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Onderzoek naar de gevoeligheid van tumorcellen uit pleuravocht voor verschillende chemotherapeutische middelen bij patiλnten met een niet-kleincellig longcarcinoom of mesothelioom


- candidate number19415
- NTR NumberNTR4775
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR9-sep-2014
- Secondary IDsN14PLU NKI-AVL
- Public TitleOnderzoek naar de gevoeligheid van tumorcellen uit pleuravocht voor verschillende chemotherapeutische middelen bij patiλnten met een niet-kleincellig longcarcinoom of mesothelioom
- Scientific TitlePeRsOnalized treatment fOr patients with pleural eFfusions due to malignant pleural mesothelioma or lung cancer in second or third line. An open label phase II study.
- ACRONYMPROOF
- hypothesisA personalized in vitro drug profiling method will allow a better prediction of responses and reduce unnecessary treatment toxicity.
- Healt Condition(s) or Problem(s) studiedMesothelioma , Non small cell lung cancer (NSCLC), Chemotherapy
- Inclusion criteria• Patients with histologically or cytologically proven malignant mesothelioma or non-small cell lung cancer that have a pleural effusion.
• Age >18 years.
• At the time of pleural fluid drainage, patients must have completed:
For MPM: at least first-line chemotherapy with a platinum (cisplatin or carboplatin) and pemetrexed combination.
For NSCLC: at least first and second line therapy according to the local guidelines.
• At the start of study treatment, patients must have documented evidence of progressive disease.
• Measurable or evaluable disease.
• Ability to understand the study and give signed informed consent prior to beginning of protocol specific procedures.
• WHO performance status ≤ 2
• Adequate organ function as evidenced by the following peripheral blood counts or serum chemistries at study entry:
o Hematology: Neutrophil count ≥ 1.5 x 109/l, Platelets ≥ 100 x 109/l, Hemoglobin ≥ 5.9 mmol/l.
o Hepatic function as defined by serum bilirubin ≤ 1.25 times the upper limit of normal (ULN), ALAT and ASAT ≤ 2.5 times the ULN, except for liver metastases then ALAT and ASAT < 5 times the ULN.
o Renal function as defined by serum creatinine ≤ 1.25 times ULN or creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula).
- Exclusion criteria• Active uncontrolled infection, severe cardiac dysfunction or non-correctable bleeding tendency.
• Any identification of a driver mutation for which a registered treatment is available
• Presence of symptomatic CNS metastases.
• Radiotherapy within 2 weeks prior to start of study treatment.
• Unstable peptic ulcer, unstable diabetes mellitus or other serious disabling condition.
• Concomitant administration of any other experimental drugs under investigation.
• Any non-resolved grade 3 or higher toxicity.
• For neurotoxicity any non-resolved grade 2 or higher toxicity
- mec approval receivedyes
- multicenter trialno
- randomisedno
- groupParallel
- Type2 or more arms, non-randomized
- Studytypeintervention
- planned startdate 1-jun-2014
- planned closingdate1-jun-2015
- Target number of participants80
- InterventionsPleural fluid that is drawn for symptom relief, will be used to isolate tumor cells for short-term culture. A small scale drug screen will be performed within 3 weeks after isolation of tumor cells. If sample tumor cells are available, a large scale drug screen using the anti-cancer compounds will be performed as well. Based on the in vitro results, an advise on both single agent and combination therapy will be provided by the committee of researchers. The treating physician will decide whether single agent or combination therapy is suitable for the patient and will determine which term therapy will be started.
Patients will be treated according to chemotherapy protocols that are routinely used in our clinic.

- Vinorelbine 25 mg/m2 x2q3w
- Gemcitabine 1250mg/m2 x2q3w
- Pemetrexed 500 mg/m2 q3w (max 1000 mg)
- Oxaliplatin 130 mg/m2 q3w
- Doxorubicin 60 mg/m2
- Cisplatin 75 mg/m2 q3w + Vinorelbine 25 mg/m2 x2q3w
- Cisplatin 75 mg/m2 q3w + Gemcitabine 1250 mg/m2 x2q3w
- Cisplatin 75 mg/m2 q3w + pemetrexed 500 mg/m2 q3w (max 1000 mg)
- Carboplatin AUC 5 + vinorelbine 25 mg/m2 x2q3w
- Carboplatin AUC 5 + gemcitabine 1250 mg/m2 x2q3w
- Carboplatin AUC 5 + pemetrexed 500 mg/m2 q3w (max 1000 mg)
- Oxaliplatin 100 mg/m2 q3w + vinorelbine 25 mg/m2 x2q3w (reduced dose oxaliplatin)
- Oxaliplatin 100 mg/m2 q3w + gemcitabine 1000 mg/m2 x2q3w (reduced dose oxali/gemci)
- Oxaliplatin 100 mg/m2 q3w + pemetrexed 500 mg/m2 xq3w (reduced dose oxaliplatin)
- Primary outcomeThe primary endpoint is accuracy of the drug profiling method, defined by the number of truly predicted responses, as a percentage of the total number of patients in the study.
- Secondary outcomeSecondary endpoints include objective response rates (ORR), progression free survival (PFS), overall survival (OS), pulmonary function and frequency and severity of adverse events.
Exploratory endpoints to identify potential biomarkers include genomic profiling and assessment of the accuracy of response evaluation by breath prints of Volatile Organic Compounds by SpiroNose.
- TimepointsEvery 6 weeks untill progression, thereafter every 12 weeks.
- Trial web site
- statusplanned
- CONTACT FOR PUBLIC QUERIESDr. P. Baas
- CONTACT for SCIENTIFIC QUERIESDr. P. Baas
- Sponsor/Initiator Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI AVL)
- Funding
(Source(s) of Monetary or Material Support)
KWF Kankerbestrijding
- PublicationsN/A
- Brief summarySummary study title: PeRsOnalized treatment fOr patients with pleural eFfusions due to malignant pleural mesothelioma or lung cancer in second or third line. An open label phase II study (Acronym: the PROOF study).

Principal Research Center: Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis.

Methodology: Open-label phase II

Scientific rationale: Prognosis of malignant pleural mesothelioma is extremely poor. There is no standard second line therapy for these patients. For metastatic NSCLC, the registrated third line therapy (erlotinib), is ineffective in the majority of these patients. We hypothesize that a personalized drug profiling method will allow a better prediction of responses and reduce unnecessary treatment toxicity.

Primairy objective: the aim of this study is to evaluate the efficacy of a personalized drug profiling method using short-term cultures of malignant cells derived from the patient's pleural fluid.

The primary endpoint is accuracy of the drug profiling method, defined by the number of truly predicted responses, as a percentage of the total number of patients in the study.

Inclusion criteria:
• Patients with histologically or cytologically proven malignant mesothelioma or non-small cell lung cancer that have a pleural effusion.
• Age >18 years.
• At the time of pleural fluid drainage, patients must have completed:
For MPM: at least first-line chemotherapy with a platinum (cisplatin or carboplatin) and pemetrexed combination.
For NSCLC: at least first and second line therapy according to the local guidelines.
• At the start of study treatment, patients must have documented evidence of progressive disease.
• Measurable or evaluable disease.
• Ability to understand the study and give signed informed consent prior to beginning of protocol specific procedures.
• WHO performance status ≤ 2
• Adequate organ function as evidenced by the following peripheral blood counts or serum chemistries at study entry:
o Hematology: Neutrophil count ≥ 1.5 x 109/l, Platelets ≥ 100 x 109/l, Hemoglobin ≥ 5.9 mmol/l.
o Hepatic function as defined by serum bilirubin ≤ 1.25 times the upper limit of normal (ULN), ALAT and ASAT ≤ 2.5 times the ULN, except for liver metastases then ALAT and ASAT < 5 times the ULN.
o Renal function as defined by serum creatinine ≤ 1.25 times ULN or creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula).

Exclusion criteria
• Active uncontrolled infection, severe cardiac dysfunction or non-correctable bleeding tendency.
• Any identification of a driver mutation for which a registered treatment is available
• Presence of symptomatic CNS metastases.
• Radiotherapy within 2 weeks prior to start of study treatment.
• Unstable peptic ulcer, unstable diabetes mellitus or other serious disabling condition.
• Concomitant administration of any other experimental drugs under investigation.
• Any non-resolved grade 3 or higher toxicity.
• For neurotoxicity any non-resolved grade 2 or higher toxicity

Number of patients: 80 patients will be registrated. 60 patients with mesothelioma and 20 patients with NSCLC.

Study treatment:
Pleural fluid that is drawn for symptom relief, will be used to isolate tumor cells for short-term culture. A small scale drug screen will be performed within 3 weeks after isolation of tumor cells. If sample tumor cells are available, a large scale drug screen using the anti-cancer compounds will be performed as well. Based on the in vitro results, an advise on both single agent and combination therapy will be provided by the committee of researchers. The treating physician will decide whether single agent or combination therapy is suitable for the patient and will determine which term therapy will be started. Patients will be treated according to chemotherapy protocols that are routinely used in our clinic and recorded in iProva. Response evaluation will be done according to modified RECIST.
- Main changes (audit trail)
- RECORD9-sep-2014 - 27-sep-2014


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