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

Leap Therapeutics

Status and phase: Completed; Phase 1

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

Treatments: Drug: DKN-01

Study type: Interventional

Funder types: Industry

Identifiers

NCT01457417

DEK-DKK1-P100 (Other Identifier)

LY2812176 (Other Identifier)

P100

Details and patient eligibility

About

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.

Full 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.

Enrollment: 32 patients

Sex: All

Ages: 30+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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32 participants in 5 patient groups

75 milligram (mg) DKN-01 Part A

Experimental group

Description:

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.

Treatment:

Drug: DKN-01

150 mg DKN-01 Part A

Experimental group

Description:

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.

Treatment:

Drug: DKN-01

300 mg DKN-01 Part A

Experimental group

Description:

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.

Treatment:

Drug: DKN-01

600 mg DKN-01 Part A

Experimental group

Description:

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.

Treatment:

Drug: DKN-01

300 mg DKN-01 Part B

Experimental group

Description:

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.

Treatment:

Drug: DKN-01