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.

Axl (also named Ark, Ufo, Tyro 7) is a transmembrane receptor tyrosine kinase.
Human Axl consists of 894 amino acids and is a single chain glycoprotein.
Together with Tyro-3 and Mer, Axl forms the TAM family of receptor tyrosine
kinases, which is characterized by two immunoglobulin-like domains (Ig1 and
Ig2) and two fibronectin type III domains (FN1 and FN2) in the extracellular
domain. Furthermore, these receptors have an intracellular tyrosine kinase
domain that is activated upon ligand stimulation. Growth arrest-specific 6
(Gas6) is the physiological ligand of Axl that binds to the Axl Ig1- and
Ig2-domains, resulting in activation of the intracellular kinase domain.
Generally, Axl is expressed in various tumor types. Axl expression is thought
to functionally contribute to tumor development. Enhanced tumor cell motility,
adherence and migration, epithelial-to-mesenchymal transition, angiogenesis and
resistance to targeted therapy and chemotherapy have been linked to Axl
expression. Gas6, the physiological ligand of Axl, is also expressed in some
cancers, potentially contributing to Axl activation through an Axl-Gas6
autocrine loop4.
enapotamab vedotin is a human IgG1 antibody that is generated by conjugation of
an Axl specific antibody with the microtubule disrupting agent monomethyl
auristatin E (MMAE) through the protease cleavable valine-citrulline (vc)
linker5-7. Enapotamab vedotin binds to the Ig1 domain of Axl and does not
compete with Gas6 for receptor binding. This is particularly relevant in tumors
that co-express Axl and Gas6, in which enapotamab vedotin is still able to bind
in the presence of Gas68.
The dominant mechanism of action for enapotamab vedotin is tumor cell killing
by MMAE mediated interference with cell division. Upon binding of enapotamab
vedotin to Axl expressed on the cell surface of tumor cells, the complex is
rapidly internalized and targeted to the lysosomes. Proteolytic cleavage of the
vc peptide linker in the lysosomes subsequently releases MMAE from the complex.
Free MMAE can diffuse within the cell where it directly binds to microtubules
and inhibits tubulin polymerization. Thereby MMAE interferes with proper
assembly of the mitotic spindle during cell division resulting in cell cycle
arrest and eventually cell death. Tubulin inhibitors primarily induce
cytotoxicity in proliferating cells and not in quiescent cells. Therefore,
proliferating tumor cells are preferentially targeted over normal cells, which
are generally quiescent. Due to its membrane permeability, MMAE can also cause
a bystander effect, e.g. cell death of proliferating Axl negative tumor cells
that surround Axl positive tumor cells5.
Unconjugated HuMax-AXL, was unable to induce in vitro cytotoxicity, and did not
inhibit tumor growth in xenograft models. However, enapotamab vedotin was
internalized after target binding, which is required for the cytotoxic function
of tubulin-inhibitor-based anti-drug conjugate (ADCs). Cytotoxic payloads were
conjugated to Axl antibodies to test their anti-tumor activity in mouse
xenograft models. Enapotamab vedotin was selected from the panel as the
clinical candidate, since it demonstrated the most potent anti-tumor activity
in vivo. Furthermore, anti-tumor efficacy of enapotamab vedotin was shown in
xenograft models derived from various tumor indications.
For more comprehensive information regarding enapotamab vedotin, refer to the
current version of the Investigator's Brochure for enapotamab vedotin

4.1 Primary Objective
• To determine the MTD and to establish the safety profile of enapotamab
vedotin in a mixed population of patients with specified solid tumors.
4.2 Secondary Objectives
• To evaluate the safety laboratory parameters of enapotamab vedotin in a mixed
population of patients with specified solid tumors.
• To establish the PK profile and evaluate immunogenicity of enapotamab vedotin
after single and multiple infusions.
• To evaluate the antitumor activity of enapotamab vedotin in a mixed
population of patients with specified solid tumors.
• To evaluate Axl expression in tumor biopsies from a mixed population of
patients with specified solid tumors.
4.3 Exploratory Objective
• To explore biomarkers predictive of response and resistance to enapotamab
vedotin.
4.4 Primary Endpoints
• Dose Limiting Toxicities (DLTs).
• Adverse events AEs: incidences of AEs, serious adverse events (SAEs),
infusion-related AEs >= grade 3 AEs, and AEs related to Investigational
Medicinal Product (IMP) during

The trial consists of a dose-escalation part with 2 arms (part I) and a dose
expansion part (part II).
Part I of this trial is a FIH, open-label, dose-escalation, safety trial of
Axl-specific antibody drug conjugate (ADC) enapotamab vedotin in a mixed
patient population with solid tumors to determine the MTD and the safety
profile of enapotamab vedotin.
Part I of this trial includes two arms for identification of the most optimal
dosing regimen:
• 1Q3W: Dosing once every 3 weeks.
o There is broad experience with 1Q3W dosing of ADCs9 and brentuximab vedotin
has received market authorization using this schedule (see Investigator*s
Brochure).
• 3Q4W: Weekly dosing for 3 weeks followed by one treatment-free week.
o Since enapotamab vedotin is expected to have a half-life in the range of 0.94
- 1.37 days a more frequent dosing schedule may improve the therapeutic window.
The less frequent dosing-arm (1Q3W) is designed as a Modified Bayesian
Continuous Reassessment Method (mCRM) incorporating Escalation With Overdose
Control (EWOC). This design is considered appropriate as the Bayesian mCRM in
general better estimates the MTD with less bias and more precision than a
classic 3+3 design10. A comprehensive comparison of the Continual Reassessment
Method (CRM) to the standard 3+3 dose escalation scheme in phase I dose-finding
studies has been described by Iasonos et. al10.
The properties of MMAE-based ADCs have been studied comprehensively and based
on the overview provided by Deslandes9 (in particular Table 1 of the article),
an U.S. Food and Drug Administration (FDA) analysis of ADCs11, in combination
with sponsor*s own development experience with tisotumab vedotin (HuMax-TF-ADC)
it is assumed that the MTD will be between 1.8 mg/kg - 2.5 mg/kg for the 1Q3W
dose schedule.
The design provides flexibility in terms of cohort sizes (allowed to vary in
CRM but not in classic 3+3 design).
In contrast, the more frequent dosing-arm (3Q4W) will be conducted as a classic
3+3 design as it consists of fewer dose-levels 5-6 and will include fewer
patients (15-36, 17 expected as compared to 28 in the 1Q3W-arm). The CRM would
need at least ~20-25 patients in order to work properly10.
The 3Q4W-arm will follow the 1Q3W-arm. Decisions in this arm will be
supplemented by information from the 1Q3W-arm which at all times will have
exposed patients at higher dose-levels than the 3Q4W-arm.
The aim of the expansion part is to provide further data on the safety,
tolerability, pharmacokinetic (PK) and anti tumor activity of the selected
dose.

Not applicable

Although there is no clinical experience with enapotamab vedotin as this is a
first-in-human (FIH) trial, while there is substantial experience with
MMAE-based ADCs as described in Investigator*s Brochure (IB), the following
notable observations in the toxicology studies with enapotamab vedotin pointing
to potential risks in human should be kept in mind.
• During infusion of enapotamab vedotin in non-clinical toxicology studies in
cynomolgus monkeys, infusion-related reactions with swelling of the eye lids,
decreased muscle tone, labored breathing, or brief loss of consciousness was
observed during the second treatment in 2 out of a total of 30 monkeys treated
with enapotamab vedotin (1Q3W x 3). Infusion-related clinical signs did not
occur or were milder during the third infusion in the monkeys when the infusion
time was prolonged from 30 to 60 min. Infusion-related reactions have also been
observed with related ADC compounds using MMAE as the toxin. Patients should be
monitored closely during infusion of enapotamab vedotin.
• Bone marrow suppression has been observed in non-clinical studies of
enapotamab vedotin and this adverse effect is expected during treatment with
MMAE-ADCs and is a common adverse finding for other MMAE-ADCs. Low neutrophil
count with increased risk of infections as well as anemia, lymphocytopenia and
thrombocytopenia might occur and hematological parameters should be monitored
during treatment.
• Enapotamab vedotin caused dose-related, reversible changes in the male
reproductive system (reduced sperm motility, lower testes and epididymides
weights, and degenerative changes in the sperm-producing epithelium in testes).
As risk mitigation, it is recommended that fertile males consider having semen
specimen obtained for storage for potential future conception.
• MMAE is metabolized mainly via the CYP3A4 pathway and is capable of
inhibiting human CYP3A4/5 enzymatic activity in vitro at concentrations that
may be achieved during clinical treatment and is a substrate for P-gp. Patients
who are receiving strong CYP3A4 or P-gp inhibitors concomitantly with
enapotamab vedotin should be closely monitored for adverse reactions.
Peripheral neuropathy has been observed frequently in patients receiving
MMAE-ADCs. Pausing of dosing or dose adjustment of enapotamab vedotinin case of
neuropathy is required (please refer to Section 7.3.2).
Important potential and newly identified risks for enapotamab vedotin include
constipation. In particular, events of constipation (<= Grade 3), some of them
leading to hospitalization, have been observed. The use of prophylactic
concomitant medication to avoid and manage constipation is described in Section
7.4.1.

Please refer to the IMPD Risk benefit assessment for the benefit-risk of
enapotamab vedotin.