Primary(Part I and Part II):- To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) in the QW and/or Q3W regimens of RO7122290 in combination with cibisatamab after pretreatment with obinutuzumab- To characterize the…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Nature and frequency of dose-limiting toxicities (DLTs; Part I only)
- Incidence, nature and severity of adverse events (AEs) graded according to
the National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) v5 with the exception of cytokine release syndrome (CRS), which is
graded according to the ASTCT grading scale for CRS (with individual signs and
symptoms of CRS graded separately using the CTCAE v5.0 grading scale)
Secondary outcome
- PK profiles and parameters derived for RO7122290, cibisatamab, and
obinutuzumab, as appropriate, including but not limited to: - Serum/plasma
concentrations - Maximum concentration (Cmax) - Time of maximum concentration
(Tmax) - Clearance (CL) - Volume of distribution (V) - Area under the curve
(AUC) - Half-life (t1/2)
-Incidence and titer of RO7122290, cibisatamab, and obinutuzumab anti-drug
antibodies (ADAs) during the study relative to the prevalence of ADA at baseline
-PK profiles and parameters derived for RO7122290, cibisatamab, and
obinutuzumab, as appropriate, including but not limited to:
- Serum/plasma concentrations
- Maximum concentration (Cmax)
- Time of maximum concentration (Tmax)
- Clearance (CL)
- Volume of distribution (V)
- Area under the curve (AUC)
- Half-life (t1/2)
-Incidence and titer of RO7122290, cibisatamab, and obinutuzumab anti-drug
antibodies (ADAs) during the study relative to the prevalence of ADA at baseline
Peripheral blood lymphocytes:
-Treatment-induced change on T-cell proliferation (CD8/Ki67).
- Objective response rate (ORR) defined as complete response (CR) + partial
response (PR)
- Disease control rate (DCR); defined as response rate (RR) + stable disease
(SD)
- Duration of response (DoR)
- Progression-free survival (PFS)
All according to the Response Evaluation Criteria
in Solid Tumors (RECIST) Version 1.1
Background summary
The management of most advanced solid tumors remains challenging because of the
high rate of tumor recurrence or the development of metastases associated with
poor prognosis. Patients with advanced solid tumors, including metastatic
colorectal cancer (mCRC), have benefitted from recent treatment modalities
beyond chemotherapy and in particular, from checkpoint inhibitor (CPI)
therapy(efficacy of single-agent CPIs in CRC has been limited to a small
percentage of patients with microsatellite instability-high [MSI-H] tumors).
However, despite recent advances with CPI treatment with response rates varying
between 20% and 30% when used as monotherapy, many patients are refractory to
or acquire resistance to these therapies (Topalian et al. 2015). The mechanisms
underlying primary and secondary resistance to various anti-tumor agents are
numerous and in many cases remain poorly understood. This makes it necessary to
define combination therapies that overcome resistance mechanisms. Regarding
cancer immunotherapy related mechanisms of resistance, multiple immune escape
mechanisms have been described, including lack of endogenous T-cell activation
and/or T-cell exhaustion (Vinay et al. 2015). For mCRC, treatment beyond the
second-line setting remains challenging and a significant unmet medical need
exists for more efficacious and better-tolerated treatments, hence the need to
explore combination therapies in this population. Patients with
microsatellite-stable (MSS) mCRC that have progressed after at least 2 previous
lines of therapy have a dismal prognosis with a median overall survival (OS) of
approximately 6.4 to 7.1 months, which underscores the need for better
treatment regimen for those patients (Grothey et al. 2013; Mayer et al. 2015;
Section 4.2.3 Rationale for Study Population).
Based on preclinical data, the therapeutic concept of providing cancer specific
exogenous T-cell activation (signal 1) and T-cell co-stimulatory signal 2 are
promising approaches to overcome such resistance mechanisms. In this context,
the purpose of this study is to investigate safety, tolerability, PK,
immunogenicity, PD, and preliminary efficacy of RO7122290 (a bispecific
monoclonal antibody providing a co-stimulatory signal to activated T-cell in
close proximity to the tumor = signal 2) in combination with cibisatamab (a
T-cell engaging bispecific monoclonal antibody= signal 1) in patients with MSS
colorectal adenocarcinoma. In addition, to inhibit or attenuate anti-drug
antibodies (ADA) responses, obinutuzumab will be used as a pre-treatment.
Study objective
Primary(Part I and Part II):
- To determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose
(RP2D) in the QW and/or Q3W regimens of RO7122290 in combination with
cibisatamab after pretreatment with obinutuzumab
- To characterize the safety and tolerability profile of RO7122290 in
combination with cibisatamab after pretreatment with obinutuzumab
Please see table 5 of the protocol for an overview of primary, secondary and
exploratory endpoints.
Study design
This is an open-label, multicenter, Phase Ib study to determine the maximum
tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) in the weekly
(QW) and/or every 3 weeks (Q3W)regimens, safety, tolerability, PK,
immunogenicity, and PD profile of RO7122290 and to evaluate preliminary
anti-tumor activity of RO7122290 in combination with cibisatamab after
pre-treatment with obinutuzumab, in participants with previously treated
metastatic, MSS colorectal adenocarcinoma.
The study consists of two parts: A QW dose-escalation part (Part I) and a
second part (Part II) in which selected dose levels of RO7122290 from Part I
will be explored Q3W. Cibisatamab will be administered Q3W in both Part I and
Part II at a flat dose of 100mg. The cycle length is defined by the period
between two cibisatamab administrations in Parts I and II (1 cycle = 21 days).
RO7122290 and cibisatamab will be administrated intravenously (IV).
Obinutuzumab will be administered(IV) as pre-treatment prior to C1D1 of
cibisatamab (Section 6.1.5.2).
Intervention
The investigational medicinal products(IMPs) for this study are:
- obinutuzumab (2000 mg single dose or 2 x 1000 mg split doses)
- cibisatamab (100 mg)
- RO7122290 (Part I starting dose will be 35 mg)
- tocilizumab (tocilizumab as rescue medicationfor CRS). 8 mg/kg IV for
participants < 30 kg. 12 mg/kg IV for participants > 30 kg
All IMPs will be administered by IV infusion.
The dose-escalation of RO7122290 will use a QW dosing schedule of RO7122290 in
combination with a Q3W dosing interval for cibisatamab. The starting dose for
RO7122290 will be 35 mg.
The design will continue until one of the pre-defined stopping criteria is
fulfilled, the dose of 500 mg RO7122290 QW has been reached, or the
pre-determined sample size of approximately 60 participants is reached,
whichever comes first.
The selection of RO7122290 dose levels in Part II will be based on emerging
clinical data, including safety, tolerability, PK, and/or PD from Part I and
Part II. In Part II, up to five RO7122290 dose levels at or below the highest
dose level cleared for safety in Part I will be explored using a less frequent
administration schedule for RO7122290 i.e., Q3W dosing interval in combination
with cibisatamab Q3W.
Study burden and risks
The general burden for the patient consists of (a.o.) the withdrawal of blood
samples, possible collection of tumor sample, undergoing scans, administration
of investigational products (intravenously) which may lead to various adverse
events.
Please refer to the Investigator's Brochures and Subject Information Sheet for
more information about the risks that come with the IMPs and study procedures.
Beneluxlaan 2a
Woerden 3446 GR
NL
Beneluxlaan 2a
Woerden 3446 GR
NL
Listed location countries
Age
Inclusion criteria
• Age >= 18 years
• Histologically confirmed adenocarcinoma originating from the colon or rectum
• Metastatic disease not amenable to local treatment
• Availability of archival tumor tissue or tissue obtained from a fresh biopsy
at screening (if archival tumor is not available)
• Tumors that are MSS or MSI-low (microsatellite instable low), as determined
by a certified laboratory
• Experienced disease progression during or within 3 months following the last
administration of approved standard therapies after patients have received at
least 2 prior lines of treatment.
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Life expectancy of >= 12 weeks
• Adequate cardiovascular, hematologic and hepatic function
• Serum creatinine within normal limits or a calculated glomerular filtration
rate of >= 60 mL/min/1.73 m2 for participants with serum creatinine levels
above or below the institutional normal value
• Serum albumin >=30 g/L (3.0 g/dL)
• Lactate dehydrogenase <= 2.5 × ULN
• For participants not receiving therapeutic anticoagulation: International
normalized ratio (INR) or activated partial thromboplastin time <= 1.5 × ULN
• Negative HIV test during screening
• Negative hepatitis B surface antigen (HBsAg) test during screening, negative
total hepatitis B core antibody (HBcAb) test during screening, or positive
total HBcAb test followed by a negative HBV DNA test during screening and
negative hepatitis C virus (HCV) antibody test during screening or positive HCV
antibody test followed by a negative HCV RNA test during screening
• Negative human T-cell lymphotropic virus type 1 test for participants from
endemic countries
• Woman of childbearing potential, Agrees to remain abstinent or use a highly
effective contraceptive method that results in a failure rate of < 1% per year
during the treatment period and for at least 2 months after the last dose of
RO7122290, for 4 months after the final dose of cibi, for at least 18 months
after the last dose of obi, and for at least 3 months after the last dose of
tocilizumab
• Male participants: During the treatment period and for at least 2 months
after the last dose of RO7122290, for at least 3 months after the last dose of
cibi, and at least 60 days after the last dose tocilizumab
Exclusion criteria
•Symptomatic, untreated, or actively progressing central nervous system (CNS)
metastases
•History of leptomeningeal disease
•Non-irradiated tumor lesions > 2 cm at critical sites where tumor swelling
induced by cibisatamab is expected to lead to significant complications
•Dyspnea or peripheral capillary oxygen saturation <92% at rest at baseline for
patients with bilateral lung lesions or metastases in the remaining lung
following lobectomy or pneumonectomy
•Pleural effusion requiring drainage procedures, pleural effusion and/or
pleural lesions involving both lungs
•Active interstitial lung disease (ILD), pneumonitis, or a history of
ILD/pneumonitis requiring treatment with steroids or history of idiopathic
pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or
idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT
scan
•Severe dyspnea at rest due to complications of advanced malignancy or
requiring supplementary oxygen therapy
•Patients with >10 bilateral pulmonary lesions
•Patients with pulmonary miliary metastatic pattern or pulmonary lymphangitic
carcinomatosis
•Significant cardiovascular/cerebrovascular disease within 6 months prior to
Day 1 of study drug administration
•Spinal cord compression not definitively treated with surgery and/or radiation
or previously diagnosed and treated spinal cord compression without evidence
that disease has been clinically stable for >=2 weeks prior to initiation of
study treatment
•History of progressive multifocal leukoencephalopathy (PML)
•Uncontrolled tumor-related pain
•Uncontrolled ascites requiring recurrent drainage procedures
•Patients with pericardial effusion
•Uncontrolled or symptomatic hypercalcemia
•Active or history of autoimmune disease or immune deficiency
•Active tuberculosis that has required treatment within 3 years prior to
initiation of study treatment or latent tuberculosis.
•Major surgical procedure, other than for diagnosis, within 4 weeks prior to
initiation of study treatment, or anticipation of need for a major surgical
procedure during the study
•History of malignancy other than CRC within 5 years prior to screening, with
the exception of malignancies with a negligible risk of metastasis or death
(e.g., 5-year OS rate>90%)
•Evidence of significant, uncontrolled concomitant diseases that could affect
compliance with the protocol or interpretation of results, including diabetes
mellitus, history of relevant pulmonary disorders, or other disease with
ongoing fibrosis
•Known active infection, or latent infection, whether bacterial, viral, fungal,
mycobacterial, or other pathogens, or any major episode of infection requiring
hospitalization or treatment with systemic antibiotics treatment must have been
completed at least 4 and 2 weeks
•Prior allogeneic stem cell or solid organ transplantation
•Treatment with a live, attenuated vaccine within 4 weeks prior to initiation
of study treatment, or anticipation of need for such a vaccine during study
treatment •Active or history of autoimmune disease or immune deficiency
•History of severe allergic or anaphylactic reactions to monoclonal antibody
therapy and to chimeric or humanized antibodies or fusion proteins
•Major surgery or significant traumatic injury <28 days prior to the first obi
infusion or anticipation of the need for major surgery during study treatment
•Current treatment with anti-viral therapy for HBV
•Treatment with any systemic anti-cancer therapy
•Treatment with investigational therapy within 28 days prior to initiation of
study treatment
•Prior treatment with any of the protocol-specified study treatments, Tcell
bispecific, CD137 (4-1BB) agonists or immune checkpoint blockade therapies
•Treatment with systemic immunostimulatory agents within 4 weeks or 5
half-lives prior to initiation of study treatment
•Treatment with systemic immunosuppressive medication within 2 weeks prior to
initiation of study treatment, or anticipation of need for systemic
immunosuppressive medication during study treatment
•AEs from prior anti-cancer therapy that have not resolved to Grade 1 or better
with the exception of alopecia of any grade and Grade <= 2 peripheral
neuropathy
•Known hypersensitivity to Chinese hamster ovary cell products, to any of the
study drugs or any of their excipients
•Any participant actively taking anti-platelet medication
•Pregnancy or breastfeeding, or intention of becoming pregnant during study
treatment or within 2 months after the final dose of RO7122290, within 4 months
after the final dose of cibi, within 18 months after the final dose of obi, and
within 3 months after the final dose of tocilizumab whichever is longer
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 | EUCTR2020-003328-17-NL |
| CCMO | NL75910.031.20 |