Clinical trial NCT01262482: Study of Oxaliplatin and Sorafenib Combination to Treat Gastric Cancer Relapsed After a Cisplatin Based Treatment
Official title: A Phase 2 Trial of Oxaliplatin and Sorafenib Combination in Patients With Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma, Relapsed After a Cisplatin Based Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (Relapsed After a Cisplatin Based Treatment)
Keywords: adenocarcinoma
gastric
gastroesophageal junction
Relapsed
sorafenib
oxaliplatin
Lead sponsor: Grupo Espanol Multidisciplinario del Cancer Digestivo
Sponsor class: OTHER
First posted: 2010-12-17
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: In Spain, the gastric carcinoma is the 5th most frequent malignant tumor in women and the 6th in men, and represents the 3rd cause of cancer-related deaths amongst women and the 4th amongst men. The average of 5-year survival rate in Spain is under 30%. The main reason of it is that, despite carrying out an adjuvant treatment, more than the 50% will present relapsed disease.

Sorafenib has been the first RAF inhibitor, both of RAF-1 and B-rRAF and its b-RAF variant V600E. Moreover, it has shown its ability to inhibit other tyrosin-quinase receptors as VEGFR 2 and 3, c-kit, Flt-3 or PDGFR. Its activity has been clearly proven in clear cell renal carcinoma.

The mechanism by which Sorafenib seems to act is not because of the existence of a mutation of RAS or RAF, but because as there is a VHL shortage the HIP produces a VEGF, bFGF or TGF overexpression that produces in turn a hyper-stimulation on the RAF/ERK/MEK pathway.

The RAF/MEK/ERK pathway and angiogenesis seem to be clearly involved in the gastric carcinoma tumorigenesis and progression. Because of that, it seems interesting to associate Sorafenib to an oxaliplatin-based chemotherapy, which has shown its effectiveness in relapsed patients after receiving cisplatin-based schemes. Moreover, there is a phase 1 trial confirming the tolerance of the oxaliplatin and Sorafenib association, describing partial responses amongst gastric cancer patients previously treated with cisplatin.


Eligibility criteria: Inclusion Criteria:

1. Gastric or gastroesophageal junction adenocarcinoma confirmed by cytology or biopsy, with unresectable or metastatic disease which have progressed to a cisplatin-fluoropyrimidine based scheme (excluded neoadjuvant treatment administered with or without concomitant radiotherapy)
2. Older than 18 years at the moment of informed consent form signature
3. Age \> 18 years
4. ECOG 0-2
5. Measurable disease by RECIST criteria. Lesions have to be measured by CT-scan or MRI
6. Life expectancy \> 12 weeks
7. Adequate medullary reserve and hepatic and renal function, defined according to the following parameters:

   1. Hemoglobin ≥ 9g/dl
   2. Neutrophils ≥ 1,5 x 10\^9/L
   3. Platelets ≥100 x 10\^9/L
   4. Total bilirubin ≤ 1,5 times the upper limit of normal (ULN)
   5. ALT (GTP) and AST (GOT) ≤ 2,5 times the upper limit of normal (ULN) (≤ 5 times the ULN in patients with hepatic metastasis)
   6. PT-INR-PTT ≤ 1,5 times the ULN. (The patients under anticoagulant treatment with dicumarin or heparin can be included if there is no previous evidence of alteration in these parameters)
   7. Creatinine clearance \> 30ml/min
8. The patients have to be able to understand the meaning of their participation in the trial and voluntary give their participation consent signing the informed consent form

Exclusion Criteria:

1. More than one line for the treatment of locally advanced disease
2. Active ischemic cardiopathy. History of cardiac disease defined as follow:

   1. Congestive cardiac failure \> class 2 from the NYHA
   2. Active coronary disease. The recruitment of patients with solved myocardial infarction is allowed, if diagnosed at least 6 months before the trial start
   3. Cardiac arrhythmia requiring treatment with antiarrhythmic drugs. (The treatment with beta-adrenergic antagonists or digoxin is allowed)
   4. Non-controlled arterial hypertension
3. Non-controlled intercurrent illness
4. Symptomatic sensitive peripheral neuropathy
5. Another malignant disease diagnosed in the past 5 years, except in situ cervix carcinoma adequately treated, non-melanoma skin carcinoma, superficial bladder tumor (Ta, Tis and T1), or any tumor treated in a curative way until 3 years prior to the recruitment
6. Pregnant or breastfeeding women. Women will have to undergo a pregnancy test within 7 days prior to the recruitment. Both men and women recruited in the trial will have to use appropriate barrier contraceptive methods during their sexual relations during the trial period and at least until two weeks after its completion. Men participating in this trial will have to continue using this contraceptive methods at least until 3 months after the treatment completion
7. Chronic diseases: AIDS, Hepatitis B and/or Hepatitis C
8. Clinically active severe infection (Grade 2 NCI-CTC version 3.0)
9. Cerebral metastasis or meningeal tumor
10. Patients requiring chronic corticosteroid treatment or high doses of corticosteroids or any other immunosuppressive treatment
11. Patients having undergone a major surgery within the 4 weeks prior to the trial start
12. Patients having completed a chemotherapy or radiotherapy treatment within the 4 weeks prior to the clinical trial start (except palliative radiotherapy, within the 2-weeks prior to the clinical trial start)
13. Previous treatment using a RAS pathway inhibitor
14. Any medical or severe psychiatric condition or drug consumption involving a serious risk for the patient if taking part in the clinical trial or that can prevent the signature of the informed consent form
15. Patients unable to swallow medication

Primary outcomes:
measure: Progression free survival
timeFrame: anticipated 3 years
Secondary outcomes:
measure: Tumoral response
timeFrame: anticipated 3 years
measure: Response duration
timeFrame: anticipated 3 years
measure: Overall survival
timeFrame: anticipated 3 years
measure: Toxicity
timeFrame: anticipated 3 years
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Sant Pau
city: Girona
country: Spain
facility: H. Josep Trueta
city: Madrid
country: Spain
facility: Centro Oncológico M.D. Anderson Spain
city: Madrid
country: Spain
facility: Hospital de Fuenlabrada
city: Madrid
country: Spain
facility: Hospital La Paz
city: Manresa
country: Spain
facility: Hospital Althaia
city: Pamplona
country: Spain
facility: Clínica Universitaria de Navarra
city: Sabadell
country: Spain
facility: Hospital Parc Taulí
city: Valencia
country: Spain
facility: Hospital General de Valencia
Study officials:
affiliation: Grupo Espanol Multidisciplinario del Cancer Digestivo
name: Marta Martin Richard, MD
role: STUDY_CHAIR
References: