Neoplasms

All Conditions

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

Anti-Infective Agents

Everolimus

Sorafenib

Sirolimus

Temsirolimus

MTOR Inhibitors

Immunosuppressive Agents

Immunologic Factors

To establish the maximally tolerated dose (MTD) of RAD001 in combination with Nexavar®

RAD001 will be administered orally once a day, daily, without interruption per 4 wk cycle for 2 cycles. MTD is established in Phase I portion of trial (2.5, 5 or 10mg). If responding, additional therapy will be given.

RAD001

A dose of 400mg of Nexavar® will be administered orally twice a day, daily, without an interruption per 4 week cycle for 2 cycles. If responding, additional therapy will be given.

Robert J Amato, DO

The purpose of this study is to see whether the combination for RAD001 and Nexavar® works better when given together than they do alone. The purpose of the first phase of this study is to determine the best dose of RAD001 given with Nexavar®, and to see what effects, good and/or bad, the study drug has on the subject and the subject's tumor. This study will also observe side effects experienced by the subject.

Despite significant progress in understanding the biology of renal cell carcinoma (RCC), it is estimated that over 35, 000 people in the United States will be diagnosed and approximately 12, 000 have died from this disease in 2005. Renal cell carcinoma presently ranks tenth as the leading cause of cancer death and constitutes 3% of all solid neoplasms.

In contrast to many other malignancies, treatment for RCC is limited. Treatment remains a highly difficult and perplexing challenge due to its resistance to both chemotherapy and hormone therapy and limited response to cytokines. Despite recent advances in our fundamental knowledge of RCC biology and development of molecular therapeutics, more clinical research will be required to best guide our use of these exciting new agents in combination regimens.

The combination of RAD001 and Nexavar®, in current clinical trials with minimal toxicity, represents a treatment regimen which should be investigated for tolerance and toxicity as well as initial phase II efficacy. The study is designed to evaluate the MTD. Following the completion of the phase I, utilizing the MTD, Phase II study is designed to evaluate the anti-tumor activity.

Phase I/II Trial of RAD001 Plus Nexavar in Patients With Kidney Cancer

Phase I/II Trial of RAD001 Plus Nexavar® For Patients With Metastatic Renal Cell Carcinoma

Novartis Pharmaceuticals

The Methodist Hospital Research Institute

400 mg (2 tablets of 200 mg) of sorafenib per oral (PO) twice daily (BID)

Sorafenib (Nexavar, BAY43-9006)

Bayer Study Director

A multicenter uncontrolled study of sorafenib in patients with unresectable and/or metastatic renal cell carcinoma (RCC) to assess the pharmacokinetic profile, safety and tolerability, and efficacy.

Phase III Study of Sorafenib in Patients With Renal Cell Carcinoma (RCC)

A Multicenter Uncontrolled Study of Sorafenib in Patients With Unresectable and/or Metastatic Renal Cell Carcinoma

The AUC(0-12h) was the observed AUC, calculated using a combination of linear and log trapezoidal rules, from pre-dose to 12 hours post-dose. The normalized AUC (AUC norm) is AUC (0-12h) divided by (dose \[mg\]/weight \[kg\]).

Cmax (maximum concentration) was measured at the time point at which the maximum concentration (Tmax) was observed. Cmin (minimum concentration) was measured at the time point at which the minimum concentration (Tmin) was observed.

Cmax (maximum concentration) was measured at the time point at which the maximum concentration (Tmax) was observed. Cmin (minimum concentration) was measured at the time point at which the minimum concentration (Tmin) was observed. The normalized variables (Cmax norm and Cmin norm) are the variables (Cmax and Cmin, see Primary Outcome Measure 2) divided by \[dose (mg)/weight (kg)\].

Progression-free survival (PFS) was defined as the time from the date of receipt of first dose of study drug to disease progression, radiological or clinical, or death, whichever was earlier. Subjects still alive without tumor progression at the time of analysis were censored at their date of last tumor evaluation.

Overall survival (OS) was measured from the date of first dose of study drug until the date of death due to any cause. Survival time for subjects still alive at the time of analysis was censored at the date of last contact.

