Clinical trial NCT01808638: Atu027 Plus Gemcitabine in Advanced or Metastatic Pancreatic Cancer (Atu027-I-02)
Official title: A PHASE Ib/IIa STUDY OF COMBINATION THERAPY WITH GEMCITABINE AND ATU027 IN SUBJECTS WITH LOCALLY ADVANCED OR METASTATIC PANCREATIC ADENOCARCINOMA
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Carcinoma, Pancreatic Ductal
Keywords: Adenocarcinoma
Pancreas
Gemcitabine
Atu027
Lead sponsor: Silence Therapeutics GmbH
Sponsor class: INDUSTRY
Collaborators: name: Granzer Regulatory Consulting & Services
name: FGK Clinical Research GmbH
First posted: 2013-03-11
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Maximum age (years): 84
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to evaluate a new treatment strategy for advanced pancreatic cancer disease by combining the new investigational medicinal product Atu027 with the standard chemotherapeutic gemcitabine. This combination aims at enhancing gemcitabine´s anti-tumor activity with Atu027.

The objectives of this clinical trial are to evaluate safety and activity of two Atu027 schedules in combination with standard gemcitabine treatment in patients with advanced or metastatic pancreatic adenocarcinoma.


Eligibility criteria: Inclusion Criteria:

Lead-in safety period:

* Subjects between the age of 18 and 84 years
* Histologically or cytologically confirmed advanced or refractory cholangiocellular carcinoma, biliary tract cancer, non-small-cell lung carcinoma, duodenal cancer, soft tissue sarcoma, ovarian carcinoma, or another non-pancreatic cancer disease indicated for gemcitabine treatment as determined by the investigator
* Subjects who have previously received chemotherapy and standard curative or palliative care is not available, not effective, or unlikely to be effective
* No option for surgical resection or radiation in curative intent
* Eastern Cooperative Oncology Group (ECOG) performance status assessment of 0 to 2
* Life expectancy of at least 3 months
* No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
* Alanine aminotransferase (ALT) ≤3.0 x upper limit of normal (ULN; ≤5 x ULN for subjects with liver metastases)
* Aspartate aminotransferase (AST) ≤3.0 x ULN (≤5 x ULN for subjects with liver involvement with cancer)
* Total bilirubin ≤2.0 x ULN (liver metastasis \<5 x ULN)
* Serum creatinine ≤1.5 x ULN
* Adequate bone marrow function: subjects should have an absolute granulocyte count of at least 1,500 (x 10e6/L) and platelet count of 100,000 (x 10e6/L) prior to the initiation of a cycle.
* Prothrombin time-international normalized ratio/partial thromboplastin time (PT-INR/PTT) \<1.5 x ULN (subjects who are being therapeutically anti-coagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists). Low-dose aspirin is permitted (≤100 mg daily).
* Women of childbearing potential must have a negative urine pregnancy test at baseline.
* Women of childbearing potential and men must be willing to use highly effective contraceptive methods during the course of the study and 6 months after.
* Subjects must be willing and able (in the opinion of the investigator) to understand the subject information and informed consent form and to comply with the study protocol and procedures.
* Subjects must be willing and able to give written informed consent.

Main part:

* Subjects between the age of 18 and 84 years
* Subjects with locally advanced or metastatic pancreatic adenocarcinoma stage III/IV indicated for gemcitabine treatment as determined by the investigator
* No option for surgical resection or radiation in curative intent
* Histological or cytological documentation of non-hematologic, malignant solid tumor
* At least one measurable lesion or evaluable disease, as per the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
* Eastern Cooperative Oncology Group (ECOG) performance status assessment of 0 to 2
* Life expectancy of at least 3 months
* No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung
* Alanine aminotransferase (ALT) \<=3.0 x upper limit of normal (ULN; \<=5 x ULN for subjects with liver metastases)
* Aspartate aminotransferase (AST) \<=3.0 x ULN (\<=5 x ULN for subjects with liver involvement with cancer)
* Total bilirubin \<=2.0 x ULN (liver metastasis \<=5 x ULN)
* Serum creatinine \<=1.5 x ULN
* Adequate bone marrow function: subjects should have an absolute granulocyte count of at least 1,500 (x 10e6/L) and platelet count of 100,000 (x 10e6/L) prior to the initiation of a cycle.
* Prothrombin time-international normalized ratio/partial thromboplastin time (PT INR/PTT) \<1.5 x ULN (subjects who are being therapeutically anti-coagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists). Low-dose aspirin is permitted (≤100 mg daily).
* Women of childbearing potential must have a negative urine pregnancy test at baseline.
* Women of childbearing potential and men must be willing to use highly effective contraceptive methods during the course of the study and 6 months after.
* Subjects must be willing and able (in the opinion of the investigator) to understand the subject information and informed consent form and to comply with the study protocol and procedures.
* Subjects must be willing and able to give written informed consent.

Exclusion Criteria:

Lead-in safety period:

* History of cardiac disease; congestive heart failure \>New York Heart Association (NYHA) functional classification system Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; new onset angina within 3 months prior to study entry or unstable angina, or ventricular cardiac arrhythmias requiring anti-arrhythmic therapy
* Poorly controlled diabetes defined as hemoglobin A1c (HbA1c) \>=7%
* Poorly controlled hypertension, defined as systolic blood pressure \>150 mmHg or diastolic pressure \>90 mmHg, despite optimal medical management
* Poorly controlled seizure disorder
* Subjects undergoing renal dialysis
* Known hypersensitivity to the study drugs or active substances or excipients of the preparations
* Pregnant or breast feeding
* Known hepatitis B or C or human immunodeficiency virus (HIV) infection (if documented in the subject's record
* Previous participation in this study
* Current or previous (within 30 days of enrolment) treatment with another investigational drug or participation in another clinical study.
* Subject is a relative of, or staff directly reporting to the investigator.
* Subject is an employee of the sponsor.
* Subject is committed under official or judicial order.
* Any other reason that the investigator considers makes the subject unsuitable to participate

Main part:

* History of cardiac disease; congestive heart failure \>New York Heart Association (NYHA) functional classification system Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; new onset angina within 3 months prior to study entry or unstable angina, or ventricular cardiac arrhythmias requiring anti-arrhythmic therapy
* Poorly controlled diabetes defined as hemoglobin A1c (HbA1c) \>=8%
* Poorly controlled hypertension, defined as systolic blood pressure \>150 mmHg or diastolic pressure \>90 mmHg, despite optimal medical management
* Poorly controlled seizure disorder
* Subjects undergoing renal dialysis
* Anticancer chemotherapy or immunotherapy during the study or before first study treatment. Subjects with recurrent disease after adjuvant treatment not progression-free for at least 6 months.
* Radiotherapy to target lesions during study or before study start
* Known hypersensitivity to the study drugs or active substances or excipients of the preparations
* Pregnant or breast feeding
* Known hepatitis B or C or human immunodeficiency virus (HIV) infection (if documented in the subject's record
* Previous participation in this study
* Current or previous (within 30 days of enrolment) treatment with another investigational drug or participation in another clinical study.
* Subject is a relative of, or staff directly reporting to the investigator.
* Subject is an employee of the sponsor.
* Subject is committed under official or judicial order.
* Any other reason that the investigator considers makes the subject unsuitable to participate

Primary outcomes:
measure: Number of subjects with adverse events
timeFrame: Baseline till follow up visit 1 (18 weeks)
measure: Subject physical examination
timeFrame: At baseline; later on in 4 week intervals till last follow up visit (1 year);
measure: Measuring of subject vital signs and body weight
timeFrame: At baseline; end of treatment (13 weeks); later on in 4 week intervals till last follow up visit (1 year)
measure: Performance of 12-lead ECG
timeFrame: At baseline; later on in 4 week intervals till end of treatment (13 weeks)
measure: Assessment of clinically significant laboratory parameters outside normal range
timeFrame: At baseline; at end of treatment (week 13 if patient withdrawn after 3 cycles); at follow up visit 1 (week 18 if patient withdrawn after 3 cycles); at each follow up visit till end of trial (1 year)
measure: Maximum concentration (Cmax), area under the curve (AUC), time to maximum concentration (tmax), and half life (t½) of the Atu027 siRNA single strand (A-strand), and of AtuFect01 and the helper lipid DPyPE
timeFrame: At end of treatment (week 13 if patient withdrawn after 3 cycles); at follow up visit 1 (week 18 if patient withdrawn after 3 cycles)
Secondary outcomes:
measure: Objective response rate
timeFrame: At baseline and in 8 week intervals till end of trial (1 year)
measure: Progression-free survival and overall survival
timeFrame: From baseline in 8 week intervals till end of trial (1 year).
measure: ECOG performance score
timeFrame: At baseline; at end of treatment (13 weeks if patient withdrawn after 3 cycles); at follow up visit 1 (18 weeks if patient withdrawn after 3 cycles); at each following follow up visit till end of trial (1 year)
measure: Biomarker response
timeFrame: At baseline; at day 1 of cycle 3; end of treatment (13 weeks if patient withdrawn after 3 cycles); follow up visit 1 (18 weeks if patient withdrawn after 3 cycles)
measure: Tumor marker response
timeFrame: At baseline; at end of treatment (13 weeks if patient withdrawn after 3 cycles); at follow up visit 1 (18 weeks if patient withdrawn after 3 cycles); at each following follow up visit till end of trial (1 year)
measure: Quality of life
timeFrame: At baseline; at day 1 of all cycles except cycle 1; at end of treatment (week 13 if patient withdrawn after 3 cycles)
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin Charité Centrum für Tumormedizin
city: Dortmund
country: Germany
facility: Klinikum Dortmund gGmbH Medizinische Klinik Mitte
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg, Innere Medizin II
city: Herne
country: Germany
facility: Medizinische Klinik III - Hämatologie/Onkologie Marienhospital Herne
city: Kassel
country: Germany
facility: Klinikum Kassel GmbH Medizinischen Klinik IV;Onkologie,
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg Nord Medizinische Klinik 5
city: Regensburg
country: Germany
facility: Klinik und Poliklinik für Innere Medizin I Universitätsklinikum Regensburg
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart Klinik Hämatologie, Onkologie und Palliativmedizin
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm Zentrum für Innere Medizin
Study officials:
affiliation: Medizinische Klinik III - Hämatologie/Onkologie Marienhospital Herne
name: Dirk Strumberg, Prof.Dr.med.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schultheis B, Strumberg D, Kuhlmann J, Wolf M, Link K, Seufferlein T, Kaufmann J, Feist M, Gebhardt F, Khan M, Stintzing S, Pelzer U. Safety, Efficacy and Pharcacokinetics of Targeted Therapy with The Liposomal RNA Interference Therapeutic Atu027 Combined with Gemcitabine in Patients with Pancreatic Adenocarcinoma. A Randomized Phase Ib/IIa Study. Cancers (Basel). 2020 Oct 26;12(11):3130. doi: 10.3390/cancers12113130.