This is a first-in-human Phase Ia/Ib, open-label, multicenter, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-tumor activity of RO7502175 as a single…
ID
Source
Brief title
Condition
- Other condition
- Metastases
Synonym
Health condition
Locally Advanced or Metastatic Solid Tumors
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety objective:
The safety objective for this study is to evaluate the safety of RO7502175 when
administered as a single agent (Phase Ia) or in combination with atezolizumab
(Phase Ib), including characterization of dose-limiting toxicities (DLTs), on
the basis of the following endpoints:
* Incidence and nature of DLTs
* 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 ECG parameters
Secondary outcome
Pharmacokinetic objectives:
The pharmacokinetic (PK) objective for this study is to characterize the
RO7502175 PK profile when administered as a single agent (Phase Ia) or in
combination with atezolizumab (Phase Ib) on the basis of the following
endpoint:
* Serum concentration of RO7502175 at specified timepoints
Activity objectives:
The activity objective for this study is to make a preliminary assessment of
the activity of RO7502175 when administered as a single agent (Phase Ia) or in
combination with 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
Immunogenicity objectives:
The immunogenicity objective for this study is to evaluate the immune response
to RO7502175 when administered as a single agent (Phase Ia) or in combination
with atezolizumab (Phase Ib) on the basis of the following endpoints:
* Prevalence of ADAs to RO7502175 at baseline (baseline prevalence) and
incidence of ADAs to RO7502175 after initiation of study treatment
(post-baseline incidence)
Biomarker objective:
The exploratory biomarker objective for this study is to identify and/or
evaluate biomarkers that are predictive of response to RO7502175 when
administered as a single agent (Phase Ia) or in combination with atezolizumab
(Phase Ib) (i.e., predictive biomarkers), can provide evidence of RO7502175
activity (i.e., PD biomarkers), are associated with progression to a more
severe disease state (i.e., prognostic biomarkers), are associated with
acquired resistance to RO7502175, 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 RO7502175 on the basis of the following endpoint:
* Relationship between RO7502175 dose and safety, PK, PD, activity, and
immunogenicity endpoints
Background summary
Current treatment options for solid tumor malignancies include chemotherapy,
radiation, surgery, targeted therapies, and immunotherapy. One form of
immunotherapy, known as checkpoint inhibitor (CPI) therapy, works by blocking
inhibitory receptors on T cells, with the goal of enhancing tumor-specific
T-cell responses, resulting in anti-tumor activity. CPIs, such as PD-(L)1
inhibitors, have demonstrated clinical efficacy and are approved for the
treatment of various cancers (Tecentriq; Keytruda; Opdivo). However, not all
cancers respond to CPIs and many tumors progress following initial treatment,
suggesting that additional immunosuppressive factors, such as regulatory T
cells (Treg cells), may be present that inhibit anti-tumor responses.
RO7502175 is an afucosylated humanized IgG1 antibody that binds to human C-C
motif chemokine receptor 8 (CCR8). RO7502175 binds to the N-terminus of CCR8
and does not block binding of CCR8 to its natural ligand. CCR8 is a chemokine
receptor that is expressed on Treg cells. Treg cells are a subset of CD4+ T
cells that are immunosuppressive and play a key role in preventing autoimmunity.
RO7502175 is designed to preferentially eliminate CCR8+ Treg cells in the tumor
microenvironment through antibody-dependent cell-mediated cytotoxicity
(ADCC)-mediated depletion, thus reversing the suppression of CD8+ effector T
cells. RO7502175 is designed to deplete intra-tumoral Treg cells, with the goal
of enhancing the host immune response against cancer cells without evoking
autoimmunity.
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and
inhibits the interaction between PD-L1 and its receptors. These are PD-1 and
B7-1 (also known as CD80), both of which function as inhibitory receptors
expressed on T cells.
Atezolizumab has been shown to block PD-L1 binding, thereby enhancing
tumor-specific T cell responses, resulting in improved anti-tumour activity.
Atezolizumab has minimal binding to Fc receptors, eliminating detectable Fc
effector function and associated antibody-mediated clearance of activated CD8+
effector T cells. Atezolizumab is approved by some health authorities for the
treatment of urothelial carcinoma (UC), NSCLC, small cell lung cancer, triple
negative breast cancer (TNBC), hepatocellular carcinoma (HCC), and melanoma.
Combination therapies that address resistance to anti-PD-L1/PD-1 therapies are
needed. Treg cells are believed to contribute to the resistance of tumors to
cancer immunotherapy, and selective Treg cell depletion may provide a mechanism
to overcome this resistance. Through the targeting of CCR8, RO7502175 is
designed to specifically deplete intra-tumoral Treg cells, with the goal of
enhancing the host immune response against cancer cells without evoking
significant autoimmunity.
More information can be found in section 1 of the research protocol.
Study objective
This is a first-in-human Phase Ia/Ib, open-label, multicenter, dose-escalation
study designed to evaluate the safety, tolerability, pharmacokinetics,
pharmacodynamics, immunogenicity, and preliminary anti-tumor activity of
RO7502175 as a single agent (Phase Ia) or in combination with atezolizumab
(Phase Ib) and to identify a recommended Phase II dose for RO7502175 in
patients with locally advanced, recurrent, or metastatic incurable solid tumor
malignancies.
