Biodistribution Study of CMD-193 in Patients With Advanced Tumours Expressing the Lewis-Y Antigen

This was a Phase 1 dose-escalation study of CMD-193, a humanized monoclonal antibody linked to the toxin calicheamicin, in subjects with advanced tumors expressing the Lewis-Y antigen. The primary study objective was to determine the biodistribution and pharmacokinetics (PK) of 111-In-CMD-193 (i.e., CMD-193 tagged with a small amount of radioactive Indium \[111-In\]), with secondary objectives of determining changes in tumor metabolism and describing the antitumor responses to CMD-193.

Subjects received a single infusion of 111-In-CMD-193 on Day 1. Collection of blood for PK and whole body gamma camera imaging for assessment of biodistribution and tumor uptake were performed on Days 1, 2, 3 or 4, 5 or 6, and 7 or 8 following the 111-In-CMD-193 infusion. Subjects were evaluated for safety for 3 hours post-infusion on Day 1 of each cycle, with subsequent safety assessments performed on Days 8 and 15. Blood for human anti-human antibody (HAHA) response was collected pre-infusion, prior to each subsequent cycle (every 3 weeks) and at study discontinuation.

CMD-193 was administered on Day 1 of each subsequent 21-day cycle as a 60 (± 5) minute intravenous (IV) infusion at a dose of 1.0 mg/m\^2 in Cohort 1 and 2.6 mg/m\^2 in Cohort 2. Each subject received up to 6 cycles of CMD-193 (including the initial infusion of 111-In-CMD-193) until disease progression, unacceptable toxicity, or withdrawal of consent. Up to 6 additional cycles of CMD-193 were permitted if approved by the Sponsor in subjects who tolerated CMD-193 treatment and had evidence of response. Pretreatment medications (e.g., paracetamol, promethazine hydrochloride) were to be administered to reduce the incidence and severity of an anticipated infusion syndrome characterized by fever and chills, and less commonly hypotension.

Restaging by computed tomography (CT) scan was performed at the end of Cycles 2, 4, and 6. Assessment of tumor metabolism was performed by positron emission tomography with 18F-labeled fluorodeoxyglucose (18F-FDG-PET) prior to Cycle 1 and at the time of restaging at the end of Cycles 2 and 4.

Eligibility Criteria:
Inclusion criteria:

1. Signed and dated Institutional Review Board (IRB)-approved informed consent before any protocol-specific screening procedures were performed.
2. Histologically confirmed malignant solid tumor that had progressed following standard therapy, or for which no standard effective treatment was available.
3. Tumor expression of Lewis-Y antigen (≥20% tumor cells positive for Lewis-Y by immunohistochemistry assay).
4. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST), including the presence of at least one measurable lesion at least 2 cm in size suitable for 18F-FDG PET imaging.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Life expectancy ≥ 18 weeks.
7. Age ≥18 years.
8. Recovery to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) ≤ Grade 1 toxicity from any significant effects of prior surgery, radiation therapy, and cancer therapy (except alopecia).
9. Renal test: serum creatinine ≤ 1.5 x upper limit of normal (ULN).
10. Hepatic tests: alanine aminotransferase (ALT) levels ≤2.5 x ULN and total bilirubin ≤1.5 x ULN.
11. Pancreatic tests: amylase ≤1.5 x ULN and lipase ≤ 1.5 x ULN.
12. Bone marrow tests: absolute neutrophil count (ANC) of ≥1500 mm\^3 (≥1.5 x 10\^9/L) and platelet count of ≥ 150,000/mm\^3 (≥150 x 10\^9/L).
13. For women of childbearing potential, a negative serum pregnancy test result no longer than 48 hours before the first dose of CMD-193. A woman of childbearing potential was one who was biologically capable of becoming pregnant. This included women who were using contraceptives or whose sexual partners were either sterile or using contraceptives.
14. All subjects who were not surgically sterile or postmenopausal must have agreed and committed to the use of a reliable method of birth control for the duration of the study and for 28 days after the last dose of CMD-193.
15. Willingness of female subjects to refrain from breastfeeding infants during the study or within 28 days after the last dose of CMD-193.

Exclusion Criteria

1. Chemotherapy, radiation therapy, other cancer therapy, or investigational agents within 21 days of the first dose of CMD-193 (42 days if the previous chemotherapy included nitrosoureas or mitomycin C).
2. Symptomatic or clinically active central nervous system (CNS) metastases. Subjects who had prior treatment with radiotherapy or surgical resection for CNS metastases were permitted if CNS metastases had remained stable and not required any treatment for at least 3 months prior to the first dose of CMD-193.
3. Significant prior allergic reaction to recombinant human or murine proteins.
4. History of cirrhosis, current or chronic hepatitis B or C infections, or other significant active liver disease.
5. Unstable or serious concurrent medical conditions. Examples included, but were not limited to, bleeding gastric ulcers, gastrointestinal bleeding, hepatitis, significant disorders of the immune system (eg, systemic lupus erythematosus), pancreatitis, congestive heart failure, serious active infections (e.g. requiring antibiotics or antiviral agents), unstable angina, recent myocardial infarction (within 6 months of screening), ongoing maintenance therapy for life-threatening ventricular arrhythmia, or uncontrolled major seizure disorder.
6. Other malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ.
7. Any other condition that, in the Investigator's judgment, would have substantially increased the risk associated with the subject's participation in this study.