Neoplasms

All Conditions

Symptoms and General Pathology

Carcinoma

Carcinoma, Squamous Cell

Recurrence

Head and Neck Neoplasms

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Antineoplastic Agents

All Drugs and Chemicals

Lenvatinib

Cetuximab

Antineoplastic Agents, Immunological

Protein Kinase Inhibitors

Enzyme Inhibitors

A 3+3 dose de-escalation design for three dose levels of lenvatinib combined with cetuximab will be used. A DLT will be defined as any toxicities of grade 3 or higher (per CTCAE v4 criteria) felt to be possibly, probably, or definitely related to lenvatinib, as well as grade 4 toxcities related to cetuximab, which occurs within 28 days following the first dose of lenvatinib in combination with cetuximab.

Lenvatinib Pill

Lara Dunn, MD

This is a phase I study, which tests the safety of different doses of lenvatinib in combination with cetuximab, to see which dose is the safest in people. This study will help find out if lenvatinib and cetuximab is a safe and useful combination for treating patients with HNSCC and cSCC.

Testing Lenvatinib and Cetuximab in Patients With Advanced Head and Neck Squamous Cell Carcinoma and Cutaneous Squamous Cell Carcinoma

A Phase I/Ib Study of Lenvatinib and Cetuximab in Patients With Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma and Cutaneous Squamous Cell Carcinoma

Memorial Sloan Kettering Cancer Center

Digestive System Diseases

Heart and Blood Diseases

Carcinoma, Hepatocellular

Thrombosis

Embolism

Embolism and Thrombosis

Vascular Diseases

Adenocarcinoma

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Chlorotrianisene

Sorafenib

Estrogens

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Patients in Lenvatinib + TACE group will take oral lenvatinib within one day of randomization and receive TACE 1 day after oral administration of lenvatinib.

Patients in Sorafenib + TACE group will take oral sorafenib within one day of randomization and receive TACE 1 day after oral administration of lenvatinib.

Lenvatinib capsules will be administered orally, once daily in continuous 28-day cycles. Body weight (BW)\>60 kilograms(kg)-Lenvatinib 12 mg (taken as three 4-mg capsules); BW\<60kg-Lenvatinib 8 mg (taken as two 4-mg capsules)

TACE will be performed one day after oral administration of lenvatinib . TACE with either cTACE or DEB-TACE can be used, depending on the condition of center.

Transarterial chemoembolization(TACE)

Sorafenib capsules will be administered orally, 400 mg twice daily (BID) oral dosing.

TACE will be performed one day after oral administration of Sorafenib. TACE with either cTACE or DEB-TACE can be used, depending on the condition of center.

Hepatocellular carcinoma (HCC) is the fourth most common cancer in China, with a crude incidence rate of 26.67 per 100,000 population. Moreover, 357,800 new liver cancer cases are predicted to be diagnosed in China in 2020. HCC represents approximately 90% of all cases of primary liver cancer. HCC has a high predilection for portal vein invasion, which occurs in 44-62% of living patients with HCC. Patients with PVTT usually have an aggressive disease course, decreased liver function reserve, limited treatment options, thus worse overall survival. Among untreated HCC patients with PVTT, the median overall survival has been reported as low as 2 to 4 months with supportive care. Sorafenib is the first-line treatment for HCC patients with PVTT, however, it has shown unsatisfactory benefit. Notably, sorafenib combined with TACE significantly improved the TTP over sorafenib alone, albeit for no more than 1 month in the median TTP, and the median OS was not significantly prolonged. A promising drug-lenvatinib was approved in China on September 2018, in the China patients subgroup analysis showed an encouraging results. Lenvatinib group had showed a significant benefit in TTP, PFS and ORR. Also median overall survival time was significantly improved in China subgroup (Lenvatinib group: 15 months VS Sorafenib group: 10.2 months). However, REFLECT didn't enrolled patients who had tumors invading the maint portal vein. The mechanisms of lenvatinib or sorafenib combined with TACE were still unknown, and clinical data were limited.

This study was to explore lenvatinib plus TACE versus sorafenib plus TACE for HCC with PVTT: efficacy and safety. Biomarkers expression of VEGFR, FGFR, FDGF-α, IL-2,etc would be detected to find the difference between the two groups, finally to analyze the relationship between clinical outcomes and biomarkers' expression. A better treatment modality to HCC with PVTT patients would be expected and promoted.

