Company decision

The purpose of this study is to estimate the maximum tolerated doses (MTD) of CRLX101 when administered in combination with weekly paclitaxel in women with recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer.

Determine through pharmacokinetic evaluation(sometimes described as what the body does to a drug, refers to the movement of drug into, through and out of the body-the time and course of its absorption, bioavailability, distribution, metabolism, and excretion) whether or not the disposition of paclitaxel is affected by the concurrent administration of CRLX101.

Recurrent ovarian cancer represents a therapeutic challenge. Patients with resistant disease, showing progression within six months of platinum-containing therapy, have a poor prognosis, with median overall survival (OS) approximately 12 months.Ultimately most patients with recurrent disease ultimately develop platinum resistance, and novel strategies are needed.

In this setting the most active agents are pegylated liposomal doxorubicin (PLD), paclitaxel and topotecan. Multiple trials have demonstrated that combination therapy produces increased toxicity without improved efficacy.

This study proposes to examine the combination of CRLX101 in combination with weekly paclitaxel. Preclinical studies show synergistic activity in the SKOV3 human ovarian cancer xenograft ovarian cancer cell lines (14), as well as in vivo (15,16), perhaps via an antiangiogenic mechanism.

Inclusion Criteria:

1. Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Histologic documentation of the original primary tumor is required via the pathology report.

2. Patient must have measurable disease or detectable (non-measurable) disease:

   Measurable disease will be defined by RECIST 1.1.

3. Patients must have adequate bone marrow, renal, hepatic, and neurologic functions

4. Patients should be free of active infection requiring parenteral antibiotics.

5. Any other prior therapy directed at the malignant tumor, including chemotherapy, bevacizumab or other biologic or targeted agents and immunologic agents, must be discontinued at least 21 days (three weeks) prior to registration.

6. Any prior radiation therapy must be discontinued at least four weeks prior to registration.

7. Major surgery within 28 days (four weeks) prior to registration.

8. Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease.

9. Patients must have a GOG performance status of 0 or 1.

10. Patients who will be enrolled under protocol amendment # 2 must have previously received bevacizumab, either discontinued due to intolerability, or progressed after at least 2 cycles of bevacizumab

Exclusion Criteria:

1. Patients who have had previous treatment with:

   • CRLX101 or with any topoisomerase I therapy;
   • Weekly paclitaxel for recurrent or persistent disease.

2. Patients with a history of other invasive malignancies, with the exception of non-melanoma skin, are excluded if:

   • There is any evidence of other malignancy being present within the last three years;
   • Previous cancer treatment contraindicates this protocol therapy.

3. Patients with known active hepatitis or HIV.

4. Patients with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first dose of study drug.

5. Patients with clinically significant cardiovascular disease.

6. Patients with serous non-healing wound, ulcer, or bone fracture.

7. Patients with active bleeding or pathologic conditions that carry high risk of bleeding

8. Patients with clinical symptoms or signs of gastrointestinal obstruction and who require parenteral hydration and/or nutrition.

9. Patients with active infection requiring parenteral antibiotics.