Antineoplastic Agents

All Drugs and Chemicals

Docetaxel

Aflibercept

Tubulin Modulators

Antimitotic Agents

Angiogenesis Inhibitors

Growth Inhibitors

aflibercept (AVE0005)

docetaxel

Clinical Sciences & Operations

The primary objective of this study is to determine the dose of aflibercept to be further studied in combination with docetaxel in Japanese cancer patients.

The secondary objectives of this study are to assess the safety profile of aflibercept, to determine the pharmacokinetics of aflibercept, to make a preliminary assessment of antitumor effects.

A Phase I Study of Intravenous Aflibercept in Combination With Docetaxel in Japanese Cancer Patients

A Phase I, Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous Aflibercept in Combination With Intravenous Docetaxel Administered Every 3 Weeks in Patients With Advanced Solid Malignancies

Regeneron Pharmaceuticals

Sanofi

Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Kidney Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

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

Endothelial Growth Factors

Mitogens

Patients receive a higher dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Patients receive a lower dose of ziv-aflibercept (VEGF Trap) IV over 1 hour on day 1. In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. At the time of disease progression, the dose of ziv-aflibercept (VEGF Trap) may be escalated to the higher dose in Arm A.

VEGF Trap

Roberto Pili

This randomized phase II trial studies how well ziv-aflibercept (VEGF Trap) works in treating patients with kidney cancer that has spread from the primary site to other places in the body (metastatic) or is unable to be removed with surgery (unresectable). Ziv-aflibercept may stop the growth of kidney cancer by blocking blood flow to the tumor.

PRIMARY OBJECTIVE:

I. To determine the effect of two different doses of AVE0005 (vascular endothelial growth factor \[VEGF\] Trap \[ziv-aflibercept\]) treatment on the progression-free proportion at 8 weeks in patients with metastatic renal cell carcinoma who had previous treatment with a tyrosine kinase inhibitor (TKI).

SECONDARY OBJECTIVES:

I. To determine the effect of AVE0005 (VEGF Trap) treatment on objective response rate in patients with metastatic renal cell carcinoma who have had previous TKI treatment.

II. To describe progression-free survival among patients who undergo dose escalation following progression on low-dose AVE0005 (VEGF Trap).

III. To evaluate the safety and tolerability of AVE0005 (VEGF Trap) in patients with metastatic renal cell carcinoma who have had previous treatment with a TKI.

OTHER PRE-SPECIFIED OBJECTIVES:

I. To determine the circulating levels of VEGF AVE0005 (VEGF-Trap) complex and correlate it with clinical activity.

II. To evaluate the modulation of specific angiogenesis-related protein expression by AVE0005 (VEGF Trap).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A (Higher dose of VEGF Trap): Patients receive a higher dose of ziv-aflibercept intervenously (IV) over 1 hour on day 1.

ARM B (Lower dose of VEGF Trap): Patients receive a lower dose of ziv-aflibercept IV over 1 hour on day 1.

In both arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients receiving treatment on Arm B may crossover and receive treatment on Arm A at the time of disease progression.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 1 year.

Ziv-Aflibercept in Treating Patients With Metastatic or Unresectable Kidney Cancer

A Randomized Phase II Study to Determine the Effect of 2 Different Doses of AVE0005 (VEGF Trap) in Patients With Metastatic Renal Cell Carcinoma

Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

Progression-free survival (PFS) was defined as time from randomization to the earlier of documentation of progression or death. The proportion of patients who are progression-free and alive at 8 weeks was estimated using the Kaplan-Meier method and the confidence interval was estimated using log transformation method.

Progression is defined using Response Evaluation Criteria In Solid Tumors (RECIST), as a 20% increase in the sum of the longest diameters of target lesions, or the appearance of new lesions, or unequivocal progression of existing nontarget lesions.

Objective response is defined as complete response (CR) or partial response (PR) determined by Solid Tumor Response Criteria (RECIST).

CR: The disappearance of all target lesions without the appearance of new lesion(s) and/or unequivocal progression of existing non-target lesions.

PR: At least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter without the appearance of new lesion(s) and/or unequivocal progression of existing non-target lesions.

To be assigned a status of CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met.

Patients who progressed on the 1 mg/kg dose (Arm B) at 8 weeks would have the opportunity to receive the 4 mg/kg dose. PFS is defined as the time from dose escalation to disease progression or death, whichever occurs first.

Disease progression is defined using Response Evaluation Criteria In Solid Tumors (RECIST), as a 20% increase in the sum of the longest diameters of target lesions, or the appearance of new lesions, or unequivocal progression of existing nontarget lesions.

National Cancer Institute (NCI)

Arm A (Higher Dose of VEGF Trap)

Arm B (Lower Dose of VEGF Trap)

Total

Age, Continuous

Sex: Female, Male

Eligible and treated patients are included in this analysis.

Study Statistician

Proportion of Patients Alive and Progression-free at 8 Weeks

Proportion of Patients With Objective Response

Only patients who progressed on the low dose (Arm B) and underwent dose escalation were included in this analysis.

Progression-free Survival (PFS) Among Patients Who Undergo Dose Escalation Following Progression on Lower-dose VEGF Trap

Circulating Levels of VEGF-Trap Complex

Angiogenesis-related Protein Expression

Overall Study

Symptoms and General Pathology

Gland and Hormone Related Diseases

Digestive System Diseases

Recurrence

Carcinoma, Ovarian Epithelial

Peritoneal Neoplasms

Fallopian Tube Neoplasms

Disease Attributes

Genital Neoplasms, Female

Fallopian Tube Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Ovarian Neoplasms

Endocrine Gland Neoplasms

Ovarian Diseases

Endocrine System Diseases

Gonadal Disorders

Abdominal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Peritoneal Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Fallopian Tube Cancer

Phase I (closed to accrual as of 3/14/2008): Patients receive VEGF Trap IV over 1 hour on day 1 of course 1. Patients then receive VEGF Trap IV over 1 hour and docetaxel IV over 1 hour on day 1 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of VEGF Trap until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 or 6 patients experience dose-limiting toxicity.

Phase II (opened to accrual as of 5/9/2008): Patients receive VEGF Trap at the MTD determined in phase I and docetaxel as in phase I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

25 mg/m\^2 given intravenously (IV) over 1 hour (+/- 10 minutes) following VEGF Trap every 3 weeks starting cycle 1 (21 day cycles)

Starting dose 2 mg/kg given IV Cycle 0. Phase I Group: Every 3 weeks beginning with Cycle 0 (Completed 03/14/2008); Phase II Group: Every 3 weeks starting cycle 1 (Opened 05/09/2008).

ziv-aflibercept

laboratory biomarker analysis

pharmacological study

Robert Coleman

This phase I/II trial is studying the side effects and best dose of VEGF Trap when given together with docetaxel and to see how well they work in treating patients with persistent or recurrent ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer. VEGF Trap may stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving VEGF Trap together with docetaxel may kill more tumor cells

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of VEGF Trap and docetaxel in patients with persistent or recurrent ovarian epithelial, primary peritoneal, or fallopian tube cancer. (Phase I \[closed to accrual as of 3/14/2008\]) II. Determine the maximum tolerated dose of VEGF Trap in these patients. (Phase I \[closed to accrual as of 3/14/2008\]) III. Determine the pharmacokinetics of VEGF Trap when administered alone and in combination with docetaxel in these patients. (Phase I \[closed to accrual as of 3/14/2008\]) IV. Determine the effects of VEGF Trap on tumor perfusion and metabolism in these patients. (Phase I \[closed to accrual as of 3/14/2008\]) V. Determine the effect of VEGF Trap and docetaxel on circulating endothelial precursors and circulating endothelial cells in these patients. (Phase I \[closed to accrual as of 3/14/2008\]) VI. Determine the frequency of clinical response (partial response and complete response) in patients treated with this regimen. (Phase II \[open to accrual as of 5/9/2008\]) VII. Determine the progression-free survival (PFS) and overall survival (OS) of patients treated with this regimen. (Phase II \[open to accrual as of 5/9/2008\])

SECONDARY OBJECTIVES:

I. Determine the duration of PFS and OS of patients treated with this regimen. (Phase II) II. Determine the frequency and severity of adverse effects of this regimen in these patients. (Phase II) III. Determine the proportion of patients with PFS at 6 months. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of VEGF Trap followed by a phase II study.

PHASE I (closed to accrual as of 3/14/2008): Patients receive VEGF Trap IV over 1 hour on day 1 of course 1. Patients then receive VEGF Trap IV over 1 hour and docetaxel IV over 1 hour on day 1 in all subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of VEGF Trap until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 or 6 patients experience dose-limiting toxicity.

PHASE II (opened to accrual as of 5/9/2008): Patients receive VEGF Trap at the MTD determined in phase I and docetaxel as in phase I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients enrolled in phase I (closed to accrual as of 3/14/2008) undergo blood sample collection periodically for pharmacokinetic studies and surrogate marker studies. These patients also undergo dynamic contrast-enhanced MRI, fludeoxyglucose F 18 positron emission tomography, and CT scan at baseline and on day 1 of courses 1 and 2 to evaluate blood flow parameters and metabolic activity of tumors. Patients enrolled in phase I (closed to accrual as of 3/14/2008) and phase II will also undergo blood collection for Anti-VEGF trap antibody.

After the completion of study treatment, patients are followed at 1 and 2 months and then periodically thereafter.

VEGF Trap and Docetaxel in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

Phase I/II and Pharmacokinetic Study of Docetaxel Plus VEGF Trap (AVE0005, NSC# 724770) in Patients With Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancer

Escalating dose levels of VEGF Trap were administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose (MTD). The MTD is defined as the highest dose level below which 2 or more patients encounter a dose limiting toxicity (DLT), graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. MTD established on absence of observed DLT(s) in either cycle 0 (single agent) or cycle 1 (combination therapy) of any given dose level.

Frequency of clinical response (partial response or complete response) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance all target lesions; Partial Response (PR): \>/= 30% decrease in sum of longest diameter (LD) of target lesions, reference baseline sum LD; Progressive Disease (PD): \>/= 20% increase in sum of LD of target lesions, reference smallest sum LD recorded since treatment started or appearance of 1+ new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum LD since treatment started.

Overall survival was defined from the date of study entry until death or date of last contact. Median survival time points calculated in the method of Kaplan-Meier. Standard RECIST criteria followed to evaluate response and progression, and all documented responses required confirmation by imaging, examination, or both, no sooner than 4 weeks after the initial documentation of response. In the absence of new symptoms, response assessment consistently done after two additional cycles of therapy.

The percentage of participants in the Phase II arm with an objective response defined as a measurable response according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Standard RECIST criteria were followed to evaluate response and progression. All documented responses were required to undergo confirmation by imaging, examination, or both, no sooner than 4 weeks after the initial documentation of response. In the absence of new symptoms, this response assessment was consistently done after two additional cycles of therapy.

Progression-Free Survival was calculated from study entry until documented disease, death or date of last contact.

Duration of the response from time response is achieved until disease progression is detected. Response assessed following treatment (every 3 weeks) for disease progression. Study duration January 2007 to May 2013, approximately six and half years.

Number of participants with adverse effects of treatment. Frequency and severity of adverse effects of treatment as assessed by NCI CTCAE v3.0 (Phase II)

Progression-free survival (PFS) defined as number of participants out of total in arm that had no disease progression as measured at 6 months. Standard RECIST criteria used to evaluate response and progression. All documented responses required confirmation by imaging, examination, or both, no sooner than 4 weeks after initial documentation of response. In the absence of new symptoms, response assessment was consistently done after two additional cycles of therapy.

Phase I VEGF Trap starting dose 2 mg/kg intravenous (IV) over 1 hour on day 1 of course 1, then VEGF Trap IV and Docetaxel 75 mg/m\^2 IV over 1 hour on day 1 in all subsequent courses. Courses repeat every 21 days. Escalating doses of VEGF Trap (2, 4, or 6 mg/kg) until maximum tolerated dose (MTD) determined.

Phase I VEGF Trap, Docetaxel

Phase II VEGF Trap 6 mg/kg (the MTD determined in Phase I) and Docetaxel 75 mg/m\^2 as in Phase I. Courses repeat every 21 days.

