GEN1029 (HexaBody®-DR5/DR5) Safety Trial in Patients With Malignant Solid Tumors

Study Overview
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Brief Summary
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The purpose of the trial is to evaluate the safety of GEN1029 (HexaBody®-DR5/DR5) in a mixed population of patients with specified solid tumors

Detailed Description
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The trial is an open-label, multi-center first-in-human trial of GEN1029 (HexaBody®-DR5/DR5). The trial consists of two parts a dose escalation part (phase 1, first-in-human (FIH) and an expansion part (phase 2a). The expansion part of the trial will be initiated once the Recommended Phase 2 Dose (RP2D) has been determined.

Official Title
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First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of GEN1029 in Patients With Malignant Solid Tumors

Conditions
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Colorectal Cancer, Non-small Cell Lung Cancer, Triple Negative Breast Cancer, Renal Cell Carcinoma, Gastric Cancer, Pancreatic Cancer, Urothelial Cancer

Intervention / Treatment
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* Biological: GEN1029 (HexaBody®-DR5/DR5)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (main): Patients with advanced and/or metastatic cancer who have no available standard therapy or who are not candidates for available standard therapy, and for whom, in the opinion of the investigator, experimental therapy with GEN1029 may be beneficial. Patient must be ≥ 18 years of age Patients must have measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 Have an acceptable hematological status Have an acceptable renal function Have an acceptable liver function Have an Eastern Cooperative Oncology Group performance status of 0 or 1 Body weight ≥ 40kg Patients both females and males, of childbearing or reproductive potential must agree to use adequate contraception from screening visit until six months after last infusion of GEN1029 Exclusion Criteria (main): Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for at least 8 weeks prior to first GEN1029 administration Have clinically significant cardiac disease Have uncontrolled hypertension as defined in the protocol Any history of intracerebral arteriovenous malformation, cerebral aneurysm, new (younger than 6 months) or progressive brain metastases or stroke 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 Investigational Medicinal Product (IMP) Have received a cumulative dose of corticosteroid ≥ 150 mg prednisone (or equivalent doses of corticosteroids) within two weeks before the first GEN1029 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 Radiotherapy within 14 days prior to first GEN1029 administration Any prior therapy with a compound targeting DR4 or DR5 History of chronic liver disease or evidence of hepatic cirrhosis

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: GEN1029 (HexaBody®-DR5/DR5)<br> | Biological: GEN1029 (HexaBody®-DR5/DR5)<br>* GEN1029 will be administered intravenously. The dose levels will be determined by the starting dose and the escalation steps taken in the trial.<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) | DLT criteria in the dose escalation phase of this trial are defined as hematologic toxicity including Grade (G) 4 neutropenia/thrombocytopenia for minimal duration of 7 days, G3/4 febrile neutropenia, >=G3 thrombocytopenia with bleeding, or G4 anemia; and non-hematologic toxicity including G4 infusion-related reactions (IRR) or anaphylaxis, G3 IRR did not resolve to =<G1 within 24 hours, >=G3 diarrhea/vomiting (did not respond to optimal treatment within 2 days), G3 nausea (did not respond to optimal treatment within 7days), or Hy's law or protocol-specified toxicities related to liver function test results or amylase and/or lipase elevations; or any >=G3 possibly related non-hematological AE, which occurred during first 2 cycles (as specified in protocol). | From Day 1 to 28 days after the first dose of study drug | 
| 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: fatal or life-threatening; results in persistent or significant disability/incapacity; constitutes a congenital anomaly/birth defect; medically significant (an event that jeopardizes the participant or may require medical or surgical intervention to prevent one of the outcomes listed above [medical and scientific judgment must be exercised in deciding whether an AE is 'medically important']); required inpatient hospitalization or prolongation of existing hospitalization. A TEAE is defined as an AE occurring or worsening during the treatment period including the safety follow-up period. | Day 1 through Day 565 (corresponding to maximum observed duration) | 
| Number of Participants With >= Grade 3 Laboratory Results | Number of participants with laboratory measurements of Grade >= 3 by NCI-CTCAE v4.03 are 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. In case a participant reported multiple severity grades for an AE, only the maximum grade was used. | Day 1 through Day 565 (corresponding to maximum observed duration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Hx-DR5-01 and Hx-DR5-05 | The Cmax of Hx-DR5-01 and Hx-DR5-05 are reported. | Predose, end of infusion, 2, 4, 24, 48, 168 and 336 hours after end of infusion on Day 1 of Cycles 1, 2, 3 | 
| Area Under Plasma Concentration-time Curve From Time Zero to Infinity (AUC[0-inf]) of Hx-DR5-01 and Hx-DR5-05 | The AUC(0-inf) of Hx-DR5-01 and Hx-DR5-05 are reported. | Predose, end of infusion, 2, 4, 24, 48, 168 and 336 hours after end of infusion on Day 1 of Cycles 1, 2, 3 | 
| Area Under Plasma Concentration-time Curve From Time Zero to the Time of Last Nonzero Concentration (AUC[0-Clast]) of Hx-DR5-01 and Hx-DR5-05 | The AUC(0-Clast) of Hx-DR5-01 and Hx-DR5-05 are reported. | Predose, end of infusion, 2, 4, 24, 48, 168 and 336 hours after end of infusion on Day 1 of Cycles 1, 2, 3 | 
| Total Clearance (CL) of Hx-DR5-01 and Hx-DR5-05 | The CL of Hx-DR5-01 and Hx-DR5-05 are reported. | Predose, end of infusion, 2, 4, 24, 48, 168 and 336 hours after end of infusion on Day 1 of Cycles 1, 2, 3 | 
| Volume of Distribution (Vss) at Steady State of Hx-DR5-01 and Hx-DR5-05 | The Vss of Hx-DR5-01 and Hx-DR5-05 are reported. | Predose, end of infusion, 2, 4, 24, 48, 168 and 336 hours after end of infusion on Day 1 of Cycles 1, 2, 3 | 
| Half-life Lambda-z (t1/2) of Hx-DR5-01 and Hx-DR5-05 | The t1/2 of Hx-DR5-01 and Hx-DR5-05 are reported. | Predose, end of infusion, 2, 4, 24, 48, 168 and 336 hours after end of infusion on Day 1 of Cycles 1, 2, 3 | 
| Time to Reach Maximum Observed Concentration (Tmax) of Hx-DR5-01 and Hx-DR5-05 | The Tmax of Hx-DR5-01 and Hx-DR5-05 are reported. | Predose, end of infusion, 2, 4, 24, 48, 168 and 336 hours after end of infusion on Day 1 of Cycles 1, 2, 3 | 
| Plasma Concentration of Hx-DR5-01 and Hx-DR5-05 | The plasma concentration of Hx-DR5-01 and Hx-DR5-05 are reported. | Predose, end of infusion, 2, 4, 24, 48, 168 and 336 hours after end of infusion on Day 1 of Cycles 1, 2, 3 | 
| Number of Participants With Antidrug Antibodies (ADAs) Positive to GEN1029 | From positive ADA samples titer values and neutralizing antibody scores (positive or negative) were determined and reported. A participant was considered positive if negative at baseline (screening) and had at least one positive post-baseline result, or positive at baseline and had at least one positive post-baseline result with a titer higher than baseline. Number of participants with ADA positive to GEN1029 are reported. | From Screening (Day -21 to -1) through Day 478 (corresponding to maximum observed duration) | 
| Change From Baseline in Anti-tumor Activity Measured by Tumor Shrinkage | Anti-tumor activity measured by tumor shrinkage was evaluated on based on of sum of the diameter(s) of all target lesions from the computerized tomography (CT) scan/positron emission tomography (PET)-CT scan. Largest tumor shrinkage is reported. | From Baseline (Day 1) through 8.8 months (corresponding to maximum observed duration) | 
| Number of Participants With Objective Response (OR) According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | The radiological evaluation was based on RECIST v1.1 using CT scan/PET-CT scan. The OR was defined as complete response (CR) or partial response (PR) per RECIST v1.1. The CR was defined as disappearance of all target and non-target lesions and reduction in short axis to <10 mm of any pathological and non-pathological lymph nodes. The PR was defined as >=30% decrease in sum of diameters of target lesions (compared to baseline), no unequivocal progression of existing non-target lesions, and no new lesion. | From Day 1 through 8.8 months (corresponding to maximum observed duration) | 
| Progression-Free Survival (PFS) According to RECIST 1.1 | The PFS was defined as the number of days from the date of first study drug administration to first progressive disease (PD) or death from any cause. The PD was defined as at least 20% (and >= 5 mm) increase in the sum of the longest diameter (LD) of target lesions, compared to the smallest sum of the target LDs recorded while in trial or the appearance of 1 or more new lesions; unequivocal progression of existing non-target lesions; and/or new lesion. The radiological evaluation based on RECIST v1.1 was assessed using CT scan/PET scan. The PFS was estimated using Kaplan-Meier method. | From Day 1 through 8.8 months (corresponding to maximum observed duration) | 
| Overall Survival (OS) According to RECIST 1.1 | Overall survival was defined as the number of days from date of first study drug administration to death due to any cause. If a subject was not known to have died, then OS was censored, and the censoring date was the latest date the subject was known to be alive (on or before the cut-off date). The OS was estimated using Kaplan-Meier method. | From Day 1 through 8.8 months (corresponding to maximum observed duration) | 
| Duration of Response (DoR) According to RECIST 1.1 | The radiological evaluation based on RECIST v1.1 was assessed using CT scan/PET-CT scan. The DoR was defined as duration from the first documentation of confirmed OR (CR or PR) to date of first progressive disease (PD) or death. | From Day 1 through 8.8 months (corresponding to maximum observed duration) | 
| Time to Response (TTR) According to RECIST 1.1 | TTR is defined as the number of days from first dose of study drug to the first documented confirmed CR or PR, which must be subsequently confirmed. | From Day 1 through 8.8 months (corresponding to maximum observed duration) |