Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Bevacizumab

Angiogenesis Inhibitors

Aflibercept

Angiogenesis Inducing Agents

Growth Inhibitors

Conventional switch of chemotherapy together with the antiangiogenic treatment: Bevacizumab and mFOLFOX6 (continuation of same regimen until progressive disease (PD) according to RECIST v1.1, followed by switch to aflibercept and FOLFIRI after PD).

Early marker-driven switch of anti-angiogenic agent and maintenance of chemotherapy: Bevacizumab and mFOLFOX6 will be administered until change of the CAF-profile and at least stable disease according to RECIST v1.1. Change to Aflibercept and mFOLFOX6 (change of bevacizumab to aflibercept and continuation of mFOLFOX6) until PD according to RECIST v1.1, followed by change to FOLFIRI after PD).

Early marker-driven switch of antiangiogenic treatment (bevacizumab to aflibercept) maintaining the chemotherapy backbone until definite radiological progression.

compared to a conventional treatment approach of changing chemotherapy and antiangiogenic agent at time of radiologic progression.

Thomas Seufferlein, Prof. Dr.

The primary objective of the two phase PERMAD trial is the evaluation of the impact of a personalized marker-driven treatment approach with early detection of progression and modification of treatment on cytokines and angiogenic factors (CAF) and efficacy.

In regard of the two parts, the primary objective of the run-in phase (n=50 patients) with conventional switch of chemotherapy together with the anti-angiogenic agent is the determination of a distinct cytokines and angiogenic factor (CAF) profile during treatment with FOLFOX and bevacizumab, which allows early detection/prediction of progressive disease. The primary objective of the marker-driven randomized part (n=150 patients) with marker-driven switch of antiangiogenic agent and maintenance of chemotherapy is the evaluation of the efficacy of an early marker-driven switch of anti-angiogenic treatment (bevacizumab to aflibercept)

This is a multicentre, multinational, open labeled, prospective, randomized, controlled phase II study designed to assess the clinical utility of an early marker driven change of anti-angiogenic treatment (bevacizumab to aflibercept) maintaining the chemotherapy backbone until definite radiological progression in first line treatment of patients with metastatic colorectal cancer. After completing the run in phase of the study, with at least 30 patients completing their first line treatment (due to progression, secondary resection or toxicity) and being evaluable for CAF analyses, the results will be reviewed by an Independent Data Monitoring Committee (IDMC). Based on that review the decision to continue with, modify or cancel the randomized part will be made.

The primary endpoint of the run-in phase with conventional switch of chemotherapy together with the anti-angiogenic agent is:

• Progression free survival (PFS1) of first line treatment

The primary endpoint of the randomized part with marker-driven switch of antiangiogenic agent and maintenance of chemotherapy is:

• Progression free survival rate at 6 months (PFSR@6) after first cycle after randomization.

PERMAD: Personalized Marker-driven Early Switch to Aflibercept in Patients With Metastatic Colorectal Cancer

Personalized Marker-driven Early Switch to Aflibercept in Patients With Metastatic Colorectal Cancer (PERMAD-Trial) - a Multicenter, Multinational, Two Part, Phase II Trial

Run-in phase with conventional switch of chemotherapy together with the anti-angiogenic agent.

Primary endpoint:

• Progression free survival (PFS1) of first line treatment Randomized part with marker-driven switch of antiangiogenic agent and maintenance of chemotherapy.

Primary endpoint:

• PFS rate at 6 months (PFSR@6) after first cycle after randomization

Randomized part with marker-driven switch of anti-angiogenic treatment

Hubertus-Wald-Cancer Center Hamburg, Germany

Sanofi

Assign Data Management and Biostatistics GmbH

University of Ulm

Prof. Dr. Thomas Seufferlein

Carcinoma

Carcinoma, Hepatocellular

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Liver Neoplasms

Liver Diseases

Doxorubicin

Liposomal doxorubicin

Chlorotrianisene

Sorafenib

Ethiodized Oil

Bilirubin

Protein Kinase Inhibitors

Enzyme Inhibitors

all patients will be treated with sorafenib

All patients will receive Sorafenib (800 mg/day) p.o. beginning two weeks before the first TACE and every day thereafter until patient death or premature withdrawal from study.

TACE will be carried out with doxorubicin (75 - 50 - 25 mg/m2, depending on serum bilirubin levels ≤ 1.5, 1.5 - 3, 3 - 5 mg/dL) : lipiodol (1:1) in a total volume of 20 mL; after administration of doxorubicin:lipiodol, additional embolisation will be carried out with bead block-endospheres. TACE will be repeated every 4 weeks for 3 cycles; additional cycles will be offered if clinically indicated (but no PEI or RF-ablation should be carried out after inclusion into the study)

Transarterial chemoembolisation (TACE)

Markus Peck-Radosavljevic, Prof. Dr.

Hepatocellular carcinoma (HCC) as the third most common cause of cancer-related death has a very poor prognosis. Aim of this open label single arm non randomized pilot trial is the evaluation of the efficacy and safety of sorafenib in combination with TACE in patients with unresectable HCC. Efficacy ad safety will be compared with a historical TACE-only group of a placebo controlled TACE-trial.

Hepatocellular carcinoma (HCC) as the third most common cause of cancer-related death has a very poor prognosis.

Aim 1: Efficacy of Sorafenib in combination with TACE TACE is an established therapy for patients with unresectable HCC and has been shown to significantly improve survival in these patients compared to no treatment. Quite often after cutting off the blood supply through the hepatic artery, the tumor induces active angiogenesis to promote collateral blood vessel growth from liver capsule arteries or collaterals from the gastroduodenal artery leading to tumor recovery and proliferation. Inhibition of this neoangiogenetic and proliferation activity after TACE by the multikinase inhibitor Sorafenib, already approved for HCC, could lead to significantly improvement in tumor control and survival in patients with advanced stage HCC.Safety will be compared with a historical TACE-only group of a placebo controlled TACE-trial.

Aim 2: Safety of Sorafenib in combination with TACE:

So far there are no reports about the safety of Sorafenib in combination with TACE. Here we evaluate the safety and tolerability of this combination until 12 weeks after the last TACE.

Aim 3: PPG-Measurement:

Development of portal hypertension in cirrhosis occurs due to two main pathophysiologic mechanisms: the increase in resistance to portal blood flow resulting from increased intrahepatic resistance and the decreased arteriolar vascular tone in the splanchnic vascular bed leading to increased splanchnic inflow of blood. Very recently, it has been shown that increased splanchnic inflow does not only result from arteriolar vasodilation due to excess NO-production in the splanchnic vascular bed but also from an increase in neoangiogenesis in the splanchnic circulation. Increased neovessel formation occurred within a few days of onset of portal hypertension both in a cirrhotic and an extrahepatic murine model of portal hypertension. Neoangiogenesis was effectively inhibited by either an antibody against VEGF-R2 or an inhibitor of VEGF-R2 autophosphorylation, resulting in a reduction of splanchnic blood flow.

Most recently, a combination of a VEGF and a PDGF blocker further decreased portal pressure in an experimental preclinical model.

As Sorafenib is a VEGF and PDGF blocker, we aim to analyze the influence of Sorafenib on portal hypertension and systemic and hepatic hemodynamics.

Aim 4: Biomarkers for treatment response:

Furthermore, we aim to analyze methylated tumor DNA in serum of patients with HCC undergoing Sorafenib treatment and TACE as possible marker of treatment response.

Sorafenib and Transarterial Chemoembolization for Hepatocellular Carcinoma

Sorafenib as Inhibitor of Collateral Tumor Vessel Growth During Transarterial Chemoembolisation (TACE) for Hepatocellular Carcinoma (HCC)- a Pilot Trial to Evaluate Safety and Biological Response

Medical University of Vienna

Univ. Prof. Dr. Markus Peck-Radosavljevic

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
PERMAD: Personalized Marker-driven Early Switch to Aflibercept in Patients With Metastatic Colorectal Cancer	NCT02331927	Metastatic Colo...	Aflibercept	18 Years -	University of Ulm
Sorafenib and Transarterial Chemoembolization for Hepatocellular Carcinoma	NCT00768937	Hepatocellular ...	Sorafenib Transarterial c...	18 Years -	Medical University of Vienna

Spots Global Cancer Trial Database for angiogenic factors