Evaluation of Ramucirumab and Dacarbazine Efficacy in Progressive Well-Differentiated Metastatic Pancreatic Neuroendocrine Tumors

Trial ID: 2024-515045-42-00
Sponsor: Martin-Luther-Universitaet Halle-Wittenberg

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Diseases & Conditions

Pancreatic neuroendocrine tumour

Objectives

The primary objective of this study is to evaluate the effect of **ramucirumab** in combination with dacarbazine on disease control in patients with progressive well-differentiated metastatic neuroendocrine tumors of the pancreas. This is clinically relevant as it aims to determine the potential efficacy of this combination therapy in managing a challenging and progressive form of cancer, potentially offering a new therapeutic option for affected patients.

Secondary objectives include investigating the tumor response, overall survival, progression-free survival, and the toxicity profile of the combination therapy. Additionally, the study aims to assess the biochemical response and quality of life of the patients. A translational research component seeks to identify predictive biomarkers, which could enhance personalized treatment strategies in the future.

Participants

The clinical trial involves participants diagnosed with **progressive well-differentiated metastatic neuroendocrine tumors of the pancreas**. The study population includes both male and female subjects, aged between 18 and 75 years, who are experiencing progressive disease despite previous treatments. Participants are required to have a histologically confirmed unresectable metastatic G1-G2 differentiated pancreatic neuroendocrine tumor, with measurable disease as per RECIST 1.1 criteria. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and a life expectancy greater than 12 weeks. Participants must have adequate renal, hepatic, bone marrow, and coagulation function. The study population was selected based on specific inclusion criteria, including the exclusion of prior therapy with dacarbazine (DTIC) or temozolomide, while allowing previous treatments such as non-DTIC-based chemotherapy, SSA analogues, everolimus, or sunitinib. The trial also considers lifestyle factors, requiring sexually active participants to be postmenopausal, surgically sterile, or using effective contraception. Female participants of childbearing potential must have a negative serum pregnancy test within seven days prior to the first dose of protocol therapy. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed as a **single-arm** pilot study to evaluate the efficacy of **ramucirumab** in combination with dacarbazine in patients with progressive well-differentiated metastatic neuroendocrine tumors of the pancreas. The trial is categorized as a Phase II therapeutic exploratory study, focusing on the safety and efficacy of the approved medicinal product. The study will involve intravenous administration of **Cyramza** (ramucirumab) as a **solution for infusion**. The trial is expected to run from October 2019 to June 2025, with a maximum treatment period of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed unresectable metastatic G1-G2 differentiated pancreatic neuroendocrine tumors, age between 18-75 years, measurable disease, and adequate organ function. The primary endpoint is the disease control rate (DCR) after six months from study entry, determined according to RECIST 1.1 or death. Secondary endpoints include objective tumor response, progression-free survival, overall survival, toxicity, biochemical response, and quality of life assessments.

Follow-up visits will be scheduled to monitor the participants' response to treatment and assess any adverse effects. The end-of-study visit will conclude the trial for each participant, evaluating the overall outcomes and collecting final data. Participants are expected to be involved in the study for up to 24 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The study aims to provide valuable insights into the potential benefits of ramucirumab in combination with dacarbazine for this patient population.

Treatment

The clinical trial involves the administration of **Cyramza** (ramucirumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 10 mg/ml and is intended for **intravenous use**. The dosing regimen specifies a maximum daily dose of 8 mg/kg, with a total maximum dose of 417 mg/kg over the course of the treatment. The maximum treatment period is set at 24 weeks. Ramucirumab is a monoclonal antibody classified under the ATC code L01XC21 and is produced by ELI LILLY NEDERLAND B.V. The active substance, ramucirumab, is derived from a protein of other origin, and it is also known by the synonym LY3009806.

In this study, ramucirumab is combined with **dacarbazine**, a standard-of-care chemotherapy agent, to evaluate its efficacy in patients with progressive well-differentiated metastatic pancreatic neuroendocrine tumors. Dacarbazine is administered according to standard dosing guidelines, which typically involve intravenous administration. The combination aims to assess the disease-control effect in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **Disease Control Rate (DCR)** after 6 months from study entry, determined according to RECIST 1.1 criteria or death. Secondary endpoints include Objective Tumor Response (ORR), Progression-Free Survival (PFS), Overall Survival (OS), toxicity, and biochemical response, which will be evaluated through tumor marker chromogranin A and, in cases of functional neuroendocrine tumors (NET), gastrin and insulin levels. Quality of life will be assessed using the EORTC QLQ-C30 questionnaire. Additionally, translational research will focus on predictive biomarkers, including circulating VEGF, ANGPT1/2, and IL8 levels, as well as immunohistochemical VEGFR2 expression.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically confirmed unresectable metastatic G1-G2 differentiated pancreatic neuroendocrine tumor (non-functional and functional NET) excluding neuroendocrine carcinomas - Age: 18-75 years - Measurable disease (RECIST 1.1) - Progressive disease under treatment with either non-DTIC-based chemotherapy, SSA analogues, everolimus or sunitinib. No prior therapy with DTIC or temozolomide. Prior TACE and SIRT allowed with a minimum of 3 months before study entry, prior PRRT with a minimum of 12 months before study entry - ECOG 0-1 - Life expectancy > 12 weeks - Adequate renal, hepatic, bone marrow and coagulation function - Sexually active patiens: postmenopausal, surgically sterile, or use of effective contraception (Pearl Index <1). Female patients of childbearing potential: negative serum pregnancy test within 7 days prior to first dose of protocol therapy. - Written informed consent

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Exclusion Criteria

Pregnancy or lactation. - Secondary malignancy in patient's history with the exception of: disease-free period > 5 years before randomization or non-melanoma skin cancer or curatively treated cervical carcinoma in situ or other noninvasive in situ neoplasm. - Allergy against dacarbazine or ramucirumab - Current enrolment or participation within the last 4 weeks in a clinical drug trial - Any arterial thromboembolic events within 6 months prior to first dose of protocol therapy. Insufficient liver function - Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management - Chronic antiplatelet therapy, once-daily aspirin use (maximum dose 325 mg/day) permitted - Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy. - History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy - Uncontrolled severe physical or mental disorders - Pathological condition present that carries a high risk of bleeding - History of gastrointestinal perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation. - Major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy. Elective or planned major surgery to be performed during the course of the clinical trial. - Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy. - officially and/or legally accomodated persons