A Study of DKN-01 in Combination With Paclitaxel or Pembrolizumab (P102)

• ClinicalTrials.gov Identifier: NCT02013154
• Recruitment Status: Completed
• First Posted: December 17, 2013
• Last Update Posted: September 10, 2021
• Sponsor: Leap Therapeutics, Inc.
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Leap Therapeutics, Inc.

Study Description

Brief Summary:

A study to evaluate the safety and tolerability of DKN-01 in combination with weekly paclitaxel or pembrolizumab in participants with relapsed or refractory Esophagogastric Malignancies

Condition or disease	Intervention/treatment	Phase
Esophageal Neoplasms; Adenocarcinoma of the Gastroesophageal Junction; Gastroesophageal Cancer; Squamous Cell Carcinoma; Gastric Adenocarcinoma	Drug: DKN-01; Drug: Paclitaxel; Drug: Pembrolizumab	Phase 1

Detailed Description:

Part A is a Dose-Escalation Study in Participants with Relapsed or Refractory Esophageal Cancer or Gastro-Esophageal Junction Tumors. Parts B, C, D and E are expansion cohorts of Patients with Relapsed or Refractory Esophageal Cancer, Gastro-Esophageal Junction Tumors and Gastric Adenocarcinoma.

Part F is a Dose-Escalation and Expansion Cohorts with DKN-01 + Pembrolizumab in Patients with Recurrent or Metastatic Esophageal Cancer, Gastroesophageal Junction Cancer or Gastric Adenocarcinoma with Wnt Signaling Alterations.

Patients who are unable to receive paclitaxel or pembrolizumab for any reason will be allowed to receive single agent DKN-01 as part of a monotherapy substudy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 151 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-part, Phase 1, Multi-center, Open-label Study of DKN-01 as a Monotherapy or in Combination With Paclitaxel or Pembrolizumab in Patients With Relapsed or Refractory Esophagogastric Malignancies
• Actual Study Start Date: May 5, 2014
• Actual Primary Completion Date: July 19, 2019
• Actual Study Completion Date: January 11, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: DKN-01 (Dose Escalation); Escalating dose of 150 milligrams (mg) up to 300 mg of DKN-01 administered on days 1 and 15 and 80 milligrams per meter squared of body surface area (mg/m2) of paclitaxel administered on days 1,8,15, and 22	Drug: DKN-01; Administered by IV infusion; Drug: Paclitaxel; Administered by IV infusion; Other Name: Taxol
Experimental: Part B: DKN-01 (Dose Confirmation); Dose of DKN-01 determined in Part A will be administered to esophageal or gastro-esophageal junction cancer patients on Days 1 and 15 and 80 mg/m2 of paclitaxel administered on Days 1,8,15,and 22	Drug: DKN-01; Administered by IV infusion; Drug: Paclitaxel; Administered by IV infusion; Other Name: Taxol
Experimental: Part C: DKN-01 (Cohort Expansion); Dose of DKN-01 determined in Part A will be administered to esophageal or gastro-esophageal junction adenocarcinoma patients on Days 1 and 15 and 80 mg/m2 of paclitaxel administered on Days 1,8,15,and 22	Drug: DKN-01; Administered by IV infusion; Drug: Paclitaxel; Administered by IV infusion; Other Name: Taxol
Experimental: Part D: DKN-01 (Cohort Expansion); Dose of DKN-01 determined in Part A will be administered to esophageal squamous cell cancer patients on Days 1 and 15 and 80 mg/m2 of paclitaxel administered on Days 1,8,15,and 22	Drug: DKN-01; Administered by IV infusion; Drug: Paclitaxel; Administered by IV infusion; Other Name: Taxol
Experimental: DKN-01 Monotherapy Substudy; Dose of DKN-01 determined in Part A will be administered to esophageal or gastro-esophageal junction cancer patients on Days 1 and 15	Drug: DKN-01; Administered by IV infusion
Experimental: Part E: DKN-01 (Cohort Expansion); Dose of DKN-01 determined in Part A will be administered to gastric adenocarcinoma with Wnt signaling alteration cancer patients on Days 1 and 15 and 80 mg/m2 of paclitaxel administered on Days 1,8,15,and 22	Drug: DKN-01; Administered by IV infusion; Drug: Paclitaxel; Administered by IV infusion; Other Name: Taxol
Experimental: Part F DKN-01 (Dose Escalation+Expansion); Escalating dose on 150mg up to 300 mg of DKN-01 administered to patients with recurrent or metastatic esophageal cancer, gastroesophageal junction cancer or gastric adenocarcinoma with Wnt signaling alterations on days 1 and 15 and 200 mg of pembrolizumab administered on day 1 of a 21 day cycle	Drug: DKN-01; Administered by IV infusion; Drug: Pembrolizumab; Administered by IV infusion; Other Name: Keytruda

Outcome Measures

Primary Outcome Measures :

1. Number of subjects with dose limiting toxicities in Study Parts A and F which will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03 [ Time Frame: Baseline to End of cycle 1 (Part A cycle is 28 days and Part F cycle is 21 days) ]
2. Number of subjects with adverse drug reactions and toxicities as evaluated by NCI CTCAE v4.03 of DKN-01 as monotherapy or in combination with paclitaxel or pembrolizumab [ Time Frame: Baseline until 30 days after last dose of study drug as assessed at a minimum of every 2 weeks ]

Secondary Outcome Measures :

1. Clinical response to treatment [ Time Frame: Baseline to study completion (approximately 3 months) ]
2. Objective Response Rate (ORR) [ Time Frame: Baseline to study completion (approximately 3 months) ]
3. Objective Disease Control Rate (ODCR) [ Time Frame: Baseline to study completion (approximately 3 months) ]
4. Duration of Response (DoR) [ Time Frame: Baseline to study completion (approximately 3 months) ]
5. Duration of CR (DoCR) [ Time Frame: Baseline to study completion (approximately 3 months) ]
6. Overall Survival (OS) [ Time Frame: Baseline to study completion (approximately 3 months) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

In advanced esophagogastric malignancies:

• Participants with histologically confirmed recurrent or metastatic esophageal or gastro-esophageal junction squamous cell or adenocarcinoma or gastric adenocarcinoma with Wnt Signaling Alterations

• Participants must be refractory or intolerant to at least one prior therapy(ies) for metastatic or locally advanced disease

  • If prior therapy consisted of palliative chemoradiation therapy, it will be considered one line of therapy
  • Prior treatment with paclitaxel as part of a definitive therapy regimen is acceptable. Patients who are unable to receive paclitaxel for any reason will be allowed to receive DKN-01 as a single agent.
  • Prior treatment anti- programmed death-1 (PD-1)/ anti-PD-ligand 1 (PD-L1) monoclonal antibody (mAb) is permitted in patients provided the patient's disease is primary refractory, and the patient is not intolerant of pembrolizumab. Patients who are not eligible to receive pembrolizumab will be allowed to receive single agent DKN-01
• Tumor tissue for mandatory evaluation
• Must have one or more tumors measurable on radiographic imaging as defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Patients with evaluable but not measurable disease per RECIST criteria may be enrolled with the approval of the medical monitor.
• Must be ≥18 years of age
• Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. A performance status of 2 on the ECOG scale may be entered upon the review and approval of the medical monitor
• Disease-free of active second/secondary or prior malignancies for equal to or over 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
• For men and women of child-producing potential, the use of effective contraceptive methods during the study and for 6 months following the last dose of study drug

Exclusion Criteria:

• New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia
• Fridericia-corrected QT interval (QTcF) > 470 msec (female) or > 450 (male), 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 HCV RNA is undetected/negative.
• Serious nonmalignant disease
• Pregnant or nursing women
• 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.
• Systemic central nervous system (CNS) malignancy or metastasis.
• 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
• Known osteoblastic bony metastasis
• History of known or suspected autoimmune disease with the specific exceptions of vitiligo, atopic dermatitis, or psoriasis not requiring systemic treatment.
• Clinically-significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis.
• Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Treatment with surgery or chemotherapy within 21 days prior to study entry (42 days for nitrosoureas or mitomycin C)
• Treatment with low dose chemotherapy concurrent with radiation within 14 days prior to study entry
• Treatment with radiation therapy within 14 days prior to study entry
• Treatment with any other investigational agent within 30 days prior to study entry
• Previously treated with an anti-DKK-1 therapy
• Participants who have a history of hypersensitivity reactions to TAXOL® or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil). Patients who exhibit these hypersensitivities will be eligible to receive single agent DKN-01.
• Significant allergy to a pharmaceutical therapy that, in the opinion of the investigator, poses an increased risk to the participant
• Treatment with corticosteroids (≥ 10 mg per day prednisone or equivalent) or other immune suppressive drugs within the 14 days prior to study entry
• Active substance abuse
• Receipt of any live vaccines within 30 days before the first dose of study treatment and while participating in the study
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis
• History of interstitial lung disease
• Intolerance or severe hypersensitivity (≥Grade 3) to pembrolizumab and/or of its excipients

Contacts and Locations

Locations

United States, California

Cedars Sinai Medical Care Foundation

Los Angeles, California, United States, 90025

United States, Connecticut

Smilow Cancer Hospital at Yale - New Haven

New Haven, Connecticut, United States, 06520

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

Massachusetts General Hospital

Boston, Massachusetts, United States, 02215

United States, North Carolina

Duke University

Durham, North Carolina, United States, 27710

United States, Tennessee

Tennessee Oncology / Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

Vanderbilt University / VICC

Nashville, Tennessee, United States, 37232

United States, Texas

Mary Crowley Cancer Center

Dallas, Texas, United States, 75251

CTRC @ The University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

Leap Therapeutics, Inc.

Merck Sharp & Dohme LLC

Investigators

• Study Director: Cyndi Sirard, MD; Leap Therapeutics, Inc.

More Information

• Responsible Party: Leap Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02013154
• Other Study ID Numbers: DEK-DKK1-P102; DKN-01; LY2812176; KEYNOTE-731 ( Other Identifier: Merck )
• First Posted: December 17, 2013
• Last Update Posted: September 10, 2021
• Last Verified: September 2021

Additional relevant MeSH terms:

Adenocarcinoma; Esophageal Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Paclitaxel; Pembrolizumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological