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

Study Overview
=================
Brief Summary
-----------------
A Phase 2 Study Evaluating the Efficacy and Safety of DKN-01 as a Monotherapy or in Combination with Paclitaxel in Patients With Recurrent Epithelial Endometrial Cancer, Epithelial Ovarian Cancer, or Carcinosarcoma

Detailed Description
-----------------
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)

Official Title
-----------------
A Phase 2 Study Evaluating the Efficacy and Safety of DKN-01 as a Monotherapy or in Combination With Paclitaxel in Patients With Recurrent Epithelial Endometrial, Epithelial Ovarian Cancer, or Carcinosarcoma

Conditions
-----------------
Endometrial Cancer, Uterine Cancer, Ovarian Cancer, Carcinosarcoma

Intervention / Treatment
-----------------
* Drug: Paclitaxel
* Drug: 300mg DKN-01
* Drug: 600mg DKN-01


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DKN-01 monotherapy in recurrent EEC<br>300mg DKN-01 monotherapy in recurrent EEC | Drug: 300mg DKN-01<br>* Administered by IV infusion<br>|
| Experimental: DKN-01+paclitaxel in recurrent EEC<br>300mg DKN-01+paclitaxel in recurrent EEC | Drug: Paclitaxel<br>* Administered by IV infusion<br>* Other names: Taxol;Drug: 300mg DKN-01<br>* Administered by IV infusion<br>|
| Experimental: DKN-01 monotherapy in recurrent EOC<br>300mg DKN-01 monotherapy in recurrent EOC | Drug: 300mg DKN-01<br>* Administered by IV infusion<br>|
| Experimental: DKN-01+paclitaxel in recurrent EOC<br>300mg DKN-01+paclitaxel in recurrent EOC | Drug: Paclitaxel<br>* Administered by IV infusion<br>* Other names: Taxol;Drug: 300mg DKN-01<br>* Administered by IV infusion<br>|
| Experimental: DKN-01 monotherapy in carcinosarcoma<br>600mg DKN-01 monotherapy in carcinosarcoma | Drug: 600mg DKN-01<br>* Administered by IV infusion<br>|
| Experimental: DKN-01 +paclitaxel in carcinosarcoma<br>600mg DKN-01 +paclitaxel in carcinosarcoma | Drug: Paclitaxel<br>* Administered by IV infusion<br>* Other names: Taxol;Drug: 600mg DKN-01<br>* Administered by IV infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Objective Response Rate (ORR) in EEC or EOC Patients | Best overall response of Complete Response (CR; disappearance of all target lesions, any pathological lymph nodes whether target or non-target must have reduction in short axis to <10mm) or Partial Response (PR; at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters) as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) | Baseline to study completion (approximately 6 months) | 
| Number of Subjects With Objective Response Rate (ORR) in Carcinosarcoma (MMMT) Patients | Best overall response of Complete Response (CR; disappearance of all target lesions, any pathological lymph nodes whether target or non-target must have reduction in short axis to <10mm) or Partial Response (PR; at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters) as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) | Baseline to study completion (approximately 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Objective Disease Control Rate (ODCR) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). | Objective Disease Control Rate (ODCR) was defined as the percentage of subjects with a Best Overall Response of Complete Response (CR; disappearance of all target lesions, any pathological lymph nodes whether target or non-target must have reduction in short axis to <10mm), Partial Response (PR; at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters), or Stable Disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify as Progressive Disease) as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) | Baseline to study completion (approximately 6 months) | 
| Overall Survival (OS) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). | Overall Survival (OS) is defined as the time from first dose of study drug until date of death due to any cause. | Baseline to study completion (maximum 17.6 months) | 
| Progression-free Survival (PFS) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). | Progression-free survival (PFS) is defined as time from first dose of study drug to first documentation of PD (per RECIST 1.1) or death due to any cause. | Baseline to study completion (maximum 7.1 months) | 
| Duration of Response (DoR) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). | Duration of Response (DoR) includes only patients that have responded with an objective disease response (PR or CR) and is defined as the time from the first tumor assessment that supports the patient's objective disease response to the time of PD or death due to any cause. | Baseline to study completion (approximately 11 months) | 
| Duration of Complete Response (DoCR) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). | Number of participants analyzed only includes patients with a CR and is otherwise defined and analyzed similar to DoR. | Baseline to study completion (approximately 11 months) | 
| Duration of Clinical Benefit (DoCB) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). | Duration of Clinical Benefit (DoCB) includes patients with a Best Overall Response of CR, PR, or SD and is defined as the time from the first tumor assessment of CR, PR or SD to the time of PD or death due to any cause. | Baseline to study completion (approximately 13.1 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
epithelial histology, Wnt pathway, DKK1, endometrial, uterine, ovarian, carcinosarcoma