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Atu027 Plus Gemcitabine in Advanced or Metastatic Pancreatic Cancer (Atu027-I-02) (Atu027-I-02)

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ClinicalTrials.gov Identifier: NCT01808638
Recruitment Status : Completed
First Posted : March 11, 2013
Last Update Posted : March 11, 2016
Sponsor:
Collaborators:
Granzer Regulatory Consulting & Services
FGK Clinical Research GmbH
Information provided by (Responsible Party):
Silence Therapeutics GmbH

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.


Condition or disease Intervention/treatment Phase
Carcinoma, Pancreatic Ductal Drug: Atu027 & gemcitabine in lead in safety period Drug: Atu027 & gemcitabine in treatment arm 1 Drug: Atu027 & gemcitabine in treatment arm 2 Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 29 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A PHASE Ib/IIa STUDY OF COMBINATION THERAPY WITH GEMCITABINE AND ATU027 IN SUBJECTS WITH LOCALLY ADVANCED OR METASTATIC PANCREATIC ADENOCARCINOMA
Study Start Date : March 2013
Actual Primary Completion Date : August 2015
Actual Study Completion Date : January 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Lead in safety period
Cohort of three subjects with non-pancreatic cancer for whom conventional treatment options have failed, will be treated. If one of the subjects in the safety cohort experiences an unacceptable toxicity, the safety cohort is expanded to six subjects.
Drug: Atu027 & gemcitabine in lead in safety period
Subjects will be treated in a 28-day cycle with Atu027 twice weekly for 4 weeks and gemcitabine once weekly for the first three weeks.

Experimental: Treatment arm 1
Subjects with advanced pancreatic cancer will be treated.
Drug: Atu027 & gemcitabine in treatment arm 1

Subjects will be treated in a 28-day cycle with Atu027 and gemcitabine once weekly for three consecutive weeks (on days 1, 8, and 15). During week four no treatment is administered.

Treatment will be continued in consecutive 28-day cycles until unacceptable toxicity or disease progression occurs.


Experimental: Treatment arm 2
Subjects with advanced pancreatic cancer will be treated.
Drug: Atu027 & gemcitabine in treatment arm 2

Subjects will be treated in a 28-day cycle with gemcitabine once weekly (on days 4, 11, and 18) and Atu027 twice weekly (on days 1, 4, 8, 11, 15, 18, 22, and 25). The 28-day combination cycle is followed by a 28-day gemcitabine monotherapy cycle.

Treatment will be continued in consecutive 28-day cycles until unacceptable toxicity or disease progression occurs.





Primary Outcome Measures :
  1. Number of subjects with adverse events [ Time Frame: Baseline till follow up visit 1 (18 weeks) ]
    Time frame will be 18 weeks if patient will be withdrawn after 3 cycles because of disease progression or toxicity.

  2. Subject physical examination [ Time Frame: At baseline; later on in 4 week intervals till last follow up visit (1 year); ]
    Additional time frames in arm 1: 8 days after baseline. Additional time frames in arm 2 and safety cohort (cycle 1 only): 4 and 15 days after baseline.

  3. Measuring of subject vital signs and body weight [ Time Frame: At baseline; end of treatment (13 weeks); later on in 4 week intervals till last follow up visit (1 year) ]

    End of treatment visit will be after 13 weeks only when patient is withdrawn after 3 cycles.

    Additional time frames in arm 1: 8 days after baseline. Additional time frames in arm 2 and safety cohort (cycle 1 only): 4 and 15 days after baseline.


  4. Performance of 12-lead ECG [ Time Frame: At baseline; later on in 4 week intervals till end of treatment (13 weeks) ]

    End of treatment visit will be after 13 weeks only when patient is withdrawn after 3 cycles.

    Additional time frames in arm 1: 8 days after baseline. Additional time frames in arm 2 and safety cohort (cycle 1 only): 4 and 15 days after baseline.


  5. Assessment of clinically significant laboratory parameters outside normal range [ Time Frame: 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) ]

    Additional time frames in arm 1: During treatment on days 1, 8, 15 of each cycle.

    Additional time frames in arm 2 and safety cohort (cycle 1 only): During treatment on days 1, 4, 8, 11, 15, 18, 22, 25 of each cycle.


  6. 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 [ Time Frame: 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) ]

    Additional time frames in arm 1: During cycles 1 and 2 of treatment on days 1, 8, 15 of each cycle; in cycle 3 and following only on day 1; Additional time frames in arm 2 and safety cohort (cycle 1 only): During the first treatment cycle on days 1, 4, 8, 11, 15, 18; in cycle 3 and following odd numbered cycles only on day 1; in all even numbered cycles no samples are taken.

    Pharmacokinetics will be assessed in subjects of the safety cohort and in the first 4 subjects per treatment arm.



Secondary Outcome Measures :
  1. Objective response rate [ Time Frame: At baseline and in 8 week intervals till end of trial (1 year) ]

    Response will be assessed by RECIST Version 1.1 using abdominal magnetic resonance imaging (MRI) or computed tomography (CT) scans.

    An objective response is defined when the overall response is complete response (CR), partial response (PR), or stable disease (SD).


  2. Progression-free survival and overall survival [ Time Frame: From baseline in 8 week intervals till end of trial (1 year). ]
    Progression-free survival and overall survival, based on the objective response definition will be analyzed using Kaplan-Meier methods.

  3. ECOG performance score [ Time Frame: 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) ]

    Additional time frames: During treatment on day 1 of each cycle.

    The ECOG performance status, and its change from baseline, will be summarized descriptively by visit and treatment arm. The ECOG performance status will also be assessed during the 1 year follow-up period of the study and results including changes to baseline will be summarized.


  4. Biomarker response [ Time Frame: 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) ]
    Serum protein markers and circulating microRNA will be analyzed and changes to baseline will be summarized descriptively by treatment arm.

  5. Tumor marker response [ Time Frame: 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) ]
    Additional time frame: At day 1 of cycle 3 and day 1 of each following second cycle; Tumor markers will be summarized descriptively for each analyzed marker.

  6. Quality of life [ Time Frame: At baseline; at day 1 of all cycles except cycle 1; at end of treatment (week 13 if patient withdrawn after 3 cycles) ]
    Different scales of quality of life assessed with the EORTC questionnaire and their changes from baseline will be summarized descriptively by visit and treatment arm.



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Ages Eligible for Study:   18 Years to 84 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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 ClinicalTrials.gov identifier (NCT number): NCT01808638


Locations
Germany
Charité - Universitätsmedizin Berlin Charité Centrum für Tumormedizin
Berlin, Germany, 13353
Klinikum Dortmund gGmbH Medizinische Klinik Mitte
Dortmund, Germany, 44137
Universitätsklinikum Freiburg, Innere Medizin II
Freiburg, Germany, 79106
Medizinische Klinik III - Hämatologie/Onkologie Marienhospital Herne
Herne, Germany, 44625
Klinikum Kassel GmbH Medizinischen Klinik IV;Onkologie,
Kassel, Germany, 34125
Klinikum Nürnberg Nord Medizinische Klinik 5
Nürnberg, Germany, 90419
Klinik und Poliklinik für Innere Medizin I Universitätsklinikum Regensburg
Regensburg, Germany, 93042
Klinikum Stuttgart Klinik Hämatologie, Onkologie und Palliativmedizin
Stuttgart, Germany, 70174
Universitätsklinikum Ulm Zentrum für Innere Medizin
Ulm, Germany, 89061
Sponsors and Collaborators
Silence Therapeutics GmbH
Granzer Regulatory Consulting & Services
FGK Clinical Research GmbH
Investigators
Principal Investigator: Dirk Strumberg, Prof.Dr.med. Medizinische Klinik III - Hämatologie/Onkologie Marienhospital Herne

Responsible Party: Silence Therapeutics GmbH
ClinicalTrials.gov Identifier: NCT01808638     History of Changes
Other Study ID Numbers: Atu027-I-02
2012-004429-26 ( EudraCT Number )
First Posted: March 11, 2013    Key Record Dates
Last Update Posted: March 11, 2016
Last Verified: March 2016

Keywords provided by Silence Therapeutics GmbH:
Adenocarcinoma
Pancreas
Gemcitabine
Atu027

Additional relevant MeSH terms:
Carcinoma, Pancreatic Ductal
Carcinoma, Ductal
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Ductal, Lobular, and Medullary
Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs