A Phase 1a/1b Open label, Multicenter, Global, Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of XMAB24306 as a Single Agent and in Combination with Atezolizumab in Patients with Locally Advanced or Metastatic Solid Tumors

There has been a longstanding interest in using cytokines that can augment
T-cell and NK-cell mediated immunity in the treatment of cancer. Initial
studies focused on IL-2, which led to the approval of aldesleukin for the
treatment of metastatic melanoma and RCC (Proleukin U.S. Package Insert). The
clinical benefit of IL-2 therapy illustrates the potential of cytokines in CIT;
however, tolerability due to systemic effects of IL-2 limits
the patient population and requires intensive inpatient monitoring. This
supports the rationale for developing novel cytokines that can enhance cancer
immunity with better tolerability, such as IL-15, with the ultimate goal of
enabling rational combinations with other emerging immunotherapies, including
immune checkpoint inhibitors targeting PD-L1/PD-1. Despite the robust activity
observed with agents targeting PD-L1/PD-1 across diverse malignancies, durable
clinical benefit appears limited to a minority of patients, and combination
therapies that address mechanisms of resistance to
anti-PD-L1/PD-1 therapies are needed (Ribas 2015; Binnewies et al. 2018; Wei et
al. 2018; Souza-Fonseca-Guimaraes et al. 2019).

XmAb24306 is an IL-15/IL15Rα-Fc fusion protein designed to preferentially
expand and activate NK-cell and CD8+ T-cell populations and is expected to
boost the anti-tumor potential of T-cell and NK-cell directed CITs. This makes
XmAb24306 an attractive combination partner for drugs targeting the PD-L1/PD-1
axis that can boost antigen-specific T cells in the tumor microenvironment.
The combination of XmAb24306 with atezolizumab or PD-1 inhibitors (e.g.,
pembrolizumab or nivolumab) in patients with solid tumors has the potential to
enhance anti-tumor immune responses beyond what can be achieved with either
agent alone and is supported by preclinical investigations involving IL-15 as
well as XmAb24306 in combination with anti-PD-L1/PD-1 agents in mouse models
(see Section 1.1.3).

XmAb24306 has not been studied in humans, and therefore its clinical benefit or
safety profile as single agent or in combination with anti-PD-L1/PD-1 agents is
unknown. To assess potential risks, XmAb24306 was evaluated in cynomolgus
monkeys at doses from 0.03 to 0.6 mg/kg Q2W, with the observed safety profile
supporting the proposed clinical investigation of XmAb24306 (see the XmAb24306
Investigator*s Brochure for details).

Key potential risks for XmAb24306 as a single agent or in combination with
anti-PD-L1/PD-1 agents are immune- and cytokine-related adverse events informed
by the XmAb24306 nonclinical studies and clinical experience with relevant
approved (e.g., Tecentriq and Proleukin U.S. Package inserts) or
investigational immunotherapies (e.g., NKTR-214 [Bentebibel et al. 2019;
Hurwitz et al. 2019], rhIL-15 [Conlon et al. 2015; Miller et al. 2018; Conlon
et al. 2019c], and ALT-803 [Margolin et al. 2018; Romee et al.2018; Wrangle et
al. 2018]). Additional detail on potential risks along with risk mitigation
strategies and management guidelines for investigators are described in Section
5.1. The PD-L1/PD-1 pathway is involved in peripheral tolerance, and blockade
of this checkpoint pathway is associated with a spectrum of immune-mediated
adverse events (Hamid et al. 2013; Robert et al. 2014, 2015). Atezolizumab has
been generally well tolerated. Adverse events with potentially immune-mediated
causes consistent with an immunotherapeutic agent, including rash,
influenza-like illness, endocrinopathies, hepatitis or transaminitis,
pneumonitis, colitis, and myasthenia gravis, have been observed. To date,
these events have been manageable with treatment (e.g., corticosteroids) or
interruption of atezolizumab treatment (see Atezolizumab Investigator's
Brochure for detailed safety results).

This Phase Ia/Ib trial will enroll patients with advanced solid tumors. Given
the relatively poor prognosis and limited treatment options for these patients,
this population is
considered appropriate for trials of novel therapeutic candidates. The Phase
Ia component will characterize the safety, tolerability, and pharmacokinetics
of increasing
doses of XmAb24306 in patients with advanced solid tumors and inform the
combination of XmAb24306 with atezolizumab (and eventually PD-1 inhibitors such
as
pembrolizumab and/or nivolumab) to be assessed in Phase Ib. The benefit-risk
ratio for XmAb24306 as a single agent (Phase Ia) or XmAb24306 in combination
with immune checkpoint inhibitors such as atezolizumab (Phase Ib) is expected
to be acceptable in this setting.

This study has been transitioned to CTIS with ID 2023-506285-31-00 check the CTIS register for the current data.

This study will evaluate the safety, tolerability, pharmacokinetics, and
activity of XmAb24306 as a single agent (Phase Ia) or in combination with a
checkpoint inhibitor targeting the PD-L1/PD-1 axis (Phase Ib) in patients with
locally advanced or metastatic solid tumors. Phase Ib will assess the
combination of XmAb24306 with the anti*PD-L1 antibody, atezolizumab. Future
evaluation of XmAb24306 in combination with anti*PD-1 antibodies, such as
pembrolizumab, is also being considered in relevant treatment settings.
Specific objectives and corresponding endpoints for the study are outlined
below.

Safety Objective (Primary Study Objective)
The safety objective for this study is to evaluate the safety of XmAb24306 when
administered
as a single agent (Phase Ia) or in combination with the anti*PD-L1/PD-1
antibody, atezolizumab,
(Phase Ib) on the basis of the following endpoints:
* Incidence and severity of adverse events, with severity determined according
to National
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0
(NCI CTCAE v5.0)
* Change from baseline in targeted vital signs
* Change from baseline in targeted clinical laboratory test results
* Change from baseline in ECGs parameters

Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to characterize the
XmAb24306 PK profile when administered as a single agent (Phase Ia) or in
combination with the anti-PD-L1/PD-1
antibody, atezolizumab, (Phase Ib) on the basis of the following endpoint:
* Serum concentration of XmAb24306 at specified timepoints The exploratory PK
objectives for this study are as follows:
* To evaluate potential relationships between drug exposure and the safety and
activity of XmAb24306 when administered as a single agent (Phase Ia) or in
combination with atezolizumab (Phase Ib) on the basis of the following
endpoints:
* Relationship between serum concentration or PK parameters for XmAb24306 and
safety endpoints
* Relationship between serum concentration or PK parameters for XmAb24306 and
activity endpoints
* To evaluate potential relationships between selected covariates and exposure
to XmAb24306 when administered as a single agent (Phase Ia) or in combination
with atezolizumab (Phase Ib) on the basis of the following endpoint:
* Relationship between selected covariates and serum concentration or PK
parameters
for XmAb24306
* To assess potential PK interactions between XmAb24306 and atezolizumab on the
basis of the following endpoints:
* Serum concentration or PK parameters for XmAb24306 given in combination with
atezolizumab compared with XmAb24306 given alone
* Serum concentration or PK parameters for atezolizumab given in combination
with XmAb24306 compared with atezolizumab given alone (based on historical data)

Activity Objective
Response will be assessed according to Response Evaluation Criteria in Solid
Tumors, Version 1.1 (RECIST v1.1) and modified RECIST v1.1 for immune-based
therapeutics (iRECIST. Objective response at a single timepoint will be
determined by the investigator according to RECIST v1.1. Objective response
per iRECIST will be calculated programmatically by the Sponsor on the basis of
investigator assessments of individual lesions at each specified timepoint.
The activity objective for this study is to make a preliminary assessment of
the activity of XmAb24306 when administered as a single agent (Phase Ia) or in
combination with the anti-PD-L1/PD-1 antibody, atezolizumab, (Phase Ib) on the
basis of the following endpoints:
* Objective response rate (ORR), defined as the proportion of patients with a
complete
response (CR) or partial response (PR) on two consecutive occasions
* 4 weeks apart, as determined by the investigator according to RECIST v1.1
* Duration of response (DOR), defined as the time from the first occurrence of
a documented objective response to disease progression or death from any cause
(whichever occurs first),as determined by the investigator according to RECIST
v1.1
* Progression-free survival (PFS) after enrollment, defined as the time from
enrollment to the first occurrence of disease progression or death from any
cause (whichever occurs first), as determined by the investigator according to
RECIST v1.1
* ORR, DOR, and PFS as based on radiographic assessment by the investigator
according to iRECIST
* Overall survival (OS) after enrollment, defined as the time from enrollment
to death from any cause

Immunogenicity Objectives
The immunogenicity objective for this study is to evaluate the immune response
to XmAb24306 when administered as a single agent (Phase Ia) or in combination
with the anti-PD-L1/PD-1 antibody, atezolizumab, (Phase Ib) on the basis of the
following endpoints:
* Prevalence of anti-drug antibodies (ADAs) to XmAb24306 at baseline and
incidence of ADAs to XmAb24306 during the study (Phase Ia)
* Prevalence of ADAs to XmAb24306 and atezolizumab at baseline and incidence of
ADAs to XmAb24306 and atezolizumab during the study (Phase Ib)
The exploratory immunogenicity objective for this study is to evaluate
potential effects of ADAs on the basis of the following endpoint:
* Relationship between ADA status and safety, PK, or activity endpoints

Biomarker Objective
The exploratory biomarker objective for this study is to identify and/or
evaluate biomarkers that are predictive of response to XmAb24306 when
administered as a single agent (Phase Ia) or in combination with the anti*PD*L1/
PD-1 antibody, atezolizumab, (Phase Ib) (i.e., predictive biomarkers), can
provide evidence of XmAb24306 activity (i.e., pharmacodynamic [PD] biomarkers),
are associated with progression to a more severe disease state (i.e.,
prognostic biomarkers), are associated with acquired resistance to XmAb24306,
are associated with susceptibility to developing adverse events or can lead to
improved adverse event monitoring or investigation, or can increase the
knowledge and understanding of disease biology and drug safety, on the basis of
the following endpoint:
* Relationship between biomarkers in blood and tumor tissue and safety, PK, PD
activity, immunogenicity, or other biomarker endpoints

Additional Objective
An additional objective for this study is to identify a recommended Phase II
dose for XmAb24306 when administered as a single agent (Phase Ia) or in
combination with the anti*PD-L1/PD-1 antibody, atezolizumab, (Phase Ib) on the
basis of the following endpoint:
* Relationship between XmAb24306 dose and safety, PK, PD activity, and
immunogenicity endpoints

This is a first-in-human (FIH) Phase Ia/Ib, open-label, multicenter, global,
dose-escalation study designed to evaluate the safety and pharmacokinetics of
XmAb24306 as a single agent (Phase Ia) or in combination with an
anti-PD-L1/PD-1 antibody such as atezolizumab (Phase Ib)
and to identify a recommended Phase II dose for XmAb24306 in patients with
locally advanced, recurrent, or metastatic incurable solid tumor malignancies
for which standard therapy does not exist, has proven to be ineffective or
intolerable, or is considered inappropriate, or for whom a
clinical trial of an investigational agent is a recognized standard of care.
Both the Phase Ia and Ib portions of the study consist of a screening period of
up to 28 days, a treatment period, and a minimum follow-up period of 90 days
after treatment. Patients considering enrollment into Phase Ib expansion
cohorts with PD-L1 selected tumors can have tissue prescreening for PD-L1
status performed prior to the 28-day screening period.
Patients who do not meet the criteria for participation in this study (screen
failure) may qualify for one re-screening opportunity (for a total of two
screenings per participant) at the investigator's discretion. Patients are not
required to re-sign the consent form if they are re-screened within 28 days
after previously signing the consent form. The investigator will record
reasons for screen failure in the screening log.
In each phase, patients will be enrolled in two stages: a dose-escalation
stage and an expansion stage. During the Phase Ia dose-escalation stage,
initial cohorts will enroll 1 patient per dose level until PD activity or a
Grade >= 2 adverse event involving a major organ not attributable to another
clearly identifiable cause or any dose-limiting toxicity (DLT) is observed
during the DLT assessment window. Subsequently, cohorts of 3-9 patients each
will be evaluated at escalating dose levels following a 3 + 3 + 3 design to
determine the maximum
tolerated dose (MTD) or maximum administered dose (MAD) for single-agent
XmAb24306 (Phase Ia). During the Phase Ib dose-escalation stage, cohorts of
3-9 patients each will be evaluated at escalating dose levels following a 3 + 3
+ 3 design to determine the MTD (or MAD) for XmAb24306 in combination with
atezolizumab.
XmAb24306 dosing frequency will initially be Q2W for both the Phase Ia and
Phase Ib. Based on an ongoing review of the overall safety, PK, and/or PD
profile of the study treatment, a Q4W and/or Q6W XmAb24306 dosing schedule may
be opened for enrollment. Dose escalation at Q2W, Q4W, and Q6W dosing
schedules may run concurrently.
To acquire additional safety, PK, and PD data to more fully inform the dose and
schedule selection for the expansion cohorts, patients may be enrolled into
backfill cohorts at XmAb24306 dose levels shown not to exceed the MTD as a
single agent (Phase Ia) or in combination with atezolizumab (Phase Ib).
For both the Phase Ia and Phase Ib, (a)provisional XmAb24306 recommended Phase
II dose(s) (RP2D) will be proposed at or below the MTD/MAD established in dose
escalation. The proposed RP2D and schedule may be different for Phase Ia and
Phase Ib, and more than one RP2D and/or schedule may be proposed for Phase Ia
and /or Phase Ib expansion.
Once the RP2D(s) and schedule(s) of XmAb24306 as a single agent (Phase Ia) or
in combination with atezolizumab (Phase Ib) has been proposed, additional
patients will be enrolled in the
expansion stage and treated at the RP2D(s) and schedule(s) . In total, up to
approximately 225-350 patients may be enrolled in this study, at approximately
40 global investigative sites.
Patients in this study will be initially assessed for eligibility during the
screening period (lasting <= 28 days). Following confirmation of eligibility,
patients will receive XmAb24306 (Phase Ia) or XmAb24306 in combination with
atezolizumab (Phase Ib) by IV infusion on the first day of every for the Q6W
Phase Ib schedule, patients will also receive atezolizumab on Day 22 (+- 1 day)
of each cycle. Cycles will be 14 days in length for the Q2W schedules, 28 days
for the Q4W schedules, and 42 days for the Q6W schedules. .
The Phase Ib portion of this study will be activated only after DLT evaluation
of at least one pharmacodynamically active dose level of single-agent XmAb24306
has been completed in a minimum of 3 patients and all relevant single-agent
safety data have been reviewed with the investigators, as well as by an
Internal Monitoring Committee (IMC). If it is deemed appropriate, the Phase Ib
portion will then initiate enrollment at one dose level below the XmAb24306
dose level that demonstrated PD activity as a single agent, using the same
dose-escalation scheme and comprehensive safety-monitoring plan as in the Phase
Ia portion.
All patients will be closely monitored for adverse events throughout the study
and for at least 90 days after the final dose of study treatment or until
initiation of another systemic anti-cancer therapy, whichever occurs first.
After this period, the Sponsor should be notified if the investigator becomes
aware of any serious adverse events that are believed to be related to prior
study drug treatment. Adverse events will be graded according to NCI CTCAE
v5.0.
To characterize the pharmacokinetics, immunogenicity response, and PD
properties of XmAb24306 as a single agent (Phase Ia) or in combination with
atezolizumab (Phase Ib), blood samples will be taken at various timepoints
before and after dosing.
Patients will undergo tumor assessments at screening (baseline) and at regular
intervals during the study, which will be measured by RECIST v1.1. iRECIST
will also be used in this study to better characterize the different patterns
of responses associated with cancer immunotherapy (CIT) and to allow a better
understanding of the preliminary activity profile of XmAb24306 as a single
agent (Phase Ia) or in combination with atezolizumab (Phase Ib). iRECIST is
intended to supplement standard RECIST v1.1 in this study to allow the
investigators to make an integrated assessment of benefit and risk for patients.
Patients may be permitted to continue study treatment even if standard RECIST
v1.1 criteria for progressive disease are met in Phase Ia or Ib, provided that
the patients meet the criteria for continued treatment. Patients who
discontinue the Phase Ia portion of the study may be permitted to cross over
into the Phase Ib portion and receive treatment with XmAb24306 in combination
with atezolizumab, provided that they meet the criteria for crossover. Patients
in the Phase Ib portion of the study who discontinue XmAb24306 for adverse
events may continue on atezolizumab therapy according to the Phase Ib schedule,
as long as they meet criteria for continued atezolizumab treatment.
All patients who discontinue XmAb24306 as a single agent (Phase Ia) or
XmAb24306 in combination with atezolizumab (Phase Ib) for reasons other than
disease progression (e.g., adverse events or achievement of a confirmed CR)
will continue tumor assessments per the schedule of activities..
Patients who permanently discontinue XmAb24306 (Phase Ia) or XmAb24306 in
combination with atezolizumab (Phase Ib) will return to the clinic for a
treatment discontinuation visit within 30 days after the final dose of study
treatment. For patients who discontinue study treatment due to disease
progression, the visit at which response assessment shows progressive disease
may be used as the treatment discontinuation visit.
Further monitoring and recording of adverse events will occur up to 90 days
after the final dose of study treatment or until initiation of another systemic
anti-cancer therapy, whichever occurs first. All patients in the study will be
followed for survival and subsequent anti-cancer therapy information
approximately every 3 months until death, loss to follow-up, o

The investigational medicinal products for this study are XmAb24306 (Phase Ia
and Ib) and atezolizumab (Phase Ib only).
XmAb24306 will be administered on Day 1 of each 2-week, 4-week or 6 week cycle
by IV infusion. The total dose of XmAb24306 for each patient will depend on
the dose level assignment and the patient*s weight on Day 1 of each cycle (or
within 72 hours prior to Day 1 of that cycle). Patients may receive the
initial (Cycle 1) dose of XmAb24306 in subsequent cycles unless the patient*s
body weight has changed by > 5% from baseline weight, in which case a new
XmAb24306 dose must be calculated. This new dose of XmAb24306 may be given in
subsequent cycles, unless the patient experiences another > 5% change in body
weight, in which case a new XmAb24306 dose must be calculated.
In the Phase Ib portion of the study, XmAb24306 will be administered prior to
atezolizumab. The atezolizumab infusion may start 90 minutes after completion
of the XmAb24306 infusion or after completion of the monitoring period
following completion of the XmAb24306 infusion, whichever is shorter.

Atezolizumab will be administered by IV infusion at a fixed dose in combination
with XmAb24306. Atezolizumab will be administered after XmAb24306 and
subsequent observation period. The dose of atezolizumab:
2 week cycle: 840 mg every 2 weeks
4 week cycle: 1680 mg every 4 weeks
6 week cycle: 1200 mg every 3 weeks

The study assessments will be per the schedule of assessments, see appendix
1,2,4,5,7,8, 10, 11, 13, 14, 16 and 17 of the protocol. Treatment will continue
until disease progresses (as defined by RECIST criteria), unacceptable toxicity
occurs, patient is out of clinicial benefit, patient withdraws or dies, or
patient discontinues the study for any other reason, after which all patients
make a final visit. The study center will contact the patient every 3 months to
collect safety and survival information.

Risks:
Adverse reactions due to XmAb24306 (including infusion-related reaction,
Allergic reaction, Capillary leak syndrome, Immune-related adverse reactions,
enlargement of spleen, lymph nodes or other organs, heart injury, high or low
blood pressure, bone marrow suppression, chills and skin rash) and atezolizumab
(including colitis, inflammation of the thyroid gland, inflammation of the
adrenal gland, inflammation of the pituitary, hepatitis, meningoencephalitis,
myasthenic syndrome / myasthenia gravis, Guillain Barré syndrome, pneumonitis,
myocarditis, infusion reactions, pancreatitis, diabetes mellitus, nephritis,
inflammation or damage to the muscles, pericardial disorders, myelitis and
facial paresis).
Response to contrast medium (used for CT scan / MRI)
Possible consequences of blood sampling (pain, bruising, infection, dizziness)
Radiation exposure on CT scan
Possible consequences of biopsy (pain, redness, swelling, bleeding)