Multicenter Dose-escalation Study of a Combination of Pazopanib and Bevacizumab in Patients With Metastatic Renal Cell Carcinoma or Others Advanced Solid Tumors (PARASOL)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Centre Leon Berard
ClinicalTrials.gov Identifier:
NCT01202032
First received: September 14, 2010
Last updated: December 24, 2013
Last verified: December 2013
  Purpose

This is an open-label, multicenter dose-escalation phase I study using a 3+3+3 design (i.e., 3 to 9 patients per dose level) in patients with mRCC or others advanced refractory solid tumors. Enrolment will be performed to include approximately ½ of patients with mRCC.

The primary endpoint is the occurrence of limiting toxicities leading to definitive discontinuation of the study drugs during the first 24 weeks in absence of progression of the disease.

Secondary endpoints included the occurrence of Dose Limiting Toxicities (DLTs) evaluated during the first two cycles; overall response rate, 6-months progression-free survival rate and Pharmacokinetic assessments.


Condition Intervention Phase
Metastatic Renal Cell Carcinoma
Advanced Refractory Solid Tumors Histologically or Cytologically Confirmed
Drug: Association of Bevacizumab (BVC)+ Pazopanib (PZP)
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Bevacizumab in Patients With Metastatic Renal Cell Carcinoma or Others Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Centre Leon Berard:

Primary Outcome Measures:
  • Determination of the Optimal Long Exposure Dose (OLED) [ Time Frame: 24 weeks for each patient ] [ Designated as safety issue: Yes ]
    The primary endpoint is the occurrence of an interruption of one drug of the association of a duration superior to 4 weeks during the first 24 weeks in absence of progression of the disease.


Secondary Outcome Measures:
  • The determination of the maximum-tolerated dose (MTD) [ Time Frame: 8 weeks for each patient ] [ Designated as safety issue: Yes ]
  • To estimate the overall response rate (ORR) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • To estimate the 6-month progression-free survival (PFS) rate [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • To characterize the pharmacokinetic (PK) profile of Pazopanib when combined with Bevacizumab. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 36
Study Start Date: July 2010
Estimated Study Completion Date: January 2014
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Association of Bevacizumab (BVC)+ Pazopanib (PZP)

    Treatment is administered in 28-day cycles, during which patients received BVC intravenously every 2 weeks and oral PZP once daily from days 1 to 28. For the first cycle, PZP is administered alone from days 1 to 14.

    The starting dose for dose escalation is BVC at 7.5 mg/kg in combination with PZP 400 mg (level 1).

    The therapy regimens for each dose level are respectively:

    BVC 7.5 mg/kg + PZP 600 mg (level 2) BVC 10 mg/kg + PZP 600 mg (level 3) BVC 10 mg/kg + PZP 800 mg (level 4). Patients who experience grades 3 to 4 adverse events have dose adjustments to one or both drugs. Dose reductions affect in priority the administration of PZP. Doses reductions to PZP are made in 200-mg decrements and to BVC to 2.5-mg/kg decrements.

    Patients with toxicities that warrant reductions at either PZP 400 mg or BVC 7.5 mg/kg are withdrawn from the study.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age >18 years.
  • Dated and signed written informed consent.
  • Histologically progressive mRCC or other advanced refractory histologically or cytologically confirmed solid tumors. In mRCC situation, only patients who have received no prior therapy or who have failed only one prior systemic therapy (except tyrosine kinase inhibitors) are allowed; for patients with other advanced refractory solid tumors, no more than three prior systemic therapy regimens (except tyrosine kinase inhibitors) are permitted.
  • ECOG performance status of 0 or 1.
  • At least one measurable site of disease as defined by RECIST criteria 1.1. based on investigator's assessment.
  • Adequate bone marrow function: absolute neutrophil count >=1.5 x 109/L, platelet count >= 100 x 109/L, and hemoglobin >= 9 g/dL.
  • Adequate liver function: AST/ALT <= 2 x upper limit of normal (ULN) and total bilirubin in the normal values.
  • Adequate coagulation function: prothrombin time (PT) or international normalized ratio (INR) <=1.2 x ULN and activated partial thromboplastin time (APTT)<=1.2x ULN.
  • Adequate renal function: serum creatinine ≤ 1.5 mg/dL (133 µmol/L) or, if greater than 1.5 mg/dL: calculated creatinine clearance ≥ 50 mL/min.
  • Absence of proteinuria confirmed by urinary dipstick test. If the dipstick test is twice positive, proteinuria will be quantified on a complete 24h urine sample: urine protein value must be <1 g /L.
  • Ability to swallow and retain oral medication.
  • Adequate contraception methods.
  • Mandatory affiliation with a health insurance company.

Exclusion Criteria:

  • Prior Pazopanib treatment.
  • Prior Bevacizumab treatment within 6 months prior to begin study treatment. Patients with any grade 3 or grade 4 toxicity during prior BVC therapy are not eligible.
  • Prior treatment with any tyrosine kinase inhibitor.
  • Concomitant participation to an other clinical study estimating a experimental agent.
  • Patients with any haematological, renal, or neurological grade 3-4 toxicity during prior systemic therapy regimens.
  • Patients with any liver injury grade 3-4 during prior systemic therapy regimens.
  • Patients with squamous non-small cell lung carcinoma.
  • Patients with high vascular and nephrologic risks [uncontrolled hypertension while receiving appropriate medication (SBP ≥ 150 mmHg and DBP ≥ 90 mmHg), significant proteinuria, low creatinine clearance level…].
  • Patients with brain metastases.
  • Clinically significant gastrointestinal abnormalities which might interfere with oral dosing:

Active peptic ulcer disease;kown intraluminal metastatic lesion/s with suspected bleeding;inflammatory bowel disease; ulcerative colitis, 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; malabsorption syndrome; major resection of the stomach or small bowel.

  • History of Gilbert's disease.
  • Patients with chronic hepatitis.
  • Any unstable or serious concurrent condition (i.e., presence of uncontrolled infection).
  • Prolongation of corrected QT interval (QTc) >480 msecs using Bazett's formula.
  • History of any one of more of the following cardiovascular conditions within the past 6 months: Cardiac angioplasty or stenting; myocardial infarction; unstable angina; symptomatic peripheral vascular disease; coronary artery by-pass graft surgery; class III or IV congestive heart failure as defined by the New York Heart Association (NYHA); history of cerebrovascular accident, 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-coagulant agents (excluding therapeutic warfarin) for at least 6 weeks are eligible.

  • Hemoptysis within 6 weeks of first dose of study drug.
  • Evidence of active bleeding or bleeding diathesis.
  • Anticoagulant treatment with curative intent.
  • Known endobronchial lesions or involvement of large pulmonary vessels by tumor.
  • Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer.
  • Radiation therapy, surgery or tumor embolization within 2 weeks prior to the first dose of study drug.
  • Chemotherapy, immunotherapy, biological therapy, hormonal therapy or treatment with an investigational agent within 14 days or 5 half-lives, whichever is longer prior to the first dose of study drug.
  • Patient unable or unwilling to discontinue predefined prohibited medications listed in the protocol for 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study.
  • Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to PZP.
  • Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
  • Clinically assessed as having inadequate venous access for PK sampling.
  • Women who are pregnant or breast feeding.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01202032

Locations
France
Centre Léon BERARD
Lyon, France, 69373
Sponsors and Collaborators
Centre Leon Berard
Investigators
Principal Investigator: SYLVIE NEGRIER, Phd Centre Léon Bérard; Lyon; FRANCE
  More Information

Additional Information:
Publications:
Coppin C, Porzsolft F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database of Systematic reviews 2008a, Issue 3. Art No.: CD001425.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Centre Leon Berard
ClinicalTrials.gov Identifier: NCT01202032     History of Changes
Other Study ID Numbers: PARASOL
Study First Received: September 14, 2010
Last Updated: December 24, 2013
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé
France: French Data Protection Authority

Keywords provided by Centre Leon Berard:
Metastatic renal cell carcinoma
Advanced solid tumors
Dose escalation
Association Pazopanib-Bevacizumab

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Neoplasms
Adenocarcinoma
Kidney Diseases
Kidney Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Urogenital Neoplasms
Urologic Diseases
Urologic Neoplasms
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Growth Inhibitors
Growth Substances
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014