Clinical Trial of Combined Fostamatinib and Paclitaxel in Ovarian Cancer

This is a phase I, open-label, non-randomized multicenter dose-escalation study with the
primary objective to determine the maximally tolerated dose (MTD) of fostamatinib when
administered with weekly paclitaxel in women with recurrent platinum-resistant ovarian,
fallopian tube, or primary peritoneal cancer.

Between 8 and 18 adult female subjects will be enrolled and receive weekly paclitaxel in
combination with increasing doses of fostamatinib. There will be three dosing intervals of
fostamatinib (100 mg bid, 150 mg bid, and 200mg bid) selected based on prior phase I studies
of single agent fostamatinib. Dose-escalation will follow a modified toxicity probability
interval (mTPI) design. In this study, up to 18 adult female subjects will be enrolled and
receive weekly paclitaxel in combination with fostamatinib at the MTD of the combination; at
least 6 patients with receive fostamatinib plus paclitaxel at the MTD.

- Inclusion Criteria

1. Patients must have histologically or cytologically confirmed epithelial ovarian,
fallopian tube, or primary peritoneal carcinoma. Histologic documentation (via
the pathology report) of the original primary tumor is required.

2. Patients must have measurable disease, according to RECIST v1.1.

3. Patients must have recurrent, platinum-resistant disease (defined as having
relapsed within 6 months of last platinum-containing regimen) or be unable to
receive further platinum therapy. There is no limit on the number of prior
treatment regimens; however, patients may not have previously received weekly
paclitaxel in the recurrent setting. Previous dose dense paclitaxel as initial
therapy is allowable.

4. Patients must have the ability to take oral medications.

5. Females, age ≥18 years.

6. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).

7. Life expectancy of greater than 3 months.

8. Patients must have normal organ and marrow function.

9. The effects of fostamatinib on the developing human fetus are unknown. For this
reason, women of childbearing potential must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry
and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while she is participating in this study, she should
inform her treating physician immediately.

10. Patients who are willing and able to comply with the protocol and study
procedures including willingness to undergo tumor biopsy or paracentesis for
tumor cells before therapy (at baseline) and after initiation of treatment
(before Cycle 2) for all subjects if this is clinically and safely feasible to do
so.

- Exclusion Criteria

1. Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 3 weeks
earlier. Hormonal therapy directed at the malignant tumor must be discontinued at
least one week prior to registration.

2. Patients who are currently receiving or have previously received any other
investigational agents within 3 weeks prior to entering the study.

3. Patients with known brain metastases, as progressive neurologic dysfunction may
develop that would confound the evaluation of neurologic and other adverse
events.

4. Patients with Grade 2 or greater neuropathy.

5. History of allergic reactions attributed to compounds of similar chemical or
biologic composition to fostamatinib or paclitaxel. Patients who are able to
tolerate paclitaxel on a desensitization protocol will be allowed.

6. Strong CYP3A4 inhibitors or inducers should not be used within 3 days of Day 1
dosing until the end of study. Moderate CYP3A4 inhibitors or inducers should be
used with caution.

7. Uncontrolled intercurrent illness

8. Pregnant women are excluded from this study because the potential for teratogenic
or abortifacient effects of fostamatinib are unknown. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment
of the mother with fostamatinib, breastfeeding should be discontinued if the
mother is treated with fostamatinib. These potential risks may also apply to
other agents used in this study.

9. Subject with known history of human immunodeficiency virus (HIV) or if known
seropositive for hepatitis C virus (HCV) or hepatitis B virus (HBV). HIV-positive
patients on combination antiretroviral therapy are ineligible because of the
potential immunosuppressive effects of and the potential for pharmacokinetic
interactions with fostamatinib. In addition, these patients are at increased risk
of lethal infections when treated with marrow-suppressive therapy.

NOTE: Patients seropositive for hepatitis B or C may be included if confirmed
hepatitis C RIBA negative or HCV RNA negative (qualitative).

10. Patients with prior malignancy, except for adequately treated basal cell or
squamous cell skin cancer, in situ cervical cancer, or other cancer from which
the subject has been disease free for at least three years.