Trial Title:
FIH, Bispecific CD276xCD3 Antibody CC-3 in Patients With Colorectal Cancer
NCT ID:
NCT05999396
Condition:
Colorectal Cancer
Conditions: Official terms:
Colorectal Neoplasms
Conditions: Keywords:
new therapy
bispecific antibody
colorectal cancer
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Open-label, multicenter, dose escalation and dose expansion part, Phase I clinical trial,
designed to gain evidence of maximally tolerated and recommended phase-II dose of CC-3 in
adult patients with CRC.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Administration of CC-3
Description:
Accelerated titration phase, Standard 3+3 titration phase, expansion phase
Arm group label:
Administration of CC-3, a bispecific CD276xCD3 antibody
Summary:
This trial is a first in human (FIH) clinical trial in patients with Colorectal cancer
(CRC) after failure of at least three lines of previous therapy aiming to evaluate safety
and efficacy of CC-3, a bispecific antibody (bsAb) with CD276xCD3 specificity developed
within DKTK. CC-3 binds to CD276 on cancer cells as well as to tumor vessels of CRC,
thereby allowing for a dual mode of anti-cancer action. CC-3 was developed in a novel
format which not only prolongs serum half-life, but most importantly reduces off-target T
cell activation with expected fewer side effects. A similar construct in this format with
PSMAxCD3 specificity is presently undergoing clinical evaluation in patients with
prostate cancer (NCT04104607), with very favorable safety and preliminary efficacy. The
optimized format that CC-3 shares with its PSMAxCD3 "sister molecule" allows for
application of effective bsAb doses with expected high anticancer activity. The clinical
trial comprises two phases: The first phase is a dose-escalation part to evaluate the
maximally tolerated dose (MTD) of CC-3. This is followed by a dose-expansion part to
defined the recommended phase II dose. A translational research program comprising, among
others, analysis of CC-3 half-life and the induced immune response will serve to better
define the mode of action of CC-3.
Detailed description:
Metastasized CRC is an aggressive malignant disease with poor prognosis after failure of
at least three lines of previous therapy, with an accordingly high medical need for new
therapeutic approaches. Except for the small population with microsatellite instability,
so far no relevant progress has been achieved in CRC by immunotherapeutics. CC-3 is
designed to direct T cells towards CRC tumor cells and additionally reacts with tumor
vessels. If successful, the trial establishes a novel type of dual anti-cancer action by
also attacking tumor blood supply and allowing for improved influx of immune effector
cells and thus holds promise as a new concept of immunotherapy for cancer patients.
The rationale for the therapeutic use of CC-3 is based on its proposed mode of action as
a bsAb being specifically designed to direct T cells via its CD3 binding part towards
tumor target cells via its CD276 binding part. Furthermore, CC-3 also reacts with tumor
vessels of CRC thereby allowing for a dual mode of anti-cancer action by also attacking
tumor blood supply and allowing for improved influx of immune effector cells. Due to its
unique ability to redirect T cells via CD3 for CD276 expressing tumor cell lysis, CC-3
can elicit repeated target cell elimination by cytotoxic T cells and a polyclonal
response of previously primed CD4+ and CD8+ T cells. Compared to other immunotherapeutics
presently being approved or in development (bsAbs with alternative formats like the
authorised bsAb blinatumomab or other antibodies or CAR T cells), CC-3 is expected to
offer the following major advantages:
(i) reduction of side effects due to its optimal bsAb format and choice of TAA, which
will allow for application of truly effective bsAb doses and accordingly increased
efficacy; (ii) CD276 enables dual targeting, thereby improving accessibility of CRC
tumors to immune effector cells, as prerequisite for therapeutic success (iii) CC-3 is an
"off the shelf drug" eliminating the preparative work required for CART cell generation
that delays treatment; (iv) the introduction of the YTE modification will allow for
prolonged half-life an thus convenient dosing scheme
Clinical trial rationale with regard to objectives and further development of CC-3
In nonclinical studies, in vitro and in vivo, proof of concept, preliminary
pharmakokinetic (PK) and pharmakodynamic (PD) effects as well as toxicology have been
evaluated as described in detail in the IB . However, due to differences between animal
models and the human situation, some aspects have to be assessed and further
characterised in humans. For example, the target mediated drug disposition (TMDD), an
effect that largely influences the serum half-life of antibody molecules particularly at
low concentrations, cannot be properly addressed in mice. Similar problems arise with the
YTE modification, which prolongs serum half-life of antibodies in humans but not in
mice.Furthermore, non-human primates (NHP) and rodents have several limitations as
predictive models for toxicity and immunogenicity evaluation of CC-3. The CD3 binding
part of CC-3 does not cross-react with CD3 of macaques and thus it is not possible to
evaluate in these NHPs dose limiting side effects. Therefore, a First in Human clinical
trial is planned for CC-3 to characterise the effects of CC-3 in humans. In general CD276
is a target antigen with particularly attractive properties. It is expressed not only on
tumor cells but also on tumor vessels, allowing for "dual targeting" of a variety of
solid tumors including (but not limited to) GI cancer. The importance of vascular
targeting for treatment of solid tumors has been elegantly demonstrated in numerous
reports.
As described in detail in the IB, CD276 is expressed on all analysed samples (n=59) of
colorectal tumor samples of patients with metastazised disease. Of note, CD276 is
expressed on the primary tumor as well as on metastasis. Therefore, the analysis of CD276
expression on the tumor comprises an exploratory objective of this trial but is not
needed for inclusion of patients.
The phase I trial is designed to confirm and further explore the safety and tolerability
of the CD276xCD3 bsAb CC-3 in adult patients with CRC after failure of at least three
lines of previous therapy. The primary objectives are to define the MTD and RP2D of CC-3
and the overall safety defined as incidence and severity of AEs under therapy with CC-3.
Furthermore, the trial aims to expand experience on pharmacokinetics, pharmacodynamics
and toxicology of CC-3 from nonclinical- studies. A focus will be on the following
specific aspects/parameters:
- PK and PD of CC-3 in humans
- Assessment of objective response rate by RECIST 1.1 on routine imaging
- Evaluatation of disease control rate (CR, PR, SD)
- Overall (OS) and progression free survival (PFS)
- Immunogenicity of CC-3 in humans based on both absolute (number and percentage of
subjects who develop human anti-human antibody (HAHA).
- Overall quality of life scores (EORTC QLQ C-30)
- Absolute changes from baseline in the tumor marker (CEA und CA 19-9)
- Absolute changes from baseline in laboratory parameters
- Change in T cell activation and cytokines from baseline
- To correlate safety and efficacy of CC-3 treatment with with clinical, biological
and patient characteristics
- To correlate the effect of CC-3 on serum cytokine levels and pharmarkodynamic
biomarkers in the peripheral blood
- To assess long-term safety and product specific safety
Dose rationale for CC-3
Considerations on a safe starting dose of 20µg for CC-3 are, besides preclinical in vitro
and in vivo data of CC-3, based on the meanwhile available PK data from a clinical study
with CC-1, an identically formatted bsAb with PSMAxCD3 - (rather than
CD276xCD3)-specificity, but also on clinical experience with MGD009, a bsAb with
CD276xCD3-specificity as well as recently published data from several clinical studies
with CD20xCD3 bsAb. The target dose of 4mg CC-3 is based on observations from the in vivo
model with humanized NSG mice, where repetitive dosing with 1.4µg CC-3 was able to
eradicate established flank tumors. This dose corresponds to approximately 4mg once per
week in humans. Further details can be found in the IB of CC-3.
Safety and expected risks of the IMP
For CC-3, so far, no clinical safety data from other clinical trials are available. CC-3
has been preclinically characterized extensively in vitro and in vivo, the toxicity of
the treatment class of bsAbs, with CRS as main class toxicity, is well known and safety
data for CC-1, an identically formatted bsAb with PSMAxCD3 (rather than
CD276xCD3)-specificity, which was extensively investigated in the ongoing clinical FIH
study is available.
In this FIH trial (NCT04104607, DKTK_PMO_1605), investigating CC-1 in patients with CRPC,
CRS was the most frequently observed toxicity, experienced by 78% of the patients.
Notably, it never exceeded grade 2 after pre-emptive tocilizumab application and resolved
in most cases without additional application of tocilizumab. Besides mild to moderate
hypertension (observed in 50% of patients), no further CC-1 related toxicities (i.e.,
anaphylactic reaction) were observed. As expected and attributable to tocilizumab
application, hematologic events (i.e. neutropenia, thrombocytopenia) were present in most
patients, and hepatotoxicity was observed in some patients.
As CC-3 is shares the biological function with CC-1 and other bsAb, a similar or even
better safety profile is expected. Especially in comparison to CC-1, with CC-3 a lower
risk for CRS is expected as the CD3 binder has been attenuated. In addition, nowdays CRS
is a well-known class toxicity of bsAb and risk mitigation strategies by e.g. application
of tocilizumab are available. The selected dosing scheme of CC-3 in this clinical trial
will not only allow for continous exposure of tumor cells to CC-3, but it is also
considered to increase the tolerability of CC-3 by introduction of priming doses.
Moreover, CC-3 is applied during daytime when dedicated experienced study personnel is
present and can ensure close monitoring of patients during and after CC-3 application.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
written signed informed consent
- Patient is able to understand and comply with the protocol for the duration of the
clinical trial including undergoing treatment and scheduled visits and examinations
- Patients with progressing metastatic CRC who were previously treated with FOLFOX,
FOLFIRI, FOLFOXIRI, TAS-102, or regorafenib, if applicable in combination with
anti-VEGFR monoclonal antibody (mAb) and anti-EGFR mAb (the latter, if RAS-wild-type
and left sided tumors).
In case of MSI-high/dMMR tumors, patients should have received checkpoint inhibitor
therapy and at least two further lines of therapy of that stated above.
In case of patients BRAF V600E mutation patients should have received: Cetuximab in
combination with encorafenib in second- or third-line treatment.
- At least one measurable lesion that can be accurately assessed at baseline by CT or
MRI and is suitable for repeated assessment per RECIST 1.1.
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
- Patient aged ≥ 18, no upper limit
- Female patients of child bearing potential (FCBP) and male patients with partners of
child bearing potential, who are sexually active, must agree to the use of two
effective forms (at least one highly effective method) of contraception. This should
be started from the signing of the informed consent and continue throughout period
of taking study treatment and for 2 months after last dose of study drug.
- For FCBP two negative pregnancy test (sensitivity of at least 25 mU/ml) prior to
first application of CC-3
- All subjects must agree to refrain from donating blood while on study drug and for 2
months after last dose of CC-3.
- Adequate bone marrow, renal, and hepatic function defined by laboratory tests within
14 days prior to study treatment:
- Hemoglobin ≥ 9 g/dl (Transfusion of packed red blood cells prior to enrolment
allowed)
- Neutrophil count ≥ 1,500/mm3
- Platelet count ≥ 75,000/µl
- Serum creatinine ≤ 1.5mg/dl or creatinine clearance ≥ 60ml/min
- hepatic function of patients without current hepatic metastasis:
- Bilirubin ≤ 1.5x upper limit of normal (ULN), in case of known Gilbert
syndrome higher values are allowed if due to increase of indirect
bilirubin
- ALT and AST ≤ 2.5 x ULN
- hepatic function of patients with current hepatic metastasis:
- Bilirubin ≤ 2.5 x upper limit of normal (ULN)
- ALT and AST ≤ 5. x ULN
Exclusion Criteria:
- Other malignancy requiring treatment within the last year except: adequately treated
non-melanoma skin cancer and low-grade non-muscle invasive papillary bladder cancer.
- Concurrent or previous treatment within 30 days in another interventional clinical
trial with an investigational anticancer therapy
- Persistent toxicity (≥ Grade 2 according to Common Terminology Criteria for Adverse
Events [CTCAE] version 5.0) caused by previous cancer therapy, excluding alopecia
and neurotoxicity
- Clinical signs of active infection (> grade 2 according to CTCAE version 5.0)
- Known cerebral/meningeal manifestation of CRC
- History of HIV infection
- Viral active or chronic hepatitis (HBV or HCV)
- Ongoing autoimmune disease
- History of relevant CNS pathology or current relevant CNS pathology (e.g. seizure,
paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injuries,
dementia, Parkinson's disease, cerebellar disease, organic brain syndrome,
psychosis, coordination or movement disorder)
- Therapeutic anticoagulation therapy
- Major surgery within 4 weeks of starting study treatment. Patients must have
recovered from any effects of major surgery.
- Patients receiving any systemic chemotherapy, mAb or radiotherapy within 2 (for mAb
4) weeks prior to study treatment or a longer period depending on the defined
characteristics of the agents used
- Heart failure NYHA III/IV
- Severe obstructive or restrictive ventilation disorder
- Known intolerance to CC-3 or other immunoglobulin drug products as well as
hypersensitivity to any of the excipients present in CC-3
- Live and live-attenuated vaccination 30 days prior to treatment
- Pregnant or breast-feeding women
- Current ileus with severely altered GI function
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University Hospital Tuebingen
Address:
City:
Tuebingen
Zip:
72076
Country:
Germany
Status:
Recruiting
Contact:
Last name:
Jonas Heitmann, PD Dr.med.
Phone:
+49 7071 29
Phone ext:
83275
Email:
kketi@med.uni-tuebingen.de
Start date:
January 12, 2024
Completion date:
March 31, 2027
Lead sponsor:
Agency:
German Cancer Research Center
Agency class:
Other
Source:
German Cancer Research Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05999396
