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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Leap Therapeutics, Inc.
ClinicalTrials.gov Identifier:
NCT01457417
First received: October 18, 2011
Last updated: September 26, 2016
Last verified: September 2016
  Purpose
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.

Condition Intervention Phase
Multiple Myeloma
Solid Tumors
Non-Small Cell Lung Cancer
Drug: DKN-01
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Two Part Phase 1 Multicenter Open-label Study of DKN-01 Given Intravenously. Part A: Dose-Escalation in Patients With Multiple Myeloma or Advanced Solid Tumors. Part B: Expansion Cohort in Patients With Relapsed / Refractory Non-Small Cell Lung Cancer (NSCLC)

Resource links provided by NLM:


Further study details as provided by Leap Therapeutics, Inc.:

Primary Outcome Measures:
  • Summary of Total Adverse Events (AE) [ Time Frame: Baseline to study completion (approximately 3 months) ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Baseline to study completion (approximately 3 months) ] [ Designated as safety issue: Yes ]
    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 Frame: Time from the date of signed informed consent to the first date of objectively determined progressive disease or death from any cause ] [ Designated as safety issue: No ]
    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:
  • Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 [ Time Frame: Cycle 1 Day 1 (first dose, all groups) ] [ Designated as safety issue: No ]
    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 1 included once per week (QW) dosing groups and every two weeks (Q2W) dosing groups.

  • Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 [ Time Frame: Cycle 1 Day 22 (Fourth Dose for QW) ] [ Designated as safety issue: No ]
    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.

  • Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 [ Time Frame: Cycle 1 Day 1 (first dose, all groups) ] [ Designated as safety issue: No ]
    Peak DKN-01 serum concentration (Cmax) after the first and fourth infusion on Cycle 1 Weeks 1 and 4, for both Parts A and B. Cycle 1 Day 1 included once per week (QW) dosing groups and every two weeks (Q2W) dosing groups.

  • Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 [ Time Frame: Cycle 1 Day 22 (Fourth dose for QW groups) ] [ Designated as safety issue: No ]
    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 Frame: Time from the date of signed informed consent to the first date of objectively determined progressive disease or death from any cause ] [ Designated as safety issue: No ]
    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 Frame: Time from the date of signed informed consent to the date of death from any cause ] [ Designated as safety issue: No ]
    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 Oncologic Patients Who Are Refractory or Intolerant to Standard/Approved Therapies [ Time Frame: Part A: Every 2 months; Part B: after 1 month and every two cycles thereafter ] [ Designated as safety issue: No ]
    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)

  • Objective Response Rate (ORR) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC) [ Time Frame: Part A: Every 2 months; Part B: after 1 month and every two cycles thereafter ] [ Designated as safety issue: No ]
    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)


Enrollment: 32
Study Start Date: January 2012
Study Completion Date: December 2013
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 75 milligram (mg) DKN-01 Part A

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.

Drug: DKN-01
DKN-01 will be administered intravenously (IV) once a week over 30 minutes (min) and 2 hours (max) for 75, 150 and 300 mg. At 600 mg, DKN-01 will be administered by IV on days 1 and 15 of each cycle. PART A - Dose Escalation: 3 participants will be treated with a 28 day cycle of DKN-01 at an assigned dose level until disease progression. Dose escalation will occur sequentially over the doses of 75, 150, 300, and 600 mg until the criteria for reaching maximum tolerated dose (MTD) are met (or highest planned dose study group is completed). Cycle 1 will define the dose limiting toxicity (DLT) that governs dose escalation. PART B - Dose Confirmation: Once the MTD is established (or the highest planned dose level), 300 mg of DKN-01 will be administered IV on days 1 and 15 of every 28 day cycle.
Other Name: Formerly LY2812176
Experimental: 150 mg DKN-01 Part A

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.

Drug: DKN-01
DKN-01 will be administered intravenously (IV) once a week over 30 minutes (min) and 2 hours (max) for 75, 150 and 300 mg. At 600 mg, DKN-01 will be administered by IV on days 1 and 15 of each cycle. PART A - Dose Escalation: 3 participants will be treated with a 28 day cycle of DKN-01 at an assigned dose level until disease progression. Dose escalation will occur sequentially over the doses of 75, 150, 300, and 600 mg until the criteria for reaching maximum tolerated dose (MTD) are met (or highest planned dose study group is completed). Cycle 1 will define the dose limiting toxicity (DLT) that governs dose escalation. PART B - Dose Confirmation: Once the MTD is established (or the highest planned dose level), 300 mg of DKN-01 will be administered IV on days 1 and 15 of every 28 day cycle.
Other Name: Formerly LY2812176
Experimental: 300 mg DKN-01 Part A

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.

Drug: DKN-01
DKN-01 will be administered intravenously (IV) once a week over 30 minutes (min) and 2 hours (max) for 75, 150 and 300 mg. At 600 mg, DKN-01 will be administered by IV on days 1 and 15 of each cycle. PART A - Dose Escalation: 3 participants will be treated with a 28 day cycle of DKN-01 at an assigned dose level until disease progression. Dose escalation will occur sequentially over the doses of 75, 150, 300, and 600 mg until the criteria for reaching maximum tolerated dose (MTD) are met (or highest planned dose study group is completed). Cycle 1 will define the dose limiting toxicity (DLT) that governs dose escalation. PART B - Dose Confirmation: Once the MTD is established (or the highest planned dose level), 300 mg of DKN-01 will be administered IV on days 1 and 15 of every 28 day cycle.
Other Name: Formerly LY2812176
Experimental: 600 mg DKN-01 Part A

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.

Drug: DKN-01
DKN-01 will be administered intravenously (IV) once a week over 30 minutes (min) and 2 hours (max) for 75, 150 and 300 mg. At 600 mg, DKN-01 will be administered by IV on days 1 and 15 of each cycle. PART A - Dose Escalation: 3 participants will be treated with a 28 day cycle of DKN-01 at an assigned dose level until disease progression. Dose escalation will occur sequentially over the doses of 75, 150, 300, and 600 mg until the criteria for reaching maximum tolerated dose (MTD) are met (or highest planned dose study group is completed). Cycle 1 will define the dose limiting toxicity (DLT) that governs dose escalation. PART B - Dose Confirmation: Once the MTD is established (or the highest planned dose level), 300 mg of DKN-01 will be administered IV on days 1 and 15 of every 28 day cycle.
Other Name: Formerly LY2812176
Experimental: 300 mg DKN-01 Part B
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.
Drug: DKN-01
DKN-01 will be administered intravenously (IV) once a week over 30 minutes (min) and 2 hours (max) for 75, 150 and 300 mg. At 600 mg, DKN-01 will be administered by IV on days 1 and 15 of each cycle. PART A - Dose Escalation: 3 participants will be treated with a 28 day cycle of DKN-01 at an assigned dose level until disease progression. Dose escalation will occur sequentially over the doses of 75, 150, 300, and 600 mg until the criteria for reaching maximum tolerated dose (MTD) are met (or highest planned dose study group is completed). Cycle 1 will define the dose limiting toxicity (DLT) that governs dose escalation. PART B - Dose Confirmation: Once the MTD is established (or the highest planned dose level), 300 mg of DKN-01 will be administered IV on days 1 and 15 of every 28 day cycle.
Other Name: Formerly LY2812176

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.
  Eligibility

Ages Eligible for Study:   30 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01457417

Locations
United States, Arizona
Scottsdale Healthcare
Scottsdale, Arizona, United States, 85258
United States, New York
New York Oncology Hematology, P.C.
Albany, New York, United States, 12206
United States, South Carolina
Greenville Hospital System University Medical Center
Greenville, South Carolina, United States, 29605
United States, Texas
Texas Oncology - Baylor, Charles A. Sammonds Cancer Center
Dallas, Texas, United States, 75246
Texas Oncology - Tyler
Tyler, Texas, United States, 75702
United States, Virginia
Virginia Oncology Associated
Norfolk, Virginia, United States, 23502
Virginia Commonwealth University - Massey Cancer Center
Richmond, Virginia, United States, 23298
United States, Washington
Northwest Cancer Specialists, P.C.
Vancouver, Washington, United States, 98684
Sponsors and Collaborators
Leap Therapeutics, Inc.
Investigators
Study Director: Cyndi Sirard, MD Heatlhcare Pharmaceuticals
  More Information

Responsible Party: Leap Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT01457417     History of Changes
Other Study ID Numbers: P100  DEK-DKK1-P100  LY2812176 
Study First Received: October 18, 2011
Results First Received: January 13, 2015
Last Updated: September 26, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by Leap Therapeutics, Inc.:
Cancer
Oncology

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Multiple Myeloma
Neoplasms, Plasma Cell
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on December 07, 2016