WHO 2010) who are progressive after a first-line chemotherapy, the availability of a novel therapeutic option with a significant clinical benefit (SD; PR; CR) in at least 30 % of the patients and with tolerable side effects would represent an important and clinical highly relevant break through in the treatment of these aggressive tumors.

There is a strong rationale for investigating PD-1/PD-L1 blockade in NEC G3 (WHO 2010). High grade NEC as well as LCNEC of the lung show a high mutational load, what is associated with a strong immunogenicity and a better response to an anti-PDL1/PD1 immunotherapy, and increased PDL1 expression has been demonstrated in high grade NEC. In intermediate NET the degree of T-cell tumor infiltration was associated with recurrence and survival and in a study with 80 patients with bronchopulmonary NEN including high grade NEC the expression of PD-L1 and PD-1 was associated with a worse prognosis. Evidence from phase 2 to 3 trials shows antiproliferative efficacy of an anti-PDL1/PD1 immunotherapy in high grade NECs. Furthermore, Merkel cell carcinomas, which are classified as high grade neuroendocrine tumors, are sucessfully treated with Avelumab.

Avelumab is a fully human antibody that binds PD-L1 and blocks the interaction between PD-L1 and PD-1. This removes the suppressive effect of PD-L1 on anti-tumor CD8+ T cells, resulting in restoration of cytotoxic T cell response.

Given the important role of PD-L1 in the suppression of T-cell responses, and the mode of action of avelumab which blocks the interaction between PD-L1 and its receptors, avelumab is being developed as a potential therapy for subjects with various tumors.

It is assumed that at least 20-30 % of patients with progressive disease after at least one first line chemotherapy will show a significant and clinically highly relevant benefit which is defined as an objective tumor response with complete remission (CR), partial remission (PR) or stable disease (SD) according to RECIST1.1.

Avelumab Treatment in Patients With Neuroendocrine Carcinomas (NEC G3) Progressive After Chemotherapy

A Phase II, Open-label, Multicenter Trial to Investigate the Clinical Activity and Safety of Avelumab in Patients With Advanced, Metastatic High Grade Neuroendocrine Carcinomas NEC G3 (WHO 2010) Progressive After Chemotherapy

assessment of serum levels in Chromatogranin A (CgA) measured at time of tumor assessments

assessment of serum levels in and Neuron specific enolase (NSE) measured at time of tumor assessments

Tumor growth rate (TGR): TGR is the percentage change in tumor volume over one month

The primary endpoint is the disease control rate (DCR) after 16 weeks of avelumab treatment. DCR is defined as the percentage of subjects with a confirmed reduction in tumor size compared to baseline (complete response (CR) and partial response (PR)) as well as fulfilling the criteria for stable disease (SD) according RECIST1.1.

Disease control rate (DCR) on other assessments. DCR is the proportion of patients with complete response, partial response and stable disease according to RECIST1.1.

Objective response rate (ORR) on every assessment. ORR is the proportion of patients with complete response (CR) or partial response (PR) according to RECIST1.1.

Best overall response (BOR). BOR is recorded from the start of the treatment until disease progression/recurrence according to RECIST1.1.

Duration of disease control: Duration of disease control is defined as the time from the first disease control (CR, PR, SD) to progression of disease (PD) according to RECIST1.1.

Time to response (TTR): TTR is the time from the first dose of trial medication to the first documentation of either complete response (CR) or partial response (PR) according to RECIST1.1.

Median Progression-free survival time (PFS). The time from first dose of trial medication to first documentation of objective tumor progression (PD) or to death due to any cause, whichever occurs first.

Overall survival (OS) and survival rate after 1 and 2 years: Overall survival is defined as the time from first dose of trial medication to date of death due to any cause. Survival rate is defined as rate of subjects surviving for at least 1 year or 2 years after first application of trial medication.

Quality of life (QoL) assessed by the EORTC QLQ-C30 questionnaire on Screening/Baseline, during Treatment on every assessment, on End of Treatment and on Safety FU visit

Reporting of number and frequency of adverse Events (AEs) during treatment with avelumab and until Safety Follow

Merck KGaA, Darmstadt, Germany

Johannes Gutenberg University Mainz

Principal Investigator

800 mg Avelumab every 2 weeks and 40 mg Cabozantinib daily

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

combination of Avelumab and Cabozantinib

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).

According to the WHO classification of 2010, Neuroendocrine neoplasms (NEN) are graded according to the Ki67 proliferation index and grouped into neuroendocrine Tumors (NET) Grade 1 (NET G1, Ki67 \<3%), NET G2 (Ki67 3-20%), and neuroendocrine Carcinomas (NEC) (G3, Ki67 \>20%). However, since the WHO 2017/2019 classification the group of gastrointestinal neuroendocrine tumors with a Ki67 ≥20% (NEN G3) is subdivided according to their morphology into highly proliferative differentiated NET G3 and poorly differentiated high grade neuroendocrine Carcinomas (NEC G3, Ki67 \> 20%), which - depending on their morphology - are subdivided into small cell as well as large cell NECs. The vast majority (60-90%) of patients with high grade NEC are metastasized at the time of diagnosis with distant metastases present in approximately two third of the patients.

The prognosis of patients with metastatic NEN G3 is poor, and median overall survival has been reported to be 5 months with a 2-year survival rate of 11 % in the SEER data base for gastrointestinal NEC. In two large series of GEP-NEC, median survival was 12-19 months for patients with best available therapy (mainly platinum based chemotherapy) and as short as 1 month for those receiving only best supportive therapy. In contrast to the "classical" undifferentiated NEC G3 with a poorly differentiated morphology and a Ki 67 \> 55%, NET G3 typically do not respond as well to a platinum based chemotherapy but a have a somewhat better prognosis with a 4-months longer median survival as compared to classical NEC G3. Therefore, according to current guidelines other treatment options like temozolomide based chemotherapy may be considered as a first line therapy in patients with differentiated "NET G3".

There is a strong and unmet medical need for a novel and effective second line treatment option for these highly aggressive and rapidly progressing tumors.

Considering the lack of any other established therapeutic option and the very limited efficacy of alternative second or third line chemotherapy in patients with NEN G3 who are progressive after a first-line chemotherapy, the availability of a novel therapeutic option with a significant clinical benefit (SD; PR; CR) in at least 40 % of the patients and with tolerable side effects would represent an important and clinical highly relevant break through in the treatment of these aggressive tumors.

Avelumab is a fully human antibody that binds PD-L1 and blocks the interaction between PD-L1 and PD-1. This removes the suppressive effect of PD-L1 on anti-tumor CD8+ T cells, resulting in restoration of cytotoxic T cell response.

In the ongoing phase II trial of the investigator (AveNEC, EudraCT No: 2016-004373-40), which is the largest immunotherapy trial in patients with NEN G3, the clinical activity and safety of the PD-L1 inhibitor avelumab is evaluated in 60 patients with advanced, metastatic NEN G3 progressive after chemotherapy. According to the interim analysis presented at ASCO 2019 a clinically meaningful response was seen in 27 % of patients with a significant longer progression free survival (mean PFS 33.5 vs 7.7 weeks) and overall survival (\> 60 weeks mean not reached vs 22.4 weeks) as compared to the non-responders.

Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL and RET which is currently being used very successfully in medullary thyroid carcinoma (MTC), which is a differentiated neuroendocrine neoplasia, in advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC).

In addition to its TKI activity, there is strong evidence that Cabozantinib modulates the tumor immune microenvironment leading to a synergistic efficacy in combination with a checkpoint inhibitor therapy.

There is an especially strong rationale for a combination therapy of the potent antiangiogenic TKI Cabozantinib with the checkpoint inhibitor Avelumab in NEN G3. Both drugs have demonstrated efficacy and safety in combination therapy studies of a checkpoint inhibitor and an antiangiogenic TKI in a variety of tumors and both drugs in monotherapy have shown clinical relevant antitumor efficacy in NEN.

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

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).

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)

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)

Evaluation of tumor growth rate (TGR): TGR is the percentage change in tumour volume over one month

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

Disease control rate (DCR: CR, PR, SD) according to iRECIST

Objective response rate (ORR) according to iRECIST

Best overall response (BOR) according to iRECIST

Duration of disease control (DDC) according to iRECIST

Time to response (TTR) according to iRECIST

Progression-free survival time (PFS) according to iRECIST

Evaluation of tumor response according to RECIST1.1

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

Number, severity, and duration of treatment-emergent AEs according to NCI-CTCAE v5.0

Treatment interruption or termination of study drugs due to adverse events

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Avelumab Treatment in Patients With Neuroendocrine Carcinomas (NEC G3) Progressive After Chemotherapy	NCT03352934	Cancer	Avelumab	18 Years -	Johannes Gutenberg University Mainz
Cabozantinib in Combination With Avelumab in Patients Refractory to Standard Chemotherapy With Advanced Neuroendocrine Neoplasias G3 (NEN G3)	NCT05289856	Cancer	combination of ...	18 Years -	Johannes Gutenberg University Mainz
Avelumab Treatment in Patients With Neuroendocrine Carcinomas (NEC G3) Progressive After Chemotherapy	NCT03352934	Cancer	Avelumab	18 Years -	Johannes Gutenberg University Mainz

Spots Global Cancer Trial Database for nec g3

Every month we try and update this database with for nec g3 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for nec g3

Every month we try and update this database with for nec g3 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for nec g3 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.