Study design
Both the Phase Ia and Ib portions of the study consist of a screening period, a
treatment period, a follow-up period, and a survival follow-up. In each phase,
patients are admitted into two phases: a dose-escalation phase and an expansion
phase.
In the escalation phases, the maximum tolerated dose (MTD) or maximum dose
administered (MAD) of R07502175 as monotherapy (Phase Ia) or in combination
with atezolizumab (Phase Ib) is determined. In the expansion phases, patients
will be treated at or below the maximum tolerated dose (MTD) or maximum dose
administered (MAD) of R07502175 as monotherapy (Phase Ia) or in combination
with atezolizumab (Phase Ib).
Patients in the Phase Ia portion of the study may be transferred to the Phase
Ib portion and treated with RO7502175 in combination with atezolizumab,
provided they meet crossover criteria.
Intervention
The investigational medicinal products for this study are RO7502175 (Phase Ia
and Ib) and atezolizumab (Phase Ib only). RO7502175 will be administered on
Day 1 of every 21-day cycle by IV infusion in the Phase Ia and Phase Ib
portions of this study. The starting dose of RO7502175 is 2 mg. Atezolizumab
(Phase Ib) will be administered by IV infusion at a fixed dose of 1200 mg on
Day 1 of each 21-day cycle in combination with RO7502175. Atezolizumab will be
administered after RO7502175 and the subsequent observation period.
Study burden and risks
Because this is a first-in-human study of RO7502175, the clinical benefit and
risks are unknown. However, the available nonclinical data showing the
anti-tumor effects of antiCCR8 as a single agent, and the synergistic
anti-tumor effects in combination with antiPD-L1, provide a strong rationale
for evaluating RO7502175 in cancer patients.
General risks
* Infusion-Related Reactions (IRR) directed against introduced recombinant
antibodies. RO7502175 is expected to have a low risk of cytokine release
syndrome. This antibody binds to CCR8 outside the ligand binding site (does not
inhibit the function of CCR8)
* Immunogenicity * ADAs (anti-drug antibodies) may develop which may affect
drug safety through allergic response and immune complex-mediated disease.
* Immune-mediated adverse events (irAEs) can involve virtually all organ systems
Risks related to treatment with atezolizumab are largely already known. These
include: rash, flu-like symptoms, endocrinopathies, hepatitis, transaminitis,
pneumonitis, colitis, and myasthenia gravis.
Risks related to treatment with RO7502175 are still largely unknown, let alone
those that could occur in combination treatment with atezolizumab.
Tregs play a critical role in immune homeostasis and skin homeostasis. A large
portion of the Tregs reside in the skin, where they are involved in hair
follicle generation, wound healing, and immune tolerance to commensal microbes.
Therefore, depletion of Tregs with RO7502175 is expected to cause a disruption
of skin homeostasis with implications for hair development, wound healing, and
tolerance to the commensal skin microbiome.
Dermatologic toxicity and rash are identified risks for other partial Treg
depletion agents, including anti-CCR4 (mogamulizumab) and anti-CD25
(RO7296682). However, skin toxicity was not observed in toxicity studies in
cynomolgus monkeys
Risk of mild neutropenia and thrombocytopenia
Grenzacherstrasse 124
Basel CH-4070
CH
Grenzacherstrasse 124
Basel CH-4070
CH
Listed location countries
Age
Inclusion criteria
- Age ><= 18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Life expectancy ><= 12 weeks
- Adequate hematologic and end-organ function
- Histologically confirmed locally advanced, recurrent, or metastatic incurable
solid tumor malignancy
- Availability of representative tumor specimens
- Measurable disease per Response Evaluation Criteria in Solid Tumors Version
1.1 (RECIST v1.1)
- For women of childbearing potential: agreement to remain abstinent (refrain
from heterosexual intercourse) or use contraception, and agreement to refrain
from donating eggs
- For men: agreement to remain abstinent (refrain from heterosexual
intercourse) or use contraception, and agreement to refrain from donating sperm
Exclusion criteria
- Pregnant or breastfeeding, or intending to become pregnant during the study
or within 5 months after the final dose of study treatment
- Symptomatic, untreated, or actively progressing central nervous system (CNS)
metastases
- History of leptomeningeal disease
- Significant cardiovascular disease within 3 months prior to initiation of
study treatment
- History of malignancy other than disease under study within 3 years prior to
screening
- Any immune-mediated adverse events related to prior cancer immunotherapy that
have not resolved completely to baseline
- Active or history of autoimmune disease or immune deficiency
- Active tuberculosis, hepatitis B or acute or chronic active EBV infection
- Positive test for human immunodeficiency virus (HIV) infection
- Positive hepatitis C virus (HCV) antibody test
- Known infection with severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2)
- Major surgical procedure or significant traumatic injury within 28 days prior
to first study drug infusion
- Prior allogeneic stem cell or organ transplantation
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-006708-34-NL |
| ClinicalTrials.gov | NCT05581004 |
| CCMO | NL82332.042.22 |