FLO +/- Pazopanib as First-line Treatment in Advanced Gastric Cancer (PaFLO)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2012 by Charite University, Berlin, Germany
Sponsor:
Information provided by (Responsible Party):
P. C. Thuss-Patience, Charite University, Berlin, Germany
ClinicalTrials.gov Identifier:
NCT01503372
First received: December 22, 2011
Last updated: January 10, 2012
Last verified: January 2012
  Purpose

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.


Condition Intervention Phase
Advanced Gastric Cancer
Drug: Pazopanib
Drug: 5-FU, Oxaliplatin, Leukovorin (FLO)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by Charite University, Berlin, Germany:

Primary Outcome Measures:
  • progression-free survival rate at 6 months [ Time Frame: 6 months after study entry ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • progression-free survival rate at 9 and 12 months [ Time Frame: 9 and 12 months after study entry ] [ Designated as safety issue: No ]
  • median progression-free survival [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • response rate [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • duration of response [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • toxicity [ Time Frame: 48 months ] [ Designated as safety issue: Yes ]
    number of patients with Adverse Events according to CTC-criteria

  • tolerability [ Time Frame: 48 months ] [ Designated as safety issue: Yes ]
    number of patients having adverse events and require interruptions and dose reductions of chemotherapy

  • overall survival [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • time to treatment failure [ Time Frame: 48 months ] [ Designated as safety issue: No ]
  • evaluation of the predictive and prognostic relevance of biomarkers [ Time Frame: 48 months ] [ Designated as safety issue: No ]
    collection of plasma samples at designated time points during treatment and measuring of angiogenic factors correlating with response rate and outcome


Estimated Enrollment: 75
Study Start Date: November 2011
Estimated Study Completion Date: May 2015
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A: FLO + Pazopanib Drug: Pazopanib
Adding Pazopanib to a standard chemotherapy consisting of FLO. 800 mg (2x400mg or 4x200mg) Pazopanib per day should be taken orally without food at least one hour before or two hours after a meal. Pazopanib will be given d1-14 each cycle (2 weeks cycles) with 12 cycles of chemotherapy FLO (d 1, each cycle). After 12 cycles chemotherapy FLO will be discontinued and Pazopanib will be given alone until disease progression
Drug: 5-FU, Oxaliplatin, Leukovorin (FLO)
Oxaliplatin 85 mg/m2 2h iv Leucovorin 200mg/m2 2h - iv FU 2600mg/m2 24h iv q2w for 12 cycles
Active Comparator: Arm B: FLO Drug: 5-FU, Oxaliplatin, Leukovorin (FLO)
Oxaliplatin 85 mg/m2 2h iv Leucovorin 200mg/m2 2h - iv FU 2600mg/m2 24h iv q2w for 12 cycles

  Eligibility

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

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.

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.
  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: NCT01503372

Contacts
Contact: Mario Lorenz + 49 30 450 553 889 magenkarzinom@charite.de
Contact: Daniela Bohnen + 49 30 450 553 889 magenkarzinom@charite.de

Locations
Germany
Charite University medicine Recruiting
Berlin, Germany, 13353
Contact: Mario Lorenz    + 49 30-450 553 889    magenkarzinom@charite.de   
Contact: Daniela Bohnen    + 49 30-450 553 889    magenkarzinom@charite.de   
Principal Investigator: Peter Thuss-Patience, Dr.         
Sub-Investigator: Kirstin Breithaupt, Dr.         
Sponsors and Collaborators
Charite University, Berlin, Germany
Investigators
Study Chair: Peter Thuss-Patience, MD Charite University medicine
  More Information

Publications:
Sun W, Powell ME, O'Dwyer P, Ansari RH, Benson AB. A phase II study: Combination of sorafenib with docetaxel and cisplatin in the treatment of metastatic or advanced unresectable gastric and gastroesophageal junction (GEJ) adenocarcinoma (ECOG 5203). ASCO Meeting Abstracts. 2008;26(15_suppl):4535.
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.

Responsible Party: P. C. Thuss-Patience, consultant physician, Charite University, Berlin, Germany
ClinicalTrials.gov Identifier: NCT01503372     History of Changes
Other Study ID Numbers: PaFLO, 2010-024379-15
Study First Received: December 22, 2011
Last Updated: January 10, 2012
Health Authority: Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Stomach Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Leucovorin
Levoleucovorin
Oxaliplatin
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Antidotes
Protective Agents
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 22, 2014