Clinical trial NCT01188785: Phase I - Escalating Dose Study of siG12D LODER (Local Drug EluteR) in Patients With Locally Advanced Adenocarcinoma of the Pancreas, and a Single Dose Study of siG12D LODER (Local Drug EluteR) in Patients With Non-operable Adenocarcinoma of the Pancreas
Official title: Phase I - Escalating Dose Study of siG12D LODER (Local Drug EluteR) in Patients With Locally Advanced Adenocarcinoma of the Pancreas, and a Single Dose Study of siG12D LODER (Local Drug EluteR) in Patients With Non-operable Adenocarcinoma of the Pancreas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pancreatic Ductal Adenocarcinoma
Pancreatic Cancer
Keywords: siRNA
RNA interference (RNAi)
Cancer
Pancreatic ductal adenocarcinoma
Pancreatic cancer
Solid tumor
Operable pancreatic ductal adenocarcinoma
Non operable pancreatic ductal adenocarcinoma
Lead sponsor: Silenseed Ltd
Sponsor class: INDUSTRY
First posted: 2010-08-25
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Phase 0 - Open label, Single dose study of siG12D LODER in Patients with operable adenocarcinoma of the pancreas.

The primary endpoint:

To assess efficacy and local distribution of siRNA out of eight high dose siG12D LODERs in patients diagnosed with operable adenocarcinoma of the pancreas.

The Secondary endpoint:

Short term tolerability and safety assessment

Phase I - This study is designed to investigate the safety of siG12D LODER (Local Drug EluteR) in patients diagnosed with adenocarcinoma of the pancreas.

The primary endpoint:

To asses efficacy of siG12D LODER and local distribution in non-operable patients by histopathology measurements, local distribution by RNA analysis.

To define the dose-limiting toxicities (DLT)

The Secondary endpoint

1. To determine the recommended Phase II dose (RP2D)
2. To define and maximum tolerated dose (MTD)
3. In the event of surgery, assessment of siG12D LODER local distribution and efficacy will be based on histopathology measurements and RNA analysis.
4. Progression free survival - only by long term follow-up

Detailed description: The investigational agent siG12D LODER (Local Drug EluteR) is a miniature biodegradable polymeric matrix that encompasses anti KRASG12D siRNA (siG12D) drug, designed to release the drug regionally within a pancreatic tumor, at a prolonged rate of 12-16 weeks.

The majority of pancreatic ductal adenocarcinomas involve mutations in the KRAS oncogene (the most common is G12D), therefore stable administration of KRASG12D siRNA has the potential to silence and lead to apoptosis of such cancer cells and thereby slow and even halt the tumor growth.

Eligibility criteria: Inclusion Criteria:

Phase 0:

Provide written informed consent and be between the ages of 18 and up, inclusive.

* Patient that is diagnosed as respectable locally pancreatic tumor
* Have a target tumor accessible for intratumoral administration by EUS (Endoscopic Ultrasound) guidance as determined by the physician performing the EUS guided LODER insertion.
* Have a Karnofsky performance status of ≥ 70%.
* Have a life expectancy of \>= 3 months.
* If female and of child-bearing potential, have a negative serum pregnancy test during screening.
* Agree to use of a barrier method of contraception if sexually active (both men and women) from the time of administration of the first treatment and for at least 8 weeks after treatment.
* Have serum creatinine \< 2.0 mg/dL, , PT, - INR \< 1.5 absolute neutrophil count (ANC) \> 1,000 x 103 cells/mL, platelets ≥ 75,000/mL, and hemoglobin \>= 10 mg/dL.
* Have screening procedures completed within 2 weeks of starting treatment.
* No other malignancy present that would interfere with the current intervention.
* Have measurable disease.

Phase I

* Provide written informed consent and be between the ages of 18 and up.
* Have an unresectable, locally advanced diagnosed or highly suspected adenocarcinoma of the pancreas. Or patients with a tumor and are not planed to undergo surgery due to a high surgical risk (e.g. coagulopathy or severe congestive heart failure).
* Allocated to receive standard of care chemo as first line treatment.
* Have a target tumor that is accessible for intratumoral administration by PTA or EUS guidance as determined by the radiologist/gastroenterologist performing the PTA/EUS injection.
* Have a Karnofsky performance status of ≥ 70%.
* Have a life expectancy of \>= 3 months.
* If female and of child-bearing potential, have a negative serum pregnancy test during screening.
* Agree to use of a barrier method of contraception if sexually active (both men and women) from the time of administration of the first treatment and for at least 8 weeks after treatment.
* Have serum creatinine \< 2.0 mg/dL, PT - INR \< 1.5, absolute neutrophil count (ANC) \> 1,000 x 103 cells/mL, platelets ≥ 75,000/mL, and hemoglobin \>= 10 mg/dL.
* Have screening procedures completed within 4 weeks of starting treatment.
* No other malignancy present that would interfere with the current intervention.
* Have measurable disease.

Exclusion Criteria:

Phase 0:

* Have distant metastasis spread (such as liver or lung, or lymph nodes metastases), peritoneal spread or malignant sites.
* Have clinically significant pancreatitis within 12 weeks of treatment.
* If female, be breast feeding.
* Have a medical condition contraindicated for both percutaneous- and endoscopic- guided delivery or any intercurrent medical illness or other medical condition that would in the judgment of the investigator compromise patient safety or the objectives of the study.
* Have a history of bleeding coagulopathy.
* Have participated in any therapeutic research study within the last 4 weeks.

Phase I:

* Have distant metastatic spread (such as liver, lung, or lymph nodes metastases), peritoneal spread or malignant sites.
* Have clinically significant pancreatitis within 12 weeks of treatment.
* If female, be breast feeding.
* Have a medical condition contraindicated for both percutaneous- and endoscopic- guided delivery or any intercurrent medical illness or other medical condition that would in the judgment of the investigator compromise patient safety or the objectives of the study.
* Have a history of bleeding coagulopathy.
* Have participated in any therapeutic research study within the last 4 weeks.

Primary outcomes:
measure: Number of Participants with Adverse Events
timeFrame: Phase 0 - 6 weeks, Phase I - 2 months
Secondary outcomes:
Other outcomes:
Locations:
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Organization
city: Ramat Gan
country: Israel
facility: Sheba Medical Center
Study officials:
affiliation: Hadassah Medical Organization
name: Ayala Hubert, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sheba Medical Center
name: Talya Golan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Shaare Zedek Medical Center
name: Amiel Segal, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Golan T, Khvalevsky EZ, Hubert A, Gabai RM, Hen N, Segal A, Domb A, Harari G, David EB, Raskin S, Goldes Y, Goldin E, Eliakim R, Lahav M, Kopleman Y, Dancour A, Shemi A, Galun E. RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget. 2015 Sep 15;6(27):24560-70. doi: 10.18632/oncotarget.4183.