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

Background:

- STAT3 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/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.

-INCLUSION CRITERIA:

1. Patients must have histologically or cytologically confirmed GI malignancies or
ovarian cancer prior to entering this study.

2. Histologically confirmed metastatic ovarian or GI malignancy with malignant ascites
amenable for paracentesis. Adjudication of malignant ascites can be made on clinical
grounds e.g. in the absence of cirrhosis or other non-malignant causes of ascites.

3. Patients who have relapsed or are refractory to at least one prior chemotherapy
regimen, and for whom no standard therapy exists. There is no limit to the number of
prior chemotherapy regimens received.

4. Patients should be off radiation therapy, chemotherapy, investigational agents,
hormonal therapy, or immunotherapy for 4 weeks (or 5 half-lives of the therapy,
whichever is longer) prior to first dose in the study, and off Bevacizumab 6 weeks.

5. Age greater than or equal to 18 years.

6. ECOG performance status <2 (Karnofsky >70%)

7. Patients must have normal organ and marrow function as defined below:

- leukocytes >3,000/mcL

- absolute neutrophil count >1,500/mcL without growth-factor support during the
past month

- platelets >100,000/mcL at all times during the screening period without platelet
transfusion within 3 weeks

-total bilirubin <2 X institutional upper limit of normal

- Hb greater than or equal to 9 g/dL without transfusion for 3 weeks

- INR < 2.0

- AST(SGOT)/ALT(SGPT) <3 X institutional upper limit of normal, or <5 ULN for
patients with liver metastasis

- Creatinine within normal institutional limits

OR

8. Patients must have recovered from any acute toxicity related to prior therapy,
including surgery. Toxicity should be < grade 1

9. Ejection fraction > 50% on echocardiogram.

10. The effects of AZD9150 on the developing human fetus are unknown. For this reason
women of child-bearing potential should use reliable methods of contraception from
the time of screening until 6 months after discontinuing study treatment. Acceptable
methods of contraception include tubal ligation, tricycle combined oral or
transdermal contraceptives, copper-banded intra-uterine devices and vasectomized
partner. It is not known whether AZD9150 has the capacity to induce hepatic enzymes
so hormonal contraceptives should be combined with a barrier method of contraception.
Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately.
Women of child-bearing potential must have a negative pregnancy test prior to entry.
Male patients should use reliable methods of contraception such as barrier
contraception i.e. condoms during sexual activities with women of child-bearing
potential and refrain from sperm donation during the trial and for a washout period
of at least 6 months. If male patients wish to father children they should be advised
to arrange for freezing of sperm samples prior to the start of study treatment.

11. Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

1. Patients who are receiving any other investigational agents.

2. History of prior JAK or STAT3 inhibitor treatment.

3. Patients with known brain metastases or spinal cord compression should be excluded
from this clinical trial because of their poor prognosis and because they often
develop progressive neurologic dysfunction that would confound the evaluation of
neurologic and other adverse events.

4. Patients must not have other invasive malignancies within the past 3 years (with the
exception of adequately treated basal or squamous cell skin cancers, carcinoma in
situ of the cervix and ductal carcinoma in situ (DCIS) of breast).

5. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD9150.

6. Incompletely healed surgical incision prior to enrolment

7. Ongoing therapy with oral or parenteral anticoagulants (e.g., heparin, warfarin).
Lowdose anticoagulants for maintenance of catheter patency are not exclusionary.

8. Any of the following cardiac criteria:

- Mean resting corrected QT interval (QTcF) > 480 msec obtained from 3
electrocardiograms (ECGs)

- Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG e.g., complete left bundle branch block, third degree heart block

9. Patients with uncontrolled hypertension (SBP> 155, DBP> 90), unstable coronary
disease (unstable angina, evidence of CHF, or MI within 6 months of study)

10. New York Heart Association (NYHA) greater than or equal to Grade II or greater.

11. History of myocardial infarction within 6months prior to screening.

12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

13. Pregnant and/or breastfeeding

14. HIV-positive patients or with history of hepatitis or with current chronic or active
hepatitis. A past history of Hepatitis A is allowed.

15. History of recurrent bacterial infections unrelated to HCC (particularly skin or
lung)

16. Bacterial peritonitis within 30 days

17. History of, or presently active or chronic viral infections (i.e. zoster or
hepatitis)

18. History of known latent or active tuberculosis, signs of active or latent
tuberculosis on chest X-ray, skin test showing an induration of >10 mm or more or
according to local recommendations.

19. Active bleeding disorders and high likelihood of bleeding or conditions or
medications known to increase the risk of bleeding. Patients with bleeding diathesis
and subjects who are receiving anticoagulation treatment with INR > 2 are excluded.

20. History of recurrent thrombosis or any thrombosis within the past 6 months

21. Family history consistent with thrombophilia or hypofibrinolysis

22. Patients who have received liver transplantation

23. History of clinically significant liver abnormalities other than liver metastasis

24. Presence of hepatic encephalopathy within 4 weeks of 1st dose

25. Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and
requirements