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Gemcitabine Plus Erlotinib in RASH-positive Patients With Metastatic Pancreatic Cancer (ML22774)

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 evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01729481
Recruitment Status : Unknown
Verified July 2017 by PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich.
Recruitment status was:  Active, not recruiting
First Posted : November 20, 2012
Last Update Posted : July 19, 2017
Roche Pharma AG
Information provided by (Responsible Party):
PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich

Brief Summary:
In the current study it is examined whether patients with good risk factors (age <75 years, total serum bilirubin < 1,5xULN, no history of cardiovascular diseases) treated with gemcitabine and erlotinib who developed skin rash of any grade during the first 4 weeks of treatment have a comparable outcome as patients who receive FOLFIRINOX.

Condition or disease Intervention/treatment Phase
Metastatic Pancreatic Adenocarcinoma Drug: Gemcitabine Drug: Erlotinib Drug: Oxaliplatin Drug: Folinic Acid Drug: Irinotecan Drug: 5-FU Phase 2

Detailed Description:

The study by Burris et al. 1997 revealed a superiority of gemcitabine vs. 5-FU in terms of improvement of general condition, pain symptoms and overall survival in patients with locally advanced or metastatic pancreatic cancer. Subsequently, gemcitabine was established as a standard treatment for locally advanced and metastatic pancreatic cancer.

In a series of studies gemcitabine was combined with other chemotherapeutic agents or targeted therapies. For the first time, the PA.03 study showed a significant improvement of overall survival. Patients who were treated with gemcitabine plus erlotinib had a survival of 6.24 months, compared with 5.91 months for those treated with gemcitabine plus placebo (HR 0.82, 95% CI 0.69-0.99, p=0.038). The one-year-survival rate was 23% for gemcitabine plus erlotinib vs. 17% for gemcitabine plus placebo.

In a subgroup analysis of the PA.03 study, patients developing a skin rash NCI CTC ≥ grade 2 had an advanced survival (one-year-survival rate 43%) vs. those with grade 1 or 0 (one-year-survival rate 16% and 9%, respectively). Later studies confirmed the correlation between skin rash and survival.

While patients developing a skin rash of any grade seem to profit most from treatment with erlotinib, the prognosis for those without rash is rather dismal. In this population, survival varied between 3.3 and 4.8 months in clinical trials (Verslype et al. 2009, Boeck et al. 2010, Manzano et al. 2010). In this patients, a modification of the treatment strategy should be considered. Which kind of treatment might lead to optimal results in these patients is not yet clear.

In patients with excellent general condition complying with further prerequisits (age <75 years, total serum bilirubin < 1,5xULN, no history of cardiovascular diseases) the French Prodige study-group could show a statistical superiority for the gemcitabine-free FOLFIRINOX-scheme in terms of overall survival, progression free survival and response rate compared to gemcitabine alone. However, this superiority was gained at the expense of treatment tolerability. During treatment with FOLFIRINOX a grade 3-4 neutropenia was observed in 5.4% and a grade 3-4 diarrhea in 12.7% of patients (Conroy et al. 2011). For patients who comply with the above-named criteria FOLFIRINOX is considered an established standard of care.

If a comparable efficacy of gemcitabine plus erlotinib with the published FOLFIRINOX data can be seen in the selected population, this would favour, due to the worse tolerability of FOLFIRINOX, the use of gemcitabine plus erlotinib.

In summary, the following selections are conducted during the study:

  1. Selection due to the inclusion criteria for treatment with FOLFIRINOX provided by Conroy et al.
  2. Selection due to the development of a skin rash within four weeks of treatment
  3. No signs of clinical tumour progression within the run-in phase within the first four weeks of treatment

Patients who do not develope a skin rash of any grade should be treated with FOLFIRINOX. The efficacy of FOLFIRINOX in rash-negative patients has not yet been investigated.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 150 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study to Evaluatate the Efficacy of Gemcitabine Plus Erlotinib for RASH-positive Patients With Metastatic Pancreatic Cancer and Friendly Risk Circumstances
Study Start Date : July 2012
Actual Primary Completion Date : July 2015
Estimated Study Completion Date : December 2017

Arm Intervention/treatment
Experimental: RASH positive

Run-In-Phase during 4 weeks:

Gemcitabine 1000 mg/m², weekly Erlotinib 100 mg, weekly

Thereafter Treatment in patients with RASH-positve outcome after 4 weeks.

Drug: Gemcitabine
1000 mg/m² iv weekly
Other Name: Gemzar

Drug: Erlotinib
100mg, once per day
Other Name: Tarceva

Active Comparator: RASH-negative

Run-In-Phase during 4 weeks:

Gemcitabine 1000 mg/m², weekly Erlotinib 100 mg, weekly

RASH-negative patients quit treatment with Gemcitabine + Erlotinib and continue treatment with FOLFIRINOX:

Oxaliplatin 85mg/m2 Irinotecan 180 mg/m2 Folinic acid 400 mg/m2 5-FU 400 mg/m2 bolus iv 5-FU 2400 mg/m2 46-hours continous infusion

Drug: Oxaliplatin
85mg/m², q2weeks
Other Name: Eloxatin

Drug: Folinic Acid
400 mg/m², q2weeks
Other Name: Leucovorin

Drug: Irinotecan
180 mg/m², q2weeks
Other Name: Campto

Drug: 5-FU
400 mg/m² Day 1; 2400 mg/m² 46 hour invusion, q2weeks
Other Name: 5-Flourouracil

Primary Outcome Measures :
  1. 1-year Survial rate of "good-risk" patients [ Time Frame: Follow-Up Phase (1.5 years) ]
    1-year Survial rate of "good-risk" patients of patients under gemcitabine plus erlotinib with RASH

Secondary Outcome Measures :
  1. Evalutation of overall response rate, disease control rate and progression free survival [ Time Frame: Approximately 12 months ]

    Evaluation of Parameters by RASH positve and negative patients:

    • ORR
    • DCR
    • PFS
    • OS

  2. Evaluation of adverse events [ Time Frame: Treatment Phase (1.5 Years) ]
    Assesment with NCI-CTCAE V4.0 Evalutation of side effects including picture documentation of skin-rash

  3. Translational Projects [ Time Frame: Approximately 24 months ]
    • Evaluation of Parameters for EGFR signal transduction
    • Evaluation Molecularbiological Parametrs of RASH
    • Picture Documentation of RASH. Corellation with clinical and molecularbiological Parameters

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically (not cytologically) confirmed metastatic pancreatic adenocarcinoma (stage IV according to UICC, each T, each N, M1 according to TNM)
  • At least one measurable index lesion (CT or MRI) according to RECIST criteria (V 1.1)
  • ECOG PS 0 and 1
  • Age 18-75 years
  • Serum bilirubin ≤1,5x ULN (a placed biliary tract stent without concurrent cholangitis is not considered a contraindication)
  • Availability of tumour samples (no cytologic samples)
  • Written informed consent by the patient for collecting blood- and tumour-samples for translational research according to study protocol
  • Live expectancy of at least three months
  • Written informed consent
  • Negative pregnancy test in women with childbearing potential (to be performed within 7 days prior to treatment start)
  • Adequate kidney-, liver- and bone-marrow function: neutrophils >= 1500/µl, platelets >= 100.000/µ, and hemoglobin >= 8g/dl, liver transaminases<= 2,5x ULN, in case of liver metastases <= 5x ULN, serum creatinine <= 1,25x ULN, creatinine clearance ≥ 30 ml/min
  • Legal capacity of the patient
  • Option for constant long-term follow-up

Exclusion Criteria:

  • Resectable pancreatic carcinoma
  • Locally advanced pancreatic cancer (non-resectable tumour without distant metastasis)
  • Previous palliative chemotherapy for metastatic or locally advanced, non-resectable pancreatic cancer
  • Previous palliative radiation or chemoradiation for locally advanced, non-resectable pancreatic cancer
  • Radiation therapy within four weeks prior to study enrolment or radiation of indicator lesions
  • Adjuvant Chemotherapy or Radiochemotherapy for pancreatic cancer ≤ 6 months prior to study ernrolment
  • All previously occurred metastatic cancers or cured neoplasias diagnosed within the last 5 years before study enrolment
  • Major surgery within 2 weeks before study start
  • Chronic diarrhea
  • Known glucuronidation-deficiency (Gilbert´s syndrome)
  • Acute or subacute ileus or chronic inflammatory bowel disease
  • Preexisting polyneuropathy > Grade I according to NCI-CTCAE v.4.0
  • Relevant comorbidities which might impair patient eligibility or safety for study participation like active infections, hepatic, renal or metabolic diseases
  • Clinically significant cardiovascular diseases within 12 months prior to study start (e.g. unstable angina pectoris, myocardial infarction, heart failure ≥ NYHA II, cardiac arrhythmias requiring treatment)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01729481

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University of Munich
Munich, Germany, 81377
Sponsors and Collaborators
Ludwig-Maximilians - University of Munich
Roche Pharma AG
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Principal Investigator: Volker Heinemann, Professor Medical Department III and Comprehensive Cancer Center
Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: PD Dr. med. Volker Heinemann, Clinical Professor, Ludwig-Maximilians - University of Munich Identifier: NCT01729481    
Other Study ID Numbers: 2011-005471-17
First Posted: November 20, 2012    Key Record Dates
Last Update Posted: July 19, 2017
Last Verified: July 2017
Additional relevant MeSH terms:
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Folic Acid
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Protective Agents
Vitamin B Complex
Growth Substances