A multicenter study comparing treatment of patients with neuroendocrine Gastro-Entero-Pancreatic (GEP) tumors with 177Lu-octreotate versus combined 177Lu-octreotate and capecitabine treatment.|
|- candidate number||2477|
|- NTR Number||NTR913|
|- Date ISRCTN created||7-mrt-2007|
|- date ISRCTN requested||6-mrt-2007|
|- Date Registered NTR||19-feb-2007|
|- Secondary IDs||N/A |
|- Public Title||A multicenter study comparing treatment of patients with neuroendocrine Gastro-Entero-Pancreatic (GEP) tumors with 177Lu-octreotate versus combined 177Lu-octreotate and capecitabine treatment.|
|- Scientific Title||A multicenter study comparing treatment of patients with neuroendocrine Gastro-Entero-Pancreatic (GEP) tumors with 177Lu-octreotate versus combined 177Lu-octreotate and capecitabine treatment.|
|- hypothesis||Chemosensitization with capecitabine improves the percentage of patients with objective tumor responses who are also treated with 177Lu-octreotate.|
|- Healt Condition(s) or Problem(s) studied||Lutetium-octreotate , Neuroendocrine tumors, Somatostatin analogues , Lutetium-177 , Chemosensitization|
|- Inclusion criteria||Inclusion criteria
1. Presence of histology proven GEP tumor(s), including bronchial carcinoids;
2. Presence of somatostatin-receptors on the known tumor lesions demonstrated by OctreoScan® within 6 months of the first dose of radiolabelled octreotate/octreotide. The uptake on the octreoscan should be at least as high as normal liver uptake on planar imaging;
3. Life expectancy greater than 12 weeks;
4. Serum creatinine £150 µmol/liter or 1.7 mg/dL, and a measured creatinine clearance (or measured GFR using plasma clearance methods, not gamma-camera based) of ³50 mL/min;
5. Hemoglobin (Hgb) concentration ³5.5 mmol/L (³8.9 g/dL); WBC ³ 2*109/L (2000/mm3); platelets ³ 100*109/L (100*103/mm3);
6. Total bilirubin £3 x ULN;
7. Serum albumin > 30 g/L, or serum albumin £ 30 g/L but normal prothrombin time;
8. Karnofsky Performance Status ³ 60;
9. Presence of at least 1 measurable site of disease;
10. Patients written voluntary informed consent to participate in the study, obtained prior to enrollment into the study. The informed consent must be maintained in the investigator's study files.
|- Exclusion criteria||1. Possible surgery with curative intent;
2. Surgery, radiotherapy, chemotherapy, or other investigational therapy within 3 months of the start of therapy;
3. Patients with known brain metastases unless these metastases have been treated and stabilized for at least six months prior to study start. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to study start;
4. Uncontrolled congestive heart failure;
5. Any subject who is taking concomitant medications which decrease renal function (such as aminoglycoside antibiotics);
6. Any subject receiving therapy with somatostatin analogues, unless the dose has been stable for at least 3 months prior to the first cycle in this study and the disease status during these 3 months has been documented by SWOG criteria as described in this study;
7. Any subject receiving therapy with short-acting somatostatin analogues in whom these analogues cannot be interrupted for 12 hours before and 12 hours after the administration of the radiolabelled somatostatin analogues, or any subject receiving therapy with long-acting somatostatin analogues in whom these analogues cannot be interrupted for at least 6 weeks before the administration of the radiolabelled somatostatin analogues, unless the uptake on the Octreoscan during continued somatostatin analogue medication is at least as high as normal liver uptake on planar imaging;
8. In patients with unusual hematological parameters, including an increased MCV (>105 fL), and especially in those who had previous chemotherapy, the advice of a hematologist should be seeked, for adequate further work-up;
9. Subjects with another significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study;
11. Prior radiation therapy to more than 25% of the bone marrow.
|- mec approval received||yes|
|- multicenter trial||yes|
|- planned startdate ||1-mrt-2007|
|- planned closingdate||1-mrt-2010|
|- Target number of participants||200|
|- Interventions||Treatment with the radioactive somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate (arm 1)
Treatment with [177Lu-DOTA0,Tyr3]octreotate and capecitabine (arm 2)|
|- Primary outcome||Efficacy and safety assessments
Objective response as determined by SWOG criteria is the main efficacy endpoint. Upon entry, subjects must have at least one measurable site of disease based on the SWOG response criteria. All lesions must be identified at baseline by physical exam, CT or MRI within 2 months prior to the start of treatment. Changes from baseline will be assessed 6 weeks after the last treatment, and 3, 6, and 12 months after the last treatment, and then every 6 months, until progression occurs. Patients who discontinue early due to clinical disease progression (unsatisfactory therapeutic effect) do not require a tumor assessment.
The overall survival of patients treated with radiolabelled somatostatin analogue will be calculated from the first day of treatment until the day of death. In patients who change to other anti-tumor treatments or who are lost to follow-up censored survival will be determined by the last regular visit. The time to progression is calculated from the first day of treatment to the day of documented progression.
For CT imaging at entry, a triphasic, contrast enhanced study should be performed with a slice distance of 5 or 8 mm, and continuous slices. For follow-up CT imaging, triphasic imaging is not mandatory: the imaging phase at which the lesions are best recognized can be repeated instead.
Tumor response will be recorded according to the SWOG criteria by the investigators. Bidimensional tumor measurements from CT or MRI scans that were performed before treatment enrollment and after completing the therapy will be recorded.
End of Study
The completion of the last day of the last study period or the date and reasons of premature discontinuation from the study, will be recorded. End-point of the follow-up period is disease progression or death. The follow-up may be ended 5 years after the conclusion of treatment. However, in all patients the collection of toxicity data (hematology, renal function) should be continued either by the investigator, referring physician, or general practitioner.
Information regarding the status of the patient, date of last contact or date of death will be collected.
|- Secondary outcome||1. Changes in serum chromogranin-A concentrations.
2. Safety of treatment as measured by the rate of adverse events and the monitoring of selected laboratory evaluations.
3. Effect of the different treatment arms on Quality of Life as measured by the EORTC QLQ-C30 questionnaire.
4. Effects on tumor growth rate (TGR).
|- Trial web site||http://www.prrt.nl|
|- CONTACT FOR PUBLIC QUERIES||Drs M. Essen, van|
|- CONTACT for SCIENTIFIC QUERIES||Dr D.J. Kwekkeboom|
|- Sponsor/Initiator ||Erasmus Medical Center, Department of Nucleair Medicine |
(Source(s) of Monetary or Material Support)
|Erasmus Medical Center, Department of Nucleair Medicine|
|- Publications||Kwekkeboom DJ, Krenning EP, de Jong M.
Peptide receptor imaging and therapy.
J Nucl Med 2000;41:1704-1713.
Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL,
Schmidt MA, Bugaj JL, de Jong M, Krenning EP. [177Lu?DOTA0Tyr3]octreotate: comparison with [111In?DTPA0]octreotide in
patients. Eur J Nucl Med 2001;28:1319-1325.
De Jong M, Valkema R, Jamar F, Kvols LK, Kwekkeboom DJ, Breeman WA, Bakker
WH, Smith C, Pauwels S, Krenning EP.
Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings. Semin Nucl Med 2002;32:133-140.
Kwekkeboom DJ, Bakker WH, Kam BL, Teunissen JJ, Kooij PP, de Herder WW,
Feelders RA, van Eijck CH, de Jong M, Srinivasan A, Erion JL, Krenning EP.
Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the
novel radiolabelled somatostatin analogue [177Lu-DOTA(0),Tyr3]octreotate. Eur J Nucl Med Mol Imaging 2003;30:417-422.
Teunissen JJM, Kwekkeboom DJ, Krenning EP. Quality of Life in patients with gastro-entero-pancreatic tumors treated with [177Lu-DOTA0,Tyr3]octreotate. J Clin Oncol 2004;22:2724-2729.
Kwekkeboom DJ, Mueller-Brand J, Paganelli G, Anthony LB, Pauwels S, Kvols
LK, O'dorisio TM, Valkema R, Bodei L, Chinol M, Maecke HR, Krenning EP.
Overview of results of Peptide receptor radionuclide therapy with 3
radiolabeled somatostatin analogs. J Nucl Med 2005;46(Suppl 1):62S-66S.
Krenning EP, Valkema R, Kwekkeboom DJ, de Herder WW, van Eijck CH, de Jong
M, Pauwels S, Reubi JC. Molecular imaging as in vivo molecular pathology for gastroenteropancreatic neuroendocrine tumors: implications for follow-up after therapy. J Nucl Med 2005;46(Suppl 1):76S-82S.
Kwekkeboom DJ, Teunissen JJ, Bakker WH, Kooij PP, de Herder WW, Feelders RA, van Eijck CH, Esser JP, Kam BL, Krenning EP. Treatment with the radiolabelled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate in patients with gastro-entero-pancreatic (GEP) tumors. J Clin Oncol 2005;23:2754-2762.
Teunissen JJM, Kwekkeboom DJ, de Jong M, Esser JP, Valkema R, Krenning EP.
Peptide receptor radionuclide therapy.
Best Pract Res Clin Gastroenterol 2005;19:595-616.
|- Brief summary||Neuroendocrine Gastro-Entero-Pancreatic (GEP) tumors are rare neoplasms that usually grow slowly and have a relatively benign course. They can be divided in carcinoids and islet-cell tumors. In inoperable and/or metastasized disease, tumor-targeted peptide radionuclide radiation therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) may be very rewarding.
From January 2000 to July 2006, 1968 treatment cycles with 177Lu-octreotate in 562 patients were administered at Erasmus MC. In an analysis in 131 GEP-tumor patients, 28% had PR and 19% had a minor response (MR, 25-50% tumor volume reduction).
The reason to study the effect of chemosensitization in the current protocol is based on the fact that such chemosensitization has been shown advantageous in a variety of tumor types treated with fractionated radiotherapy. Also, chemosensitization with 5-FluoroUracil (5-FU) in combination with 90Y-labelled antibody radioimmunotherapy is feasible and safe. Lastly, the results of the combination of 5-FU with 111In-DTPA-octreotide treatment compare favourably to treatment with 111In-DTPA-octreotide only.
The prodrug of 5-FU, capecitabine, was also shown effective in combination with concomitant external beam radiotherapy. It has the advantage over 5-FU of oral administration. Additionally, higher concentrations in many tumor tissues of the enzyme thymidine phosphorylase, which converts the prodrug to its active form, may be another advantage of capecitabine over 5-FU. The mechanism by which halogenated pyrimidines such as 5-FU potentiate radiation damage is their incorporation in the DNA, making it more susceptible to radiation therapy. Also, 5-FU inreferes with the cellular mechanisms that repair sublethal cell damage.
Until now, no controlled comparative studies with radiolabelled octreotide or octreotate have been performed. The differences between the results in the currently available reports may be partly due to differences in treatment protocols and in patient selection. Therefore, a controlled study comparing the best strategies for PRRT is warranted. For the reasons outlined above, 177Lu-octreotate and a combination of capecitabine and 177Lu-octreotate are likely candidates.
A two-armed randomized controlled study is proposed to address the main question, whether there are clinically important differences in response rate between 177Lu-octreotate and the combination of capecitabine and 177Lu-octreotate, when used to treat patients with somatostatin-receptor positive GEP tumors.
|- Main changes (audit trail)|
|- RECORD||19-feb-2007 - 7-mrt-2007|
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