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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02013154
Recruitment Status : Active, not recruiting
First Posted : December 17, 2013
Last Update Posted : July 16, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Leap Therapeutics, Inc.

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.

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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
Study Start Date : January 2014
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


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




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) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02013154


Locations
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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 Corp.
Investigators
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Study Director: Cyndi Sirard, MD Leap Therapeutics, Inc.
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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    Key Record Dates
Last Update Posted: July 16, 2020
Last Verified: July 2020
Additional relevant MeSH terms:
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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