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

Carcinoma, Pancreatic Ductal Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01808638
• Other study ID #: Atu027-I-02
• Secondary ID: 2012-004429-26
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: March 4, 2013
• Last updated: March 10, 2016
• Start date: March 2013
• Est. completion date: January 2016

Study information

• Verified date: March 2016
• Source: Silence Therapeutics GmbH
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medicinal Devices (BfArM)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: January 2016
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 84 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Pancreatic Ductal

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
Germany	Charité - Universitätsmedizin Berlin Charité Centrum für Tumormedizin	Berlin
Germany	Klinikum Dortmund gGmbH Medizinische Klinik Mitte	Dortmund
Germany	Universitätsklinikum Freiburg, Innere Medizin II	Freiburg
Germany	Medizinische Klinik III - Hämatologie/Onkologie Marienhospital Herne	Herne
Germany	Klinikum Kassel GmbH Medizinischen Klinik IV;Onkologie,	Kassel
Germany	Klinikum Nürnberg Nord Medizinische Klinik 5	Nürnberg
Germany	Klinik und Poliklinik für Innere Medizin I Universitätsklinikum Regensburg	Regensburg
Germany	Klinikum Stuttgart Klinik Hämatologie, Onkologie und Palliativmedizin	Stuttgart
Germany	Universitätsklinikum Ulm Zentrum für Innere Medizin	Ulm

Sponsors (3)

Lead Sponsor	Collaborator
Silence Therapeutics GmbH	FGK Clinical Research GmbH, Granzer Regulatory Consulting and Services

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of subjects with adverse events	Time frame will be 18 weeks if patient will be withdrawn after 3 cycles because of disease progression or toxicity.	Baseline till follow up visit 1 (18 weeks)	Yes
Primary	Subject physical examination	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.	At baseline; later on in 4 week intervals till last follow up visit (1 year);	Yes
Primary	Measuring of subject vital signs and body weight	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.	At baseline; end of treatment (13 weeks); later on in 4 week intervals till last follow up visit (1 year)	Yes
Primary	Performance of 12-lead ECG	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.	At baseline; later on in 4 week intervals till end of treatment (13 weeks)	Yes
Primary	Assessment of clinically significant laboratory parameters outside normal range	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.	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)	Yes
Primary	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	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.	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)	No
Secondary	Objective response rate	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).	At baseline and in 8 week intervals till end of trial (1 year)	No
Secondary	Progression-free survival and overall survival	Progression-free survival and overall survival, based on the objective response definition will be analyzed using Kaplan-Meier methods.	From baseline in 8 week intervals till end of trial (1 year).	No
Secondary	ECOG performance score	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.	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)	No
Secondary	Biomarker response	Serum protein markers and circulating microRNA will be analyzed and changes to baseline will be summarized descriptively by treatment arm.	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)	No
Secondary	Tumor marker response	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.	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)	No
Secondary	Quality of life	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.	At baseline; at day 1 of all cycles except cycle 1; at end of treatment (week 13 if patient withdrawn after 3 cycles)	No