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Metastatic Renal Cell CarcinomaPhase 1PARASOLNCT01202032

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

A Phase 1 study testing Association of Bevacizumab (BVC)+ Pazopanib (PZP) in people with Metastatic Renal Cell Carcinoma and Advanced Refractory Solid Tumors Histologically or Cytologically Confirmed, run by Centre Leon Berard at 1 site in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Association of Bevacizumab (BVC)+ Pazopanib (PZP)
How many people
36 participants
Where
1 siteFrance
Study dates
Jul 2010to Mar 2013
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
Show all 13Show fewer
  • 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.

Who cannot join

  • 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.
Show all 30Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

France1 site

  • Centre Léon BERARD

    Lyon, 69373

Other trials in France

About this study

Official title: Bevacizumab in Patients With Metastatic Renal Cell Carcinoma or Others Advanced Solid Tumors

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.

Read the detailed description

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 (ORR), 6-months progression-free survival rate and Pharmacokinetic assessments.

The following definitions will be used:

DLT:

The Dose Limiting Toxicities (DLTs) are defined as the occurrence during the first two cycles of any grade 4 toxicity, and of any following events:

  • clinical evidence of congestive heart failure,
  • any arterial thromboembolic event,
  • grade 3 venous thrombosis,
  • grade 3 thrombocytopenia >=7 days or associated with bleeding,
  • grade 3 hypertension uncontrolled (>=160/90 mmHg) with medications,
  • grade 3 elevations in AST/ALT or total bilirubin. Any other grade 3 toxicity >=7 days is also considered as a DLT, with exception of fatigue.

MTD:

The determination of the maximum-tolerated dose (MTD) will be conducted on a 3 + 3 + 3 design. Cohorts of 3 to 9 patients will be sequentially enrolled in 3 steps to receive one of four escalated doses of Pazopanib in combination with Bevacizumab to establish the MTD (step 1: patients 1 to 3; step 2: patients 4 to 6; step 3: patients 7 to 9).

The MTD is considered to be exceeded if DLT is observed during the first 2 cycles (i.e., 56 days) in at least 2 out of 3 or 3 out of 6 patients evaluable for MTD in the two first steps, then in at least 3 out of 9 patients after completion of enrolment (step 3).

When the MTD will be established, patients already involved in the follow-up phase at a dose level above the MTD should decrease to the MTD.

Note: in an exploratory way (i.e., with simulation) the possibility to take into account for the determination of the MTD the occurrence of recurrent grade 2 events or the combination of synergic grade 2-3 toxicities as "1/2 DLT" will be investigated in the study.

Optimal Long Exposure Dose (OLED):

To determine the Optimal Long Exposure Dose (OLED), all patients which will not experience a Dose Limiting Toxicity (DLT) during the first two cycles will continue the treatment and will be followed until week 24, in order to record toxic reactions of lesser severity or mixed toxicities leading to definitive discontinuation of the study drug, in the absence of progression of the disease.

The OLED is defined as the dose level (less than or equal to the MTD) for which the occurrence of sub-acute limiting toxicities leading to definitive discontinuation of the study drug is compatible with further phase II studies.

In practice, if <=2/7-8 patients or <=3/9 patients treated at a dose level <=MTD and followed until week 24 experience sub-acute limiting toxicities, that dose level will be considered as the OLED.

ORR:

The overall response rate (ORR) is defined as the proportion of patients with a complete response (CR) or partial response (PR) - target lesions and tumor response according to RECIST guidelines.

Progression-Free Survival (PFS):

Progression-free survival (PFS) is defined as the time from the date of first study drug administration to the date of the first observation of documented disease progression or death due to any cause. PFS will be determined based on tumor assessment (RECIST criteria) and survival information.

Being tested
Association of Bevacizumab (BVC)+ Pazopanib (PZP)
Keywords
Metastatic renal cell carcinoma, Advanced solid tumors, Dose escalation, Association Pazopanib-Bevacizumab
Medical subject headings
Carcinoma, Renal Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Association of Bevacizumab (BVC)+ Pazopanib (PZP)Drug

    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.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Determination of the Optimal Long Exposure Dose (OLED)

    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.

    Measured: 24 weeks for each patient

Secondary outcomes (4)

  1. The determination of the maximum-tolerated dose (MTD)

    Measured: 8 weeks for each patient

  2. To estimate the overall response rate (ORR)

    Measured: 24 weeks

  3. To estimate the 6-month progression-free survival (PFS) rate

    Measured: 24 weeks

  4. To characterize the pharmacokinetic (PK) profile of Pazopanib when combined with Bevacizumab.

    Measured: 8 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Sep 2010 (estimated)
  2. Study startJul 2010
  3. Primary completionJan 2013
  4. Study completionMar 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
36 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01202032
Sponsor's protocol ID
PARASOL
Acronym
PARASOL
Status last verified
May 2016
First submitted
14 Sep 2010
Last updated
18 May 2016
Results posted
No
Data monitoring committee
Yes

Publications

  • Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003 Jun;9(6):669-76. doi: 10.1038/nm0603-669.

    PubMed 12778165

  • Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002 Nov 1;20(21):4368-80. doi: 10.1200/JCO.2002.10.088.

    PubMed 12409337

  • Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A, Stafford JA, Luttrell DK, Cheung M. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther. 2007 Jul;6(7):2012-21. doi: 10.1158/1535-7163.MCT-07-0193.

    PubMed 17620431

  • Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, Epstein RJ, Baker KL, McCann L, Crofts T, Pandite L, Figlin RA. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010 Jan 20;28(3):475-80. doi: 10.1200/JCO.2008.21.6994. Epub 2009 Dec 14.

    PubMed 20008644

  • Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22;370(9605):2103-11. doi: 10.1016/S0140-6736(07)61904-7.

    PubMed 18156031

  • Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 Nov 20;26(33):5422-8. doi: 10.1200/JCO.2008.16.9847. Epub 2008 Oct 20.

    PubMed 18936475

  • Belot A, Grosclaude P, Bossard N, Jougla E, Benhamou E, Delafosse P, Guizard AV, Molinie F, Danzon A, Bara S, Bouvier AM, Tretarre B, Binder-Foucard F, Colonna M, Daubisse L, Hedelin G, Launoy G, Le Stang N, Maynadie M, Monnereau A, Troussard X, Faivre J, Collignon A, Janoray I, Arveux P, Buemi A, Raverdy N, Schvartz C, Bovet M, Cherie-Challine L, Esteve J, Remontet L, Velten M. Cancer incidence and mortality in France over the period 1980-2005. Rev Epidemiol Sante Publique. 2008 Jun;56(3):159-175. doi: 10.1016/j.respe.2008.03.117. Epub 2008 Jun 10.

    PubMed 18547762

  • Remontet L, Esteve J, Bouvier AM, Grosclaude P, Launoy G, Menegoz F, Exbrayat C, Tretare B, Carli PM, Guizard AV, Troussard X, Bercelli P, Colonna M, Halna JM, Hedelin G, Mace-Lesec'h J, Peng J, Buemi A, Velten M, Jougla E, Arveux P, Le Bodic L, Michel E, Sauvage M, Schvartz C, Faivre J. Cancer incidence and mortality in France over the period 1978-2000. Rev Epidemiol Sante Publique. 2003 Feb;51(1 Pt 1):3-30.

    PubMed 12684578

  • Diaz JI, Mora LB, Hakam A. The Mainz Classification of Renal Cell Tumors. Cancer Control. 1999 Nov;6(6):571-579. doi: 10.1177/107327489900600603.

    PubMed 10756388

  • Nelson EC, Evans CP, Lara PN Jr. Renal cell carcinoma: current status and emerging therapies. Cancer Treat Rev. 2007 May;33(3):299-313. doi: 10.1016/j.ctrv.2006.12.005. Epub 2007 Feb 27.

    PubMed 17329029

  • Lam JS, Belldegrun AS, Pantuck AJ. Long-term outcomes of the surgical management of renal cell carcinoma. World J Urol. 2006 Aug;24(3):255-66. doi: 10.1007/s00345-006-0055-5. Epub 2006 Feb 15.

    PubMed 16479388

  • Mickisch G, Carballido J, Hellsten S, Schulze H, Mensink H; European Association of Urology. Guidelines on renal cell cancer. Eur Urol. 2001 Sep;40(3):252-5. doi: 10.1159/000049783.

    PubMed 11684839

  • Yagoda A, Abi-Rached B, Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol. 1995 Feb;22(1):42-60. No abstract available.

    PubMed 7855619

  • Negrier S, Perol D, Ravaud A, Chevreau C, Bay JO, Delva R, Sevin E, Caty A, Escudier B; French Immunotherapy Intergroup. Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: results of a randomized controlled trial. Cancer. 2007 Dec 1;110(11):2468-77. doi: 10.1002/cncr.23056.

    PubMed 17932908

  • Negrier S, Perol D, Ravaud A, Bay JO, Oudard S, Chabaud S, Fargeot P, Delva R, Deplanque G, Gravis G, Escudier B; French Immunotherapy Group. Randomized study of intravenous versus subcutaneous interleukin-2, and IFNalpha in patients with good prognosis metastatic renal cancer. Clin Cancer Res. 2008 Sep 15;14(18):5907-12. doi: 10.1158/1078-0432.CCR-08-0236.

    PubMed 18794104

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Association of Bevacizumab (BVC)+ Pazopanib (PZP) in people with Metastatic Renal Cell Carcinoma and Advanced Refractory Solid Tumors Histologically or Cytologically Confirmed, run by Centre Leon Berard at 1 site in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 May 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Determination of the Optimal Long Exposure Dose (OLED) (time frame: 24 weeks for each patient). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01202032, which also lists 29 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 May 2016.

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