AZD9150, a STAT3 Antisense Oligonucleotide, in People With Malignant Ascites

Phase 2

Terminated

Conditions: Ascites
Gastrointestinal Neoplasms
Ovarian Cancer
Ovarian Neoplasms
Gastrointestinal Cancer

Interventions: Drug: AZD9150

Registration Number: NCT02417753

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

- Some people with gastrointestinal or ovarian cancer also have ascites. That is free fluid built up in the abdomen. Researchers want to see if a new drug can affect some of the immune cells in the ascites. This may also treat the cancer.

Objective:

- To look at the immune markers the ascites of people with gastrointestinal or ovarian cancer.

Eligibility:

- Adults age 18 and older with a malignancy of the gastrointestinal tract (GI) tract or metastatic ovarian cancer. As a result, they have ascites in the abdomen.

Design:

* Participants will be screened with:

* Medical history, physical exam, and blood tests.

* Echocardiogram: sound waves make images of the heart.

* Electrocardiogram: measures electrical activity of the heart.

* Paracentesis: a needle will be inserted in the abdomen and will remove some of the ascites fluid.

* They may have a tumor biopsy.

* Participants will get AZD9150 through a vein for 3 hours. They will get this 6 times in cycle 1 and 4 times all other cycles. Each cycle is 28 days.

* Each cycle, participants will:

* Have a physical exam.

* Have blood tests weekly.

* Be asked about how they feel and any medicines they are taking.

* After every 2 cycles (about every 2 months), participants will have scans and x-rays of their tumor.

* Participants will have paracentesis 2 more times during the study. They will have another echocardiogram.

* At the end of therapy, participants will have a physical exam and blood tests. They will be asked about how they feel and any medicines they are taking.

Detailed Description: Background:

* Signal transducer and activator of transcription 3 (STAT)3 is considered to be a promising cancer drug target because of its pleiotropic involvement in tumorigenesis. STAT3 not only regulates the expression of many genes which are directly important for the survival of tumor cells, but it is also an important factor in non-tumor cells in the tumor microenvironment involved in immune evasion of tumor cells, angiogenesis, and metastasis.

* AZD9150 is an antisense oligonucleotide designed to target and down-regulate expression of human STAT3 mRNA.

* By focusing on patients with malignant ascites it will be more feasible for us to sample the tumor environment and to do it more frequently than, for example, conventional tumor tissue biopsies. Malignant ascites is a relatively common occurrence in ovarian and gastrointestinal malignancies, impacting greatly on quality of life.

Objectives:

-To measure changes in immune parameters in the malignant ascites of patients with advanced cancer following therapy with AZD9150.

Select Eligibility:

* Age greater than or equal to 18 years.

* Histologically confirmed metastatic ovarian or GI malignancy with malignant ascites. Patients must have ascites amenable for paracentesis.

* Patient that have relapsed or have been refractory to at least one prior chemotherapy regimen, or patients for whom no standard therapy exists

Design:

* Up to N=15 eligible patients will receive AZD9150 at the following schedule:

* Cycle 1 only: AZD9150 will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22.

* Cycle 2 and beyond: AZD9150 will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle.

* Patients will be re-staged every 8 weeks.

* Patients will undergo a baseline pretreatment paracentesis which will be repeated on Cycle 1 Days 8 and 15. An optional paracentesis may be attempted on D57 or off treatment (whichever happens first). Immune subsets analysis at baseline in biopsy/ascites/peripheral blood mononuclear cells (PBMC) and post AZD9150 in surgical specimen, ascites and PBMC will be analyzed. STAT3 activation status will also be assessed in tumor cells isolated from malignant ascites at various time points.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
AZD9150 in People with Malignant Ascites	AZD9150	AZD9150 over a 28 day cycle

Primary Outcome Measures

Name	Time	Method
Changes in Immune Parameters in the Malignant Ascites of Patients With Advanced Cancer Following Therapy With AZD9150	1.5 years	Participants were to undergo research paracentesis. Ascitic fluid was to be obtained and processed for changes in the percentages of memory cluster of differentiation 8 (CD8) + cells, regulatory T cells, plasmacytoid dendritic cell (pDC), B cells and natural killer (NK) cells will be analyzed by flow cytometry.

Secondary Outcome Measures

Name	Time	Method
Effect on Signal Transducer and Activator of Transcription 3(STAT3)-Dependent & Associated Signaling Both in Tumor Cells, Peripheral Blood and the Microenvironment, Including Modulations in Chemokine and Cytokine Response Following Treatment With AZD9150	1.5 years	Serum samples were to be collected from participants and assessed for interferon, cytokine and chemokine levels including interferon, ϒ-interferon inducible protein (IP-10), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), and interleukin 12/p70 (IL-12/p70).
Reduction in Tyrosine-phosphorylated Signal Transducer and Activator of Transcription 3 (STAT3) Phospho- Signal Transducer and Activator of Transcription 3 (p- STAT3) Expression, Comparing Before and After Therapy, in Ascites and Peripheral Blood	1.5 years	Measure the reduction in tyrosine-phosphorylated STAT3 (p=STAT3) expression.
Response Rate (RR) in Patients With Malignant Ascites Treated With AZD9150	1.5 years	Response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and is measured from the time measurement criteria are met for complete response or partial response (whichever is recorded first) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
Count of Participants With Serious and Non Serious Adverse Events	4 months and 15 days	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Progression Free Survival (PFS) in Patients With Malignant Ascites Treated With AZD9150	1.5 years	PFS is the time interval from start of treatment to documented evidence of progressive disease. Progressive disease was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Progressive disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). in addition to the relative increase of 29%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Overall Survival (PFS) in Patients With Malignant Ascites Treated With AZD9150	1.5 years	OS is defined as the time from the first day of treatment to the day of death.