Time to progression (TTP) was defined as the time from date of receipt of first dose of study drug to disease progression, radiological or clinical. Subjects without tumor progression at the time of analysis were censored at their last date of tumor evaluation.

The DC was defined as subjects who had a best response rating of complete response (CR), partial response (PR), or stable disease (SD) according to Response Evaluation Criteria in Solid Tumors (RECIST) that was maintained for at least 28 days from the first demonstration of that rating. CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target). PR: at least a 30% decrease in the sum of longest diameters (LD) of target lesions taking as reference the baseline sum LD. SD: steady state of disease; do not qualify for PR or progressive disease (PD).

The best overall response was defined as the number of subjects with a confirmed CR, PR, SD, or PD. Tumor response was evaluated using RECIST. PD: at least a 20% increase in the sum of LD of measured lesions taking as ref. the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Appearance of new lesions will also constitute PD. In exceptional circumstances, unequivocal progression of a non-measured lesion may be accepted as evidence of disease progression.

Overall response duration was to be calculated for subjects who had a confirmed PR or CR, defined as the time from first assessment showing a PR or CR to progression or death.

Time to objective response was defined as the time from the date of receipt of first dose of study drug to first assessment showing a confirmed PR or CR.

Bayer

Acronyms used: Gastrointestinal (GI), Genitourinary (GU), Not Otherwise Specified (NOS), Absolute Neutrophil Count (ANC), Aspartate aminotransferase (AST), Partial Thromboplastin Time (PTT), Alanine aminotransferase (ALT), Common Terminology Criteria for Adverse Events (CTCAE)

Taiwan

China

ECOG 0

ECOG 1

Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale that measures how cancer affects a patient. The scale ranges from 0 (fully active) to 5 (dead). Subjects entering this study must have had an ECOG score of 0 or 1 (restricted in physically strenuous activity but ambulatory).

Eastern Cooperative Oncology Group (ECOG) Scale

Low-risk (no risk factors)

Intermediate-risk (1 or 2 risk factors)

The 5 Motzer risk factors correlate with overall survival in metastatic RCC. Patients with no factors (low-risk) have a favorable survival risk, patients with 1 or 2 risk factors survive a shorter time and constitute an intermediate-risk group, and those with 3 or more risk factors have the poorest survival and represent a poor-risk group.

Motzer risk factors

Clear cell

Predominantly clear cell

Patients were categorized into 1 or 2 subgroups depending on the tumor histology: Clear cell or predominantly clear cell.

Renal Cell Carcinoma subtype

Time since first progression was defined as the time from the first progression of the patient's disease after initial diagnosis until randomization into this study.

Time since first progression

Time since initial diagnosis was the mean time from initial diagnosis to randomization into the study.

Time since initial diagnosis

The median for ´Overall Survival (OS)´ and the median for ´Overall Response Duration´ reported are the median of each distribution including the censored data. The correct estimates of these medians were not evaluable.

Therapeutic Area Head

AUC (0-12h)

AUC norm

A full pharmacokinetics (PK) profile was obtained in 32 of the 39 patients after at least 21 days of uninterrupted twice daily (BID) dosing.

Pharmacokinetics Measured as Area Under Curve (AUC[0-12h])

Cmax

Cmin

A full PK profile was obtained in 32 of the 39 patients after at least 21 days of uninterrupted BID dosing.

Pharmacokinetics Measured as Concentration (Cmax at Tmax and Cmin at Tmin)

Cmax norm

Cmin norm

Pharmacokinetics Measured as Concentration (Cmax Normalized at Tmax and Cmin Normalized at Tmin)

All subjects who received at least 1 dose of drug (the intent to treat \[ITT\] population) were included in the analysis. Thirty-nine patients received at least 1 dose of drug.

Progression Free Survival (PFS)

Overall Survival (OS)

Time to Progression (TTP)

disease control

no disease control

not evaluated

Disease Control (DC)

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Overall Best Response

All subjects who received at least 1 dose of drug (the intent to treat \[ITT\] population) were included in the analysis. Thirty-nine patients received at least 1 dose of drug. The overall response duration was determined on the 5 subjects who had a PR.

Overall Response Duration

All subjects who received at least 1 dose of drug (the intent to treat \[ITT\] population) were included in the analysis. Thirty-nine patients received at least 1 dose of drug. Time to objective response was determined on the 5 subjects who had a PR.

Time to Objective Response

Behaviors and Mental Disorders

Digestive System Diseases

Depression

Depressive Disorder

Fatigue

Colorectal Neoplasms

Behavioral Symptoms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Quality of Life

Sunitinib

During the study three questionnaires must repeatedly be completed in by the patients: the BDI (PC) a depression scale, the EORTC-QLQ a quality of life assessment and the CIS20r, a fatigue scale and patients must fill in their medication on a list.

Questionnaires

C.M.L. van Herpen, MD, Phd

The purpose of this study is to assess the influence of Sunitinib and Sorafenib on fatigue, quality of life and depression in patients with metastatic renal cell or colorectal cancer or GIST. In order to get more insight in the mechanism of vascular endothelial growth factor (VEGF) related fatigue and if possible to come to a resolution for this side effect.

When cure is not longer possible, cancer patients enter the palliative phase. For many types of cancer several treatment options are available. The goal of this treatment is to prolong survival, but maintenance or even improvement of quality of life is of equal importance. The currently available systemic treatment options consist of conventional cytotoxic therapy, hormonal therapy, immunotherapy and the so-called targeted therapies. Combinations of these therapies are also being used. Targeted therapy concerns the application of a new class of drugs that are specifically directed against one or more well-defined molecular targets that are relevant for carcinogenesis, cell cycle regulation, tumour progression, metastasis, tumour angiogenesis and/or apoptosis. Today, the most successful drugs in this class are directed against the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). There is an explosive development ongoing in this field and many new drugs become available that have new targets or inhibit a combinations of targets. Meanwhile, targeted therapy has shown efficacy in many types of cancer and is registered for several indications.

The toxicity profile of targeted therapies is still largely unknown, and the aetiology of many known side effects has not been clarified. This implies that the effective treatment of side effects is in an early phase of development. Given the impact of side effects on the quality of life of a patient, increased knowledge on this topic is urgently required. Currently only a few systematic studies are available that address this issue. At the moment, three targeted therapies that are directed against VEGF are registered and used in the Netherlands: Sunitinib (Sutent®) and Sorafenib (Nexavar ®) both oral drugs and Bevacizumab (Avastin®), an intravenously drug.

In this study we will focus on fatigue, quality of life and depression in patients with metastatic cancer, treated with Sunitinib and Sorafenib. Fatigue is one of the most frequent side effects of targeted therapy that are directed against VEGF and that can have a huge influence on the quality of life. The incidence of fatigue in patients using Sunitinib in phase I studies was 70% and the fatigue was often dose limiting. (1-4) In phase II-III studies the incidence was 27% - 51%. 5,6 In a phase III randomized, double-blind placebo-controlled trial of Sorafenib the incidence of fatigue in the Sorafenib group was 37% and in the placebo group 28%. (7) It is possible that fatigue is a symptom of depression or anxiety, alternatively, prolonged fatigue in itself can lead to depression or anxiety.8 There has been found a significant and positive correlation between anxiety and depressive symptoms and fatigue after treatment for cancer.

Study on the Influence of Sunitinib and Sorafenib on Fatigue, QoL, Depression in Patients With Metastatic RCC or GIST

Study on the Influence of Sunitinib and Sorafenib on Fatigue, Quality of Life and Depression in Patients With Metastatic Renal Cell Cancer or GIST

Radboud University Medical Center

Vaccines

Angiogenesis Inhibitors

Growth Inhibitors

Combination of autologous dnp irradiated modified cells with sunitinib treatments

Primary or metastatic tumor resected in an Israeli hospital will be used to derive autologous cell lines used for vaccinations following DNP modifications in combination with the regular Sunitinib treatments. Immunological and clinical followup of the patients will be performed

Autologous renal cell vaccine based on DNP modified cells

Hovav Nechushtan, MD PhD

zoya bezalel, BSC

Hovav Nechushtan, MD PHD

While different lines of evidence support the notion that renal cell cancer is amenable for immunologic vaccination, up to now the clinical benefit associated with vaccines has been limited. One reason being probably the whole immunological state of the patients with RCC in which the tumor releases various substances promoting tolerance of the immune system towards the carcinoma. Recent data demonstrates that sunitinib has effects on the immune system which might enhance effectivity of anti tumor vaccines.

Since in kidney cancer it is quite common to resect primary tumor when there are few metastasis or or metastatic tumor resected (if there are few metastasis), the investigators plan to use these tumor source to grow autologous carcinoma cell lines and use a method used world wide for many years and in our institution for over a decade to modify these cells by dinitro phenol and use irradiated cell for patients vaccination in combination with sunitinib treatments.

The investigators will monitor clinical and immunological parameters in these patients.

Background: Renal cell carcinoma (RCC) constitutes around 3% of all solid tumors and cure for metastatic sidease is reported for less than 5% of patients. Together with melanoma it is considered the most immune responsive tumor, moreover it is a common practice to resect primary tumor or large metastasis even in the metastatic settings. Antiangiogenesis treatments are currently the favored antitumor drugs, however their use has rarely resulted in complete response/ cure. Recently it has been demonstrated that these drugs can elicit a shift in the immune environment in RCC patients (improved T1 responses reduced Treg responses).Our department has experience in the treatment 200 melanoma patients with cellular vaccination and in the preparation of primary tumor cell lines from various tumors including RCC. Interestingly , immune modulators such as antiCTLA-4 Ab have demonstrated impressive activity in patients previously vaccinated with cellular vaccinations.

Working hypothesis: Vaccination with autologous cellular vaccines of RCC patients will induce clinical and immunological responses and help in formulation of better combined vaccination strategies in this cancer. Our aims are: 1) Growth and characterization of primary RCC cell lines,2)vaccination with autologous cellular vaccines in combination with sunitinib. 3) Clinical and immunologic characterizations for derivation of prognostic and predictive factors.

Methods: primary or metastatic tumor resected in one of several Israeli hospitals will be used to derive autologous cell lines used for vaccinations following DNP modifications in combination with the regular Sunitinib treatments. Immunological and clinical followup of the patients will be performed and primary cell lines will be grown for further in-vitro testing including possible future use for allogeneic vaccines. Expected result Good safety profile combined with significant clinical and immunological responses are expected.

Importance: This research might result in clinical benefit to the treated patients and will be important in the formulation of effective immune strategies in kidney cancer.

Probable implications to Medicine: RCC vaccine in combination with other therapies has the potential to lead to longer survival and even cure the proposed study will help in the formulation of such a vaccine.

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.
Phase I/II Trial of RAD001 Plus Nexavar in Patients With Kidney Cancer	NCT00448149	Carcinoma, Rena...	RAD001 Sorafenib	18 Years -	The Methodist Hospital Research Institute
Phase III Study of Sorafenib in Patients With Renal Cell Carcinoma (RCC)	NCT00586105	Carcinoma, Rena...	Sorafenib (Nexa...	18 Years -	Bayer
Study on the Influence of Sunitinib and Sorafenib on Fatigue, QoL, Depression in Patients With Metastatic RCC or GIST	NCT00979329	Renal Cell Canc... Colorectal Canc... GIST	Questionnaires	18 Years -	Radboud University Medical Center
Autologous Vaccination of Stage 4 Renal Cell Carcinoma Combined With Sunitinib	NCT00890110	Renal Cell Canc...	Autologous rena...	15 Years - 70 Years	Hadassah Medical Organization
Phase I/II Trial of RAD001 Plus Nexavar in Patients With Kidney Cancer	NCT00448149	Carcinoma, Rena...	RAD001 Sorafenib	18 Years -	The Methodist Hospital Research Institute
Study on the Influence of Sunitinib and Sorafenib on Fatigue, QoL, Depression in Patients With Metastatic RCC or GIST	NCT00979329	Renal Cell Canc... Colorectal Canc... GIST	Questionnaires	18 Years -	Radboud University Medical Center

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