Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
drksid header

  DRKS00003840

Trial Description

start of 1:1-Block title

Title

Panitumumab in Combination With Cisplatin/Gemcitabine Chemotherapy in Patients With Cholangiocarcinomas - a Randomized Clinical Phase II Study

end of 1:1-Block title
start of 1:1-Block acronym

Trial Acronym

PiCCA

end of 1:1-Block acronym
start of 1:1-Block url

URL of the Trial

[---]*

end of 1:1-Block url
start of 1:1-Block public summary

Brief Summary in Lay Language

The purpose of this study is to determine the efficacy of panitumumab plus
cisplatin/gemcitabine (CisGem) combination chemotherapy in KRAS wild-type biliary tract
cancer patients without systemic pre-treatment, compared to the historical data and to the
randomised control group without the antibody, which verifies the historically based
assumption.

end of 1:1-Block public summary
start of 1:1-Block scientific synopsis

Brief Summary in Scientific Language

The rationale of the study is the assessment of the clinical activity of Panitumumab in
conjunction with standard Cisplatin/Gemcitabine chemotherapy in patients with
cholangiocarcinomas and gall bladder carcinomas in 1st-line therapy.

Cholangiocarcinoma (CCA) is an epithelial cancer originating from the bile ducts with
features of cholangiocyte differentiation. CCA is the second most common primary hepatic
malignancy, and epidemiologic studies suggest its incidence is increasing in Western
countries. Hepatobiliary malignancies account for 13% of the 7.6 million annual
cancer-related deaths worldwide and CCA accounts for approximately 20% of the deaths from
hepatobiliary malignancies (Kubicka and Manns 2000; Kubicka 2004; Blechacz and Gores 2008;
Malek et al. 2007).

The only curative option for patients with gallbladder- or bile duct cancer is surgical
resection. Advanced CCA has a devastating prognosis. There are only limited numbers of
studies about the systemic treatment options for biliary cancers. Gallbladder and bile duct
carcinomas are moderately chemotherapy-sensitive tumors. The objective response rates in
phase II studies with 5-FU or gemcitabine monochemotherapy are between 10 - 30 % (Kubicka et
al. 2001b). Higher response rates between 20 - 50 % have been observed in phase II studies
with combination chemotherapy, in particular with the combination of gemcitabine/cisplatin
(Kubicka 2004; Malek et al. 2007).

Recently for the first time an improvement of overall survival has been demonstrated in a
large randomized phase III trial with chemotherapy combination of cisplatin and gemcitabine
(n=206) compared to gemcitabine mono-chemotherapy (n=204) (Valle et al. 2009). Median
overall survival was 8,2 month in the monotherapy arm versus 11,7 month in the combination
arm (p=0.002). As a consequence of this study the combination of Cisplatin (25mg/m² d1,8)
and Gemcitabine (1000mg/m² d1,8) should be considered as the standard first line
chemotherapy for patients with irresectable cholangio- or gallbladder carcinomas.

The growing understanding of the molecular pathogenesis of CCA opens new therapeutic options
for molecular targeting (Blechacz and Gores 2008). In particular EGFR signaling appears to
be important for tumor growth of CCA. Inhibition of EGFR signaling has been shown to
significantly suppress CCA cell growth (Blechacz and Gores 2008). In addition EGFR can
directly be activated by bile acids and promote CCA cell proliferation, a potential
explanation for the tropism exerted by CCA for the biliary tree. It has been shown that EGFR
activation is sustained in CCA by failure to internalize the ligand-receptor complex, a
homeostatic mechanism essential for receptor inactivation. EGFR phosphorylation results in
activation of the downstream kinases p42/44 MAPK and p38 MAPK, which in turn increase
cyclooxygenase 2 expression in CCA cells.

Further evidence for the essential contribution of EGFR-signalling comes from studies with
IL-6 (Blechacz and Gores 2008). IL-6 is a key cytokine in the pathogenesis of CCA. IL-6 is
produced at high levels by CCA cells, and elevated IL-6 serum concentrations have been
reported in CCA patients. It has been shown that there is a cross-communication between IL-6
and EGFR resulting in IL-6 mediated overexpression of EGFR.

Recently the first results of a randomized phase II study of gemcitabine and oxaliplatin
(GEMOX) alone or in combination with cetuximab in patients with advanced biliary cancer have
been reported (Malka et al. 2009). The primary objective of the study was a 4-month PFS rate
of more than 60% in the experimental arm with cetuximab. The included patients were not
monitored for RAS or B-RAF mutations. However compared to GEMOX chemotherapy (n=51),
GEMOX+cetuximab (n=50) showed an increased 4-month PFS-rate (50% versus 61%) and an improved
median PFS (5 versus 7 months). This is the first evidence from a randomized trial that
anti-EGFR therapy may be effective for patients with cholangiocarcinomas and gallbladder
carcinomas.

KRAS is a downstream molecule in the EGFR-pathway. Recently it has been shown that oncogenic
RAS mutations are predictive for poor efficacy of an anti-EGFR-therapy in colorectal cancer.
Conversely patients with colorectal cancers harbouring KRAS wild-type showed frequently
dramatic tumor responses upon anti-EGFR-treatment, indicating that colorectal cancers with
KRAS wild type are highly susceptible for an anti-EGFR-therapy. Although dysregulation of
KRAS is commonly observed in malignancies, mutations of KRAS have only been described in 12%
to 54% of intrahepatic CCA (Kubicka et al. 2001a; Blechacz and Gores 2008, Gruenberger et al
2009). This is in sharp contrast to pancreatic ductal carcinoma where KRAS mutations are
present in approximately 90% of cancers. Thus, despite shared developmental ontology between
the pancreatic ducts and the biliary tree, their adult cancers are different and may explain
the negative result of a phase III studies in pancreatic cancer with Cetuximab
(anti-EGFR-antibody).

Very preliminary and sparse data from a recent small phase II study with cetuximab do not
allow to speculate whether the RAS status does predict the response in cholangiocarcinomas
similarly to colorectal cancers (Gruenberger et al. 2009). However, due to the clear
evidence of absence of efficacy in mutant KRAS colorectal cancer, the presumptive population
"enrichment" should be applied in this first trial on biliary duct cancer, which is to focus
on KRAS wild type patients.

Since most of the patients with CCA are treated in large centers a chemotherapy protocol
with limited numbers of intravenous infusions appears to be very comfortable for patients
with CCA. A further argument for the investigation of Cisplatin/Gemcitabine/Panitumumab in a
randomized phase II study is the fact that the 3-week interval of the Cis/Gem protocol fits
very well into the 3-week interval of the Panitumumab schedule.

end of 1:1-Block scientific synopsis
start of 1:1-Block organizational data

Organizational Data

  •   DRKS00003840
  •   2012/05/09
  •   2011/03/21
  •   yes
  •   [---]*
  •   [---]*
end of 1:1-Block organizational data
start of 1:n-Block secondary IDs

Secondary IDs

  •   2010-018850-11 
  •   NCT01320254  (ClinicalTrials.gov)
end of 1:n-Block secondary IDs
start of 1:N-Block indications

Health Condition or Problem studied

  •   Cholangiocarcinomas
  •   C22.1 -  Malignant neoplasm: Intrahepatic bile duct carcinoma
end of 1:N-Block indications
start of 1:N-Block interventions

Interventions/Observational Groups

  •   Drug: Cisplatin, Gemcitabine, Panitumumab
  •   Drug: Cisplatin, Gemcitabine
end of 1:N-Block interventions
start of 1:1-Block design

Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   II
  •   [---]*
end of 1:1-Block design
start of 1:1-Block primary endpoint

Primary Outcome

- progression-free survival rate; time frame: 6 months; The progression-free survival rate at six months (primary endpoint) is defined as the number of patients recorded to be free of progression (according to RECIST) at this time point, divided by the number of patients randomized to the respective arm.

end of 1:1-Block primary endpoint
start of 1:1-Block secondary endpoint

Secondary Outcome

- Tumor response; time frame: 48 weeks; Tumor response according to RECIST criteria within the first 48 weeks of treatment
- Progression-free survival; time frame: 3 years; Progression-free survival (PFS) will be defined as the time from randomisation to the time of disease progression or relapse (according to RECIST) or death, or to the date of last assessment without any such event (censored observation).
- Overall survival; time frame: 3 years; The duration of overall survival (OS) will be determined by measuring the time interval from randomisastion to the date of death or last observation (censored).
- Number of Participants with Adverse Events as a Measure of Toxicity/Safety; time frame: 3 years
- Translational research; time frame: 3 years; assessment/ correlation of tumor response with KRAS (mandatory)
alterations in cholangiocarcinomas and gallbladder cancer (EGFR, PTEN, BRAF)through optional translational research

end of 1:1-Block secondary endpoint
start of 1:n-Block recruitment countries

Countries of Recruitment

  •   Germany
end of 1:n-Block recruitment countries
start of 1:n-Block recruitment locations

Locations of Recruitment

  •  
  •  
  •  
  •  
  •  
  •  
  •  
  •  
  •  
  •  
  •  
  •  
  •  
  •  
  •  
  •  
end of 1:n-Block recruitment locations
start of 1:1-Block recruitment

Recruitment

  •   [---]*
  •   2011/06/30
  •   92
  •   Multicenter trial
  •   National
end of 1:1-Block recruitment
start of 1:1-Block inclusion criteria

Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
end of 1:1-Block inclusion criteria
start of 1:1-Block inclusion criteria add

Additional Inclusion Criteria

- Signed,dated informed consent before start of specific protocol procedures

- Histologically/cytologically documented diagnosis of cholangiocarcinoma or gall
bladder carcinoma

- At least one measurable site of disease following RECIST V. 1.1 criteria

- Wild-type KRAS status as assessed by standardized PCR

- Unresectable, locally advanced or metastatic disease

- Age > 18 years old

- ECOG Performance Status 0 or 1

- Life expectancy of at least 12 weeks

- Adequate bone marrow, liver (with stenting for any obstruction, if required) and
renal function (lab. assessment within 7 days prior to screening):

- Hemoglobin > 10.0 g/dl

- Leukocyte count > 3.000/mm3 ; absolute neutrophil count (ANC) > 1.500/mm3

- Platelet count 100.000/mm³

- Total bilirubin < 5,0 times the upper limit of normal

- ALT and AST < 3 x upper limit of normal

- Alkaline phosphatase < 5 x ULN

- PT-INR/PTT < 1.5 x upper limit of normal [Patients who are being therapeutically
anticoagulated with an agent such as coumarin or heparin will be allowed to
participate provided that no prior evidence of underlying abnormality in these
parameters exists.]

- Serum creatinine < 1.5 x upper limit of normal and creatinine clearance > 60 ml/min

- Magnesium ≥ lower limit of normal; calcium ≥ lower limit of normal

- The patient is willing and able to comply with the protocol for the duration of the
study, including hospital visits for treatment and scheduled follow-up visits and
examinations

- Negative pregnancy test performed within 7 days prior to the start of treatment, and
willingness to use highly effective methods of contraception (per institutional
standard) during treatment and for 6 months (male or female) after the end of
treatment (adequate: oral contraceptives, intrauterine device or barrier method in
conjunction with spermicidal jelly)

end of 1:1-Block inclusion criteria add
start of 1:1-Block exclusion criteria

Exclusion Criteria

- KRAS mutation

- Clinically significant cardiovascular disease (incl. myocardial infarction, unstable
angina, symptomatic congestive heart failure, serious uncontrolled cardiac
arrhythmia) ≤ 1 year before enrollment

- History of interstitial lung disease, e.g. pneumonitis or pulmonary fibrosis or
evidence of interstitial lung disease on baseline chest CT scan.

- History of HIV infection or chronic hepatitis B

- Active clinically serious infections (> grade 2 NCI-CTC version 3.0)

- Pre-existing neuropathy > grade 1 (NCI CTCAE), except for loss of tendon reflex
(patellar tendon reflex)

- Symptomatic or known brain metastases.A scan to confirm the absence of brain
metastases is not required -Patients with seizure disorder requiring medication (such
as steroids or anti- epileptics)

- History of organ allograft

- Patients with evidence or history of bleeding diathesis

- Patients undergoing renal dialysis

- Patients with second primary cancer,except adequately treated basal skin cancer or
carcinoma in-situ of the cervix

- Any condition that is unstable or could jeopardize the safety of the patient and
their compliance in the study

- No prior anti-cancer chemotherapy,radiotherapy(excluding palliative radiotherapy
administered more than 4 weeks prior to study entry),endocrine or immunotherapy

- Investigational drug therapy outside of this trial during or within 4weeks of study
entry

- Major surgery within 4 weeks of starting the study and patients must have recovered
from effects of major surgery

- Prior anti-EGFR therapy

- Autologous bone marrow transplant or stem cell rescue within 4 months of study

- Breast-feeding patients

- Substance abuse, medical, psychological or social conditions that may interfere with
the patient's understanding of the informed consent procedure, participation in the
study or evaluation of the study results

end of 1:1-Block exclusion criteria
start of 1:n-Block addresses

Addresses

  • start of 1:1-Block address primary-sponsor
    • Hannover Medical School
    end of 1:1-Block address primary-sponsor
    start of 1:1-Block address contact primary-sponsor
    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
    end of 1:1-Block address contact primary-sponsor
  • start of 1:1-Block address scientific-contact
    • Hannover Medical School
    • Arndt Vogel, PD Dr. MD 
    end of 1:1-Block address scientific-contact
    start of 1:1-Block address contact scientific-contact
    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
    end of 1:1-Block address contact scientific-contact
  • start of 1:1-Block address public-contact
    • Arndt Vogel, PD Dr. MD 
    end of 1:1-Block address public-contact
    start of 1:1-Block address contact public-contact
    end of 1:1-Block address contact public-contact
end of 1:n-Block addresses
start of 1:n-Block material support

Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
    end of 1:1-Block address materialSupport
    start of 1:1-Block address contact materialSupport
    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
    end of 1:1-Block address contact materialSupport
end of 1:n-Block material support
start of 1:1-Block state

Status

  •   Recruiting ongoing
  •   [---]*
end of 1:1-Block state
start of 1:n-Block publications

Trial Publications, Results and other Documents

  • [---]*
end of 1:n-Block publications
The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   11
  •   2013/10/30
* This entry means the parameter is not applicable or has not been set.