SCC of the lung is an aggressive malignant disease with poor prognosis after failure of
established therapies. Any drug employed after second-line treatment is associated with only
limited clinical benefit. Therefore, there is a high medical need for new therapeutic
approaches in this patient population. The clinical effects of immune checkpoint inhibitors
in NSCLC have proven the potential of T-cell based immunotherapy in this entity. The
rationale for the therapeutic use of CC-1 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 PSMA binding part. Furthermore, CC-1 also reacts with tumor vessels of NSCLC
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 PSMA-expressing tumor cell lysis, CC-1 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-1 is expected to offer the following major advantages:
(i) Reduction of off-target T cell activation and thus reduction of side effects due to its
optimized format (ii) The possibility to tightly steer anti-target activity via serum
level-controlled antibody application which, in contrast to CAR T cells, allows for
termination of activity if desired.
On the background of the poor prognosis of patients with SCC of the lung after second-line
therapy, the bsAb CC-1 holds promise as a new treatment option of immunotherapy for these
patients.
The planned study will include patients with SCC of the lung with detectable PSMA expression
on tumor cells after second line treatment. PSMA expression is to be determined by central
immunohistochemical assessment of fresh or kryopreserved tumor samples. Only patients with
proven PSMA expression on tumor cells as defined by ≥10% positivity of tumor cells can be
included. The requirement of ≥10% positivity of tumor cells for PSMA expression cells is in
line with definitions of positivity for target antigen expression employed for other
antibodies used in cancer treatment, for example the human epidermal receptor protein-2
(HER2)-specific antibodies trastuzumab and pertuzumab. Both antibodies are approved for the
treatment of HER2-positive breast cancer, and HER2 positivity is given if ≥10% of tumor cells
show staining for HER2 as assessed by immunohistochemistry .
PSMA-positivity is estimated for about 50% of screened patients with SCC of the lung.
Further as a translational research program the investigators implemented PSMA-PET CTs at
different time points. PSMA positivity in PSMA-PET CT has been described on several tumor
entities including tumors of the lung. In line, PSMA expression has been described on tumor
cells and neovasculature of tumor in lung cancer, especially SCC of the lung. However, a
correlation of PSMA-PET positive tumors with immunhistochemical PSMA evaluation has so far
not been described.
The implementation of PSMA-PET as additional imaging to routine CT, will further improve
treatment for patients with SCC of the lung as results of PSMA-PET may replace biopsy in
future patients. A maximum of three PSMA-PET CTs may be performed.
Study rationale with regard to objectives and further development of CC-1
In nonclinical studies, in vitro and in vivo, proof of concept, preliminary PK and PK/PD
effects as well as toxicology have been evaluated. 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. Furthermore, non-human primates (NHP) and rodents have
several limitations as predictive models for toxicity and immunogenicity evaluation of CC-1.
The CD3 binding part of CC-1 does not cross-react with CD3 of macaques and thus it is not
possible to evaluate in these NHPs dose limiting side effects. Likewise, although CC-1 is
cross-reactive with macaque-PSMA, PSMA distribution in macaques significantly differs from
that in humans. The same holds true for rodents.
Due to the high medical need for patients with SCC of the lung after second-line treatment,
the planned phase I trial is designed to confirm and further explore the safety and
tolerability of the PSMAxCD3 bsAb CC-1 in adult patients with SCC of the lung. The primary
objective is incidence and severity of adverse events (AEs) under therapy with CC-1.
Furthermore, the trial aims to expand experience on pharmacokinetics, pharmacodynamics and
toxicology of CC-1 from nonclinical studies to the human situation in relation to the PK,
expected efficacy and safety. A focus will be on the following specific aspects/parameters:
- Pharmacokinetics and pharmacodynamics of CC-1 in humans
- Immunogenicity of CC-1 in humans based on both absolute (number and percentage of
subjects who develop human anti-human antibody (HAHA).
- Absolute changes from baseline in laboratory parameters
- Change in cytokines from baseline
- Assessment of response rate by RECIST on routine imaging
- Evaluation of PSMA PET CT in a translational research program
- Overall and progression free survival
Rationale for preemptive IL-6R blockade by Tocilizumab
As described above, in the planned study the investigators exploit the strategy to use
tocilizumab rather to prevent development of CRS in the first place than to treat CRS once it
has arisen.
This strategy holds promise to increase the safety of study patients and timely study
conduct. By starting the study treatment with CC-1 directly with prophylactic tocilizumab,
all study patients will benefit from the expected advantage of this combination with regard
to safety and can be treated with sufficiently high doses of CC-1 to achieve dose levels high
enough to hopefully result in efficacy effects.
The rationale for preemptive IL-6R blockade by tocilizumab treatment is based on i. The
firmly established efficiency and safety of tocilizumab for the treatment of CRS
ii. Lack of clear evidence for increased tumor growth as potential drawback of IL-6R blockage
iii. Observations that IL-6 activity, while being responsible for the undesirable sequelae of
CRS, appears not to be required for the therapeutic activity of CC-1 CRS that was induced by
therapy with the approved bsAb blinatumomab was reported to be successfully treated by
tocilizumab. Most importantly, despite rapid disappearance of clinical CRS symptoms, the
therapeutic activity of the bsAb blinatumomab was maintained. Furthermore, tocilizumab was
also used in the very recent FIH study with the REGN1917 (CD20xCD3) antibody.
Our own nonclinical studies demonstrate that tocilizumab does not impair the therapeutic
activity of CC-1, neither in vitro nor in vivo. This is in contrast to steroids which are
currently recommended and used as pre- and concomitant treatment to prevent CRS upon
blinatumomab therapy.
Due to the mechanism of action of tocilizumab, there is a theoretical risk of tumor
development or tumor progression due to immune modulation. On the basis of the current
literature derived from large studies conducted in Japan, the USA and Europe, however, there
is no evidence for an increased tumor risk upon application of tocilizumab. Only one Japanese
study described a minimally increased risk of de novo lymphoma development. However, this
could not be confirmed in any other study. Especially for lung cancer, there is no evidence
for an increased incidence rate. Interestingly, high systemic IL-6 levels are associated with
dismal prognosis in NSCLC. Furthermore, tocilizumab is currently being investigated in
several Phase I/II studies for the treatment of solid and hematological neoplasia without
evidence for an influence on tumor pathophysiology. Based on these findings, no relevant
negative effects of tocilizumab on the efficacy and safety of CC-1 are expected.
Inclusion Criteria:
- • Existence of a written informed consent
- Patient is able to understand and comply with the protocol for the duration of
the study including undergoing treatment and scheduled visits and examinations
- SCC of the lung with detectable PSMA expression by tumor cells after second line
treatment. PSMA expression is to be determined by central immunohistochemical
assessment of fresh or cryopreserved tumor samples. Only patients with proven
PSMA expression by tumor cells as defined by ≥10% positivity of tumor cells can
be included.
- Life expectance of > 3 months
- At least one measurable lesion that can be accurately assessed at baseline by CT
or MRI and is suitable for repeated assessment
- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
- Patient aged ≥ 18, no upper age limit
- Female patients of child bearing potential 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 1 month (female patients) / 3
months (male patients) after last dose of study drug. Postmenopausal or evidence
of non-childbearing status. For women of childbearing potential: negative urine
or serum pregnancy test within 21 days prior to study treatment and confirmed
prior to treatment on day 1. Postmenopausal or evidence of non-childbearing
status is defined as:
- Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
- Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post
menopausal range for women under 50
- Radiation-induced oophorectomy with last menses >1 year ago
- Chemotherapy-induced menopause with >1 year interval since last menses
- Surgical sterilisation (bilateral oophorectomy or hysterectomy)
- Adequate bone marrow, renal, and hepatic function defined by laboratory tests
within 14 days prior to study treatment:
Neutrophil count ≥ 1,500/mm3 Platelet count ≥ 100,000/µl Bilirubin ≤ 1.5 x upper limit of
normal (ULN) ALT and AST ≤ 2.5 x ULN PT-INR/PTT ≤ 1.5 x ULN Creatine kinase ≤ 2.5 x ULN
Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 ml/min
Exclusion Criteria:
- • Other malignancy within the last 5 years except: adequately treated non-melanoma
skin cancer, carcinoma in situ of the cervix, carcinoma in situ of the breast,
histological finding of prostate cancer of TNM stage T1
- PSMA expression <10% by tumor cells
- 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 (≤ 2 grade)
- Clinical signs of active infection (> grade 2 according to CTCAE version 5.0)
- Cerebral/Meningeal manifestation of the SCC of the lung
- History of HIV infection
- Immunocompromised patients
- Viral active or chronic hepatitis (HBV or HCV)
- History of 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)
- Epilepsy requiring pharmacologic treatment
- 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 or radiotherapy within 2 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 history of GI-perforation
- Known intolerance to CC-1, tocilizumab or other immunoglobulin drug products as
well as hypersensitivity to any of the excipients present in the respective drug
products (CC-1, tocilizumab)
