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Phase II Study of Sunitinib Rechallenge in Patients With Metastatic Renal Cell Carcinoma

Primary Purpose

Metastatic Renal Cell Carcinoma

Status

Terminated

Phase

Phase 2

Locations

Netherlands

Study Type

Interventional

Intervention

Sunitinib

About this trial

This is an interventional treatment trial for Metastatic Renal Cell Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with histologically or cytologically confirmed clear-cell mRCC.
Patients who progressed on first-line treatment with sunitinib and who had clinical benefit defined as a response (according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria) or SD for more than 6 months on this treatment.
Patients who progressed after second-line treatment (mTOR inhibitor or other treatment as long as patients are not treated with a Vascular Endothelial Growth Factor (VEGF) targeted Tyrosine Kinase Inhibitor (TKI), see exclusion criteria), or who progressed after a treatment-free interval of at least 3 months since discontinuation of first-line sunitinib treatment.
Patients with radiological (and/or clinical) confirmed progressive disease according to RECIST 1.1 criteria.
Measurable or evaluable disease as defined by RECIST 1.1.
WHO performance status 0-2.
Life expectancy of at least 12 weeks.
Age 18 years or older.
Able to receive oral medication.
Able to provide written informed consent.
Adequate hematologic function: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, Hb ≥ 6.0 mmol/L.
Patients with brain metastases are eligible if they have been stable for at least two months post-radiation therapy or surgery.
No other current malignant disease, except for basal cell carcinoma of the skin.
Adequate hepatic function: serum bilirubin ≤ 1.5 x Upper Limit of Normal (ULN), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2.5 x ULN (or ≤ 5 times ULN if liver metastases are present).
Renal function: estimated glomerular filtration rate ≥ 40 ml/min.
Patients with reproductive potential must use effective contraception. Female patients must have a negative pregnancy test.

Exclusion Criteria:

Patients treated with any VEGF targeted TKI (sorafenib, pazopanib, axitinib, dovitinib) as second-line treatment after progression on first-line sunitinib treatment.
Uncontrolled hypertension. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen. Blood pressure must be stable on at least 2 separate measurements on at least 2 separate days.
Active infection or serious intercurrent illness.
Presence of unstable angina, recent myocardial infarction (within the previous 3 months).
Macroscopic hematuria.
Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patient's compliance.
Any other major illness that, in the investigator's judgment, substantially increases the risk associated with the subject's participation in the study.-

Sites / Locations

VU Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sunitinib

Arm Description

Patients will be treated in repeated 6-week cycles with 50 mg sunitinib orally daily for 4 weeks followed by 2 weeks off.

Outcomes

Primary Outcome Measures

Progression free survival

To investigate the proportion of patients with metastic Renal Cell Carcinoma retreated with sunitinib that is progression-free at 3 months.

Secondary Outcome Measures

Clinical benefit rate

To assess the clinical benefit rate (ORR and SD), median Progression Free Survival (mPFS) and Overall Survival (OS) in individuals retreated with sunitinib.

Effects of sunitinib rechallenge on LAMP1/2 proteins

To assess the effects of sunitinib rechallenge on Lysosome-associated membrane protein 1/2(LAMP1/2) proteins in Peripheral Blood Mononuclear Cells and tumor tissue.

The immunological effects of sunitinib rechallenge

To assess the immunological effects of sunitinib rechallenge on the number and activation state of circulating Dendritic Cell(DC), Myeloid-Derived Suppressor cell (MDSC) and Regulatory T-cell (Tregs).

Mass spectrometry-based identification of phosphorylated proteins in tumor tissue during treatment

To study phosphoproteomic profiles of tumors before rechallenge and at the time of progression. LC-MS/MS-based phospho-proteomics for the identification of sunitinib response and resistance biomarkers

Concentrations of sunitinib

To assess sunitinib drug levels and tumor tissue concentrations of sunitinib.

Effect of retreatment

To evaluate the effect of retreatment with sunitinib on the quality of life.

Full Information

NCT ID

NCT02071641

First Posted

September 27, 2013

Last Updated

April 6, 2017

Sponsor

Amsterdam UMC, location VUmc

1. Study Identification

Unique Protocol Identification Number

NCT02071641

Brief Title

Phase II Study of Sunitinib Rechallenge in Patients With Metastatic Renal Cell Carcinoma

Official Title

Phase II Study of Sunitinib Rechallenge in Patients With Metastatic Renal Cell Carcinoma

Study Type

Interventional

2. Study Status

Record Verification Date

April 2017

Overall Recruitment Status

Terminated

Study Start Date

October 2012 (undefined)

Primary Completion Date

September 2016 (Actual)

Study Completion Date

September 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Amsterdam UMC, location VUmc

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

Targeted therapies are associated with (acquired) resistance after a median of 5-11 months of treatment, resulting in disease progression, while almost no tumors are intrinsically resistant in the first line setting. The investigators recently published that tumor cell resistance to sunitinib may be directly related to lysosomal sequestration of sunitinib. This resistance mechanism was shown to be transient, since a drug-free culture period could normalize the lysosomal storage capacity for sunitinib and resulted in recovery of drug sensitivity. In two reports it has been suggested that patients with metastatic Renal Cell Carcinoma who responded to sunitinib in the first-line setting may benefit from rechallenge with sunitinib after failure of second-line treatment. However, these data are retrospective. A prospective trial to investigate a rechallenge with sunitinib is needed to determine whether this strategy is of benefit for patients with mRCC with prior clinical benefit to sunitinib but who stopped treatment because of overt clinical resistance.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Renal Cell Carcinoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sunitinib

Arm Type

Experimental

Arm Description

Patients will be treated in repeated 6-week cycles with 50 mg sunitinib orally daily for 4 weeks followed by 2 weeks off.

Intervention Type

Drug

Intervention Name(s)

Sunitinib

Primary Outcome Measure Information:

Title

Progression free survival

Description

To investigate the proportion of patients with metastic Renal Cell Carcinoma retreated with sunitinib that is progression-free at 3 months.

Time Frame

After 3 months of treatment

Secondary Outcome Measure Information:

Title

Clinical benefit rate

Description

To assess the clinical benefit rate (ORR and SD), median Progression Free Survival (mPFS) and Overall Survival (OS) in individuals retreated with sunitinib.

Time Frame

progression free at 3 months

Title

Effects of sunitinib rechallenge on LAMP1/2 proteins

Description

To assess the effects of sunitinib rechallenge on Lysosome-associated membrane protein 1/2(LAMP1/2) proteins in Peripheral Blood Mononuclear Cells and tumor tissue.

Time Frame

Blood samples will be collected at baseline, t=4 wk, t=6 wk, t=12 wk and at the end of study treatment (disease progression and/or death)

Title

The immunological effects of sunitinib rechallenge

Description

Time Frame

Blood samples will be collected at baseline, t=4 wk, t=6 wk, t=12 wk and at the end of study treatment (disease progression and/or death).

Title

Mass spectrometry-based identification of phosphorylated proteins in tumor tissue during treatment

Description

Time Frame

Blood samples will be collected at baseline, t=4 wk, t=6 wk, t=12 wk and at the end of study treatment (disease progression and/or death).

Title

Concentrations of sunitinib

Description

To assess sunitinib drug levels and tumor tissue concentrations of sunitinib.

Time Frame

Blood samples will be collected at baseline, t=4 wk, t=6 wk, t=12 wk and at the end of study treatment (disease progression and/or death).

Title

Effect of retreatment

Description

To evaluate the effect of retreatment with sunitinib on the quality of life.

Time Frame

progression free at 3 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with histologically or cytologically confirmed clear-cell mRCC. Patients who progressed on first-line treatment with sunitinib and who had clinical benefit defined as a response (according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria) or SD for more than 6 months on this treatment. Patients who progressed after second-line treatment (mTOR inhibitor or other treatment as long as patients are not treated with a Vascular Endothelial Growth Factor (VEGF) targeted Tyrosine Kinase Inhibitor (TKI), see exclusion criteria), or who progressed after a treatment-free interval of at least 3 months since discontinuation of first-line sunitinib treatment. Patients with radiological (and/or clinical) confirmed progressive disease according to RECIST 1.1 criteria. Measurable or evaluable disease as defined by RECIST 1.1. WHO performance status 0-2. Life expectancy of at least 12 weeks. Age 18 years or older. Able to receive oral medication. Able to provide written informed consent. Adequate hematologic function: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, Hb ≥ 6.0 mmol/L. Patients with brain metastases are eligible if they have been stable for at least two months post-radiation therapy or surgery. No other current malignant disease, except for basal cell carcinoma of the skin. Adequate hepatic function: serum bilirubin ≤ 1.5 x Upper Limit of Normal (ULN), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2.5 x ULN (or ≤ 5 times ULN if liver metastases are present). Renal function: estimated glomerular filtration rate ≥ 40 ml/min. Patients with reproductive potential must use effective contraception. Female patients must have a negative pregnancy test. Exclusion Criteria: Patients treated with any VEGF targeted TKI (sorafenib, pazopanib, axitinib, dovitinib) as second-line treatment after progression on first-line sunitinib treatment. Uncontrolled hypertension. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen. Blood pressure must be stable on at least 2 separate measurements on at least 2 separate days. Active infection or serious intercurrent illness. Presence of unstable angina, recent myocardial infarction (within the previous 3 months). Macroscopic hematuria. Presence of any significant central nervous system or psychiatric disorder(s) that would hamper the patient's compliance. Any other major illness that, in the investigator's judgment, substantially increases the risk associated with the subject's participation in the study.-

Facility Information:

Facility Name

VU Medical Center

City

Amsterdam

ZIP/Postal Code

1081 HV

Country

Netherlands

12. IPD Sharing Statement

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Phase II Study of Sunitinib Rechallenge in Patients With Metastatic Renal Cell Carcinoma

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