A Study of DKN-01 as a Monotherapy or in Combination With Paclitaxel in Patients With Recurrent Epithelial Endometrial or Epithelial Ovarian Cancer or Carcinosarcoma

This study employs a "basket" design to concurrently investigate DKN-01 as monotherapy and in combination with paclitaxel in patients with recurrent epithelial endometrial cancer (EEC), epithelial ovarian cancer (EOC), or carcinosarcoma (malignant mixed Mullerian tumor [MMMT]. Thus, 6 distinct patient groups are being independently investigated:

• 300mg DKN-01 monotherapy in recurrent EEC (Group 1)
• 300mg DKN-01+paclitaxel in recurrent EEC (Group 2)
• 300mg DKN-01 monotherapy in recurrent EOC (Group 3)
• 300mg DKN-01+paclitaxel in recurrent EOC (Group 4)
• 600mg DKN-01 monotherapy in recurrent carcinosarcoma (MMMT) (Group 5)
• 600mg DKN-01+paclitaxel in recurrent carcinosarcoma (MMMT) (Group 6)

Inclusion criteria

• Diagnosis:

• Epithelial Endometrial Cancer: histologically confirmed diagnosis (by either primary surgical specimen or biopsy for recurrence) of recurrent previously treated EEC.
• Epithelial Ovarian Cancer: histologically confirmed diagnosis (by either primary surgical specimen or biopsy for recurrence) of recurrent platinum-resistant/refractory EOC, primary peritoneal, or fallopian tube cancer (i.e., disease recurrence within 6 months of completion of or progression during platinum-based chemotherapy).
• Carcinosarcoma/Malignant Mixed Mullerian Tumors: histologically confirmed diagnosis (by either primary surgical specimen or biopsy for recurrence) of recurrent uterine or ovarian carcinosarcoma (MMMT). Patients must have had only 1 prior chemotherapeutic regimen for management of carcinosarcoma that may have been included chemotherapy (including in adjuvant setting), chemotherapy and radiotherapy, and/or consolidation/maintenance therapy.
• Refractory or intolerant to at least one prior standard therapy(ies) for metastatic or locally advanced disease (see Inclusion Criterion #1c for Groups 5-6).

• If prior therapy consisted of palliative chemoradiation therapy, it will be considered one line of therapy.
• Prior treatment with paclitaxel as part of definitive therapy regimen is acceptable, provided the patient is not intolerant of paclitaxel.
• Patients who are not eligible to receive paclitaxel will be allowed to receive single agent DKN-01.
• Tumor tissue for mandatory pre-treatment and on-treatment biopsies.
• One or more tumors measurable on radiographic imaging as defined by RECIST 1.1.
• Ambulatory and ≥18 years of age.
• ECOG performance status (PS) of 0 or 1

a. ECOG PS of 2 may be eligible upon the review and approval of the Medical Monitor.

• Estimated life expectancy of at least 3 months, in the judgment of the Investigator.
• Disease-free of active second/secondary or prior malignancies for ≥2 years with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or breast.
• Acceptable liver, renal, hematologic and coagulation function
• Females of child bearing potential and male partners of female patients must agree to use adequate contraception during the study and for 6 months after their last dose of study drug.
• Reliable and willing to make themselves available for the duration of the study and are willing to follow study-specific procedures.
• Provided written informed consent prior to any study-specific procedures.

Exclusion criteria

• Patients with the following pure histologies of endometrial or ovarian cancer are not eligible for enrollment: germ cell, sex cord stroma, or sarcoma.
• New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.
• Fridericia-corrected QT interval (QTcF) > 470 msec (female) or history of congenital long QT syndrome.
• Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry requiring systemic therapy.
• Known to be human immunodeficiency virus (HIV) positive, have hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb), unless hepatitis C virus ribonucleic acid (HCV RNA) undetected/negative.
• History of major organ transplant (i.e., heart, lungs, liver, or kidney).
• History of autologous/allogenic bone marrow transplant.
• Serious nonmalignant disease
• Pregnant or nursing.
• History of osteonecrosis of the hip or have evidence of structural bone abnormalities in the proximal femur on MRI scan that are symptomatic and clinically significant.
• Symptomatic central nervous system (CNS) malignancy or metastasis.
• Known osteoblastic bony metastasis
• Treatment with surgery or chemotherapy within 21 days prior to study entry (42 days for nitrosoureas or mitomycin C)
• Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to study entry.
• Clinically significant peripheral neuropathy at the time of study entry. Patients with pre-existing peripheral neuropathy will be allowed to receive single agent DKN-01
• History of hypersensitivity reactions to paclitaxel or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil). Patients who exhibit these hypersensitivities will be eligible to receive single agent DKN-01
• Prior radiation therapy within 14 days prior to study entry
• Currently receiving any other investigational agent or received an investigational agent within last 30 days of study entry.
• Previously treated with an anti-DKK1 therapy
• Significant allergy to a pharmaceutical therapy that, in the opinion of the Investigator, poses an increased risk to the patient
• Active substance abuse