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PiCCA Study (Panitumumab in Combination With Cisplatin/Gemcitabine) (PiCCA)

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.
ClinicalTrials.gov Identifier: NCT01320254
Recruitment Status : Completed
First Posted : March 22, 2011
Last Update Posted : October 12, 2017
Information provided by (Responsible Party):
Hannover Medical School

Tracking Information
First Submitted Date  ICMJE March 21, 2011
First Posted Date  ICMJE March 22, 2011
Last Update Posted Date October 12, 2017
Study Start Date  ICMJE June 2011
Actual Primary Completion Date September 12, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 21, 2011)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2011)
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE PiCCA Study (Panitumumab in Combination With Cisplatin/Gemcitabine)
Official Title  ICMJE Panitumumab in Combination With Cisplatin/Gemcitabine Chemotherapy in Patients With Cholangiocarcinomas - a Randomized Clinical Phase II Study
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cholangiocarcinomas
Intervention  ICMJE
  • Drug: Cisplatin, Gemcitabine, Panitumumab
    Cisplatin 25mq/sq.m. at day 1+8 and Gemcitabine 1000mg/sq.m. at day 1 + 8 Panitumumab 9mg/kg BW at day 1
    Other Names:
    • Vectibix (Panitumumab)
    • Gemzar (Gemcitabine)
    • Cisplatin 0.5mg/ml solution medac (Cisplatin)
  • Drug: Cisplatin, Gemcitabine
    Cisplatin 25mq/sq.m. at day 1+8 and Gemcitabine 1000mg/sq.m. at day 1 + 8
    Other Names:
    • Gemzar (Gemcitabine)
    • Cisplatin 0.5mg/ml solution medac (Cisplatin)
Study Arms  ICMJE
  • Experimental: Cisplatin, Gemcitabine and Panitumumab
    Experimental Arm with cisplatin 25mg/sq.m. at day 1 + 8, gemcitabine 1000mg/ sq.m.at day 1 + 8 and panitumumab 9mg/kg BW at day 1. Cycle will be repeated every 3 weeks.
    Intervention: Drug: Cisplatin, Gemcitabine, Panitumumab
  • Active Comparator: Cisplatin and Gemcitabine
    Cisplatin 25mg/sq.m. at day 1 + 8 and Gemcitabine 1000 mg/sq.m. at day 1 + 8. Cycle will be repeated every 3 weeks.
    Intervention: Drug: Cisplatin, Gemcitabine
Publications * Vogel A, Kasper S, Bitzer M, Block A, Sinn M, Schulze-Bergkamen H, Moehler M, Pfarr N, Endris V, Goeppert B, Merx K, Schnoy E, Siveke JT, Michl P, Waldschmidt D, Kuhlmann J, Geissler M, Kahl C, Evenkamp R, Schmidt T, Kuhlmann A, Weichert W, Kubicka S. PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer-a randomised biomarker-driven clinical phase II AIO study. Eur J Cancer. 2018 Mar;92:11-19. doi: 10.1016/j.ejca.2017.12.028. Epub 2018 Feb 3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 11, 2017)
Original Estimated Enrollment  ICMJE
 (submitted: March 21, 2011)
Actual Study Completion Date  ICMJE September 12, 2016
Actual Primary Completion Date September 12, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01320254
Other Study ID Numbers  ICMJE EudraCT-Nr.: 2010-018850-11
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Hannover Medical School
Original Responsible Party Dr. Bernd Eisele MD, Medical School Hannover represented by KS MHH
Current Study Sponsor  ICMJE Hannover Medical School
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Arndt Vogel, PD Dr. MD Hannover Medical School
PRS Account Hannover Medical School
Verification Date October 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP