Prospective Translational Study Investigating Possible Molecular prEdictors of Resistance to First-Line pazopanIb (PIPELINE)

July 8, 2020 updated by: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Prospective Translational Study Investigating Possible Molecular prEdictors of Resistance to First-Line pazopanIb in Metastatic reNal Cell Carcinoma

This is a prospective, single-arm, monocentric translational study designed to evaluate possible biomarkers of resistance to the first line of therapy with pazopanib in patients with metastatic renal cell carcinoma (mRCC) who have not received systemic therapy in both the adjuvant and metastatic phases.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

a prospective, single-arm, monocentric translational study

Study Type

Interventional

Enrollment (Actual)

25

Phase

  • Phase 2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 88 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Signed Informed Consent Form
  • Unresectable advanced or metastatic renal cell carcinoma (RCC) with component of clear cell histology and/or component of sarcomatoid histology that has not been previously treated with any systemic agent, including treatment in the adjuvant setting
  • Availability of a representative formalin-fixed paraffin-embedded fractional Fokker-Planck equation (FFPE) tumor specimen collected within 24 months of starting first-line pazopanib that enables the definitive diagnosis of renal cell carcinoma (RCC) (the archival specimen must contain adequate viable tumor tissue to enable candidate biomarkers status; the specimen may consist of a tissue block or at least 15 unstained serial sections; for core needle biopsy specimens at least two cores should be available for evaluation)
  • Measurable disease as defined by RECIST v1.1
  • Age ≥18 years

Hematology Absolute neutrophil count (ANC)≥1.5 X 109/L Hemoglobin ≥9 g/dL (5.6 mmol/L) Platelets ≥100 X 109/L Prothrombin time (PT) or international normalized ratio (INR)b ≤1.5 X upper limit of normal (ULN) Activated partial thromboplastin time (aPTT) ≤1.5 X upper limit of normal (ULN) Hepatic Total bilirubin ≤1.5 X upper limit of normal (ULN) Alanine amino transferase (ALT) and Aspartate aminotransferase (AST)c 2.5 X upper limit of normal (ULN) Patients with documented liver metastases <5 X upper limit of normal (ULN) Renal Serum creatinine 1.5 mg/dL (133 µmol/L) Or, if >1.5 mg/dL: Calculated creatinine clearance (ClCR) (reference appropriate appendix) ≥30 mL/min to ≥ 50 mL/min Urine Protein to Creatinine Ratio (UPC; appropriate appendix)<1 Or, 24-hour urine protein <1g

- Eastern Cooperative Oncology Group (ECOG) performance Status 0-1

Exclusion Criteria:

  • Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to: active peptic ulcer disease, known intraluminal metastatic lesion/s with risk of bleeding, inflammatory bowel disease (e.g. ulcerative colitis, Chrohn's disease), or other gastrointestinal conditions with increased risk of perforation, history of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
  • History of any one or more of the following cardiovascular conditions within the past 6 months:

cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) - Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 millimetre (s) of mercury (mmHg) or diastolic blood pressure (DBP) of ≥ 90 millimetre (s) of mercury (mmHg)].

Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement. These three values should be averaged to obtain the mean diastolic blood pressure and the mean systolic blood pressure. The mean SBP / DBP ratio must be <140/90 millimetre (s) of mercury (mmHg) (OR 150/90 millimetre (s) of mercury (mm Hg), if this criterion is approved by Safety Review Team) in order for a subject to be eligible for the study

- History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible

  • Major surgery or trauma within 28 days prior to first dose of pazopanib and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery).
  • Evidence of active bleeding or bleeding diathesis.
  • Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage Note: Lesions infiltrating major pulmonary vessels (contiguous tumour and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions).
  • Large protruding endobronchial lesions in the main or lobar bronchi are excluded; however, endobronchial lesions in the segmented bronchi are allowed.
  • Lesions extensively infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in the wall of the bronchi are allowed.
  • Recent hemoptysis (½ teaspoon of red blood within 8 weeks before first dose of study drug).
  • Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
  • Treatment with any of the following anti-cancer therapies:
  • chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of Pazopanib

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: pazopanib
Pazopanib 800 mg (2x400mg ) taken orally daily as per clinical practice
Drug: Pazopanib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
A panel of possible predictive candidate biomarkers of resistance to anti-angiogenic targeted tyrosine kinase inhibitor (TKI)
Time Frame: 18 months
using next-generation sequencing (NGS) methods for future research. This will be done by within-patient comparison of metastatic tissue samples taken on commencement of first-line pazopanib, and secondly on development of TKI resistance
18 months
The Overall Response Rate (ORR)
Time Frame: 18 months
evaluate per RECIST v.1.1 criteria in mRCC patients treated with first-line pazopanib in order to either correlate circulating angiogenic factors (CAFs) levels and gene candidate biomarkers status to clinical outcome when resistance develops
18 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Identification of other protein markers circulating in blood,
Time Frame: 18 months
To obtain serial blood samples from patients whilst they are being treated with pazopanib
18 months
compare the frequency of previously defined promising circulating predictive biomarkers for pazopanib treatment
Time Frame: 18 months
between blood samples taken at commencement of therapy (baseline) and at the time of progressive disease (PD) as per RECIST 1.1 criteria as well as changes of interleukin 8 (IL-8), c-Met and hematopoietic growth factor (HGF) expression between metastatic tumour tissue samples in order to better understand changes in the tumor and in the levels of circulating angiogenic factors as resistance develops.
18 months
Collect Data
Time Frame: 18 months
prospective and retrospective demographic, clinical and pathological data on patients who enter the study, enabling current and future correlation of biomarkers to clinical outcomes
18 months
Perform subgroup analyses
Time Frame: 18 months
comparing the tissue and blood biomarkers identified in patients who developed secondary resistance with those biomarkers identified in patients who have primary resistance.
18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Investigators

  • Principal Investigator: Giuseppe Procopio, MD, Fondazione IRCCS Istituto Nazionale Tumori

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 25, 2015

Primary Completion (Actual)

February 8, 2017

Study Completion (Actual)

February 8, 2017

Study Registration Dates

First Submitted

July 2, 2020

First Submitted That Met QC Criteria

July 2, 2020

First Posted (Actual)

July 8, 2020

Study Record Updates

Last Update Posted (Actual)

July 10, 2020

Last Update Submitted That Met QC Criteria

July 8, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • INT 146-14

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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