Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Docetaxel

Sunitinib

Tubulin Modulators

Antimitotic Agents

Angiogenesis Inhibitors

Growth Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Sunitinib (Sutent) 37.5 mg in schedule 2/1; Sunitinib (Sutent) 37.5 mg in continuous dosing (post discontinuation of axotere) and in accordance with Investigator decision

Sunitinib (Sutent)

Taxotere

Pfizer CT.gov Call Center

This study is to evaluate the safety of SU011248 (Sunitinib/Sutent) in combination with docetaxel in patients with metastatic or locally recurrent breast cancer who have not received chemotherapy treatment in the advanced disease setting.

Study Of SU011248 In Combination With Docetaxel In Patients With Metastatic Breast Cancer

Exploratory Evaluation Of A Sequential Administration Of Docetaxel And SU011248 In Women With Advanced Breast Cancer

Median Tmax = time for maximum plasma concentration (Cmax) for SU011248, SU012662, and combined SU011248 and SU012662 (total drug); collected C1D2, C2D3. Paired observation.

Mean Cmax = maximum plasma concentration for SU011248, SU012662, and combined SU011248 and SU012662 (total drug) measured as nanograms per milliliter (ng/mL); collected C1D2, C2D3. Paired observation; Cmax dose corrected C2D3 (dose correction if predose concentrations of SU011248 or SU012662 were \> 5% of Cmax).

Mean AUC24 = area under plasma concentration-time profile from time 0 to 24 hours for SU011248, SU012662, and combined SU011248 and SU012662 (total drug) measured in nanograms times hour per milliliter (ng\*hr/mL); collected C1D2, C2D3. Paired observation; AUC24 dose corrected C2D3 (dose correction if predose concentrations of SU011248 or SU012662 were \> 5% of Cmax).

Mean AUClast = area under the plasma concentration-time profile from time 0 (predose) to the last measurable concentration; collected C1D2, C2D3. Data did not allow calculation of AUClast; not summarized; AUC summarized in outcome measure: Area under the plasma concentration-time curve from time zero (0) to 24 hours (AUC24): Sunitinib (SU011248), Sunitinib Metabolite (SU012662), and Total Drug PK Parameters.

Mean Ctrough=plasma concentration-time profile at time 0 (predose); collected C1D2, C1D15, and C2D1. Calculated by setting concentration values below the limit of quantification to zero.

Median Tmax = time to maximum plasma concentration (Cmax) for Docetaxel; collected C1D1, C2D1. Paired observation.

Mean Cmax = maximum plasma concentration for Docetaxel; collected C1D1, C2D1. Paired observation; Cmax dose corrected (dose correction if predose concentrations of SU011248 or SU012662 were \> 5% of Cmax).

Mean AUC24 = area under the plasma concentration-time profile from time 0 to 24 hours; collected C1D1, C2D1. Paired observation.

Mean AUC48 = area under the plasma concentration-time profile from time 0 to 48 hours; collected C1D1, C2D1. Paired observation.

Mean AUC24_48 = area under the plasma concentration-time profile from 24 to 48 hours; collected C1D1, C2D1. Paired observation.

Mean AUClast = area under the plasma concentration-time profile from time 0 (predose) to the last measurable concentration; collected C1D1, C2D1. Paired observation.

Mean Thalf (t1/2) = terminal elimination half life; collected C1D1, C2D1. Paired observation.

Median time (50 percent \[%\]) from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first; based on Investigator assessment. PFS calculated as (Weeks) = (first event date minus first dose date plus 1) divided by 7.

Number of subjects with objective response based on Investigator assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response.

Number of subjects with clinical benefit based on Investigator assessment of confirmed complete response (CR), partial response (PR), or stable disease (SD) according to RECIST for at least 24 weeks on study.

Median duration (50%) of tumor response based on Investigator assessment for a subgroup of subjects with objective disease response: who have not progressed or died due to any cause; with a response and subsequent progression or death due to any cause for duration of response (DR). DR defined as time from start of first documented objective tumor response (CR or PR) to first documented objective tumor progression or death due to any cause, whichever occurs first. DR calculated as (Weeks) = (the end date for DR minus first subsequent confirmed CR or PR plus 1) divided by 7.

Pfizer

Director, Clinical Trial Disclosure Group

Sunitinib (SU011248) orally (PO) for 2 weeks every 3 weeks (2 weeks on, then 1 week off = Schedule 2/1) starting on Day 2 (Cycle 2, Day 3 only for those subjects included in the Pharmacokinetic \[PK\] study); starting dose 37.5 milligrams (mg) daily (QD). Docetaxel (Taxotere) administered Day 1 of each cycle via intravenous (IV) infusion every 3 weeks; starting dose 75 mg/m2.

Sunitinib in Combination With Docetaxel

18 to 44 years

45 to 64 years

> = 65 years

Age, Customized

Sex: Female, Male

Pfizer ClinicalTrials.gov Call Center

SU011248 C1D2

SU011248 C2D3

SU012662 C1D2

SU012662 C2D3

Total drug C1D2

Total drug C2D3

Evaluable set of subjects for PK analysis is subjects in ITT population who completed sampling for PK profiles for both SU011248 and docetaxel; ITT population = all subjects enrolled in study who received at least 1 dose of study medication (SU011248 or docetaxel).

Time to Reach Maximum Plasma Concentration (Tmax): Sunitinib (SU011248), Sunitinib Metabolite (SU012662), and Total Drug PK Parameters

SU011248 C1D2 vs C2D3. Due to the exploratory nature of the study, no statistical hypothesis testing was done since the primary purpose was to assess the tolerability of the combination of SU011248 with docetaxel.

Evaluable set of subjects for PK analysis

Maximum Observed Plasma Concentration (Cmax): Sunitinib (SU011248), Sunitinib Metabolite (SU012662), and Total Drug PK Parameters

Area Under the Plasma Concentration-time Profile From Time Zero (0) to 24 Hours (AUC24): Sunitinib (SU011248), Sunitinib Metabolite (SU012662), and Total Drug PK Parameters

Area Under the Curve From Time 0 to Last Quantifiable Concentration (AUClast): Sunitinib (SU011248), Sunitinib Metabolite (SU012662), and Total Drug PK Parameters

SU011248 C1D15 (n=18)

SU011248 C2D1 (n=11)

SU012662 C1D15 (n=18)

SU012662 C2D1 (n=11)

Total drug C1D2 (n=12)

Total drug C1D15 (n=18)

Total drug 21D1 (n=11)

Evaluable set of subjects for PK analysis; (n) = Number of observations above lower limit of quantification (NALQ). No participants analyzed for SU011248 C1D2 and SU012662 C1D2; standard deviation for Total drug C1D2 confirmed as 0.00 (median, minimum, and maximum = 0.20).

Trough Plasma Concentration (Ctrough) at Time Zero (0): Sunitinib (SU011248), Sunitinib Metabolite (SU012662), and Total Drug PK Parameters

C1D1

C2D1

Time to Reach Maximum Plasma Concentration (Tmax): Docetaxel PK Parameters

Maximum Observed Plasma Concentration (Cmax): Docetaxel PK Parameters

Area Under the Plasma Concentration-time Curve From Time Zero (0) to 24 Hours (AUC24): Docetaxel PK Parameters

ITT population = all subjects enrolled in study who received at least 1 dose of study medication (SU011248 or docetaxel).

Progression-Free Survival (PFS) Based on Investigator Assessment

Overall confirmed objective response rate (CR + PR)

Number of Subjects With Objective Response of Complete Response or Partial Response Based on Investigator Assessment

Clinical Benefit Rate (CR + PR + SD \> = 24 weeks)

Number of Subjects With Clinical Benefit of Complete Response, Partial Response, or Stable Disease Based on Investigator Assessment

ITT; subgroup of subjects with objective disease response

Duration of Tumor Response Based on Investigator Assessment

Area Under the Plasma Concentration-time Curve From Time Zero (0) to 48 Hours (AUC48): Docetaxel PK Parameters

Area Under the Curve From Time 24 Hours to 48 Hours (AUC24_48) : Docetaxel PK Parameters

Area Under the Curve From Time 0 to Last Quantifiable Concentration (AUClast): Docetaxel PK Parameters

Plasma Elimination Half-life (t1/2): Docetaxel PK Parameters

Overall Study

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Kidney Neoplasms

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

Sunitinib, SUTENT, 50 mg daily p.o., on schedule 4/2, for 2 cycles. Two weeks of rest prior to surgery (week 11 and 12).

Radical nephrectomy at the end of week 12. Sunitinib 50 mg/d, schedule 4/2, reintroduced 2 weeks after surgery (week 14, may be postponed by one or two weeks if wound healing delay or surgical complications). Treatment until disease progression, unacceptable toxicity or consent withdrawal. Dose reduction depending on the type and severity of toxicity.

At the end of the treatment period patients will be treated at the discretion of the Investigator.

Sunitinib (SUTENT)

Stephane OUDARD, MD

The aim of this study is to identify and/or validate biomarkers and imaging markers to predict and monitor the activity of a new class of therapeutic agents called antiangiogenics for the treatment of metastatic renal cell carcinoma (mRCC). Suntinib, approved for this indication, will be administred before and after nephrectomy and biomarkers sampling and imaging will be operated to monitor the activity and identify prognostic factors in mRCC.

BACKGROUND Sunitinib, SUTENT, is a promising multi-target TKI in the treatment of metastatic renal cell carcinoma after cytokine failure. In previous phase II studies, ORR is 40% and TTP = 8,7 months. A phase III randomized trial of Sunitinib versus interferon alpha as first-line therapy for patients with mRCC showed a significantly longer PFS in the Sunitinib group (11 months) than in the interferon group (5 months), hazard ratio of 0.42 (95% CI, 0.32 to 0.54, p \< 0.001). Initial approval in second line treatment of mRCC was extended to first line therapy on 11-01-2007.

Mechanisms of action involved in the therapeutic effects of antiangiogenic compounds are not fully elucidated. As of today, there are no validated biomarkers or imaging markers to predict and monitor the activity of this type of compound.

Recent findings in the field of cancer biology, tumor angiogenesis, immunology and imaging provide several biomarker candidates that can be assessed in metastatic renal cell carcinoma.

BASIC RESEARCH Biomarkers It seems interesting to measure the different biological markers that could be modulated by this antiangiogenic therapeutic. Some of them are known as prognostic factors in the metastatic renal carcinoma, others are directly linked to the mechanism of action of Sunitinib. Due to the biopsy prior to treatment initiation and nephrectomy after treatment initiation, it will be possible to evaluate biomarkers modification and to assess the potential link with the tumour response.

VHL gene alterations (mutations, deletions, and hypermethylations) are observed at high frequencies of up to 80% in cases of clear-cell renal cell carcinoma. The molecular mechanisms involved in angiogenesis in the presence of such genetic alterations are not yet well known. The functions of the pVHL/aHIF/VEGF/angiogenesis pathway will be investigated in all the renal cell carcinoma obtained from the biopsy and nephrectomy. Molecular markers defined by VHL status, expression and proteomic profiling may be helpful in predicting the responders.

Sunitinib is a potent inhibitor of the tyrosine kinase activity of several receptors: VEGFR-2, the main receptor responsible for mediating the proangiogenic effects of vascular endothelial growth factor (VEGF), expressed by vascular endothelial cells; PDGFR, the receptor for the platelet-derived growth factor (PDGF), expressed in pericytes which serve as structural supporting cells for endothelial cells. Consistent with its biochemical activity, Sunitinib inhibits the in vitro mitogenic response of human umbilical vein endothelial cells (HUVECs) stimulated by VEGF or bFGF (basic fibrosblast growth factor), another proangiogenic factor.

VEGF gene polymorphisms In physiologic and pathologic conditions, important variations in VEGF blood levels have been reported to correlate with constitutional VEGF-A gene polymorphisms located in intronic regions. Moreover, VEGF-A polymorphisms have been described as predisposition and prognostic factors in several human malignancies such as bladder, breast, melanoma, prostate and head and neck carcinomas. Hence, it is interesting to see whether these polymorphisms could affect tumor and clinical presentation and correlate with VEGF-levels and response to antiangiogenic treatment with sunitinib.

Immunology Tumor angiogenesis can impact immune response in renal cell carcinoma patients. A naturally occurring CD4+ T cell subset, regulatory CD4+CD25+ T cells, has emerged as the dominant T cell population governing peripheral self- tolerance by inhibiting effector T cell. The ability of anti-angiogenic therapy to block VEGF may allow better maturation of dendritic cells and a reduction of the number of regulatory CD4+CD25+T cells.

The aim of this project will be to test whether the administration of Sunitinib modulates the concentrations of regulatory CD4+CD25+T cells, and if a correlation between the immunology parameters and the response can be observed.

