Multiple Myeloma, Solid Tumors, Non-Small Cell Lung Cancer
Conditions
Keywords
Cancer, Oncology
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.
Interventions
DRUGDKN-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.
Sponsors
Leap Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 | Cycle 1 Day 1 (first dose, all groups) | 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. |
| Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 | Cycle 1 Day 1 (first dose, all groups) | 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. |
| 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 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) |
| 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) |
Countries
United States
Participant flow
Recruitment details
Eight sites in the United States participated in the study and 7 of them enrolled patients. The Date of First Enrollment was 16 Jan 2012, and the Date of Last Completed was 06 Dec 2013.
Pre-assignment details
Part A enrolled patients with histologically or cytologically confirmed multiple myeloma or advanced solid tumors. A dose escalation procedure was followed. Part B enrolled patients with non-small cell lung cancer. Following screening (up to 28 days prior to first treatment) if entry criterion was met, patients were eligible for enrollment.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 3 |
| 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 will be guided by the incidence of DLTs during the first cycle. | 3 |
| 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) was 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. | 4 |
| 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. | 3 |
| 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. | 19 |
| Total | 32 |
Baseline characteristics
| Characteristic | 75 Milligram (mg) DKN-01 Part A | 150 mg DKN-01 Part A | 300 mg DKN-01 Part A | 600 mg DKN-01 Part A | 300 mg DKN-01 Part B | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants | 2 Participants | 9 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 10 Participants | 17 Participants |
| Age, Continuous | 57.7 years STANDARD_DEVIATION 7.77 | 66.3 years STANDARD_DEVIATION 8.62 | 65.0 years STANDARD_DEVIATION 19.2 | 68.3 years STANDARD_DEVIATION 8.96 | 65.4 years STANDARD_DEVIATION 9.25 | 65.0 years STANDARD_DEVIATION 10.29 |
| Region of Enrollment United States | 3 participants | 3 participants | 4 participants | 3 participants | 19 participants | 32 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants | 1 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 10 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 16 / 19 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 1 / 4 | 0 / 3 | 6 / 19 |
Outcome results
Primary
Progression Free Survival (PFS) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC)
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.
Time frame: Time from the date of signed informed consent to the first date of objectively determined progressive disease or death from any cause
Population: Patients with advanced NSCLC receiving the study drug at 300 mg every 2 weeks in Part B
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Progression Free Survival (PFS) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC) | 2.2 months |
Primary
Summary of Patients With Adverse Events (AE)
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.
Time frame: Baseline to study completion (approximately 3 months)
Population: Safety analyses were based on the full analysis set (FAS), which was defined as all patients who received at least one dose of study treatment during Part A or Part B of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | SAE related to study drug | 0 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE | 3 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One SAE | 1 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | Retracted SAE | 1 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One AE | 3 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 1 Mild | 0 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 2 Moderate | 2 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 3 Severe | 0 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 4 Life Threatening | 1 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 5 Death | 0 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE Grade ≥ 3 assessed as study drug related | 0 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Related | 1 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Not Related | 2 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Drug Withdrawal | 0 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Study Discontinuation | 0 Patients |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE with Outcome of Death | 0 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | Retracted SAE | 2 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 4 Life Threatening | 0 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 3 Severe | 2 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 2 Moderate | 1 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One SAE | 2 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One AE | 3 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Drug Withdrawal | 1 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Not Related | 1 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Related | 2 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | SAE related to study drug | 0 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE | 3 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE with Outcome of Death | 0 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE Grade ≥ 3 assessed as study drug related | 0 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 5 Death | 0 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Study Discontinuation | 0 Patients |
| 150 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 1 Mild | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Study Discontinuation | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | Retracted SAE | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | SAE related to study drug | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 1 Mild | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 2 Moderate | 1 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 3 Severe | 3 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 4 Life Threatening | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 5 Death | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE Grade ≥ 3 assessed as study drug related | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Related | 3 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE with Outcome of Death | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Not Related | 1 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Drug Withdrawal | 0 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One AE | 4 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One TEAE | 4 Patients |
| 300 mg DKN-01 Part A (QW) | Summary of Patients With Adverse Events (AE) | At Least One SAE | 1 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | Retracted SAE | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 4 Life Threatening | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | SAE related to study drug | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One SAE | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One TEAE | 3 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Related | 1 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Study Discontinuation | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Drug Withdrawal | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE Grade ≥ 3 assessed as study drug related | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 5 Death | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 3 Severe | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Not Related | 2 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One AE | 3 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 1 Mild | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One TEAE with Outcome of Death | 0 Patients |
| 600 mg DKN-01 Part A (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 2 Moderate | 3 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | Retracted SAE | 2 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One SAE | 7 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | SAE related to study drug | 0 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One AE | 16 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 2 Moderate | 6 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 1 Mild | 0 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 3 Severe | 9 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Study Discontinuation | 0 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE Grade ≥ 3 assessed as study drug related | 0 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One TEAE with Outcome of Death | 1 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Related | 8 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 4 Life Threatening | 0 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One TEAE | 16 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 5 Death | 1 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Not Related | 8 Patients |
| 300 mg DKN-01 Part B (Q2W) | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Drug Withdrawal | 3 Patients |
| Total | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 3 Severe | 14 Patients |
| Total | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 4 Life Threatening | 1 Patients |
| Total | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Study Discontinuation | 0 Patients |
| Total | Summary of Patients With Adverse Events (AE) | SAE related to study drug | 0 Patients |
| Total | Summary of Patients With Adverse Events (AE) | At Least One TEAE Leading to Drug Withdrawal | 4 Patients |
| Total | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 5 Death | 1 Patients |
| Total | Summary of Patients With Adverse Events (AE) | At Least One TEAE with Outcome of Death | 1 Patients |
| Total | Summary of Patients With Adverse Events (AE) | TEAE Grade ≥ 3 assessed as study drug related | 0 Patients |
| Total | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Related | 15 Patients |
| Total | Summary of Patients With Adverse Events (AE) | Retracted SAE | 5 Patients |
| Total | Summary of Patients With Adverse Events (AE) | At Least One TEAE | 29 Patients |
| Total | Summary of Patients With Adverse Events (AE) | TEAE of Maximum Relationship - Not Related | 14 Patients |
| Total | Summary of Patients With Adverse Events (AE) | At Least One SAE | 11 Patients |
| Total | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 1 Mild | 0 Patients |
| Total | Summary of Patients With Adverse Events (AE) | TEAE of Maximum CTCAE - Grade 2 Moderate | 13 Patients |
| Total | Summary of Patients With Adverse Events (AE) | At Least One AE | 29 Patients |
Primary
Summary of Total Adverse Events (AE)
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.
Time frame: Baseline to study completion (approximately 3 months)
Population: Safety analyses were based on the full analysis set (FAS), which was defined as all patients who received at least one dose of study treatment during Part A or Part B of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total AEs | 39 Events |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total DLTs | 0 Events |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total TEAEs | 39 Events |
| 75 Milligram (mg) DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total SAEs | 2 Events |
| 150 mg DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total AEs | 58 Events |
| 150 mg DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total TEAEs | 58 Events |
| 150 mg DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total SAEs | 7 Events |
| 150 mg DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total DLTs | 0 Events |
| 300 mg DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total TEAEs | 35 Events |
| 300 mg DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total SAEs | 3 Events |
| 300 mg DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total AEs | 35 Events |
| 300 mg DKN-01 Part A (QW) | Summary of Total Adverse Events (AE) | Total DLTs | 0 Events |
| 600 mg DKN-01 Part A (Q2W) | Summary of Total Adverse Events (AE) | Total SAEs | 0 Events |
| 600 mg DKN-01 Part A (Q2W) | Summary of Total Adverse Events (AE) | Total DLTs | 0 Events |
| 600 mg DKN-01 Part A (Q2W) | Summary of Total Adverse Events (AE) | Total AEs | 11 Events |
| 600 mg DKN-01 Part A (Q2W) | Summary of Total Adverse Events (AE) | Total TEAEs | 9 Events |
| 300 mg DKN-01 Part B (Q2W) | Summary of Total Adverse Events (AE) | Total TEAEs | 87 Events |
| 300 mg DKN-01 Part B (Q2W) | Summary of Total Adverse Events (AE) | Total AEs | 87 Events |
| 300 mg DKN-01 Part B (Q2W) | Summary of Total Adverse Events (AE) | Total SAEs | 11 Events |
| 300 mg DKN-01 Part B (Q2W) | Summary of Total Adverse Events (AE) | Total DLTs | 0 Events |
| Total | Summary of Total Adverse Events (AE) | Total TEAEs | 228 Events |
| Total | Summary of Total Adverse Events (AE) | Total AEs | 230 Events |
| Total | Summary of Total Adverse Events (AE) | Total DLTs | 0 Events |
| Total | Summary of Total Adverse Events (AE) | Total SAEs | 23 Events |
Secondary
Objective Response Rate (ORR) in Oncologic Patients Who Are Refractory or Intolerant to Standard/Approved Therapies
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)
Time frame: Part A: Every 2 months; Part B: after 1 month and every two cycles thereafter
Population: All patients with NSCLC who received at least one dose of study treatment during Part A or Part B of the study. One Patients from the 300 mg QW treatment group, and two patients from 300 mg Q2W treatment group did not have assessments performed after Baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Objective Response Rate (ORR) in Oncologic Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 0 Participants |
| 150 mg DKN-01 Part A (QW) | Objective Response Rate (ORR) in Oncologic Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 0 Participants |
| 300 mg DKN-01 Part A (QW) | Objective Response Rate (ORR) in Oncologic Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 0 Participants |
| 600 mg DKN-01 Part A (Q2W) | Objective Response Rate (ORR) in Oncologic Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 0 Participants |
| 300 mg DKN-01 Part B (Q2W) | Objective Response Rate (ORR) in Oncologic Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 1 Participants |
Secondary
Objective Response Rate (ORR) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC)
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)
Time frame: Part A: Every 2 months; Part B: after 1 month and every two cycles thereafter
Population: FAS : NSCLC - All patients with NSCLC who received at least one dose of study treatment during Part A or Part B of the study. Two patients in treatment group 300 mg Q2W did not have assessments performed after Baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Objective Response Rate (ORR) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC) | 0 participants |
| 150 mg DKN-01 Part A (QW) | Objective Response Rate (ORR) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC) | 0 participants |
| 600 mg DKN-01 Part A (Q2W) | Objective Response Rate (ORR) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC) | 0 participants |
| 300 mg DKN-01 Part B (Q2W) | Objective Response Rate (ORR) in Patients With Relapsed or Refractory Non-small Cell Lung Cancer (NSCLC) | 1 participants |
Secondary
Overall Survival (OS) in Patients With Relapsed or Refractory NSCLC
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).
Time frame: Time from the date of signed informed consent to the date of death from any cause
Population: For patients who are still alive as of the data cut-off date, OS time will be censored on the date of the patient's last contact (last contact for patients in post-discontinuation = last Date of Contact in Long Term Follow-up eCRF).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Overall Survival (OS) in Patients With Relapsed or Refractory NSCLC | 6.6 Months |
Secondary
Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01
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.
Time frame: Cycle 1 Day 1 (first dose, all groups)
Population: All patients who received at least one dose of study treatment during Part A or Part B of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 | 22756.09897 ng/mL | Standard Deviation 7665.992335 |
| 150 mg DKN-01 Part A (QW) | Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 | 47838.87113 ng/mL | Standard Deviation 4193.154016 |
| 300 mg DKN-01 Part A (QW) | Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 | 130105.94600 ng/mL | Standard Deviation 25705.162094 |
| 600 mg DKN-01 Part A (Q2W) | Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 | 183063.33233 ng/mL | Standard Deviation 34635.447386 |
| 300 mg DKN-01 Part B (Q2W) | Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 | 119837.93546 ng/mL | Standard Deviation 43565.776017 |
Secondary
Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01
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.
Time frame: Cycle 1 Day 22 (Fourth dose for QW groups)
Population: All patients who received at least one dose of study treatment during Part A of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 | 43203.11520 ng/mL | Standard Deviation 25085.681036 |
| 150 mg DKN-01 Part A (QW) | Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 | 105148.29720 ng/mL | Standard Deviation 29480.395189 |
| 300 mg DKN-01 Part A (QW) | Pharmacokinetic: Maximum Plasma Concentration (Cmax) of DKN-01 | 224382.14533 ng/mL | Standard Deviation 28438.20978 |
Secondary
Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01
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.
Time frame: Cycle 1 Day 1 (first dose, all groups)
Population: All patients who received at least one dose of study treatment during Part A or Part B of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 | 1942552.08830 hr*ng/mL | Standard Deviation 780226.768012 |
| 150 mg DKN-01 Part A (QW) | Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 | 4381685.27190 hr*ng/mL | Standard Deviation 402701.016054 |
| 300 mg DKN-01 Part A (QW) | Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 | 10860453.92050 hr*ng/mL | Standard Deviation 2319628.494223 |
| 600 mg DKN-01 Part A (Q2W) | Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 | 18103276.11133 hr*ng/mL | Standard Deviation 1250736.327819 |
| 300 mg DKN-01 Part B (Q2W) | Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 | 18398867.35928 hr*ng/mL | Standard Deviation 5107540.116369 |
Secondary
Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01
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.
Time frame: Cycle 1 Day 22 (Fourth Dose for QW)
Population: All patients who received at least one dose of study treatment during Part A study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 | 5663382.27007 hr*ng/mL | Standard Deviation 3919446.471337 |
| 150 mg DKN-01 Part A (QW) | Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 | 15815320.60770 hr*ng/mL | Standard Deviation 5614032.150398 |
| 300 mg DKN-01 Part A (QW) | Pharmacokinetics: Area Under the Concentration - Time Curve (AUC) of DKN-01 | 25639949.52467 hr*ng/mL | Standard Deviation 4567585.003954 |
Secondary
Progression Free Survival (PFS) in Patients Who Are Refractory or Intolerant to Standard/Approved Therapies
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.
Time frame: Time from the date of signed informed consent to the first date of objectively determined progressive disease or death from any cause
Population: All patients who received at least one dose of study treatment during Part A or Part B of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 75 Milligram (mg) DKN-01 Part A (QW) | Progression Free Survival (PFS) in Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 3.4 Months |
| 150 mg DKN-01 Part A (QW) | Progression Free Survival (PFS) in Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 2.4 Months |
| 300 mg DKN-01 Part A (QW) | Progression Free Survival (PFS) in Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 2.1 Months |
| 600 mg DKN-01 Part A (Q2W) | Progression Free Survival (PFS) in Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 2.1 Months |
| 300 mg DKN-01 Part B (Q2W) | Progression Free Survival (PFS) in Patients Who Are Refractory or Intolerant to Standard/Approved Therapies | 2.2 Months |