A Phase 1 Study of SGN-PDL1V in Advanced Solid Tumors

PD-L1 is expressed in numerous human adenocarcinomas, including, but not
limited to ovarian, NSCLC, gastric cancer and gastroesophageal junction
carcinoma, esophageal, endometrial, breast, bladder, cervical, colon, and
pancreatic. Additionally, PD-L1 is expressed disproportionally high in cancers
with mucinous histologies regardless of the tumor type. The high expression of
PD-L1 on tumor cells is associated with tumorigenesis, metastatic potential,
immune suppression, chemoresistance, and poor prognosis. Targeting PD-L1 with
the ADC SGN-PDL1V has been studied in a series of preclinical disease models in
vitro and in vivo. In vitro models have shown effective target binding and
internalization of the ADC into cells as
well as cellular toxicity. In vivo, SGN-PDL1V demonstrated tumor growth-delay
and tumor regression in a series of relevant tumor models.
Based on the evidence of preclinical effectiveness to date, SGN-PDL1V can be a
new therapeutic option with the potential of delaying the development of new
metastatic lesions and/or controlling or reducing disease burden. Subjects may
also derive other benefits from participating in this phase 1 trial because of
the regimented routine that subjects undergo such as routine physical
examinations, laboratory draws, and radiological examinations.

This study has been transitioned to CTIS with ID 2023-506604-18-00 check the CTIS register for the current data.

Primary:
- To evaluate the safety and tolerability of SGN-PDL1V in subjects with
advanced solid tumors.
- To identify the maximum tolerated dose (MTD) of SGN-PDL1V in subjects with
advanced solid tumors.
- To identify a recommended dose and schedule for SGN-PDL1V.

Secondary:
- To assess the antitumor activity of SGN-PDL1V.
- To assess the pharmacokinetics (PK) of SGN-PDL1V.
- To assess the immunogenicity of SGN-PDL1V.

Exploratory:
- To characterize the pharmacodynamics of SGN-PDL1V.
- To assess the pharmacokinetic/pharmacodynamic (PK/PD) relationships of
SGN-PDL1V.
- To assess exploratory markers of clinical outcomes, PK, and pharmacodynamics.
- To assess patient reported outcomes (PRO) for quality of life (QoL) per
validated tools (Part C in head and neck squamous cell carcinoma (HNSCC)
subjects only).

This is a phase 1, open-label, multicenter study designed to evaluate the
safety, tolerability, PK, and antitumor activity of SGN-PDL1V in adults with
select advanced solid tumors. The study will include multiple tumor types for
the dose escalation (Part A), followed by cohorts for dose and schedule
optimization (Part B, optional), and disease-specific cohorts in dose expansion
(Part C).

The study will include dose escalation (Part A) enrolling subjects with HNSCC,
non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC) or
esophageal squamous cell carcinoma (SCC) who have programmed death -ligand 1
(PD-L1) expression >=1 by combined positive score (CPS), tumor proportion score
(TPS), or immune cell score (%IC) based on historical testing. The initial
dosing schedule to be tested will be Day 1 and Day 8 of a 21-day cycle (2Q3W).
The initial dose level to be evaluated in the 2Q3W
schedule is 0.5 mg/kg. Dose escalation will proceed by increments of 0.25
mg/kg, up to the dose level of 2.5 mg/kg, if tolerated. At any time, an
alternative dosing schedule (eg, Day 1, Day 8, and Day 15 of a 28-day cycle
[3Q4W], or Day 1 and Day 15 of a 28-day cycle [2Q4W], or Day 1 of a 21-day
cycle [Q3W]) may be activated with additional subjects. The initial dose for
the alternative dosing schedule will be the same as the dose cleared in the
initial dosing schedule (ie, 2Q3W) as long as the dose intensity is the same or
lower. The modified toxicity probability interval (mTPI) dose escalation rule
will be applied separately to each dosing schedule. Not all alternative dosing
schedules will necessarily be evaluated.

At the completion of dose escalation, dose and schedule optimization (Part B)
may be activated to additionally evaluate up to two of the SGN-PDL1V dosing
schedules recommended from Part A in 2 different tumor types. This part will
allow optimization of the dose and schedule that will be recommended for
expansion. The choice of which schedule(s) to open for enrollment will be made
by the sponsor in consultation with the Safety Monitoring Committee (SMC), on
the basis of available data on safety, dose-limiting toxicity (DLT), PK, and
initial antitumor activity. Subjects as described in Part A will be enrolled in
Part B. Up to 2 dosing schedules in 2 different tumor types may be evaluated in
parallel cohorts with up to 10 subjects per schedule per tumor type. Subjects
participating in Part B will be randomized to allocate to different dose and
schedules with equal probability for a specific tumor type. If, following Part
A, there is sufficient evidence to support bringing a dosing schedule forward
for SGN-PDL1V, Part B may be omitted, provided at least 6 subjects have been
dosed at the recommended dose and schedule. The optimal recommended dose and
schedule for further evaluation in the Part C disease-specific expansion
cohorts will be determined on the basis of safety, PK, preliminary antitumor
activity, and relevant pharmacodynamic and biomarker data.

Dose expansion (Part C) in HNSCC with PD-L1 expression >=20 by TPS or CPS and
NSCLC with PD-L1 expression >=50 by TPS will be activated by the sponsor in
consultation with the SMC using the dose and schedule identified by Part A
and/or Part B. Two additional disease-specific cohorts for HNSCC and NSCLC with
PD-L1 expression <20 and <50, respectively, by TPS or CPS may be activated. An
additional signal-seeking cohort in subjects with melanoma, ovarian cancer,
TNBC, or esophageal SCC may be activated. A biology cohort including HNSCC,
NSCLC, TNBC, esophageal SCC, melanoma or ovarian cancer may also be activated.
The recommended dose and schedule for Part C will be determined in Parts A or B.

Dose escalation (Part A):
* Approximately 45 subjects will be treated to evaluate the safety,
tolerability, and PK of SGN-PDL1V, and to identify the MTD and recommended dose
and schedule. The dose-escalation portion of the trial will be conducted using
the modified toxicity probability interval (mTPI) design (Ji 2010) to evaluate
safety and tolerability, and to identify the MTD of SGN-PDL1V. If the MTD is
not reached, safety, PK, pharmacodynamics, and biomarker analyses, as well as
preliminary antitumor activity, will be used to determine a recommended dose
and schedule. Decisions on dose escalation, dose level modification, and
subsequent cohort size will be made by the sponsor in consultation with the
SMC. Note: For each new dose escalation cohort recommended for initiation by
the SMC, no more than 1 subject should receive treatment within a 24 hour
period. De-escalation to a lower dose level may be performed at any time by the
sponsor in consultation with the SMC. At any time, an additional alternate
dosing schedule for dose escalation (3Q4W, 2Q4W or Q3W) may be activated by the
sponsor in consultation with the SMC. The initial dose for an alternate dosing
schedule will be the same as the highest dose cleared in the original dosing
schedule as long as the dose intensity will be the same or lower. The mTPI dose
escalation rules will be applied separately to each dosing schedule. Not all
alternative schedules will necessarily be evaluated.
* Dose-limiting toxicities (DLTs) will be evaluated during dose escalation. The
DLT evaluation period will be the first cycle. A DLT is defined as any of the
below criteria related to SGN-PDL1V treatment during the DLT evaluation period,
excluding toxicities clearly related to disease progression or intercurrent
illness. Grading will be according to the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.

Dose and schedule optimization (Part B):
o Approximately 40 subjects with HNSCC, NSCLC, TNBC, or esophageal SCC who have
PD-L1 expression >=1 by CPS, TPS, or %IC based on historical testing may be
enrolled (up to 10 subjects per tumor type per schedule) to evaluate up to 2
different dosing schedules to optimize the dose and schedule for SGN-PDL1V.
Subjects participating in Part B will be randomized to allocate to different
dose and schedules with equal probability for a specific tumor type.
o If there is sufficient evidence to support bringing a dose and schedule
forward for SGN-PDL1V based on dose escalation (Part A), Part B may be omitted.

Dose expansion (Part C): Subjects with PD-L1 expression >=20 and >=50, HNSCC and
NSCLC, respectively, by TPS or CPS (approximately 40 subjects with HNSCC and
NSCLC each) will be enrolled. Additional disease-specific expansion cohorts in
subjects who have PD-L1 expression <20 and <50, for HNSCC and NSCLC,
respectively, by TPS or CPS (approximately 40 subjects with HNSCC and NSCLC
each) will be enrolled. A signal-seeking cohort in subjects with melanoma,
ovarian cancer, TNBC or esophageal SCC (approximately 40 subjects total) may
also start enrollment. A biology cohort (approximately 30 subjects with HNSCC,
NSCLC, esophageal SCC, melanoma, TNBC or ovarian cancer) may be activated based
on the data generated in Parts A and B of the study. Subjects in the biology
cohort will be gated based on data generated from other expansion cohorts and
must have accessible tumors to provide additional tissue for multiple (up to 3)
biopsies to enable biomarker studies of SGN-PDL1V, comparing pre- and
post-treatment tumor samples to characterize the clinical mechanism of action
(MOA) and correlates of sensitivity/resistance at the MTD or recommended dose.
Note: Part C will be initiated in France and Germany following submission of
data from Parts A and B to the appropriate regulatory authorities.

An SMC consisting of site investigators, the study medical monitor, drug safety
representative, and the study biostatistician will monitor the safety of
subjects and make dosing recommendations throughout dose escalation and dose
expansion. The SMC may recommend further evaluation of safety at a given dose
(ie, enro

SGN-PDL1V, referred to as the investigational product, is comprised of a human
antibody which targets the PD-L1 inhibitory molecule (a member of the B7 family
of immune checkpoint molecules) conjugated to the tubulin-disrupting
antimitotic agent, monomethylauristatin E (MMAE) via a cleavable peptide
linker. SGN-PDL1V will be administered intravenously.

This study is not very different from standard care. The tests and procedures
that will be performed during this study mostly replace the ones the subject
would have as part of standard care. Blood samples will be taken for safety and
research tests and to check on the subject's disease. These are extra blood
samples just for the study but there will also be blood draws for normal
medical care.