FIH, Bispecific CD276xCD3 Antibody CC-3 in Patients With Colorectal Cancer

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT05999396

Studienbeginn:
Januar 2024

Letztes Update:
26.02.2024

Wirkstoff:
Administration of CC-3

Indikation (Clinical Trials):
Colorectal Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
German Cancer Research Center

Collaborator:
-

Kontakt

Juliane Walz, Prof. Dr.
Kontakt:
Phone: +49 7071 29
Phone (ext.): 83275
E-Mail: kketi@med.uni-tuebingen.de» Kontaktdaten anzeigen

Jonas Heitmann, Dr.
Kontakt:
Phone: +49 7071 29
E-Mail: kketi@med.uni-tuebingen.de» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

University Hospital Tuebingen
72076 Tuebingen
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Jonas Heitmann, PD Dr.med.
Phone: +49 7071 29
Phone (ext.): 83275
E-Mail: kketi@med.uni-tuebingen.de» Ansprechpartner anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

1. Safety 1-Adverse Events Assessment (Time Frame - Day 1 Day 2 Day 3 Day 8 +/- 1 day Day 9 Day 15 +/- 1 day Every 7 days +/- 2 days after Treatment week 3 7 days +/- 2 days after last CC-3 28 days +/- 2 days after last CC-3 28 days after FU +/- 3 days):
Dose escalation and dose expansion part: Characterization of the safety of CC-3 in patients with metastasized CRC, and to define the recommended phase-II dose (RP2D) of CC-3 Adverse events should be documented and recorded continuously. Patients have to be followed for AEs from visit T1V1( treatment week1 Visit 1) up to last clinical trial visit or until all drug-related toxicities have been resolved, whichever is later, or until the investigator assesses AEs as "chronic" or "stable". Each occurrence of an AE must be reported once indicating the CTC (Version 5.0) grade. If the CTC grading of an ongoing AE changes this has to be reported. If an event stops and later restarts, all occurrences must be reported. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) v26.0 or higher. All AEs will be graded according to the CTCAEv5.0, except for cytokine release syndrome, which will be graded according to modified criteria by Lee et al. (Lee et al., 2019).

2. Safety 2 -Blood Chemistry-Transaminases (Time Frame - Day 1 Day 2 Day 3 Day 8 +/- 1 day Day 9 Day 15 +/- 1 day Every 7 days +/- 2 days after Treatment week 3 7 days +/- 2 days after last CC-3 28 days +/- 2 days after last CC-3 28 days after FU +/- 3 days):
AST/SGOT in [U/l] ALT/SGPT in [U/l)

3. Safety 3-Hematology-haemoglobin (Time Frame - Day 1 Day 2 Day 3 Day 8 +/- 1 day Day 9 Day 15 +/- 1 day Every 7 days +/- 2 days after Treatment week 3 7 days +/- 2 days after last CC-3 28 days +/- 2 days after last CC-3 28 days after FU +/- 3 days):
haemoglobin in [g/l]

4. Safety 3-Hematology-Red Blood Cells (Time Frame - Day 1 Day 2 Day 3 Day 8 +/- 1 day Day 9 Day 15 +/- 1 day Every 7 days +/- 2 days after Treatment week 3 7 days +/- 2 days after last CC-3 28 days +/- 2 days after last CC-3 28 days after FU +/- 3 days):
RBC in [cells/µl]

5. Safety 3-Hematology-thrombocytes (Time Frame - Day 1 Day 2 Day 3 Day 8 +/- 1 day Day 9 Day 15 +/- 1 day Every 7 days +/- 2 days after Treatment week 3 7 days +/- 2 days after last CC-3 28 days +/- 2 days after last CC-3 28 days after FU +/- 3 days):
PLT in [cells/µl]

6. Safety 3-Hematology-White Blood Cells (Time Frame - Day 1 Day 2 Day 3 Day 8 +/- 1 day Day 9 Day 15 +/- 1 day Every 7 days +/- 2 days after Treatment week 3 7 days +/- 2 days after last CC-3 28 days +/- 2 days after last CC-3 28 days after FU +/- 3 days):
WBC in [cells/µl]

Geprüfte Regime

Administration of CC-3:
Accelerated titration phase, Standard 3+3 titration phase, expansion phase

Quelle: ClinicalTrials.gov

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