Trial Review

Technical difficulties have been reported by some users of the search function and is being investigated by technical staff. Thank you for your patience and apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01503372




Registration number
NCT01503372
Ethics application status
Date submitted
22/12/2011
Date registered
4/01/2012
Date last updated
12/02/2019

Titles & IDs
Public title
FLO +/- Pazopanib as First-line Treatment in Advanced Gastric Cancer
Scientific 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
Secondary ID [1] 0 0
2010-024379-15
Secondary ID [2] 0 0
PaFLO
Universal Trial Number (UTN)
Trial acronym
PaFLO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced Gastric Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Stomach

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Pazopanib
Treatment: Drugs - 5-FU, Oxaliplatin, Leukovorin (FLO)

Experimental: Arm A: FLO + Pazopanib -

Active Comparator: Arm B: FLO -


Treatment: Drugs: 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

Treatment: Drugs: 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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
progression-free survival rate at 6 months
Timepoint [1] 0 0
6 months after study entry
Secondary outcome [1] 0 0
progression-free survival rate at 9 and 12 months
Timepoint [1] 0 0
9 and 12 months after study entry
Secondary outcome [2] 0 0
median progression-free survival
Timepoint [2] 0 0
48 months
Secondary outcome [3] 0 0
response rate
Timepoint [3] 0 0
48 months
Secondary outcome [4] 0 0
duration of response
Timepoint [4] 0 0
48 months
Secondary outcome [5] 0 0
toxicity
Timepoint [5] 0 0
48 months
Secondary outcome [6] 0 0
tolerability
Timepoint [6] 0 0
48 months
Secondary outcome [7] 0 0
overall survival
Timepoint [7] 0 0
48 months
Secondary outcome [8] 0 0
time to treatment failure
Timepoint [8] 0 0
48 months
Secondary outcome [9] 0 0
evaluation of the predictive and prognostic relevance of biomarkers
Timepoint [9] 0 0
48 months

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/11/2011
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
14/12/2017
Sample size
Target
Accrual to date
Final
75
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Germany
State/province [1] 0 0
Berlin

Funding & Sponsors
Primary sponsor type
Other
Name
Charite University, Berlin, Germany
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01503372
Trial related presentations / publications
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. doi: 10.1200/JCO.2006.08.0887.
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.
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.
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.
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.
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, Jager 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.
Moehler M, Al-Batran SE, Andus T, Anthuber M, Arends J, Arnold D, Aust D, Baier P, Baretton G, Bernhardt J, Boeing H, Bohle 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, Hocht S, Hofheinz RD, Hofler H, Hohler T, Holscher AH, Horneber M, Hubner J, Izbicki JR, Jakobs R, Jenssen C, Kanzler S, Keller M, Kiesslich R, Klautke G, Korber 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, Monig S, Piso P, Pistorius S, Porschen R, Rabenstein T, Reichardt P, Ridwelski K, Rocken C, Roetzer I, Rohr P, Schepp W, Schlag PM, Schmid RM, Schmidberger H, Schmiegel WH, Schmoll HJ, Schuch G, Schuhmacher C, Schutte 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. No abstract available. German.
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Peter Thuss-Patience, MD
Address 0 0
Charite University medicine
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries