A Phase 1, Open-Label, Dose Escalation Study of ANA773 Tosylate, an Oral Prodrug of a Toll-like Receptor-7 Agonist in Patients with Advanced Cancer

ANA773 tosylate is a drug that stimulates the innate immune system.  It is a prodrug, which means that the drug itself isn’t active – but after it enters the body, it undergoes modification to a metabolite, ANX6784, which is active.  ANA773 tosylate is administered as a prodrug so that it can be given orally.  It stimulates toll-like receptor 7, which is one of a family of receptors that activate the innate immune system.  The innate immune system is thought to constitute and evolutionarily older defense strategy and can be triggered to defend the host from infection and tumors in a non-specific manner.

The primary end-point of the study is to determine the safety profile of ANA773 tosylate administration including identification of dose-limiting toxicity (DLT) and maximum tolerated dose (MTD).  Secondary objectives include to determine the pharmacokinetic profile of ANA773 following oral administration of ANA773 tosylate, to determine the immunological effects of ANA773 tosylate administration, to determine the recommended phase 2 doses and schedules of ANA773 tosylate, and to determine, preliminarily, evidence of ANA773 tosylate anti-tumor activity.

Inclusion Criteria (conditions the patient must meet)

1. are informed of, and willing and able to comply with, the investigational nature of the study, and have signed an informed consent form in accordance with institutional and regulatory guidelines
2. are male or female adults 18 years of age or older, inclusive
3. Male and female patients who are not surgically sterile must use an effective contraceptive method (e.g., condom and spermicide, IUD, Depo Provera) for the duration of time on study, and males must continue use for 3 months after the last ANA773 tosylate dose
   
4. Women of child-bearing potential (i.e., women who are pre-menopausal and not surgically sterile) must have a negative serum or urine pregnancy test prior to dosing on Day 1.
5. Cytologically or histologically confirmed advanced malignancy refractory to standard of care therapy, or for whom no standard of care therapy is available
6. at least 4 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosurea) and recovered
7. at least 4 weeks since prior radiotherapy and recovered
8. measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST)
9. target lesions in previously irradiated sites are considered measurable if there is clear disease progression after radiotherapy
10. asymptomatic, previously treated (by surgical resection or radiotherapy) brain metastasis may be allowed provided patient is neurologically stable and off steroids and anticonvulsants for ≥ 4 weeks
11. patients must have ECOG performance status (PS) of 0 – 2
12. resolution of all acute toxic effects of prior therapy or surgical procedures to ≤ Grade 1 (except alopecia)
13. life expectancy 3 months or greater
14. at least 8 weeks since prior steroids
15. at least 12 weeks since prior radio-immunotherapy
16. patients must have adequate organ function

Exclusion Criteria
Patients who exhibit any of the following conditions at screening will not be eligible for admission into the study:

1. major surgery, radiation therapy or systemic therapy for their cancer within 4 weeks of dosing
2. prior high-dose chemotherapy requiring hematopoietic stem cell rescue
3. prior treatment with more than 2 systemic chemotherapy regimens
4. prior radiation to > 25% of bone marrow
5. concurrent anticancer or immunosuppressive treatment
6. ongoing treatment with an investigational agent or participation in another clinical trial
7. participation in any investigational drug study within 28 days prior to ANA773 tosylate administration. (Patient must have recovered from all acute effects of previously administered investigational agents)
8. ongoing cardiac dysrhythmias of NCI CTCAE grade ≥ 2, atrial fibrillation of any grade, or QTc interval > 450 msec for males and > 470 msec for females
9. hypertension not controlled by medications (>150/100 despite optimal medical therapy)
10. positive status for human immunodeficiency virus (HIV) or hepatitis B or C
11. pregnant or breastfeeding
12. active infection uncontrolled by appropriate antibacterial, antiviral or antifungal therapy
13. any medical condition which in the opinion of the investigator places the patient at an unacceptably high risk for toxicities
14. inability to give written informed consent or to comply with protocol requirements
15. anticoagulant therapy or anti-platelet therapy within 2 weeks prior to study
16. history of autoimmune disorder (e.g., autoimmune vasculitis)
17. life-threatening illness or organ system dysfunction compromising safety evaluation
18. uncontrolled intercurrent illness, including any of the following:
    • cerebrovascular accident or transient ischemic attack within 6 months of study entry
    • unstable angina pectoris
    • EKG evidence of acute ischemia
19. Psychiatric illness/social situations that would limit compliance with study requirements
20. other malignancy within the past 5 years except curatively treated non lifethreatening malignancies, i.e., cutaneous basal cell or squamous cell carcinoma or carcinoma in situ of the cervix
21. concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient’s ability to tolerate protocol therapy

Treatment Regimen
ANA773 tosylate capsules will be administered orally with water in the morning every other day for 14 days, followed by 14 days without treatment. All doses are to be administered in the morning after fasting at least 8 hours prior to dosing and 2 hours after dosing. Patients will receive up to 6 cycles of study treatment on this protocol.

Each treatment cycle will be 28 days with doses administered every other day for 14 days followed by a 14 day rest period. Patients who achieve a complete response (CR), which has been confirmed, will receive one additional treatment cycle. Other patients deriving benefit (PR or SD) may continue treatment for up to 6 cycles (24 weeks) on this protocol. Patients who achieve a partial response or exhibit stable disease at the completion of 6 treatment cycles may continue to receive ANA773 tosylate under an extension protocol at the discretion of the principal investigator in consultation with the sponsor.

After completion of study treatment, patients will return for a follow-up visit at 1 month and will be contacted by phone at 3 months.