Enapotamab Vedotin (HuMax-AXL-ADC) Safety Study in Patients With Solid Tumors

Study Overview
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Brief Summary
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The purpose of the trial is to determine the maximum tolerated dose and to establish the safety profile of HuMax-AXL-ADC in a mixed population of patients with specified solid tumors

Detailed Description
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The trial consists of two parts; a dose escalation part (phase I, first in-human (FIH)) and an expansion part (phase IIa). The dose escalation part has 2 dosing schedules: 1 dose every 3 weeks (1Q3W) dose regimen, and 3 doses every 4 weeks (3Q4W) dosing regimen. The Expansion part of the trial will further explore the recommended phase 2 dose and dosing regimens of HuMax-AXL-ADC as determined in dose escalation part.

Official Title
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First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of Axl-specific Antibody-drug Conjugate (Enapotamab Vedotin, HuMax®-AXL-ADC) in Patients With Solid Tumors

Conditions
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Ovarian Cancer, Cervical Cancer, Endometrial Cancer, Non Small Cell Lung Cancer (NSCLC), Thyroid Cancer, Melanoma, Sarcoma, Solid Tumors

Intervention / Treatment
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* Biological: Enapotamab vedotin (HuMax-AXL-ADC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For the dose escalation part: Patients with selected, relapsed or refractory solid tumors who have failed available standard therapy or who are not candidates for standard therapy. For the expansion part: Patients with advanced and/or metastatic solid tumors who are not candidates for standard therapy Patients must have measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST). For the expansion patients must provide a tumor tissue sample from archival tissue or fresh biopsy at enrolment Age ≥ 18 years. Acceptable renal function Acceptable liver function Acceptable hematological status Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Life expectancy of at least three months. Patients, both females and males, of childbearing/reproductive potential must agree to use adequate contraception while included in the trial and for six months after the last infusion of HuMax-AXL-ADC Patients must provide a signed informed consent form before any trial relates activities are carried out. Exclusion Criteria: Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for at least 4 weeks prior to first IMP administration. Have clinically significant cardiac disease Known congestive heart failure and/ or a known decreased cardiac ejection fraction of < 45%. A baseline QT interval as corrected by Fridericia's formula (QTcF) > 480 msec, a complete left bundle branch block (defined as a QRS interval ≥ 120 msec in left bundle branch block form) or an incomplete left bundle branch block. Uncontrolled hypertension Have received granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage colony stimulating factor support 3 weeks prior to first IMP administration. Have received a cumulative dose of corticosteroid > 150 mg prednisone (or equivalent doses of corticosteroids) within two weeks before the first Investigational Medicinal Product (IMP) administration. History of ≥ grade 3 allergic reactions to monoclonal antibody therapy as well as known or suspected allergy or intolerance to any agent given in the course of this trial. Major surgery within four weeks before first IMP administration. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases or stroke. Any anticancer therapy including; small molecules, immunotherapy, chemotherapy monoclonal antibodies or any other experimental drug within five half-lives but maximum four weeks before first infusion. Accepted exceptions are bisphosphonates, denosumab and gonadotropin-releasing hormone agonist or antagonist. Prior therapy with a conjugated or unconjugated auristatin derivative/vinca-binding site targeting payload. Radiotherapy within 14 days prior to first IMP administration. Known past or current malignancy other than inclusion diagnosis, except for: Cervical carcinoma of Stage 1B or less. Non-invasive basal cell or squamous cell skin carcinoma. Non-invasive, superficial bladder cancer. Prostate cancer with a current prostate specific antigen (PSA) level < 0.1 ng/mL. Breast cancer in BRCA1 or BRCA2 positive ovarian cancer patients. Any curable cancer with a complete response (CR) of > 2 years duration. Melanoma patients with an lactate dehydrogenase (LDH) ≥ 3 x upper limit normal (ULN). Ongoing significant, uncontrolled medical condition including: o Serious, non-healing wound, skin ulcer (of any grade), or bone fracture. Grade 2 or higher peripheral neuropathy. Clinically significant active viral, bacterial or fungal infection Known human immunodeficiency virus seropositivity. Known positive serology for hepatitis B (unless due to vaccination or passive immunization due to immunoglobulin therapy) Known positive serology for hepatitis C (unless due to immunoglobulin therapy) Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial result History of organ allograft (except for corneal transplant) or autologous or allogeneic bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of IMP Body weight < 40 kg Women who are pregnant or breast feeding. Pulmonary hemorrhage or hemoptysis > 2.5 ml blood within 6 weeks unless cause has been addressed and is medically resolved. History of acute pneumonitis.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enapotamab vedotin (HuMax-AXL-ADC)<br>Participants in all cohorts of the trial (both in escalation and expansion phase) will be administered enapotamab vedotin (HuMax-AXL-ADC) intravenously (IV). | Biological: Enapotamab vedotin (HuMax-AXL-ADC)<br>* Enapotamab vedotin (HuMax-AXL-ADC) will be administered intravenously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-limiting Toxicities (DLTs) for Dose-escalation Part | The DLTs were defined as Grade (G) 4 neutropenia or G4 thrombocytopenia for a minimal duration of 7 days, G3 and G4 febrile neutropenia, >=G3 hemorrhage associated with >=G3 thrombocytopenia, G4 anemia; Stevens Johnson syndrome, toxic epidermal necrolysis, >=G3 cutaneous vasculitis; G3 neuropathy (not improved to G1 within 3 weeks following pausing of dosing) and G4 neuropathy; G3 infusion-related reactions (IRR) that did not resolve to G1 or baseline within 24 hours; G4 IRR or G4 anaphylaxis events; >= G3 diarrhoea and/or vomiting persisting >48 hours or G3 nausea lasting 7 days (both despite optimal medical management); or any >=G3 related non-hematological AEs, which occurred during the Cycle 1 and regarded as medically important as assessed by the Data Monitoring Committee (excluding Grade 3 fatigue or non-hematological laboratory abnormalities as specified in protocol). | From Day 1 to Day 21 of first cycle for 1Q3W dosing regimen and from Day 1 to Day 28 of first cycle for 3Q4W dosing regimen | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is defined as an AE that meets one of the following criteria: requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, is a congenital anomaly/birth defect, is medically important, results in death, or is life-threatening. In this trial, a TEAE was defined as an AE occurring or worsening between the first dose of enapotamab vedotin and 30 days after the last dose received. | Day 1 through Day 1130 (maximum observed duration) | 
| Number of Participants With Treatment-emergent Infusion-related AEs and TEAEs Related to Enapotamab Vedotin | Number of participants with treatment-emergent infusion-related AEs and TEAEs related to enapotamab vedotin is reported. | Day 1 through Day 1130 (maximum observed duration) | 
| Number of Participants With >= Grade 3 TEAEs as Assessed by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 | Number of participants with TEAEs of >= Grade 3 as assessed by NCI-CTCAE v4.03 is reported. The NCI-CTCAE is a descriptive terminology is used for AE reporting. The NCI-CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE, based on this general guideline: Grade 1 as mild AE, Grade 2 as moderate AE, Grade 3 as severe AE, Grade 4 as life-threatening or disabling AE, and Grade 5 as death. If a participant reported multiple severity grades for an AE, only the maximum grade was used. | Day 1 through Day 1130 (maximum observed duration) | 
| Number of Participants With Grade 3 or 4 Laboratory Results | Number of participants with laboratory measurements graded as Grade 3 or 4 by NCI-CTCAE v 4.03 is reported. | Day 1 through Day 1130 (maximum observed duration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Conjugated Enapotamab Vedotin for 1Q3W Dose-escalation Part | The AUC0-inf of conjugated enapotamab vedotin for 1Q3W dose-escalation part is reported. Sample scheduling of the 3Q4W dosing regimen did not allow calculation of the specific outcome measure. | Predose, end of infusion (EOI), and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of Conjugated Enapotamab Vedotin for 1Q3W Dose-escalation Part | The AUC0-last of conjugated enapotamab vedotin for 1Q3W dose-escalation part is reported. Sample scheduling of the 3Q4W dosing regimen did not allow calculation of the specific outcome measure. | Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3 | 
| Maximum Observed Plasma Concentration (Cmax) of Conjugated Enapotamab Vedotin for Dose-escalation Part | The Cmax of conjugated enapotamab vedotin for dose-escalation part is reported. | For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose and EOI on Days 1 and 8 of Cycles 1 and 3; and predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3 | 
| Total Clearance (CL) of Conjugated Enapotamab Vedotin in Dose-escalation Part | The total CL of conjugated enapotamab vedotin in dose-escalation part is reported. | For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3 | 
| Time of Maximum Plasma Concentration (Tmax) of Conjugated Enapotamab Vedotin for Dose-escalation Part | The Tmax of conjugated enapotamab vedotin for dose-escalation part is reported. | For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3 | 
| Half-life Lambda-z (t1/2) of Conjugated Enapotamab Vedotin for Dose-escalation Part | The t1/2 of conjugated enapotamab vedotin for dose-escalation part is reported. | For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3 | 
| Volume of Distribution at Steady State (Vss) of Conjugated Enapotamab Vedotin for Dose-escalation Part | The Vss of conjugated enapotamab vedotin for dose-escalation part is reported. | For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3 | 
| AUC0-inf of Free Toxin Monomethyl Auristatin E (MMAE) for 1Q3W Dose-escalation Part | The AUC0-inf of MMAE for 1Q3W dose-escalation part is reported. Sample scheduling of the 3Q4W dosing regimen did not allow calculation of the specific outcome measure. | Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3 | 
| AUC0-last of MMAE for 1Q3W Dose-escalation Part | The AUC0-last of MMAE for 1Q3W dose-escalation part is reported. Sample scheduling of the 3Q4W dosing regimen did not allow calculation of the specific outcome measure. | Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3 | 
| Cmax of MMAE for Dose-escalation Part | The Cmax of MMAE for dose-escalation part is reported. | For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose and EOI on Days 1 and 8 of Cycles 1 and 3; and predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3 | 
| Total CL of MMAE in Dose-escalation Part | The total CL of MMAE in dose-escalation part is reported. | For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3 | 
| Tmax of MMAE for Dose-escalation Part | The Tmax of MMAE for dose-escalation part is reported. | For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3 | 
| t1/2 of MMAE for Dose-escalation Part | The t1/2 of MMAE for dose-escalation part is reported. | For 1Q3W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3; For 3Q4W dosing regimen: Predose, EOI, and 2 and 5 hours after EOI on Day 15 of Cycles 1 and 3 | 
| Number of Participants With Antidrug Antibodies (ADAs) Confirmed Positive to Enapotamab Vedotin | The ADA assessment was performed according to a tiered approach. First samples were screened for an ADA response; positively screened samples were analyzed in a confirmation method. Subsequently confirmed positive samples were analyzed for titre and the presence of neutralizing antibodies. Number of participants with ADA confirmed positive to enapotamab vedotin is reported. | Day 1 through Day 1130 (Dose-escalation part: Predose of Day 1 of Cycles 1 to 12, end of treatment [EOT], and 30 days after last study drug; Expansion part: Predose on Day 1 of Cycles 1 to 5, then every fourth cycle until PD) | 
| Number of Participants With Objective Response (OR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) As Assessed by Investigator | Radiological evaluation based on RECIST v1.1 was performed by the investigator using computed tomography (CT) scans/ magnetic resonance imaging (MRI) scans/ positron emission tomography (PET) scans. The OR was defined as confirmed CR or confirmed PR per RECIST v1.1. The changes in tumor measurements that were confirmed by repeat assessments performed no less than 4 weeks after initial response are called confirmed responses. The CR was defined as disappearance of all target and non-target lesions and all pathological lymph nodes must have decreased to < 10 mm in short axis. The PR was defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions taking as reference the baseline sum of LD. | Day 1 through 44.5 months (maximum observed duration) | 
| Number of Participants With Best Cancer Antigen 125 (CA-125) Response | The best CA-125 response was evaluated in participants with ovarian cancer. A CA-125 partial response was defined as at least a 50% reduction in CA-125 levels in blood from a pretreatment sample. Participants who had a CA-125 partial response and had CA-125 level falls to within the reference range (0-35 units/mL) were classified as CA-125 complete responders. The response was confirmed and maintained for at least 28 days. The best overall response (CA-125 partial response and CA-125 complete response) is reported. | From Screening (within 2 weeks before starting of the study treatment) through Day 1130 (maximum observed duration) | 
| Duration of Response (DoR) Based on RECIST v1.1 as Assessed by Investigator for Expansion Part | The DoR was defined as the number of months from the first documentation of objective tumor response (CR or PR) to the date of first progressive disease (PD) or death. The OR was defined as confirmed CR or confirmed PR per RECIST v1.1. The changes in tumor measurements that were confirmed by repeat assessments performed no less than 4 weeks after initial response are called confirmed responses. The CR was defined as disappearance of all target and non-target lesions and all pathological lymph nodes must have decreased to < 10 mm in short axis. The PR was defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions taking as reference the baseline sum of LD. The PD was defined as at least 20% increase in the sum of LD of target lesions taking as reference the smallest sum of the LD recorded since the treatment started or the appearance of one or more new target and non-target lesions and/or unequivocal progression of existing non-target lesions. | Day 1 through 44.5 months (maximum observed duration) | 
| Progression Free Survival (PFS) as Assessed by Investigator | The PFS was defined as the number of months from the date of first study drug administration to first PD or death. The PD was defined as at least 20% increase in the sum of longest diameters of target lesions taking as reference the smallest sum of the longest diameters recorded since the treatment started or the appearance of one or more new lesions. The PFS was estimated using Kaplan-Meier method. | Day 1 through 44.5 months (maximum observed duration) | 
| Overall Survival (OS) | Overall survival was defined as the number of months from date of first study drug administration to death. The OS was estimated using Kaplan-Meier method. | Day 1 through 44.5 months (maximum observed duration) | 
| Change in AXL Expression (Total Tumor H-score) From Baseline to EOT Visit for Expansion Part | Change in AXL expression (total humor H-score in membrane or cytoplasm) from Baseline to EOT visit for the expansion part is reported. The H-score captures both the intensity and proportion of AXL positive tumor cells and was defined by the formula: H-score = (1 × % 1+ tumor cells) + (2 × % 2+ tumor cells) + (3 × % 3+ tumor cells); where '1+' indicates weak staining intensity, '2+' indicates medium staining intensity, and '3+' indicates strong staining intensity. The H-score values ranges from 0 to 300. Lower H-scores represent lower AXL expression in the tumor sample, while higher scores represent stronger AXL expression in the tumor samples. | Baseline (Study Days -21 to 1) and EOT visit (Day 1100) |