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 (P204)

• ClinicalTrials.gov Identifier: NCT03395080
• Recruitment Status: Completed
• First Posted: January 10, 2018
• Results First Posted: June 9, 2023
• Last Update Posted: July 12, 2023
• Sponsor: Leap Therapeutics, Inc.
• Information provided by (Responsible Party): Leap Therapeutics, Inc.

Tracking Information

• First Submitted Date: January 2, 2018
• First Posted Date: January 10, 2018
• Results First Submitted Date: January 17, 2023
• Results First Posted Date: June 9, 2023
• Last Update Posted Date: July 12, 2023
• Actual Study Start Date: March 5, 2018
• Actual Primary Completion Date: September 9, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 24, 2023)

• Number of Subjects With Objective Response Rate (ORR) in EEC or EOC Patients [ Time Frame: Baseline to study completion (approximately 6 months) ]
  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)
• Number of Subjects With Objective Response Rate (ORR) in Carcinosarcoma (MMMT) Patients [ Time Frame: Baseline to study completion (approximately 6 months) ]
  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)

• Original Primary Outcome Measures (submitted: January 8, 2018): To determine the objective response rate (ORR). [ Time Frame: Baseline to study completion (approximately 6 months) ]

Current Secondary Outcome Measures (submitted: March 24, 2023)

• Number of Subjects With Objective Disease Control Rate (ODCR) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). [ Time Frame: Baseline to study completion (approximately 6 months) ]
  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)
• Overall Survival (OS) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). [ Time Frame: Baseline to study completion (maximum 17.6 months) ]
  Overall Survival (OS) is defined as the time from first dose of study drug until date of death due to any cause.
• Progression-free Survival (PFS) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). [ Time Frame: Baseline to study completion (maximum 7.1 months) ]
  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.
• Duration of Response (DoR) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). [ Time Frame: Baseline to study completion (approximately 11 months) ]
  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.
• Duration of Complete Response (DoCR) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). [ Time Frame: Baseline to study completion (approximately 11 months) ]
  Number of participants analyzed only includes patients with a CR and is otherwise defined and analyzed similar to DoR.
• Duration of Clinical Benefit (DoCB) in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). [ Time Frame: Baseline to study completion (approximately 13.1 months) ]
  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.

Original Secondary Outcome Measures (submitted: January 8, 2018)

• To determine the objective disease control rate (ODCR). [ Time Frame: Baseline to study completion (approximately 6 months) ]
• To determine overall survival (OS). [ Time Frame: Baseline to study completion (approximately 6 months) ]
• To determine progression-free survival (PFS). [ Time Frame: Baseline to study completion (approximately 6 months) ]
• To evaluate the adverse drug reactions and toxicities as evaluated by NCI CTCAE, version 4.03 as DKN-01 as monotherapy or in combination with paclitaxel [ Time Frame: Baseline to study completion (approximately 6 months) ]
• To evaluate additional measures of efficacy, including time to progression (TTP) [ Time Frame: Baseline to study completion (approximately 6 months) ]
• To evaluate additional measures of efficacy, including duration of response (DoR) [ Time Frame: Baseline to study completion (approximately 6 months) ]
• To evaluate additional measures of efficacy, including duration of complete response (DoCR) [ Time Frame: Baseline to study completion (approximately 6 months) ]
• To evaluate additional measures of efficacy, including time to treatment failure (TTTF). [ Time Frame: Baseline to study completion (approximately 6 months) ]

Current Other Pre-specified Outcome Measures (submitted: January 17, 2023)

• 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) [ Time Frame: Baseline to study completion (approximately 6 months) ]
• Dickkopf-1 (DKK1) Concentration in Serum and Plasma Relative to Safety and Efficacy Outcomes in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT). [ Time Frame: Baseline to study completion (approximately 6 months) ]
• 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 [ Time Frame: Baseline to study completion (approximately 6 months) ]
• Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 [ Time Frame: Baseline to study completion (approximately 6 months) ]
• Maximum Plasma Concentration (Cmax) [ Time Frame: Baseline to study completion (approximately 6 months) ]
• Time Taken to Reach the Maximum Plasma Concentration (Tmax) [ Time Frame: Baseline to study completion (approximately 6 months) ]
• Area Under the Curve (AUC) [ Time Frame: Baseline to study completion (approximately 6 months) ]
• 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) [ Time Frame: Baseline to study completion (approximately 6 months) ]
• 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 [ Time Frame: Baseline to study completion (approximately 6 months) ]
• Concentration of DKN-01 Antibodies in Human Serum in Patients With Recurrent EEC or EOC or Carcinosarcoma (MMMT) [ Time Frame: Baseline to study completion (approximately 6 months) ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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)

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Endometrial Cancer
• Uterine Cancer
• Ovarian Cancer
• Carcinosarcoma

Intervention

• Drug: Paclitaxel
  Administered by IV infusion
  Other Name: Taxol
• Drug: 300mg DKN-01
  Administered by IV infusion
• Drug: 600mg DKN-01
  Administered by IV infusion

Study Arms

• Experimental: DKN-01 monotherapy in recurrent EEC
  300mg DKN-01 monotherapy in recurrent EEC
  Intervention: Drug: 300mg DKN-01
• Experimental: DKN-01+paclitaxel in recurrent EEC
  300mg DKN-01+paclitaxel in recurrent EEC
  Interventions:

  • Drug: Paclitaxel
  • Drug: 300mg DKN-01
• Experimental: DKN-01 monotherapy in recurrent EOC
  300mg DKN-01 monotherapy in recurrent EOC
  Intervention: Drug: 300mg DKN-01
• Experimental: DKN-01+paclitaxel in recurrent EOC
  300mg DKN-01+paclitaxel in recurrent EOC
  Interventions:

  • Drug: Paclitaxel
  • Drug: 300mg DKN-01
• Experimental: DKN-01 monotherapy in carcinosarcoma
  600mg DKN-01 monotherapy in carcinosarcoma
  Intervention: Drug: 600mg DKN-01
• Experimental: DKN-01 +paclitaxel in carcinosarcoma
  600mg DKN-01 +paclitaxel in carcinosarcoma
  Interventions:

  • Drug: Paclitaxel
  • Drug: 600mg DKN-01

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 9, 2021): 111
• Original Estimated Enrollment (submitted: January 8, 2018): 94
• Actual Study Completion Date: January 27, 2021
• Actual Primary Completion Date: September 9, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: gender identity

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03395080
• Other Study ID Numbers: DEK-DKK1-P204
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Leap Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Leap Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Cynthia Sirard, MD; Leap Therapeutics
• Principal Investigator: Rebecca Arend, MD; University of Alabama at Birmingham

• PRS Account: Leap Therapeutics, Inc.
• Verification Date: May 2023