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 regimens of fostamatinib (100 mg bid, 150 mg bid, and 200mg bid) selected based on the FDA approved doses and 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 will receive fostamatinib plus paclitaxel at the MTD. A total of up to 30 patients will be enrolled in this study.

• Inclusion Criteria

• 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.
• Patients must have measurable disease, according to RECIST v1.1.
• 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.
• Patients must have the ability to take oral medications.
• Females, age ≥18 years.
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
• Life expectancy of greater than 3 months.
• Patients must have normal organ and marrow function.
• Patients with a diagnosis of hypertension are required to have adequate blood pressure control prior to enrollment, defined as blood pressure ≤ 140/90 mmHg.
• 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.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial if the anti-retroviral therapy is not an excluded concurrent medication.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated and the suppressive therapy is not an excluded concurrent medication.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load and the HCV therapy is not an excluded concurrent medication.
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
• Patients who are willing and able to comply with the protocol and study procedures.

Tumor biopsy or paracentesis for tumor cells before therapy (at baseline) and after initiation of treatment (before Cycle 2) for at least 75% of subjects if this is clinically and safely feasible to do so. For patients who have had tumor tissue sampled within 6 months of enrollment and no intervening anti-neoplastic therapy, archived tissue may satisfy the requirement of the pre-treatment biopsy with permission of the protocol chair.

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial, with permission of the protocol chair.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
• The effects of fostamatinib on the developing human fetus are unknown. For this reason and because spleen tyrosine kinase inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing 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 or her partner is participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.
• Exclusion Criteria

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study. Hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration.
• Patients who have not recovered (CTCAE v4.03 grade ≤1) from adverse events due to agents administered more than 4 weeks earlier, unless those events are deemed to have returned to baseline, are irreversible, or are unlikely to develop into a life-threatening condition at the permission of the Protocol Chair (e.g., alopecia).
• Patients who are currently receiving or have previously received any other investigational agents within 3 weeks prior to entering the study.
• Patients with known untreated brain metastases, as progressive neurologic dysfunction may develop that would confound the evaluation of neurologic and other adverse events.
• Patients with Grade 2 or greater neuropathy.
• 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.
• 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.
• Uncontrolled intercurrent illness
• 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.