Imaging Radiological evaluation of tumor response is also challenging with anti-angiogenic drugs. Criteria based solely on size may be inadequate for evaluation of anti-angiogenic therapy efficacy. The unbridled expansion of tumor vessels leads to development of abnormal vessels, with distinct microvascular characteristics: high perfusion (blood flow), and porous walls leaking molecules into the interstitium (permeability).

New imaging techniques as dynamic contrast-enhanced CT are being developed to quantify and characterize these unique properties, and may be used as markers of response to angiogenesis inhibitors. Imaging assays of angiogenic status therefore offer the potential to clinically measure anti angiogenic effects of drugs on the tumor vessels themselves, effects that may not be reflected in changing tumor dimensions. These effects may be detectable hours or days from time of treatment initiation, rather than in weeks or months needed typically to detect a change in tumor size. Exploration of local tumor vascular architecture can help to understand mechanism of action of Sunitinib. This vasculature seems to be of poor functionality and tumor vascularization cannot be adequately assessed only by global index such as global tumor blood flow. In addition, exploration of renal tumor vascularization with contrast-enhanced US will be performed to compare blood flow determined by CT and US.

Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma

A Study of Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma With Sunitinib BEFORE and AFTER Nephrectomy

National Cancer Institute, France

Assistance Publique - Hôpitaux de Paris

Anti-Infective Agents

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Immunosuppressive Agents

Immunologic Factors

Everolimus (RAD001)

Daniel J. George, M.D.

This is a single center, Phase Ib study of Sunitinib and RAD001 in patients with advanced RCC. The study design is a phase I interpatient dose-escalation with a dose expansion at the maximum tolerated dose (MTD) in patients with metastatic RCC . In the dose escalation portion, patients will be treated with sunitinib, given in an intermittent schedule (2 weeks of daily dosing followed by one week off drug. RAD001 will be given daily. Escalation of both drugs will occur as tolerated. Treatment will be arbitrarily divided into 3-week cycles, with dose limiting toxicity (DLT) determined by Cycle 2 Day 0.

Escalation of both drugs will occur as tolerated. Treatment will be arbitrarily divided into 3-week cycles, with dose limiting toxicity (DLT) determined by Cycle 2 Day 0. Dose levels will be evaluated one at a time beginning with 3 patients. If 1/3 patients demonstrate DLT (as defined in section Complete), then enrollment will proceed to the next dose level. 1/3 patients develops a DLT, then 3 more patients will be accrued to this dose level. If 0-1/6 patients demonstrate DLT, then enrollment will proceed to the next dose level. However, if 2 or more patients out of 6 demonstrate DLT at a dose level, then enrollment will proceed at the next lowest dose level. The highest dose level not resulting in greater than 1/6 DLT will be considered the MTD. Dose expansion will then proceed at this dose level.

Once the maximum tolerated dose has been established for this regimen a dose expansion of 20 patients with metastatic RCC will be undertaken. Up to 10 patients with a positive FDG- PET scan at baseline (defined by 1 or more target lesions demonstrating an SUV \> 5.0) will begin treatment per Figure 2B. Patients 1-10 will begin Sunitinib on Day 0 and begin RAD001 on Day 14 after repeat FDG-PET scan. Patients 11-20, will have a 2 week lead-in period of RAD001 and will begin Sunitinib 2 weeks later on Day 0. After repeat FDG-PET scan. Both groups of patients will repeat PET scan at Day 14 of cycle 2. Patients with negative FDG PET scans (SUV \< 5.0 in all lesions) will not undergo repeat scanning. Patients will undergo evaluations for tumor response every 12 weeks with appropriate measurement studies (CT, MRI, bone scan). In the setting of a mixed response (progressive disease in 1 or more lesions but continued regression or stable disease below baseline in other lesions) patients may continue on study if it is determined by the PI, treating physician and patient that there is ongoing clinical benefit to the patient.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study Of SU011248 In Combination With Docetaxel In Patients With Metastatic Breast Cancer	NCT00291577	Breast Neoplasm...	Sunitinib (Sute... Taxotere	18 Years -	Pfizer
Biological, Pathological and Imagery Markers in the First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma	NCT00930345	Metastatic Rena...	Sunitinib (SUTE...	18 Years -	Assistance Publique - Hôpitaux de Paris
A Phase Ib Study of Rad001 and Sutent to Treat Renal Cell Carcinoma	NCT00788060	Renal Cell Carc...	Everolimus (RAD... Sunitinib (Sute...	18 Years -	Duke University

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