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Phase II Study to Evaluatate the Efficacy of Gemcitabine Plus Erlotinib for RASH-positive Patients With Metastatic Pancreatic Cancer and Friendly Risk Circumstances

Phase 2
18 Years
75 Years
Open (Enrolling)
Metastatic Pancreatic Adenocarcinoma

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Trial Information

Phase II Study to Evaluatate the Efficacy of Gemcitabine Plus Erlotinib for RASH-positive Patients With Metastatic Pancreatic Cancer and Friendly Risk Circumstances

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.

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

- 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)

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

1-year Survial rate of "good-risk" patients

Outcome Description:

1-year Survial rate of "good-risk" patients of patients under gemcitabine plus erlotinib with RASH

Outcome Time Frame:

Follow-Up Phase (1.5 years)

Safety Issue:


Principal Investigator

Volker Heinemann, Professor

Investigator Role:

Principal Investigator

Investigator Affiliation:

Medical Department III and Comprehensive Cancer Center


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

September 2012

Completion Date:

September 2015

Related Keywords:

  • Metastatic Pancreatic Adenocarcinoma
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms