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

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.

Eligibility

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

Conditions6

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