Study of DKN-01 and Gemcitabine/Cisplatin in Patients With Carcinoma to Primary to the Intra- or Extra-Hepatic Biliary System or Gallbladder

Study Overview
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Brief Summary
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DKN-01 is a humanized monoclonal antibody (Mab) with neutralizing activity against Dkk-1 and is being developed as an anti-neoplastic agent. This study is designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of DKN-01 in combination with gemcitabine and cisplatin in patients with carcinoma primary to the intra- or exta-hepatic biliary system or gallbladder.

Detailed Description
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In Part A, escalating doses of DKN-01 will be administered to different cohorts of patients to evaluate safety and dose limiting toxicities (DLTs) and to establish the maximum tolerated dose of DKN-01 when administered in combination with gemcitabine and cisplatin. Part B is an expansion cohort in which patients are treated at the MTD of DKN-01 (or highest dose tested if the MTD is not defined) to further characterize safety, tolerability, pharmacokinetics and efficacy within the defined patient population.

Official Title
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A Dose Escalation and Cohort Expansion Study of DKN-01 in Combination With Gemcitabine and Cisplatin in Patients With Advanced Carcinoma Primary to the Intra- or Extra-hepatic Biliary System or Gallbladder

Conditions
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Carcinoma of Intrahepatic and Extra-hepatic Biliary System, Carcinoma of Gallbladder, Bile Duct Cancer, Cholangiocarcinoma

Intervention / Treatment
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* Drug: DKN-01
* Drug: gemcitabine
* Drug: cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has carcinoma primary to the intra- or extra-hepatic biliary system or gall bladder. Patient must have sufficient tumor tissue available for submission. For patients who have received prior cryotherapy, radiofrequency ablation, radioembolization, ethanol injection, transarterial chemoembolization (TACE) or photodynamic therapy, at least 28 days must have elapsed since that therapy, and lesions that have not been treated with local therapy must be present and measurable. Patients may have received prior adjuvant chemotherapy with gemcitabine with or without cisplatin, as long as 6 months have elapsed since last treatment. Patients must have one or more tumors measurable on radiographic imaging as defined by RECIST. ECOG PS of 0 or 1. Patients with an ECOG PS of 2 may be entered upon review and approval of the medical monitor. Estimated life expectancy of at least 3 months. Disease-free of active second/secondary or prior malignancies for ≥ 2 years with the exception of currently treated basal cell or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or breast. Adequate hematological, renal, hepatic and coagulation laboratory test results. Women of child bearing potential and men must agree to use adequate contraception during the study and for 6 months after their last dose of study drug. Available for the duration of the study and are willing to follow study-specific procedures. Provide written informed consent Exclusion Criteria: New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months, or unstable arrhythmia. Have 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. Known to be human immunodeficiency virus (HIV) positive or has untreated, active hepatitis B. History of major organ transplant. History of an autologous/allogenic bone marrow transplant. Serious nonmalignant disease. Pregnant or nursing. 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. Symptomatic central nervous system (CNS) malignancy or metastasis. Clinically significant peripheral neuropathy Known osteoblastic bony metastasis. Treatment with surgery or chemotherapy within 21 days prior to study entry or radiation within 14 days of study entry. Previously treated with an anti-Dkk-1 therapy. Other exclusions apply

Ages Eligible for Study
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Minimum Age: 30 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: 150 mg DKN-01 Part A<br>Patients will receive 150 mg of DKN-01 followed by gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 of each 21-day cycle. | Drug: DKN-01<br>* Administration by intravenous (IV) infusion.<br>* Other names: LY2812176;Drug: gemcitabine<br>* Administered by IV infusion.<br>* Other names: Gemzar;Drug: cisplatin<br>* Administered by IV infusion<br>* Other names: Platinol;|
| Experimental: 300 mg DKN-01 Part A<br>Patients will receive 300 mg of DKN-01 followed by gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 of each 21-day cycle. | Drug: DKN-01<br>* Administration by intravenous (IV) infusion.<br>* Other names: LY2812176;Drug: gemcitabine<br>* Administered by IV infusion.<br>* Other names: Gemzar;Drug: cisplatin<br>* Administered by IV infusion<br>* Other names: Platinol;|
| Experimental: MTD mg DKN-01 Part B<br>Patients are treated at the maximum tolerated dose (MTD) of DKN-01 (or highest dose tested in Part A if the MTD is not defined) followed by gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on Days 1 and 8 of each 21-day cycle. | Drug: DKN-01<br>* Administration by intravenous (IV) infusion.<br>* Other names: LY2812176;Drug: gemcitabine<br>* Administered by IV infusion.<br>* Other names: Gemzar;Drug: cisplatin<br>* Administered by IV infusion<br>* Other names: Platinol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and dose-limiting toxicities as determined in Part A. | Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 4.03). | End of Cycle 1 (Day 21) | 
| Composite Safety parameters as assessed by new or changing physical examinations, vital signs, electrocardiograms (ECGs), clinical laboratories, concomitant medication reviews, and assessment of adverse events. |  | Parts A and B: at a minimum Days 1, 8, 15 of each treatment cycle. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - AUC | Plasma levels will be measured during the treatment period. | Cycle 1 - Days 1 and 8, Cycle 2 - Day 1 | 
| Pharmacokinetics - Cmax | Plasma levels will be measured during the treatment period. | Cycle 1 - Days 1 and 8, Cycle 2 - Day 1 | 
| Pharmacokinetics - Tmax | Plasma levels will be measured during the treatment period. | Cycle 1 - Days 1 and 8, Cycle 2 - Day 1 | 
| Efficacy - Response to treatment evaluated using the Response Evaluation Criteria in Solid Tumors guidelines (RECIST 1.1) | Response to treatment evaluated using the Response Evaluation Criteria in Solid Tumors guidelines (RECIST 1.1). | At baseline, prior to the start of Cycle 3, and every 2 cycles thereafter until disease progression or death |