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NEXT: Subsequent Exposure to Tyrosine Kinase Inhibition at Recurrence After Adjuvant Therapy in Renal Cell Carcinoma (PrE0801)

Primary Purpose

Renal Cell Carcinoma

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Axitinib

About this trial

This is an interventional treatment trial for Renal Cell Carcinoma focused on measuring RCC, Clear Cell Renal Cell Carcinoma, ccRCC, Metastatic RCC, Recurrent RCC, Kidney Cancer, Kidney Neoplasms, Axitinib, AG-013736, Tyrosine Kinase Inhibition, TKI

Eligibility Criteria

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

Inclusion Criteria:

Locally recurrent or metastatic RCC requiring systemic therapy following treatment (tx) with sorafenib, sunitinib, pazopanib, or placebo on an adjuvant study
Required to have primary or recurrence tumor samples containing clear cell variant RCC with <50% of any other histology
Recurrence must occur ≥ 3 months following end of exposure to the adjuvant intervention
Received ≥ 3 six week cycles of prior adjuvant tx with sorafenib, sunitinib, pazopanib or placebo in the adjuvant setting on a clinical trial, or recurrence >3 months of tx on an adjuvant placebo arm
Required to have measurable recurrent or metastatic disease that is not curable by standard radiation therapy or surgery
Male or female, ≥ 18 years old
ECOG PS 0 or 1
Blood pressure (B/P) must be controlled at time of enrollment. Tx with antihypertensive medication(s) is allowed. Controlled B/P is defined as in clinic measurement of systolic B/P ≤ 140 mm Hg AND diastolic B/P ≤ 90 mm Hg. If B/P is uncontrolled at time of planned enrollment, tx or optimization with antihypertensive medication(s) may be initiated in order to control B/P. Patient may be considered for enrollment when this has happened.
Women must not be pregnant or breastfeeding
Men and women who are of reproductive potential must be willing to employ an effective method of birth control/contraception
Willingness and ability to comply with scheduled visits, tx plans, laboratory tests, and other study procedures
Ability to understand and willingness to sign an IRB-approved informed consent
Adequate organ function as evidenced by the following, obtained within 28 days prior to registration:
- Absolute neutrophil count (ANC) ≥ 1250 cells/mm³
- Platelet count ≥ 75,000 cells/mm³
- Hemoglobin ≥ 9.0 g/dL
- Total direct serum bilirubin ≤ 1.5x upper limit of normal (ULN)
- ALT and AST ≤ 2.5 x ULN unless there are liver metastases in which case AST and ALT ≤ 5.0 x ULN
- Serum creatinine <1.5 x ULN or calculated creatinine clearance ≥ 45 mL/min
- Urine protein <2+ by urine dipstick
Resolution of all previous tx-related toxicity to ≤ grade 1 or back to baseline
No major surgery <4 weeks or radiation therapy <2 weeks of starting study tx. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated.
No clinically significant gastrointestinal abnormalities
No current use or anticipated need for tx with drugs that are known potent CYP3A4 inhibitors
No current or anticipated need for tx with drugs that are known CYP3A4 or CYP1A2 inducers
No current requirement of anticoagulant therapy with oral vitamin K antagonists
No untreated brain metastases, spinal cord compression, or carcinomatous meningitis. Patients must be off oral (systemic) steroids prior to registration. Inhalational steroids, e.g., for asthma, emphysema are permissible.
No serious uncontrolled medical disorder or active infection that would impair their ability to receive study tx
None of the following conditions within the 6 months prior to study drug: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep vein thrombosis or pulmonary embolism
No known HIV or AIDS-related illness
No other active malignancy
No dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of the protocol
No other severe acute/chronic medical or psychiatric condition or lab abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study

Sites / Locations

Missouri Valley Cancer Consortium
Cleveland Clinic, Taussig Cancer Institute
University of Pennsylvania, Abramson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Axitinib

Arm Description

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

Outcomes

Primary Outcome Measures

Progression-free Survival

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.

Secondary Outcome Measures

Overall Response Rate

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

Biospecimen Banking for IL-8 and VEGF-A

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.

Biospecimen Banking for SNPs Analysis

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.

Tumor Tissue Banking

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.

Full Information

NCT ID

NCT01649180

First Posted

July 21, 2012

Last Updated

July 26, 2021

Sponsor

PrECOG, LLC.

Collaborators

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT01649180

Brief Title

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

Acronym

PrE0801

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2017

Overall Recruitment Status

Terminated

Why Stopped

Closed due to prolonged enrollment timelines

Study Start Date

July 2012 (undefined)

Primary Completion Date

January 2016 (Actual)

Study Completion Date

March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

PrECOG, LLC.

Collaborators

Pfizer

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

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

Renal Cell Carcinoma

Keywords

RCC, Clear Cell Renal Cell Carcinoma, ccRCC, Metastatic RCC, Recurrent RCC, Kidney Cancer, Kidney Neoplasms, Axitinib, AG-013736, Tyrosine Kinase Inhibition, TKI

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

3 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Axitinib

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Axitinib

Other Intervention Name(s)

AG-013736, Tyrosine Kinase Inhibitor (TKI)

Intervention Description

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

Primary Outcome Measure Information:

Title

Progression-free Survival

Description

Time Frame

Assessed every 12 weeks up to 36 months

Secondary Outcome Measure Information:

Title

Overall Response Rate

Description

Time Frame

Assessed every 12 weeks up to 36 months

Title

Biospecimen Banking for IL-8 and VEGF-A

Description

Time Frame

Baseline and 8 weeks

Title

Biospecimen Banking for SNPs Analysis

Description

Time Frame

Baseline

Title

Tumor Tissue Banking

Description

Time Frame

Baseline

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Locally recurrent or metastatic RCC requiring systemic therapy following treatment (tx) with sorafenib, sunitinib, pazopanib, or placebo on an adjuvant study Required to have primary or recurrence tumor samples containing clear cell variant RCC with <50% of any other histology Recurrence must occur ≥ 3 months following end of exposure to the adjuvant intervention Received ≥ 3 six week cycles of prior adjuvant tx with sorafenib, sunitinib, pazopanib or placebo in the adjuvant setting on a clinical trial, or recurrence >3 months of tx on an adjuvant placebo arm Required to have measurable recurrent or metastatic disease that is not curable by standard radiation therapy or surgery Male or female, ≥ 18 years old ECOG PS 0 or 1 Blood pressure (B/P) must be controlled at time of enrollment. Tx with antihypertensive medication(s) is allowed. Controlled B/P is defined as in clinic measurement of systolic B/P ≤ 140 mm Hg AND diastolic B/P ≤ 90 mm Hg. If B/P is uncontrolled at time of planned enrollment, tx or optimization with antihypertensive medication(s) may be initiated in order to control B/P. Patient may be considered for enrollment when this has happened. Women must not be pregnant or breastfeeding Men and women who are of reproductive potential must be willing to employ an effective method of birth control/contraception Willingness and ability to comply with scheduled visits, tx plans, laboratory tests, and other study procedures Ability to understand and willingness to sign an IRB-approved informed consent Adequate organ function as evidenced by the following, obtained within 28 days prior to registration: Absolute neutrophil count (ANC) ≥ 1250 cells/mm³ Platelet count ≥ 75,000 cells/mm³ Hemoglobin ≥ 9.0 g/dL Total direct serum bilirubin ≤ 1.5x upper limit of normal (ULN) ALT and AST ≤ 2.5 x ULN unless there are liver metastases in which case AST and ALT ≤ 5.0 x ULN Serum creatinine <1.5 x ULN or calculated creatinine clearance ≥ 45 mL/min Urine protein <2+ by urine dipstick Resolution of all previous tx-related toxicity to ≤ grade 1 or back to baseline No major surgery <4 weeks or radiation therapy <2 weeks of starting study tx. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated. No clinically significant gastrointestinal abnormalities No current use or anticipated need for tx with drugs that are known potent CYP3A4 inhibitors No current or anticipated need for tx with drugs that are known CYP3A4 or CYP1A2 inducers No current requirement of anticoagulant therapy with oral vitamin K antagonists No untreated brain metastases, spinal cord compression, or carcinomatous meningitis. Patients must be off oral (systemic) steroids prior to registration. Inhalational steroids, e.g., for asthma, emphysema are permissible. No serious uncontrolled medical disorder or active infection that would impair their ability to receive study tx None of the following conditions within the 6 months prior to study drug: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, deep vein thrombosis or pulmonary embolism No known HIV or AIDS-related illness No other active malignancy No dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of the protocol No other severe acute/chronic medical or psychiatric condition or lab abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Stephen Keefe, MD

Organizational Affiliation

University of Pennsylvania Health System

Official's Role

Study Chair

Facility Information:

Facility Name

Missouri Valley Cancer Consortium

City

Omaha

State/Province

Nebraska

ZIP/Postal Code

68106

Country

United States

Facility Name

Cleveland Clinic, Taussig Cancer Institute

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

University of Pennsylvania, Abramson Cancer Center

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

Data is proprietary.

Citations:

PubMed Identifier

19652060

Citation

Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, Dutcher JP. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009 Sep 20;27(27):4462-8. doi: 10.1200/JCO.2008.21.7034. Epub 2009 Aug 3.

Results Reference

background

PubMed Identifier

19010843

Citation

Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, Wu EY, McTigue MA, Murray BW, Kania RS, O'Connor P, Shalinsky DR, Bender SL. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008 Nov 15;14(22):7272-83. doi: 10.1158/1078-0432.CCR-08-0652.

Results Reference

background

PubMed Identifier

17959415

Citation

Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J, Trask PC, Kim S, Rini BI. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol. 2007 Nov;8(11):975-84. doi: 10.1016/S1470-2045(07)70285-1. Epub 2007 Oct 23.

Results Reference

background

PubMed Identifier

21679004

Citation

Escudier B, Gore M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D. 2011;11(2):113-26. doi: 10.2165/11591240-000000000-00000.

Results Reference

background

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

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