Hepatocellular carcinoma (HCC) is the fourth most common cancer in China, with a crude incidence rate of 26.67 per 100,000 population. Moreover, 357,800 new liver cancer cases are predicted to be diagnosed in China in 2020, and HCC is by far the most common subtype of primary liver cancer and is the second most frequent cause of cancer-related death in the country. Approximately 80% of liver cancers are attributed to chronic infection with hepatitis B virus (HBV) and hepatitis C virus; other factors, including diabetes mellitus, non-alcoholic fatty liver disease, alcohol consumption, and tobacco use, have also been found to be potential risk factors for liver cancer HCC has a high predilection for portal vein invasion, which occurs in 44-62% of living patients with HCC. Portal vein tumour thrombosis (PVTT) usually portends a worse prognosis, with a median survival time of only 2.7-4.0 months in untreated patients. Despite advancements in understanding the molecular aetiology of HCC, the outcomes for patients with this disease who develop PVTT remain unsatisfactory.

Several treatment strategies for patients with inoperable HCC who developed PVTT have been attempted, including first-line targeted therapy with sorafenib, transarterial chemoembolisation (TACE), TACE plus sorafenib, percutaneous radiofrequency ablation (RFA), and radiotherapy. However, the prognosis of patients with HCC who are complicated by PVTT remains poor, and the optimal treatment modality for such patients has not been established to date.

Notably, sorafenib combined with TACE significantly improved the TTP over sorafenib alone, albeit for no more than 1 month; the median TTP was less than 3 months, and the median OS was not significantly prolonged.

In the recent phase III global multicentre REFLECT study, lenvatinib, the only other available first-line anti-angiogenic drug, did not improve overall survival (OS). However, lenvatinib as an oral multikinase inhibitor that targets VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET and KIT, median time of PFS was 8.9 months (95% CI 7.4-9.2) for patients in the lenvatinib group compared to 3.7 months (95% CI 3.6-5.4) for patients in the sorafenib group. Lenvatinib also showed a greater objective response rate (ORR) than did sorafenib group. ORR was 40.6% (95% CI 36.2-45.0) for patients in the lenvatinib group compared to 12.4% (95% CI 9.4-15.4) for patients in the sorafenib group, and TTP was 7.4 (95% CI 7.2-9.1) VS 3.7 (95% CI 3.6-3.9). What's more, in the Chinese patients subgroup analysis showed an encouraging results, lenvatinib group not only showed significant improvement in PFS, TTP, ORR, but also in median OS time ( Lenvatinib group: 15 months VS sorafenib group 10.2 months). However, REFLECT didn't enrolled patients who had tumors invading the maint portal vein.

However, the mechanism of sorafenib combined with TACE was unknown, and clinical data of TACE plus lenvatinib for HCC had not been reported until now. As our preliminary experimental results showed that lenvatinib combined with TACE show a 91.7% clinical benefit in 11 cases HCC with PVTT (7 PR cases, 4 SD cases) , the median TTP was 6.5 months, during the preliminary experimental trail hadn't observed any fatal adverse event occurred.

In addition to these supporting data, lenvatinib plus TACE showed a potential benefit to HCC with PVTT patients. This study was to explore lenvatinib plus TACE versus sorafenib plus TACE for HCC with PVTT: efficacy and safety. Biomarkers expression of VEGFR, FGFR, PDGF-α, IL-2,etc would be detected to find the difference between the two groups, finally to analyze the relationship between clinical outcomes and biomarkers' expression.

Lenvatinib Plus TACE Versus Sorafenib Plus TACE for HCC With PVTT

Exploring Lenvatinib Plus TACE Versus Sorafenib Plus TACE for Hepatocellular Carcinoma Patients With Portal Vein Tumor Thrombus: Efficacy, Safety and Outcome Analysis

The primary endpoint was TTP (defined as the date of randomization until progression).

Treatment response was evaluated according to mRECIST combined with contrast-enhanced dynamic CT or magnetic resonance imaging.

ORR defined as the rate of patients with complete response or partial response according to mRECIST.

OS defined as the date of randomization to death from any cause.

AEs(adverse events) evaluated by the CTC-AE 5.0.

Beijing Ditan Hospital

Chief of Oncology

Tin Fluorides

Neoadjuvant therapy with lenvatinib to complete a 3-week course, stopping 1 week before the planned date of PA procedure " LENVABLA " protocol, version 1.3 du 25/05/2021 12/55

- Adjuvant therapy with lenvatinib for 3 months starting after the PA evaluation (± 14 days) The daily dose of lenvatinib will be 12 mg (≥60 kg) or 8 mg (\<60 kg). Lenvatinib will be taken within 2 hours after a light meal, preferably in the morning.

The design of study is summarized as follows:

* Neoadjuvant phase with lenvatinib for 21 days (rationale: compromise between expected benefit and acceptable tolerance without compromising ablation procedure)
* PA of HCC in a curative intent (radiofrequency, microwave or electroporation)
* Adjuvant phase with lenvatinib for 3 months (rationale: compromise between expected benefit and acceptable tolerance without compromising ablation procedure)

Pierre NAHON, MD-PhD

Percutaneous ablation (PA) is the only non-surgical curative treatment of hepatocellular carcinoma (HCC). Due to its excellent tolerance, particularly in patients with portal hypertension or bearing comorbidities, it now represents in France nearly 70% of the first-line curative treatment of "in Milan" tumours. For HCC less than 3 cm, ideal indication for percutaneous ablations, results of monopolar radiofrequency ablation (mRFA), are excellent with only 5% of reported non-tumoral control after a first procedure. In addition to mRFA the arsenal of ablations has grown considerably with the emergence of new techniques which allow the expansion of indications for PA, especially in patients with poor prognostic tumors or relatively advanced beyond the Milan criteria. In this setting, multibipolar mode using no touch technique (mbpRFAnt) increases the tumour volume than can be ablated, allowing the removal of large tumors\> 5 cm. Inadequate tumour control is then de facto greater in these situations, around 20%. Difficult-to-access tumors can furthermore be treated by percutaneous irreversible electrotroporation (IRE).

Despite a tumor burden accessible for curative ablation, a phenotype of "aggressive" HCC characterized by high rates of local recurrences is yet to be defined. Up to now, several characteristics might define this subtype with a poor-prognosis and include 1) high serum alpha-foetoprotein (AFP) levels, 2) radiological infiltrative form, and 3) histological macrotrabecular subtype. Based on these characteristics, median recurrence-free survival of these patients is usually below 10 months.

High serum AFP level is a well-known predictor of HCC recurrence following curative procedure. In patients treated by percutaneous ablation, regardless of the technique used and irrespective of tumor burden, high baseline serum AFP level has tenaciously been reported as an independent predictor or recurrence..

More recently, the radiological description of infiltrative HCC (as opposed to mass-forming) has been identified as an aggressive from of HCC with a poor prognosis even when eligible for ablation. This aspect is often associated with infra-clinical invasion of the portal veins (PV), leading to poor prognosis. Finally, a "massive macrotrabecular" (MTM) histological subtype of HCC associated with specific molecular features has recently been described. This MTM-HCC subtype, reliably observed in 12% of patients eligible for curative treatment, represents an aggressive form of HCC is an independent predictor of early and overall recurrence following PA, which is retained even after patient stratification according to common clinical, biological, and pathological features of aggressiveness.

The idea of optimizing HCC curative treatments using adjuvant biotherapy, particularly in patients with poor-prognosis tumors in curative intent, is particularly attractive. One trial in adjuvant setting was conducted, the STORM trial, that tested the benefit of sorafenib in curative intent of in Milan HCC. This negative trial included patients within Milan HCC, with an expected low rate of recurrence with only few patients treated by PA.

Lenvatinib is a multikinase inhibitor which has been recently approved as firs-line therapy for advanced HCC. The investigators assume that lenvatinib could have also a synergistic local action with PA in two ways. First, given as neoadjuvant regimen, lenvatinib by reducing tumor and liver perfusion could decrease the global heat sink effect associated with loco-regional blood microcirculation during PA. Second, by carrying on in adjuvant treatment, lenvatinib could decrease the magnitude of non-specific inflammatory angiogenesis around the treatment zone, therefore reducing the risk of locoregional (intrasegmental) cells tumor spreading or promotion.

Given the dismall prognosis of the aforementioned poor-prognosis HCC eligible for PA with an overall median recurrence-free survival below 10 months, the investigators hypothesis is that addition of Lenvatinib as neo- and adjuvant therapy might increase tumour control in these difficult-to-treat patients. Patients combining either high serum AFP levels, infiltrative form or MTM-HCC histological subtype represent 30% of BCLC A stage HCC patients in expert centers, and are the ideal candidates for such trials.

Therefore, the first aim of this proposal is to assess the benefit of lenvatinib in neo- and adjuvant setting combined with curative percutaneous ablation for BCLC A HCC patients considered at high risk of local recurrence (high AFP or infiltrative form or macrotrabecular massive subtype).