Phase II: VEGF Trap, Docetaxel

Phase II VEGF Trap, Docetaxel

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Clear cell

Endometrioid

Mixed

Serous

Transitional cell

Unclassified

Histological classification of participant cancer based on pathology report from most recent pre-registration diagnostic biopsy or surgery, confirmed within 14 days after registration for baseline measurements/data.

Participant Cancer Histology

Robert Coleman, MD / Professor

Maximum Tolerated Dose of VEGF Trap (Phase I)

Complete Response

Partial Response

Number of Participants With Clinical Response (Partial Response or Complete Response) According to the Response Evaluation Criteria in Solid Tumors (RECIST)

Median Overall Survival (OS) (Phase II)

Overall Objective Response Rate According to RECIST (Phase II)

Median Progression-Free Survival (PFS) (Phase II)

Number analyzed represents those Phase II participants with response as documented in Outcome Measure 2.

Overall Median Duration of Response (Phase II)

Number of Participants With Treatment-related Adverse Effects as Assessed by NCI CTCAE v3.0 (Phase II)

Phase I, 2 participants had partial response and 3 were stable disease for a total of 5 responses but only 2 had a Clinical Response (confirmed).

Phase II, 46 participants was evaluable out of 49 enrolled for response/toxicity.

Number of Participants With PFS (Phase II)

Complete Study Participation

Phase 1: VEGF Trap Escalating Dose

Phase 2: MTD VEGF Trap + Docetaxel

The primary objective of this study is to determine the recommended phase II dose of AVE0005 in combination with S-1 in Japanese cancer patients.

The secondary objectives of this study are to assess the safety profile of AVE0005, to determine the pharmacokinetics of AVE0005, to make a preliminary assessment of antitumor effects.

A Phase I Study of Intravenous Aflibercept in Combination With S-1 in Japanese Cancer Patients

A Single Agent-combination Hybrid Phase I, Open-label, Dose-escalation Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous AVE0005 (VEGF Trap)Administered Every 2 Weeks in Combination With Oral S-1 in Patients With Advanced Solid Malignancies

Trial Transparency Team

Blood and Lymph Conditions

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Bone marrow biopsy

bone marrow aspiration

For test of free VEGF Trap compared to bound VEGF Trap and for routine clinical testing during treatment

Venipuncture

Stephen Strickland, MD

RATIONALE: Aflibercept may stop the growth of cancer cells by blocking blood flow to the cancer.

PURPOSE: This phase II trial is studying how well aflibercept works in treating patients with advanced refractory, relapsed, or untreated acute myeloid leukemia.

OBJECTIVES:

Primary

* To determine the response rate to aflibercept as a single agent in adult patients with advanced refractory, relapsed, or untreated acute myeloid leukemia (AML).
* To determine the 3-month progression-free survival following treatment with at least 4 courses of aflibercept in these patients.

Secondary

* To determine if there is any correlation between pre-treatment expression of VEGFR1 or VEGFR2 by marrow myeloblasts and disease response to aflibercept.
* To determine if bone marrow microvessel density (MVD) pre-treatment correlates with disease response to aflibercept, and if any decrease in MVD following treatment correlates with changes in bone marrow blast percentage (disease response).
* To assess changes in circulating endothelial cells (CEC) and circulating endothelial progenitor cells (EPC) as pharmacodynamic markers of aflibercept activity and possible correlates of disease response to aflibercept.
* To measure blood levels of free VEGF versus VEGF bound by aflibercept post-treatment to determine if the chosen dose of aflibercept is sufficient to bind all detectable soluble VEGF in these patients.
* To characterize the population pharmacokinetics of aflibercept with its associated interpatient variability and to explore for demographic and clinical covariates.
* To derive individual estimates of the duration over which VEGF-saturating aflibercept concentrations were systematically present and to examine their distribution across the population.
* To explore the potential relationship between the systemic-free and bound aflibercept levels and safety and efficacy data.

OUTLINE: This is a multicenter study.

Patients receive aflibercept IV over 1 hour on day 1. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo bone marrow and blood sample collection periodically for pharmacokinetic/pharmacodynamic studies. Samples are analyzed for peak plasma-free aflibercept levels after the first infusion, trough plasma-free and bound aflibercept levels prior to each subsequent infusion and 60 days after the last infusion, and anti-aflibercept antibody via ELISA methods; circulating endothelial cells (CEC's) via ELISA and flow cytometry to determine if there is correlation between changes in circulating endothelial cells and changes in bone marrow blast percentage (i.e., disease response); myeloblast expression of VEGFR-1 and VRGFR-2 via immunohistochemistry (IHC); endothelial progenitor cells colony forming units (EPC-CFU's) to determine via in situ staining if changes in circulating endothelial progenitors following treatment with aflibercept correlates with disease response, and if there is a subpopulation of patients identified by pre-treatment circulating EPC-CFU's that may benefit from aflibercept; and bone marrow microvessel density (MVD) determination via immunohistochemistry.

After completion of study treatment, patients are followed for 60 days.

A Multi-Center Phase 2 Study of VEGF Trap as a Single Agent in Acute Myeloid Leukemia

A Multi-Center Phase 2 Study of Vascular Endothelial Growth Factor (VEGF) Trap as a Single Agent in Acute Myeloid Leukemia

As determined by the International Working Group: Complete response: bone marrow blast(BMB) percentage (%) \<=5% of nucleated cells and no detectable extramedullary disease; Partial response: BMB \>5% but decreased by at least 50% pre-treatment (pre-tx) value OR extramedullary disease still present; Stable disease: BMB \>5% and decreased or increased by \<50% of pre-tx value and no new extramedullary disease; Progressive disease: BMB \>=20% and an increase of at least 50% of pre-tx value and/or appearance of at least 50% in circulating blasts

Density of microscopically small blood vessels in bone marrow biopsies

Blood levels of free VEGF Trap compared to bound VEGF trap to determine if the chosen level of VEGF Trap is sufficient to bind all detectable soluble VEGF in this group of patients

Patients who undergo a minimum of 4 cycles of treatment and who have either a complete or partial response to treatment or who have stable disease and who are free of progressive disease at 12 weeks

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I Study of Intravenous Aflibercept in Combination With Docetaxel in Japanese Cancer Patients	NCT00545246	Neoplasms	aflibercept (AV... docetaxel	20 Years -	Sanofi
Ziv-Aflibercept in Treating Patients With Metastatic or Unresectable Kidney Cancer	NCT00357760	Metastatic Rena...	VEGF Trap	18 Years -	National Cancer Institute (NCI)
VEGF Trap and Docetaxel in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer	NCT00436501	Fallopian Tube ... Malignant Tumor... Recurrent Ovari...	docetaxel ziv-aflibercept laboratory biom... pharmacological...	18 Years -	National Cancer Institute (NCI)
VEGF Trap and Docetaxel in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer	NCT00436501	Fallopian Tube ... Malignant Tumor... Recurrent Ovari...	docetaxel ziv-aflibercept laboratory biom... pharmacological...	18 Years -	National Cancer Institute (NCI)
A Phase I Study of Intravenous Aflibercept in Combination With S-1 in Japanese Cancer Patients	NCT00479076	Neoplasms	aflibercept (AV... S-1	20 Years -	Sanofi
A Multi-Center Phase 2 Study of VEGF Trap as a Single Agent in Acute Myeloid Leukemia	NCT00601991	Leukemia	VEGF Trap Bone marrow bio... bone marrow asp... Venipuncture	18 Years -	Vanderbilt-Ingram Cancer Center
A Phase I Study of Intravenous Aflibercept in Combination With Docetaxel in Japanese Cancer Patients	NCT00545246	Neoplasms	aflibercept (AV... docetaxel	20 Years -	Sanofi
A Phase I Study of Intravenous Aflibercept in Combination With Docetaxel in Japanese Cancer Patients	NCT00545246	Neoplasms	aflibercept (AV... docetaxel	20 Years -	Sanofi

Spots Global Cancer Trial Database for vegf trap

Every month we try and update this database with for vegf trap cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for vegf trap

Every month we try and update this database with for vegf trap cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for vegf trap cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.