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

Study Overview
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Brief Summary
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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

Detailed Description
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This is a dose-escalating, open-label study conducted in multiple parts (Part A dose-escalation, Parts B-F expansion cohorts, and a monotherapy substudy). Parts A-E (DKN-01 plus paclitaxel) and the DKN-01 monotherapy substudy includes 28-day cycle treatment cycles; Part F (DKN-01 plus pembrolizumab) includes 21-day treatment cycles. Depending on their cancer type, subjects with histologically confirmed recurrent or refractory esophageal, gastro-esophageal junction tumors, or gastric adenocarcinoma will be enrolled in each study part to receive DKN-01 150 mg or 300 mg in combination with paclitaxel or pembrolizumab. Subjects who are unable to receive paclitaxel or pembrolizumab for any reason are allowed to receive single agent DKN-01 300 mg as part of a monotherapy substudy. Results are reported by treatment group, irrespective of the study part in which the subject was enrolled.

Official Title
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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

Conditions
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Esophageal Neoplasms, Adenocarcinoma of the Gastroesophageal Junction, Gastroesophageal Cancer, Squamous Cell Carcinoma, Gastric Adenocarcinoma

Intervention / Treatment
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* Drug: DKN-01 150 mg
* Drug: Paclitaxel
* Drug: Pembrolizumab
* Drug: DKN-01 300 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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-01 150 mg plus paclitaxel<br>DKN-01 150 mg administered on Days 1 and 15 and paclitaxel 80 mg per meter squared of body surface area (mg/m2) administered on Days 1, 8, 15, and 22 | Drug: DKN-01 150 mg<br>* Administered by IV infusion<br>Drug: Paclitaxel<br>* Administered by IV infusion<br>* Other names: Taxol;|
| Experimental: DKN-01 300 mg plus paclitaxel<br>DKN-01 300 mg administered on Days 1 and 15 and paclitaxel 80 mg per meter squared of body surface area (mg/m2) administered on Days 1, 8, 15, and 22 | Drug: Paclitaxel<br>* Administered by IV infusion<br>* Other names: Taxol;Drug: DKN-01 300 mg<br>* Administered by IV infusion<br>|
| Experimental: DKN-01 150 mg plus pembrolizumab<br>DKN-01 150 mg administered on Days 1 and 15 and pembrolizumab 200 mg administered on Day 1 | Drug: DKN-01 150 mg<br>* Administered by IV infusion<br>Drug: Pembrolizumab<br>* Administered by IV infusion<br>* Other names: Keytruda;|
| Experimental: DKN-01 300 mg plus pembrolizumab<br>DKN-01 300 mg administered on Days 1 and 15 and pembrolizumab 200 mg administered on Day 1 | Drug: Pembrolizumab<br>* Administered by IV infusion<br>* Other names: Keytruda;Drug: DKN-01 300 mg<br>* Administered by IV infusion<br>|
| Experimental: DKN-01 300 mg monotherapy<br>DKN-01 300 mg administered on Days 1 and 15 | Drug: DKN-01 300 mg<br>* Administered by IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with dose limiting toxicities in each treatment arm |  | Baseline to End of Cycle 1 (each cycle is 28 days, except each cycle is 21 days when DKN-01 is administered with pembrolizumab) | 
| Number of subjects with treatment emergent adverse events related to study treatment (DKN-01 as monotherapy or in combination with paclitaxel or pembrolizumab) |  | Baseline until 30 days after last dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) |  | Baseline to study completion (approximately 3 months) | 
| Duration of Response (DoR) |  | Baseline to study completion (approximately 3 months) | 
| Overall Survival (OS) |  | Baseline to study completion (approximately 3 months) | 
| Progression Free Survival (PFS) |  | Baseline to study completion (approximately 3 months) |