A Study of DKN-01 in Multiple Myeloma or Advanced Solid Tumors

Phase 1

Completed

Conditions: Multiple Myeloma
Solid Tumors
Non-Small Cell Lung Cancer

Interventions: Drug: DKN-01

Registration Number: NCT01457417

Lead Sponsor: Leap Therapeutics, Inc.

Brief Summary: The purpose of this trial is to characterize the safety and toxicity of DKN-01 by determining a maximum-tolerated dose and associated dose limiting toxicity. To evaluate the pharmacodynamic response in patients with cancer. To characterize the pharmacokinetic parameters of DKN-01 in cancer patients who are intolerant to standard/approved therapies.

Detailed Description: Part A of this trial consists of 4 treatment arms of DKN-01. It is a dose escalation study in patients with multiple myeloma or advanced solid tumors. Patients must be refractory or intolerant to all standard/approved therapy(ies). At each dose level, 3 subjects will be treated. If none of the 3 subjects develop a dose limiting toxicity after a minimum of 4 weeks of treatment, subsequent dose escalation will proceed according to the same schedule. Part B consists of dose confirmation in patients with NSCLC. Patients must be refractory or intolerant to all standard/approved therapy(ies). Approximately 15 patients may be enrolled in Part B.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 32

Inclusion Criteria

Part A: Patients with histological or cytological confirmed multiple myeloma or advanced solid tumors. For multiple myeloma, must have symptomatic myeloma as defined by the International Myeloma Working Group inclusive of measurable serum and/or urine monoclonal protein (M-protein) or for those without elevations they must have measurable increased concentrations of free light chains

Part B: Patients with previously treated, histologically confirmed advanced NSCLC with progressive disease requiring therapy

Parts A and B:

Refractory or intolerant to all standard/approved therapy(ies)
Patients with solid tumors must have one or more metastatic tumors measurable on computed tomography (CT) scan using Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Radiation for symptomatic lesions outside the central nervous system (CNS) must have been completed at least 2 week prior to study enrollment
Treated brain metastases will be allowed, if they are asymptomatic. Patients must be off corticosteroids for at least 2 week prior to study entry
Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1
Life expectancy of at least 3 months
Ambulatory patients greater than or equal to (≥) 30 years of age
Females with child bearing potential must have a negative serum pregnancy test within 7 days of study entry
Acceptable liver function, renal function, hematologic status
Urinalysis - No clinically significant abnormalities
Acceptable coagulation status:
- Prothrombin Time/Partial Thromboplastin Time (PT/PTT) ≤ 1.2 x upper limit of normal (ULN) (unless receiving anticoagulation therapy - eligibility based upon INR)
- International Normalization Ratio (INR) ≤ 1.6 (unless receiving anticoagulant therapy)
  - Receiving warfarin; INR ≤ 3.0 and no active bleeding
For men and women of child-producing potential, the use of effective contraceptive methods during the study and for women 18 months following the last dose of study drug
Available for the study duration and willing to follow procedures
Serum calcium:
- Solid tumors only: within normal limits
- Multiple myeloma: ≤ 11.5 milligrams per deciliter (mg/dL)

Exclusion Criteria

History of osteonecrosis of the hip or evidence of structural bone abnormalities in the proximal femur on magnetic resonance imaging (MRI) scan considered clinically significant or may impact the interpretation of the scan. Degenerative changes of the hip joint are not exclusionary
Unable to tolerate the confinement/noise of an MRI scanner or have any contraindication for MRI
New York Heart Association Class 3 or 4, cardiac disease, myocardial infarction, unstable arrhythmia, or evidence of ischemia
Have Fridericia-corrected QT interval (QTcF) > 470 millisecond (msec) (female) or > 450 (male), or history of congenital long QT syndrome.
Active, uncontrolled bacterial, viral, or fungal infections
Pregnant or nursing women
Radiation therapy, surgery, or chemotherapy, within 1 month prior to study entry
Previously treated with an anti-Dickkopf-related protein 1 (DKK-1) therapy
Significant allergy to a biological pharmaceutical therapy
History of major organ transplant
Had an autologous or allogenic bone marrow transplant, current acute leukemia, colon, prostate, breast or small cell lung cancer, osteoblastic lesions, concomitant disease known to influence calcium metabolism including hyperparathyroidism, hyperthyroidism and/or Paget's disease of bone
Unwillingness / inability to comply with procedures
Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
Serious nonmalignant disease
Receiving other investigational agent or have received other investigational agent within last 30 days or 5 half-lives, whichever is longer
Receiving lithium chloride (LiCl)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
300 mg DKN-01 Part B	DKN-01	Dose Confirmation: Once the MTD had been established or the highest planned dose level completed, 300 mg of DKN-01 was administered as IV on days 1 and 15 of every 28 day cycle.
75 milligram (mg) DKN-01 Part A	DKN-01	DKN-01: DKN-01 was administered intravenously (IV) once a week over a minimum of 30 minutes and up to a maximum of 2 hours for dose levels of 75 mg, 150 mg and 300 mg. At the 600 mg dose level, DKN-01 was administered by IV on days 1 and 15 of each cycle. PART A - Dose Escalation: Study group of 3 participants were treated with a 28 day cycle of DKN-01 at an assigned dose level until disease progression. Dose escalation occurred sequentially over the doses of 75, 150, 300, and 600 mg until the criteria for reaching the maximum tolerated dose (MTD) were met or the highest planned dose study group was completed. Cycle 1 defined the dose limiting toxicity (DLT) period that governs dose escalation. The dose escalation method was guided by the incidence of DLTs during the first cycle.
150 mg DKN-01 Part A	DKN-01	DKN-01: DKN-01 was administered intravenously (IV) once a week over a minimum of 30 minutes and up to a maximum of 2 hours for dose levels of 75 mg, 150 mg and 300 mg. At the 600 mg dose level, DKN-01 was administered by IV on days 1 and 15 of each cycle. PART A - Dose Escalation: Study group of 3 participants were treated with a 28 day cycle of DKN-01 at an assigned dose level until disease progression. Dose escalation occurred sequentially over the doses of 75, 150, 300, and 600 mg until the criteria for reaching the maximum tolerated dose (MTD) were met or the highest planned dose study group was completed. Cycle 1 defined the dose limiting toxicity (DLT) period that governs dose escalation. The dose escalation method was guided by the incidence of DLTs during the first cycle.
300 mg DKN-01 Part A	DKN-01	DKN-01: DKN-01 was administered intravenously (IV) once a week over a minimum of 30 minutes and up to a maximum of 2 hours for dose levels of 75 mg, 150 mg and 300 mg. At the 600 mg dose level, DKN-01 was administered by IV on days 1 and 15 of each cycle. PART A - Dose Escalation: Study group of 3 participants were treated with a 28 day cycle of DKN-01 at an assigned dose level until disease progression. Dose escalation occurred sequentially over the doses of 75, 150, 300, and 600 mg until the criteria for reaching the maximum tolerated dose (MTD) were met or the highest planned dose study group was completed. Cycle 1 defined the dose limiting toxicity (DLT) period that governs dose escalation. The dose escalation method was guided by the incidence of DLTs during the first cycle.
600 mg DKN-01 Part A	DKN-01	DKN-01: DKN-01 was administered intravenously (IV) once a week over a minimum of 30 minutes and up to a maximum of 2 hours for dose levels of 75 mg, 150 mg and 300 mg. At the 600 mg dose level, DKN-01 was administered by IV on days 1 and 15 of each cycle. PART A - Dose Escalation: Study group of 3 participants were treated with a 28 day cycle of DKN-01 at an assigned dose level until disease progression. Dose escalation occurred sequentially over the doses of 75, 150, 300, and 600 mg until the criteria for reaching the maximum tolerated dose (MTD) were met or the highest planned dose study group was completed. Cycle 1 defined the dose limiting toxicity (DLT) period that governs dose escalation. The dose escalation method was guided by the incidence of DLTs during the first cycle.

Primary Outcome Measures

Name	Time	Method
Summary of Total Adverse Events (AE)	Baseline to study completion (approximately 3 months)	Total Adverse Events (AE), total treatment emergent adverse events (TEAE), total Serious Adverse Events (SAE), and total dose-limiting toxicity (DLT) for both Parts A and B.
Summary of Patients With Adverse Events (AE)	Baseline to study completion (approximately 3 months)	Number of patients who had Adverse Events (AE) including treatment related treatment emergent adverse events (TEAE), Common Toxicity Criteria for Adverse Effects (CTCAE), and Serious Adverse Events (SAE) for both Parts A and B. Severity was coded to NCI CTCAE version 4.02. For maximum severity and relationship, patients were counted only once in the most severe or most related category.
Progression Free Survival (PFS) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC)	Time from the date of signed informed consent to the first date of objectively determined progressive disease or death from any cause	For Part B only. The distribution of PFS was estimated using the Kaplan-Meier (KM) method. PFS was defined as the time from the date of signed informed consent to the first date of objectively determined progressive disease (Progression is defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and International Multiple Myeloma Working Group (IMWG)) or death from any cause. For patients who were still alive at the time of analysis (ie, data cut-off date) and without evidence of tumor progression, PFS was censored at the date of the most recent objective progression-free observation.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01	Cycle 1 Day 22 (Fourth Dose for QW)	Area under the DKN-01 serum concentration-time profile curve during the dosing interval (AUC0-tau) after the first and fourth infusion for both Parts A and B. Cycle 1 day 22 included only QW dosing groups.
Objective Response Rate (ORR) in Oncologic Patients Who Are Refractory or Intolerant to Standard/Approved Therapies	Part A: Every 2 months; Part B: after 1 month and every two cycles thereafter	For both Parts A and B. Objective response rate is defined as the number of patients with overall best response of complete response (CR) or partial response (PR)
Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01	Cycle 1 Day 22 (Fourth dose for QW groups)	Peak DKN-01 serum concentration (Cmax) after the fourth infusion on Cycle 1 Weeks 1 and 4, for both Parts A and B. Cycle 1 day 22 included only QW dosing groups.
Progression Free Survival (PFS) in Patients Who Are Refractory or Intolerant to Standard/Approved Therapies	Time from the date of signed informed consent to the first date of objectively determined progressive disease or death from any cause	For both Parts A and B. PFS was defined as the time from the date of signed informed consent to the first date of objectively determined progressive disease (Progression is defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and International Multiple Myeloma Working Group (IMWG)) or death from any cause. For patients who were still alive at the time of analysis (i.e, data cut-off date) and without evidence of tumor progression, PFS was censored at the date of the most recent objective progression-free observation.
Overall Survival (OS) in Patients With Relapsed or Refractory NSCLC	Time from the date of signed informed consent to the date of death from any cause	For Part B only. OS was defined as the time from the date of signed informed consent to the date of death from any cause. For patients who were still alive as of the data cut-off date, OS time was censored on the date of the patient's last contact (last contact for patients in post-discontinuation was the last date of contact in long-term follow-up eCRF).
Objective Response Rate (ORR) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC)	Part A: Every 2 months; Part B: after 1 month and every two cycles thereafter	FAS : For both Parts A and B. Objective response rate is defined as the number of patients with overall best response of complete response (CR) or partial response (PR)

Trial Locations

Locations (8): New York Oncology Hematology, P.C.
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Albany, New York, United States
Texas Oncology - Tyler
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Tyler, Texas, United States
Texas Oncology - Baylor, Charles A. Sammonds Cancer Center
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Dallas, Texas, United States
Virginia Oncology Associated
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Norfolk, Virginia, United States
Virginia Commonwealth University - Massey Cancer Center
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Richmond, Virginia, United States
Northwest Cancer Specialists, P.C.
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Vancouver, Washington, United States
Scottsdale Healthcare
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Scottsdale, Arizona, United States
Greenville Hospital System University Medical Center
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Greenville, South Carolina, United States