Multicenter, 19 hepatology or hepatoGastroenterology and radiology departments in 11 French hospitals (inclusion of patients in 10 centers).

A pilot interventional, prospective, multicenter study.

The design of study is summarized as follows:

* Neoadjuvant phase with lenvatinib for 21 days (rationale: compromise between expected benefit and acceptable tolerance without compromising ablation procedure)
* PA of HCC in a curative intent (radiofrequency, microwave or electroporation)
* Adjuvant phase with lenvatinib for 3 months (rationale: compromise between expected benefit and acceptable tolerance without compromising ablation procedure) Lenvatinib doses will be adapted according to SmPC.

Constitution of a biobank with :

* paraffin and frozen tumoral and non tumoral biopsy sampled at before and after one month of neoadjuvant lenvatinib (second biopsies at the time of the PA procedure)
* Serum, plasma samples before the neoadjuvant lenvatinib, before PA procedure, at 1,3 months of the adjuvant lenvatinib and at month 6.

Neoadjuvant and Adjuvant Lenvatinib in HCC Patients Treated by Percutaneous Ablative

Lenvatinib in Neo-adjuvant and Adjuvant Therapy for Poor-prognosis BCLC A HepatoCellular Carcinoma Treated by Percutaneous Ablation Procedure in a Curative Intent: Multicentre Pilot Therapeutic Trial

patients will meet this endpoint if they are alive with or without HCC recurrenceat 1and 2 years after EP. procedures. Causes and date of death will be specified when applicable during this timeframe.

Adverse events related : fatigue, arterial hypertension, hand-foot skin syndrome to Lenvatinib will be monitored according to manufacturer guidelines and recommendation

Absence of tumour cells (binary scale :0/1)

Assessment of intra and extra tumoral inflammatory infiltrate (semi quantitative scale: 0=non, 1=mild, 2=intense)

change in gene expression following sequential whole exome sequencing (binary scale 0/1 with clustering analyses)

Accounting for treatment returns. checking respect of scheduled lenvatinib administered

Consittution of a sequential biobank comprising liver tissue : histological outcome

Consittution of a sequential biobank comprising liver tissue : histological

Changes in PIGF (UI/mL), VEGF-A (UI/mL), VEGF-C (UI/mL), sVEGFR2 (UI/mL), sVEGFR3 (UI/mL), MET (UI/mL), sKIT (UI/mL), Ang2 (UI/mL), AFP (UI/mL), PIVKA (UI/mL) (changes expressed by median comparison)

Recurrence rate local will be assessed using imaging techniques as recommended by international guidelines (3-months US and MRI during two years). Patients who will meet primary endpoint will be alive 1 year afterPA procedure without evidence of local recurrence on 3-months US/MRI evaluations.

Evaluation performed by MRI : Assessment of complete response versus incomplete response (persistence of active tumour).

Evaluation performed by MRI

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Testing Lenvatinib and Cetuximab in Patients With Advanced Head and Neck Squamous Cell Carcinoma and Cutaneous Squamous Cell Carcinoma	NCT03524326	Head and Neck S... Cutaneous Squam... Head and Neck C... Head and Neck C...	Lenvatinib Pill Lenvatinib Pill Lenvatinib Pill Cetuximab Lenvatinib Pill Lenvatinib Pill	-	Memorial Sloan Kettering Cancer Center
Lenvatinib Plus TACE Versus Sorafenib Plus TACE for HCC With PVTT	NCT04127396	Carcinoma, Hepa... Portal Vein Tum...	Lenvatinib Pill Transarterial c... Sorafenib Transarterial c...	18 Years - 75 Years	Beijing Ditan Hospital
Lenvatinib Plus TACE Versus Sorafenib Plus TACE for HCC With PVTT	NCT04127396	Carcinoma, Hepa... Portal Vein Tum...	Lenvatinib Pill Transarterial c... Sorafenib Transarterial c...	18 Years - 75 Years	Beijing Ditan Hospital
Neoadjuvant and Adjuvant Lenvatinib in HCC Patients Treated by Percutaneous Ablative	NCT05113186	Hepatocellular ...	Lenvatinib Pill	18 Years - 99 Years	Assistance Publique - Hôpitaux de Paris
Neoadjuvant and Adjuvant Lenvatinib in HCC Patients Treated by Percutaneous Ablative	NCT05113186	Hepatocellular ...	Lenvatinib Pill	18 Years - 99 Years	Assistance Publique - Hôpitaux de Paris

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