Neoplasms

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Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Recurrence

Carcinoma, Renal Cell

Kidney Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Adenocarcinoma

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Axitinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Axitinib will be given orally and will continue until progression of disease.

Axitinib 5 mg orally with food every 12 hours. One cycle=28 days.

Stephen Keefe, MD

The purpose of this study is to see how well the study drug, axitinib, helps control renal (kidney) cancer that has come back (recurrent) or spread (metastatic). Patients must have already been treated as a participant in a clinical trial with sunitinib, sorafenib, pazopanib or placebo (sugar pill) after their initial surgery.

This study will examine the effect of adjuvant tyrosine kinase inhibition (TKI) therapy (sorafenib, sunitinib or pazopanib) on subsequent exposure to TKI with axitinib in the first-line recurrent or metastatic setting.

Approximately 64,770 cases of cancer involving the kidney and renal pelvis were diagnosed in the United States in 2012 and 13,570 deaths occurred from these tumors. The rate of Renal Cell Carcinoma (RCC) has increased by 2% per year for the past 65 years. The reason for this increase in unknown but smoking and obesity are risk factors for the development of RCC. Early stage disease is typically treated with resection with definitive intent with partial or radical nephrectomy. Patients with metastatic disease are often treated with systemic therapy with palliative intent. Systemic therapeutic options include so-called targeted therapies, and less often chemotherapy and immunomodulatory therapies (interferon alpha and interleukin-2).

The Food and Drug Administration (FDA) has approved six targeted agents for the treatment of advanced and metastatic renal cell carcinoma that fall into two general classes - vascular endothelial growth factor (VEGF) inhibitors and inhibitors of mammalian target of rapamycin (mTOR). On the basis of several randomized phase III studies, vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor therapy has become the generally preferred treatment for recurrent and metastatic ccRCC (clear cell Renal Cell Carcinoma) in the first-line setting. Treatment of ccRCC with VEGF-inhibition in the first-line metastatic setting, is associated with a progression-free survival of approximately 11 months. Vascular endothelial growth factor (VEGF) inhibitor therapy in the second-line remains active, but to a lesser degree - progression-free survival (PFS) has been reported to be between 5 and 7 months.

Adjuvant treatment of high-risk, early-stage ccRCC with VEGFR2 TKI therapy following definitive resection has become an area of active investigation. The ASSURE trial (ECOG 2805) recently completed accrual, and other adjuvant trials - i.) SORCE (sorafenib for 3 or 1 year versus placebo), ii.) S-Trac (sunitinib versus placebo) - are in accrual.

Axitinib (AG-013736, Pfizer Inc.), a receptor-tyrosine kinase inhibitor that is selective for VEGFR1, 2, and 3, is an important new agent for use in metastatic RCC. Axitinib has been examined extensively in RCC, and it has been shown to be safe, well-tolerated, and highly active. On January 27, 2012, the FDA approved axitinib for the treatment of advanced RCC after failure of one prior systemic therapy.

NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma

NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition (TKI) at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma (RCC)

Progression-free survival is defined as the time from registration to disease progression or death, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Best overall response was evaluated using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v 1.0). Response is defined as complete response or partial response.

Complete Response (CR): disappearance of all target lesions Partial Response (PR): \>=30% decrease in the sum of the longest diameter of target lesions

To bank biospecimens for the retrospective determination of whether baseline or changes in cytokine levels of IL-8 and VEGF-A predict response to treatment in this setting. Banking of plasma and serum is optional but strongly encouraged.

Note: The assays to assess cytokine levels of IL-8 and VEGF-A were not performed because the study stopped early and only 3 patients were enrolled. Therefore, the analysis to evaluate the associations between response and IL-8 as well as VEGF-A was not done.

To bank biospecimens for the retrospective determination of whether baseline single nucleotide polymorphisms (SNPs) in angiogenesis-related genes predict response to treatment (candidate gene approach). Banking of PBMC is optional but strongly encouraged.

Note: The SNP genotyping analysis was not performed because the study stopped early and only 3 patients were enrolled. Therefore, the analysis to evaluate the association between baseline SNPs in angiogenesis-related genes and response was not be done.

To bank tumor tissue (formalin-fixed, paraffin-embedded tumor blocks) for retrospective examination of the molecular pathophysiologic mediators of tumorigenesis and progression such as phospho-protein expression of MAPK signaling network intermediates in endothelial cells. Banking of tumor tissue is optional but strongly encouraged.

Note: None of the 3 patients submitted tumor tissues so the analysis won't be performed.

Pfizer

PrECOG, LLC.

Adverse events were routinely assessed by the treating clinician according to the schedule above.

Axitinib will be given orally and will continue until progression of disease.

Axitinib: Axitinib 5 mg orally with food every 12 hours. One cycle=28 days.

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

PrECOG Statistician

Progression-free Survival

Overall Response Rate

Only 3 patients were enrolled. Analysis to evaluate the associations between response and IL-8 as well as VEGF-A was not done.

Biospecimen Banking for IL-8 and VEGF-A

Only 3 patients were enrolled. Analysis to evaluate the association between baseline SNPs in angiogenesis-related genes and response was not be done.

Biospecimen Banking for SNPs Analysis

None of the 3 patients submitted tumor tissues so the analysis was unable to be performed.

Tumor Tissue Banking

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Adenocarcinoma, Bronchiolo-Alveolar

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Adenocarcinoma of Lung

Lung Adenocarcinoma

Erlotinib Hydrochloride

Erlotinib

Jacques De Grève, MD PhD

Nicolas Fontaine, Mr

Current chemotherapy for advanced non-small cell lung cancer, not amenable for curative local treatment (surgery or chemoradiotherapy), has a modest life-prolonging effect and can improve quality of life. There is however no potential for long-term cure for these patients.

Chemotherapy also produces variable and often significant toxicity. Current retrospective evidence suggests that significant clinical responses can be obtained when patients whose cancer cells have an EGFR TKD mutation are treated with an EGFR TKI.

The ease of administration and toxicity profile of TKI compare favourably with that of chemotherapy, even single agents such as for example gemcitabine The present study will establish the clinical benefit rate of TKI as a first line treatment in patients with EGFR mutations and thus estimate the proportion of patients who might benefit for a prolonged period from a treatment with a modest toxicity profile.

Patients with stage IV NSCLC and some patients with advanced locoregional disease (stage III) are in general incurable and have a low probability for long-term survival.

Current systemic treatment in good PS patients (PS 0-1) consists of a cisplatin doublet (e.g. cisplatin plus a second drug: vinorelbine, gemcitabine, paclitaxel, docetaxel). The median and one year survival obtained with this treatment ranges between 8-10 months and 25 - 35 % respectively (1,2). Progression-free survival is a median of 5 month or less in randomized studies (3). Response rates obtained are less than 25% in metastatic disease and up to 75% in advanced locoregional disease.

Receptor tyrosine kinase inhibitors (RTKI's) are active drugs in patients with NSCLC pre-treated with cisplatin and/or docetaxel containing chemotherapy (2,4). Recently it has been shown that the EGFR1 kinase inhibitor erlotinib added to best supportive care (BSC) prolonged survival compared to BSC alone in patients with advanced NSCLC failing 1st or 2nd line chemotherapy (5).

A small number of preliminary reports have indicated that the objective response rate with these RTKI's as first line treatment in some patient populations with advanced NSCLC could be around 20 % (6), The objective (mainly partial) response in the phase II studies with pre-treated patients ranges from 10 - 15 % according to the level of pre-treatment but the control of the disease (stable disease) and improvement of symptoms without demonstrated objective response has been reported to be as high as 40 to 50 % (2,4). The addition of RTKI's or placebo to the current standard doublets (e.g. cisplatin, gemcitabine or taxol/carboplatin) has not been shown to impact on response rate, time to treatment failure or survival in large phase III randomised trials in advanced NSCLC patients not selected for EGFR expression (7,8).

Recently, mutations in the intracellular EGFR kinase domain that increase sensitivity of the receptor to RTKI's have been discovered (9,10). These studies suggest that the response/resistance to treatment could be strongly correlated to the presence/absence of such mutations. It is presently unclear whether patients who achieve stable disease under RTKI treatment do have receptor mutations, of which nature such mutations could be or what other biological pathways modulate the responsiveness/resistance.

Mutations have been observed in about 10 % or less of the tumours examined. Most mutations in the EGFR kinase domain have been found in adenocarcinoma of non-smokers or minimal smokers.

Recent data have established that an EGFR mutation can be found in 30% of adenocarcinoma of the lung if the smoking history is maximally 15 years. The probability of finding a mutation is approximately 50% in never-smokers with adenocarcinoma (11).

In contrast to the rather low objective response rate, the clinical benefit rate of treatment with RTKI is around 40 % in a general population of non-small lung cancer (9,10), more than can be accounted for by mutational analysis. EGFR gene amplification might be another determinant for sensitivity, but the biological factors leading to disease stabilisation in some patients with non-activated EGFR are presently unknown.

Several humanized monoclonal antibodies (huMoAb) that can inhibit the EGFR-1 receptor have been developed as well. Of these, cetuximab (ErbituxÒ) has been developed most extensively, especially in head and neck (12) and colorectal cancer (13,14), but other, fully humanized antibodies (huMoAb) (ABX-EGF, EMD 72000) are under development.

Cetuximab has been assessed in NSCLC, especially in combination with first-line and second-line chemotherapy (15), but no data are currently available with respect to single agent activity.

The two types of currently available drugs targeting the EGFR-1, the RTKI's such as gefitinib and erlotinib and huMoAb such as cetuximab and ABX-EGF, are generally well tolerated and devoid of significant grade 3-4 toxicity.

While there are strong indications that the major responses obtained with RTKI's could strongly correlate with the presence of tyrosine kinase domain mutations in addition to the known mechanism of action of these drugs (16,17), this is at present yet not so clear for the monoclonal antibodies directed against the extracellular domain of the receptor.

Some recent data suggest that EGFR gene amplification might also correlate with response to TKI (18).

Patients with Stage IV and some advanced stage III NSCLC are at present incurable and first-line chemotherapy has had only a palliative and a life prolonging effect at a cost of variable toxicity.

On the other hand the response rate to TKI in patients with a NSCLC carrying a mutant receptor is probably high as can be inferred from the comparison of the prevalence of such mutations and the response rate to these agents in an unselected population (16).

It seems therefore reasonable to explore in a first-line setting the potential of EGFR-1 targeted therapy, as these drugs have a very favourable toxicity profile and might induce prolonged palliation.

There are currently no data that would suggest that delaying chemotherapy in this patient population in well controlled conditions and for a limited time period (sufficient to evaluate the efficacy of more novel first-line treatments) might affect the efficacy of subsequent chemotherapy. There are also no data that suggest that prior administration of drugs targeted at the EGFR-1 will induce resistance to subsequent chemotherapy. The distinct respective mechanisms of action of these drugs and chemotherapy also do not suggest this to be likely.

In other diseases such as prostate cancer and oestrogen receptor-positive breast cancer, the availability of hormonal treatments permits prolonged and at times long-term disease control with limited discomfort. It is possible that a similar scenario could be obtained with an anti-EGFR treatment in NSCLC carrying a mutant EGFR.

Therefore it seems justified to expand previous second-line phase II experience with anti-EGFR strategies to patients with incurable stage III-IV NSCLC without prior therapy and a mutant EGFR. The informed consent towards these patients before entry in the study will clearly state that until now the first-line standard of care has been chemotherapy, which leads to a small overall survival benefit compared to the supportive treatment only and that participation in the current study will delay this treatment within a tightly controlled setting.

In the current trial the RTKI erlotinib will be used. Prior experience with this drug has been obtained in phase II and III studies. In the phase II setting, in an unselected pretreated population, a response rate of 12.3% and a median survival of 8.4 months could be obtained (19). In phase III, placebo-controlled studies, combination of erlotinib with concurrent chemotherapy does not provide a survival advantage (gemcitabine and cisplatin in TALENT (20) and paclitaxel and carboplatin in TRIBUTE (21). Several hypotheses can explain these results: lack of selection of patients; antagonism between cytostatic and cytotoxic agents (negative interaction with chemotherapy when given concurrently); chemotherapy and EGFR inhibitors target the same cell population since chemotherapy directly or indirectly affects EGFR function/expression and thereby reducing the effects of EGFR inhibitors. These results are in contrast to the significant survival benefit seen in the phase III randomized placebo-controlled study in NSCLC following failure of 1st or 2nd line chemotherapy (BR21). The response rate was 9% in the erlotinib treated patients, with significant increase in progression free survival (from 8 to 9,7 wks) and increased survival (from 4.7 mth to 6.7 mth, p\< 0.001). In that study the biological parameters that correlate with response (mutation status, EGFR gene amplification and EGFR immunohistochemistry) are still under study.

Survival benefit correlated best with the presence of EGFR expression by immunohistochemistry and EGFR gene polysomy (22).

First-Line EGFR-1 Tyrosine Kinase Inhibition in Patients With NSCLC With Mutant EGFR Gene

Prospective Evaluation of Small Molecule EGFR-1 Tyrosine Kinase Inhibition as a First-Line Treatment in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Harbouring a Mutant EGFR Gene

Hoffmann-La Roche

AZ-VUB

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma	NCT01649180	Renal Cell Carc...	Axitinib	18 Years -	PrECOG, LLC.
First-Line EGFR-1 Tyrosine Kinase Inhibition in Patients With NSCLC With Mutant EGFR Gene	NCT00339586	Lung Neoplasms Non-Small Cell ... Adenocarcinoma,...	Erlotinib	18 Years -	AZ-VUB
First-Line EGFR-1 Tyrosine Kinase Inhibition in Patients With NSCLC With Mutant EGFR Gene	NCT00339586	Lung Neoplasms Non-Small Cell ... Adenocarcinoma,...	Erlotinib	18 Years -	AZ-VUB

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