Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00004010

Trial Description

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Title

Pazopanib With 5-Fluorouracil, Leucovorin and Oxaliplatin (FLO) as 1st-line Treatment in Advanced Gastric Cancer; a Randomized Phase-II-study of the Arbeitsgemeinschaft Internistische Onkologie

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Trial Acronym

PaFLO

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URL of the Trial

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Brief Summary in Lay Language

The prognosis of advanced gastric cancer and adenocarcinoma of the gastro-esophageal (GE)
junction is poor. Even with modern chemotherapy the median survival ranges around 8-10
months.

Inhibition of neoangiogenesis seems to be a very promising approach in gastric cancer.

Vascular endothelial growth factor (VEGF) acts as one of the most potent stimulating agents
of angiogenesis, and several strategies targeting the VEGF signaling pathway have been
developed, including anti-VEGF antibodies, soluble receptors binding directly to VEGF
ligand, anti-VEGF receptor (VEGFR) antibodies and VEGFR tyrosine kinase inhibitors. The
breakthrough in the clinical development of anti-angiogenic therapy against colorectal
cancer came in 2003 with a large prospective, randomized clinical trial of bevacizumab, a
monoclonal antibody directed against VEGF. Anti-angiogenic therapy has introduced a highly
effective, completely new mode of action in this area and is the new standard of care in
advanced colorectal cancer.

The concept of VEGF inhibition is also very promising in gastric cancer. Bevacizumab was
investigated in combination with irinotecan and cisplatin in a phase-II trial, including 47
patients with gastric and GE-junction carcinoma. Bevacizumab could safely be given and could
improve time to tumor progression by 75% compared to historical controls. Several phase-II
trials confirm the tolerability and promising efficacy of bevacizumab in gastric cancer
(Bevacizumab + Docetaxel/Oxaliplatin; FOLFOX + Bevacizumab; Docetaxel/Cisplatin/Irinotecan +
Bevacizumab). These results were so promising that randomized phase-III trials in the
1st-line and perioperative setting are under way (AVAGAST-trial: Cisplatin /Capecitabine +/-
bevacizumab 1st line ; MAGIC-B-trial : ECX +/- bevacizumab perioperative).

Tyrosin kinase inhibitors which inhibit VEGF receptors and EGFR are also investigated in
gastric cancer with promising efficacy. Pazopanib, an orally available tyrosine kinase
inhibitor, selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2
and -3, c-kit and platelet derived growth factor receptor (PDGF-R), which results in
inhibition of angiogenesis in tumors in which these receptors are upregulated. Pazopanib has
the advantage of being an orally available anti-angiogenesis component.

Pazopanib shows promising activity in phase-II trials in renal cell cancer, breast cancer,
soft tissue sarcoma and non small cell lung cancer. A phase-III trial of pazopanib in renal
cell cancer (NCT00334282) is completed and resulted in the approval of Pazopanib for this
disease. A phase-III trial in soft tissue sarcoma (NCT00753688) is currently performed.

In phase-I trials, pazopanib was investigated in combination with FOLFOX and
Capecitabine/Oxaliplatin. FOLFOX could be administered in full dose with 800 mg pazopanib.
In Cape/Ox, capecitabine had to be reduced to 850mg/m² bd.

5-FU- and oxaliplatin-based regimens are one of the established treatment standards for
1st-line therapy in metastatic gastric cancer. The efficacy of 5-FU, leukovorin and
oxaliplatin (FLO) compared to 5-FU, cisplatin could be confirmed in a randomized phase-III
trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). FLO has a favorable
toxicity profile. In Germany, FLO is a widely used combination for advanced gastric cancer
and is a recommended regimen in the new German S3-guidelines 2011.

The investigators therefore want to examine FLO + pazopanib.

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Brief Summary in Scientific Language

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00004010
  •   2012/12/19
  •   2011/12/22
  •   yes
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Secondary IDs

  •   2010-024379-15 
  •   NCT01503372  (ClinicalTrials.gov)
  •   PaFLO  (Charite University, Berlin, Germany)
  •   2010-024379-15 
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Health Condition or Problem studied

  •   Advanced Gastric Cancer
  •   C16 -  Malignant neoplasm of stomach
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Interventions/Observational Groups

  •   Drug: Pazopanib
  •   Drug: 5-FU, Oxaliplatin, Leukovorin (FLO)
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   II
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Primary Outcome

- progression-free survival rate at 6 months; time frame: 6 months after study entry

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Secondary Outcome

- progression-free survival rate at 9 and 12 months; time frame: 9 and 12 months after study entry
- median progression-free survival; time frame: 48 months
- response rate; time frame: 48 months
- duration of response; time frame: 48 months
- toxicity; time frame: 48 months; number of patients with Adverse Events according to CTC-criteria
- tolerability; time frame: 48 months; number of patients having adverse events and require interruptions and dose reductions of chemotherapy
- overall survival; time frame: 48 months
- time to treatment failure; time frame: 48 months
- evaluation of the predictive and prognostic relevance of biomarkers; time frame: 48 months; collection of plasma samples at designated time points during treatment and measuring of angiogenic factors correlating with response rate and outcome

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

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  •   2011/11/30
  •   75
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

- Subjects must provide written informed consent prior to performance of study-specific
procedures or assessments, and must be willing to comply with treatment and follow
up.

- Age ≥ 18 years.

- Histologically confirmed adenocarcinoma of the stomach or the gastroesophageal
junction with either metastatic or locally advanced disease, incurable by operation.

- Eastern Cooperative Oncology Group (ECOG) performance status of < or = 2

- At least one unidimensional, measurable tumor parameter (according to RECIST 1.1)

- No preceding cytotoxic therapy (neoadjuvant or adjuvant treatment allowed if finished
> 6 months before inclusion)

- Adequate organ system function.

- Men and women must perform an adequate contraception.

- Female subjects who are lactating should discontinue nursing prior to the first dose
of study drug and should refrain from nursing throughout the treatment period and for
14 days following the last dose of study drug.

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Exclusion Criteria

- Prior malignancy, except for curatively treated basal cell carcinoma of the skin and
in situ carcinoma of the cervix.

- Overexpression of HER-2, defined as IHC 3+ or IHC 2+ and FISH positive.

- Known hypersensitivity against 5-FU, leukovorin, oxaliplatin or other platinum
compounds or pazopanib.

- History or clinical evidence of central nervous system (CNS) metastases or
leptomeningeal carcinomatosis.

- Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding or the absorption of investigational product

- Presence of uncontrolled infection.

- Corrected QT interval (QTc) > 480 ms using Bazett's formula.

- 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, NYHA
III or IV congestive heart failure.

- Poorly controlled hypertension.

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

- 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.

- Evidence of active bleeding or bleeding diathesis.

- Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.

- Hemoptysis in excess of 2.5 ml within 8 weeks of 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.

- Unable or unwilling to discontinue use of prohibited medications for at least 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.

- Treatment with any of the following anti-cancer therapies: radiation therapy, surgery
or tumor embolization within 14 days prior to the first dose of pazopanib OR
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. A neoadjuvant or adjuvant chemotherapy must be finished
at least 6 month before study entry.

- Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is
progressing in severity, except alopecia.

- Grade 3 or 4 diarrhea.

- Peripheral polyneuropathy > NCI Grade.

- Pregnant or lactating women.

- Men or women who are planning a pregnancy within the next six months.

- Participation in another clinical trial with investigational agents within the last
30 days prior to study start.

- The patient is a colleague or employed by the study investigator or by an involved
institution including the sponsor of the study.

- Patient is detained in a psychiatric unit or imprisoned.

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Addresses

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    • Charite University, Berlin, Germany
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    • Charite University medicine
    • Peter Thuss-Patience, MD 
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  • start of 1:1-Block address public-contact
    • Mario Lorenz 
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

  •   Shah MA, Ramanathan RK, Ilson DH, Levnor A, D'Adamo D, O'Reilly E, Tse A, Trocola R, Schwartz L, Capanu M, Schwartz GK, Kelsen DP. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2006 Nov 20;24(33):5201-6.; 17114652
  •   Moehler MH, Hartmann JT, Lordick F, et al. An open-label, multicenter phase II trial of sunitinib for patients with chemorefractory metastatic gastric cancer. ASCO Meeting Abstracts. 2010;28(15_suppl):e14503.
  •   Moehler M, Al-Batran SE, Andus T, Anthuber M, Arends J, Arnold D, Aust D, Baier P, Baretton G, Bernhardt J, Boeing H, Böhle E, Bokemeyer C, Bornschein J, Budach W, Burmester E, Caca K, Diemer WA, Dietrich CF, Ebert M, Eickhoff A, Ell C, Fahlke J, Feussner H, Fietkau R, Fischbach W, Fleig W, Flentje M, Gabbert HE, Galle PR, Geissler M, Gockel I, Graeven U, Grenacher L, Gross S, Hartmann JT, Heike M, Heinemann V, Herbst B, Herrmann T, Höcht S, Hofheinz RD, Höfler H, Höhler T, Hölscher AH, Horneber M, Hübner J, Izbicki JR, Jakobs R, Jenssen C, Kanzler S, Keller M, Kiesslich R, Klautke G, Körber J, Krause BJ, Kuhn C, Kullmann F, Lang H, Link H, Lordick F, Ludwig K, Lutz M, Mahlberg R, Malfertheiner P, Merkel S, Messmann H, Meyer HJ, Mönig S, Piso P, Pistorius S, Porschen R, Rabenstein T, Reichardt P, Ridwelski K, Röcken C, Roetzer I, Rohr P, Schepp W, Schlag PM, Schmid RM, Schmidberger H, Schmiegel WH, Schmoll HJ, Schuch G, Schuhmacher C, Schütte K, Schwenk W, Selgrad M, Sendler A, Seraphin J, Seufferlein T, Stahl M, Stein H, Stoll C, Stuschke M, Tannapfel A, Tholen R, Thuss-Patience P, Treml K, Vanhoefer U, Vieth M, Vogelsang H, Wagner D, Wedding U, Weimann A, Wilke H, Wittekind C; AWMF; AWMF. [German S3-guideline "Diagnosis and treatment of esophagogastric cancer"]. Z Gastroenterol. 2011 Apr;49(4):461-531. doi: 10.1055/s-0031-1273201. Epub 2011 Apr 7. German.; 21476183
  •   El-Rayes BF, Patel B, Zalupski M, et al. A phase II study of bevacizumab, docetaxel, and oxaliplatin in gastric and GEJ cancer. ASCO Meeting Abstracts. 2009;27(15S):4563.
  •   Li J, Kortmansky JS, Saif M, et al. Phase II study of mFOLFOX6 with bevacizumab (Bev) in metastatic gastric and esophageal (GE) adenocarcinoma. ASCO Meeting Abstracts. 2010;28(15_suppl):TPS203.
  •   Enzinger PC, Ryan DP, Regan EM, et al. Phase II trial of docetaxel, cisplatin, irinotecan, and bevacizumab in metastatic esophagogastric cancer. ASCO Meeting Abstracts. 2008;26(15_suppl):4552.
  •   Hutson TE, Davis ID, Machiels JP, et al. Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT). ASCO Meeting Abstracts. 2007;25(18_suppl):5031.
  •   Slamon D, Gomez HL, Kabbinavar FF, et al. Randomized study of pazopanib + lapatinib vs. lapatinib alone in patients with HER2-positive advanced or metastatic breast cancer. ASCO Meeting Abstracts. 2008;26(15_suppl):1016.
  •   Sleijfer S, Papai Z, Le Cesne A, et al. Phase II study of pazopanib (GW786034) in patients (pts) with relapsed or refractory soft tissue sarcoma (STS): EORTC 62043. ASCO Meeting Abstracts. 2007;25(18_suppl):10031.
  •   Altorki N, Guarino M, Lee P, et al. Preoperative treatment with pazopanib (GW786034), a multikinase angiogenesis inhibitor in early-stage non-small cell lung cancer (NSCLC): A proof-of-concept phase II study. ASCO Meeting Abstracts. 2008;26(15_suppl):7557.
  •   Brady J, Middleton M, Midgley RS, et al. A phase I study of pazopanib in combination with FOLFOX 6 or capeOx in subjects with colorectal cancer. ASCO Meeting Abstracts. 2009;27(15S):4133.
  •   Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):36-46. doi: 10.1056/NEJMoa073149.; 18172173
  •   Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, Rethwisch V, Seipelt G, Homann N, Wilhelm G, Schuch G, Stoehlmacher J, Derigs HG, Hegewisch-Becker S, Grossmann J, Pauligk C, Atmaca A, Bokemeyer C, Knuth A, Jäger E; Arbeitsgemeinschaft Internistische Onkologie. Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie. J Clin Oncol. 2008 Mar 20;26(9):1435-42. doi: 10.1200/JCO.2007.13.9378.; 18349393
  •   Sun W, Powell M, O'Dwyer PJ, Catalano P, Ansari RH, Benson AB 3rd. Phase II study of sorafenib in combination with docetaxel and cisplatin in the treatment of metastatic or advanced gastric and gastroesophageal junction adenocarcinoma: ECOG 5203. J Clin Oncol. 2010 Jun 20;28(18):2947-51. doi: 10.1200/JCO.2009.27.7988. Epub 2010 May 10.; 20458043
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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   5
  •   2016/01/14


* This entry means the parameter is not applicable or has not been set.