Carbonic anhydrase IX (CA IX) has been implicated in the progression of most solid tumours and expression has been demonstrated in clinical samples from a variety of solid cancers. High expression is often associated with high grade or metastatic disease and poor prognosis. CA IX is not expressed in normal tissue, potentially providing a cancer-associated target that would not likely result in significant interruption of normal biologic function in organs not affected by cancer. A humanized monoclonal antibody CA9hu-1 has shown robust activity in a variety of tumour models including models of ovarian, prostate, breast, pancreatic, colon and lung where tumour growth and metastasis are inhibited when CA9hu-1 is used as a monotherapy. Enhancement of chemotherapy has also been demonstrated in several models in combination with CA9hu-1. CA IX is also expressed by tumour-associated cells (angiogenic endothelium, tumour-associated macrophages), which also drive cancer progression. Thus, targeting CA IX with CA9hu-1 in cancer patients is expected to affect multiple pathways and multiple tumour compartments that are important to tumour progression. Taken together, there is strong rationale for developing hu-CA91 for the treatment of advanced cancer. The present study was designed to establish safety and toxicity profile and maximum tolerated dose of CA9hu-1, evaluate pharmacokinetics, investigate the presence of anti-drug antibody, to document anti-tumour activity at a clinically relevant dose, and to document the use of \[18F\]FLT-PET as a biomarker for detection of early tumour response at a clinically relevant dose.
Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
Histologically proven solid tumors (Clear Cell Renal Cell Carcinoma Metastatic, Triple-Negative Breast Cancer, Head and Neck Cancer, Non-small-cell Lung Carcinoma, Malignant Mesothelioma) refractory to conventional treatment, or for which no conventional therapy is considered appropriate by the Investigator or is declined by the patient
Life expectancy of at least 12 weeks
World Health Organization (WHO) performance status of 0 or 1
Ongoing toxic manifestations of previous treatments (Grade 2 or greater according to NCI-CTCAE v4.02) with the exception of alopecia or certain Grade 2 toxicities, which in the opinion of the investigator and CDD should not exclude the patient - these should be discussed on a case by case basis
Symptomatic brain metastases or spinal cord compression
Patients who have received prior radiotherapy to their lungs will not be eligible for this trial.
Female patients who are able to become pregnant (or already pregnant or lactating). However, those patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral; injected or implanted hormonal contraception and condom; have an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective at the first administration of CA9hu-1, throughout the trial and for six months afterwards are considered eligible. Breast feeding should be discontinued if the mother is treated with CA9hu-1.
Single group
CA9hu-1
DrugHumanized monoclonal antibody to human carbonic anhydrase IX
Number of adverse events to CA9hi-1 and grading their severity according to the National Cancer Institute's Common Terminology Criteria for adverse Events (NCI CTCAE) Version 4.02.
The primary objective of this outcome is to establish the safety and toxicity profile of hu-CA91.
Number of patients reaching the dose levels of 750 mg of CA9hu-1 without any dose limiting toxicities.
The objective of this outcome is to perform a dose escalation of of CA9hu-1 to levels of 750mg without any dose limiting toxicities.
Number of patients reaching pharmacologically active dose measurement of CA9hu-1
The objective of this outcome is to determine number of patients in whom the pharmacologically active dose of CA9hu-1 wil be reached by measurement of plasma concentrations of the CA9hu-1. In order to reach the proposed pharmacologically active dose, the plasma levels of 200 +/- 100 nM are necessary.
Maximum tolerated dose of CA91hu-1
The objective is to determine a dose at which no more than one patient out of up to six patients at the same dose level experience a highly probable or probable CA9hu-1 related dose limiting toxicity.
Half-life of CA9-hu-1
Measurement of CA9hu-1 half-life after human administration provides basic PK descriptive data.
Peak Plasma Concentration (Cmax) of CA9hu-1
The measurement of Cmax after CA9hu-1 administration will provide basic PK descriptive parameter of the drug.
Area under the plasma concentration versus time curve (AUC)
The measurement of AUC after CA9hu-1 administration will provide basic PK parameter of the drug.
Anti-drug antibodies
Analyses of plasma samples for presence of anti-drug antibodies following CA9hu-1 administration
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