Clinical trial NCT03395080: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Endometrial Cancer
Uterine Cancer
Ovarian Cancer
Carcinosarcoma
Keywords: epithelial histology
Wnt pathway
DKK1
endometrial
uterine
ovarian
carcinosarcoma
Lead sponsor: Leap Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2018-01-10
Enrollment: 111
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

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

Eligibility criteria: Inclusion Criteria:

1. Diagnosis:

   1. Epithelial Endometrial Cancer: histologically confirmed diagnosis (by either primary surgical specimen or biopsy for recurrence) of recurrent previously treated EEC.
   2. 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).
   3. 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.
2. 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).

   1. If prior therapy consisted of palliative chemoradiation therapy, it will be considered one line of therapy.
   2. Prior treatment with paclitaxel as part of definitive therapy regimen is acceptable, provided the patient is not intolerant of paclitaxel.
   3. Patients who are not eligible to receive paclitaxel will be allowed to receive single agent DKN-01.
3. Tumor tissue for mandatory pre-treatment and on-treatment biopsies.
4. One or more tumors measurable on radiographic imaging as defined by RECIST 1.1.
5. Ambulatory and ≥18 years of age.
6. 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.
7. Estimated life expectancy of at least 3 months, in the judgment of the Investigator.
8. 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.
9. Acceptable liver, renal, hematologic and coagulation function
10. 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.
11. Reliable and willing to make themselves available for the duration of the study and are willing to follow study-specific procedures.
12. Provided written informed consent prior to any study-specific procedures.

Exclusion Criteria:

1. Patients with the following pure histologies of endometrial or ovarian cancer are not eligible for enrollment: germ cell, sex cord stroma, or sarcoma.
2. New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia.
3. Fridericia-corrected QT interval (QTcF) \> 470 msec (female) or history of congenital long QT syndrome.
4. Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of study entry requiring systemic therapy.
5. 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.
6. History of major organ transplant (i.e., heart, lungs, liver, or kidney).
7. History of autologous/allogenic bone marrow transplant.
8. Serious nonmalignant disease
9. Pregnant or nursing.
10. 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.
11. Symptomatic central nervous system (CNS) malignancy or metastasis.
12. Known osteoblastic bony metastasis
13. Treatment with surgery or chemotherapy within 21 days prior to study entry (42 days for nitrosoureas or mitomycin C)
14. Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to study entry.
15. 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
16. 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
17. Prior radiation therapy within 14 days prior to study entry
18. Currently receiving any other investigational agent or received an investigational agent within last 30 days of study entry.
19. Previously treated with an anti-DKK1 therapy
20. Significant allergy to a pharmaceutical therapy that, in the opinion of the Investigator, poses an increased risk to the patient
21. Active substance abuse

Primary outcomes:
measure: Number of Subjects With Objective Response Rate (ORR) in EEC or EOC Patients
timeFrame: Baseline to study completion (approximately 6 months)
measure: Number of Subjects With Objective Response Rate (ORR) in Carcinosarcoma (MMMT) Patients
timeFrame: Baseline to study completion (approximately 6 months)
Secondary outcomes:
measure: Number of Subjects With Objective Disease Control Rate (ODCR) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT).
timeFrame: Baseline to study completion (approximately 6 months)
measure: Overall Survival (OS) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT).
timeFrame: Baseline to study completion (maximum 17.6 months)
measure: Progression-free Survival (PFS) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT).
timeFrame: Baseline to study completion (maximum 7.1 months)
measure: Duration of Response (DoR) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT).
timeFrame: Baseline to study completion (approximately 11 months)
measure: Duration of Complete Response (DoCR) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT).
timeFrame: Baseline to study completion (approximately 11 months)
measure: Duration of Clinical Benefit (DoCB) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT).
timeFrame: Baseline to study completion (approximately 13.1 months)
Other outcomes:
measure: Number of Subjects With Response to Therapy in Patients With and Without Activating β-catenin Mutations and/or Wnt Signaling Genetic Alterations in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT)
timeFrame: Baseline to study completion (approximately 6 months)
measure: Dickkopf-1 (DKK1) Concentration in Serum and Plasma Relative to Safety and Efficacy Outcomes in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT).
timeFrame: Baseline to study completion (approximately 6 months)
measure: Number of Subjects With Adverse Drug Reactions and Toxicities as Evaluated by NCI CTCAE v5.0 of DKN-01 600 mg +/- Paclitaxel in Patients With Recurrent Carcinosarcoma (MMMT) in Carcinosarcoma (MMMT) Patients
timeFrame: Baseline to study completion (approximately 6 months)
measure: Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
timeFrame: Baseline to study completion (approximately 6 months)
measure: Maximum Plasma Concentration (Cmax)
timeFrame: Baseline to study completion (approximately 6 months)
measure: Time Taken to Reach the Maximum Plasma Concentration (Tmax)
timeFrame: Baseline to study completion (approximately 6 months)
measure: Area Under the Curve (AUC)
timeFrame: Baseline to study completion (approximately 6 months)
measure: Number of Subjects With Adverse Drug Reactions and Toxicities as Evaluated by NCI CTCAE v4.03 as DKN-01 as Monotherapy or in Combination With Paclitaxel in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT)
timeFrame: Baseline to study completion (approximately 6 months)
measure: Number of Subjects With Adverse Drug Reactions and Toxicities to Study Treatment Regimen in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT) as Evaluated by NCI CTCAE v5.0
timeFrame: Baseline to study completion (approximately 6 months)
measure: Concentration of DKN-01 Antibodies in Human Serum in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT)
timeFrame: Baseline to study completion (approximately 6 months)
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Scottsdale
country: United States
facility: HonorHealth
state: Arizona
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Kansas City
country: United States
facility: HCA Midwest Health System Clinical Research
state: Missouri
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Hilliard
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center - University of Oklahoma Health Sciences Center
state: Oklahoma
city: Germantown
country: United States
facility: The University of Tennessee West Cancer Center
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert and Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Leap Therapeutics
name: Cynthia Sirard, MD
role: STUDY_DIRECTOR
affiliation: University of Alabama at Birmingham
name: Rebecca Arend, MD
role: PRINCIPAL_INVESTIGATOR
References: