Safety and Bioimaging Trial of DS-8895a in Patients With Advanced EphA2 Positive Cancers

This was a Phase 1, dose-escalation, non-randomized, open-label, single-center study of DS-8895a in patients with advanced or metastatic Ephrin type-A receptor 2 (EphA2)-positive cancers. The primary study objective was to determine the safety of DS-8895a, with secondary objectives of determining the biodistribution, tumor uptake (bioimaging), pharmacokinetics (PK), antitumor and pharmacodynamic response, and correlations between pharmacodynamics and clinical outcomes, as appropriate.

Patients received an initial \^89Zr trace-labelled infusion of DS-8895a on Day 1, followed by safety assessments, positron emission tomography (PET) imaging, and PK sampling over a 1-week period. DS-8895a was infused again on Days 8, 22, and 36. The Day 36 infusion of DS-8895a was also trace labelled with \^89Zr, with subsequent PET imaging and PK sampling. Four dose levels (1, 3, 10 and 20 mg/kg) were to be evaluated, with 3 to 6 patients entered at each dose level. Patients who responded or had stable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at the Day 50 restaging may have continued to receive biweekly treatment with DS-8895a until disease progression, with restaging performed by computed tomography (CT) scans every 6 weeks.

Eligibility Criteria:
Inclusion Criteria:

1. Advanced or metastatic EphA2 positive cancer (based on immunohistochemistry of archived or fresh tumor tissue).
2. Malignant tumor that was refractory to standard treatment.
3. At least one reference tumor \> 1 cm in size for assessment of tumor uptake of \^89Zr-Df-DS-8895a.
4. Expected survival of at least 3 months.
5. Eastern Cooperative Oncology Group performance status ≤ 1.
6. Within the last week prior to the first study drug administration, laboratory parameters for vital functions were to be in the normal range. Out-of-range values that were not clinically significant were permitted, except that the following parameters were to be in the specified ranges:

   * Neutrophil count ≥ 1.5 x 10\^9/L
   * Platelet count ≥ 90 x 10\^9/L
   * International normalized ratio ≤ 1.5
   * Serum aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x the upper limit of normal (ULN); ≤ 5 x ULN if liver metastases
   * Serum bilirubin ≤ 1.5 x ULN
7. Calculated creatinine clearance ≥ 55 mL/min.
8. Age ≥ 18 years.
9. Able and willing to give valid written informed consent.

Exclusion Criteria:

1. Active central nervous system metastases. Definitively treated metastases were allowed if stable for 6 weeks off therapy.
2. Known immunodeficiency or human immunodeficiency virus positivity.
3. Serious illnesses, e.g., serious infections requiring antibiotics, bleeding disorders, or any condition that in the opinion of the Investigator would have interfered with the ability of the patient to fulfill the study requirements.
4. Other malignancy, apart from non-melanoma skin cancer, within 3 years prior to the first study drug administration that in the opinion of the investigator had \> 10% risk of relapse within 12 months.
5. Significant allergic reaction to prior antibody infusions.
6. Chemotherapy, radiotherapy, or investigational agent within 4 weeks prior to the first study drug administration.
7. Regular corticosteroid, non-steroidal anti-inflammatory drug (other than paracetamol or low-dose aspirin) or other immunosuppressive treatment within 3 weeks prior to the first study drug administration (intermittent dosing permitted if less than 4 doses within a 3-day period).
8. Mental impairment that could have compromised the ability to give informed consent and comply with the requirements of the study.
9. Lack of availability for clinical follow-up assessments.
10. Pregnancy or breastfeeding.
11. Women of childbearing potential: Refusal or inability to use effective means of contraception.