Clinical trial NCT02988817: Enapotamab Vedotin (HuMax-AXL-ADC) Safety Study in Patients With Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Ovarian Cancer
Cervical Cancer
Endometrial Cancer
Non Small Cell Lung Cancer (NSCLC)
Thyroid Cancer
Melanoma
Sarcoma
Solid Tumors
Lead sponsor: Genmab
Sponsor class: INDUSTRY
First posted: 2016-12-09
Enrollment: 306
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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
2. Patients must have measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST).
3. For the expansion patients must provide a tumor tissue sample from archival tissue or fresh biopsy at enrolment
4. Age ≥ 18 years.
5. Acceptable renal function
6. Acceptable liver function
7. Acceptable hematological status
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. Life expectancy of at least three months.
10. 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
11. Patients must provide a signed informed consent form before any trial relates activities are carried out.

Exclusion Criteria:

1. Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for at least 4 weeks prior to first IMP administration.
2. Have clinically significant cardiac disease
3. 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.
4. Uncontrolled hypertension
5. Have received granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage colony stimulating factor support 3 weeks prior to first IMP administration.
6. 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.
7. 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.
8. Major surgery within four weeks before first IMP administration.
9. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases or stroke.
10. 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.
11. Prior therapy with a conjugated or unconjugated auristatin derivative/vinca-binding site targeting payload.
12. Radiotherapy within 14 days prior to first IMP administration.
13. 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.
14. Melanoma patients with an lactate dehydrogenase (LDH) ≥ 3 x upper limit normal (ULN).
15. Ongoing significant, uncontrolled medical condition including:

    o Serious, non-healing wound, skin ulcer (of any grade), or bone fracture.
16. Grade 2 or higher peripheral neuropathy.
17. Clinically significant active viral, bacterial or fungal infection
18. Known human immunodeficiency virus seropositivity.
19. Known positive serology for hepatitis B (unless due to vaccination or passive immunization due to immunoglobulin therapy)
20. Known positive serology for hepatitis C (unless due to immunoglobulin therapy)
21. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial result
22. 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
23. Body weight \< 40 kg
24. Women who are pregnant or breast feeding.
25. Pulmonary hemorrhage or hemoptysis \> 2.5 ml blood within 6 weeks unless cause has been addressed and is medically resolved.
26. History of acute pneumonitis.

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicities (DLTs) for Dose-escalation Part
timeFrame: 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
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: Day 1 through Day 1130 (maximum observed duration)
measure: Number of Participants With Treatment-emergent Infusion-related AEs and TEAEs Related to Enapotamab Vedotin
timeFrame: Day 1 through Day 1130 (maximum observed duration)
measure: Number of Participants With >= Grade 3 TEAEs as Assessed by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03
timeFrame: Day 1 through Day 1130 (maximum observed duration)
measure: Number of Participants With Grade 3 or 4 Laboratory Results
timeFrame: Day 1 through Day 1130 (maximum observed duration)
Secondary outcomes:
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of Conjugated Enapotamab Vedotin for 1Q3W Dose-escalation Part
timeFrame: Predose, end of infusion (EOI), and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3
measure: 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
timeFrame: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3
measure: Maximum Observed Plasma Concentration (Cmax) of Conjugated Enapotamab Vedotin for Dose-escalation Part
timeFrame: 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
measure: Total Clearance (CL) of Conjugated Enapotamab Vedotin in Dose-escalation Part
timeFrame: 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
measure: Time of Maximum Plasma Concentration (Tmax) of Conjugated Enapotamab Vedotin for Dose-escalation Part
timeFrame: 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
measure: Half-life Lambda-z (t1/2) of Conjugated Enapotamab Vedotin for Dose-escalation Part
timeFrame: 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
measure: Volume of Distribution at Steady State (Vss) of Conjugated Enapotamab Vedotin for Dose-escalation Part
timeFrame: 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
measure: AUC0-inf of Free Toxin Monomethyl Auristatin E (MMAE) for 1Q3W Dose-escalation Part
timeFrame: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3
measure: AUC0-last of MMAE for 1Q3W Dose-escalation Part
timeFrame: Predose, EOI, and 2 and 5 hours after EOI on Day 1 of Cycles 1 and 3
measure: Cmax of MMAE for Dose-escalation Part
timeFrame: 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
measure: Total CL of MMAE in Dose-escalation Part
timeFrame: 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
measure: Tmax of MMAE for Dose-escalation Part
timeFrame: 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
measure: t1/2 of MMAE for Dose-escalation Part
timeFrame: 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
measure: Number of Participants With Antidrug Antibodies (ADAs) Confirmed Positive to Enapotamab Vedotin
timeFrame: 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)
measure: 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
timeFrame: Day 1 through 44.5 months (maximum observed duration)
measure: Number of Participants With Best Cancer Antigen 125 (CA-125) Response
timeFrame: From Screening (within 2 weeks before starting of the study treatment) through Day 1130 (maximum observed duration)
measure: Duration of Response (DoR) Based on RECIST v1.1 as Assessed by Investigator for Expansion Part
timeFrame: Day 1 through 44.5 months (maximum observed duration)
measure: Progression Free Survival (PFS) as Assessed by Investigator
timeFrame: Day 1 through 44.5 months (maximum observed duration)
measure: Overall Survival (OS)
timeFrame: Day 1 through 44.5 months (maximum observed duration)
measure: Change in AXL Expression (Total Tumor H-score) From Baseline to EOT Visit for Expansion Part
timeFrame: Baseline (Study Days -21 to 1) and EOT visit (Day 1100)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic - Phoenix
state: Arizona
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: New Haven
country: United States
facility: Yale University, Smilow Cancer Center at Yale New Haven Hospital
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine, Winship Cancer Institute
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Huntsman Cancer Institute
state: Utah
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center
state: Wisconsin
city: Leuven
country: Belgium
facility: Universitair Ziekenhuizen Leuven
state: Flemish Brabant
city: Bruxelles
country: Belgium
facility: Institut Roi Albert II - Cliniques Universitaires Saint Luc
city: Jette
country: Belgium
facility: Universitair Ziekenhuis Brussel - Oncologisch Centrum
city: Kortrijk
country: Belgium
facility: Medische oncologie, Oncologisch Centrum - AZ Groeninge
city: Leuven
country: Belgium
facility: U.Z. Leuven Gasthuisberg, Department of General Medical Oncology
city: Liege
country: Belgium
facility: CHU de Liège, Medical Oncology et. Domaine Universitaire du Sart Tilman
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Copenhagen University Hospital
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Rotterdam
country: Netherlands
facility: Erasmus MC, Medical Oncology
city: Utrecht
country: Netherlands
facility: UMC Utrecht Cancer Center
city: Barcelona
country: Spain
facility: Hospital Unversitario Vall D'hebron
city: Barcelona
country: Spain
facility: Oncologia Mèdica/ Medical Oncology Department Institut Catalá d'Oncologia (ICO)
city: Girona
country: Spain
facility: University Hospital of Girona
city: Madrid
country: Spain
facility: Hospital Universitario 12 Octubre Servicio de Oncologia Medica
city: Málaga
country: Spain
facility: Hospital Virgen de la Victoria
city: Zaragoza
country: Spain
facility: University Hospital Lozano Blesa, Aragón Health Research Institute (IIS Aragón)
city: London
country: United Kingdom
facility: University College London Hospitals
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust Clinical Trials Unit
city: Newcastle
country: United Kingdom
facility: Sir Bobby Robson Clinical Trials Unit at the Northern Centre for Cancer Care, Freeman Hospital
city: Sutton
country: United Kingdom
facility: The Royal Marsden Hospital
Study officials:
affiliation: Universitair Ziekenhuizen Leuven
name: Ignace Vergote, Professor
role: PRINCIPAL_INVESTIGATOR
References: