Clinical trial NCT02252211: Safety and Bioimaging Trial of DS-8895a in Patients With Advanced EphA2 Positive Cancers
Official title: A Phase I Safety and Bioimaging Trial of DS-8895a in Patients With Advanced or Metastatic EphA2 Positive Cancers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Solid Tumor
Metastatic EphA2 Positive Cancer
Keywords: EphA2 positive cancer
DS-8895a monoclonal antibody
Lead sponsor: Ludwig Institute for Cancer Research
Sponsor class: OTHER
Collaborators: name: Daiichi Sankyo Co., Ltd.
name: Austin Health
First posted: 2014-09-30
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Patients were enrolled in sequential cohorts following a 3+3 dose-escalation scheme.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Primary outcomes:
measure: Number of Patients With Treatment-emergent Adverse Events
timeFrame: Continuously for up to 58 weeks
Secondary outcomes:
measure: Number of Patients With Tumor Uptake of ^89Zr-Df-DS-8895a
timeFrame: Up to Day 43
measure: Number of Patients With Best Overall Tumor Response
timeFrame: Up to 58 weeks
measure: Mean Area Under the Serum Concentration Curve of ^89Zr-Df-DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Mean Volume of Distribution at Steady State of ^89Zr-Df-DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Mean Total Serum Clearance of ^89Zr-Df-DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Mean Maximum Serum Concentration of ^89Zr-Df-DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Mean Elimination Half-life of ^89Zr-Df-DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Mean Area Under the Serum Concentration Curve of DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Mean Volume of Distribution at Steady State of DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Mean Total Serum Clearance of DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Mean Maximum Serum Concentration of DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Mean Elimination Half-life of DS-8895a Following the First Infusion
timeFrame: Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
measure: Number of Patients With Pharmacodynamic (Metabolic) Response
timeFrame: Day 29 and Day 50
measure: Number of Patients With Human Anti-Human Antibody Positivity
timeFrame: Up to 43 Weeks
Other outcomes:
Locations:
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
Study officials:
affiliation: Austin Health, Melbourne, Australia
name: Andrew Scott, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Austin Health, Melbourne, Australia
name: Hui Gan, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gan HK, Parakh S, Lee FT, Tebbutt NC, Ameratunga M, Lee ST, O'Keefe GJ, Gong SJ, Vanrenen C, Caine J, Giovannetti M, Murone C, Scott FE, Guo N, Burvenich IJG, Paine C, Macri MJ, Kotsuma M, Senaldi G, Venhaus R, Scott AM. A phase 1 safety and bioimaging trial of antibody DS-8895a against EphA2 in patients with advanced or metastatic EphA2 positive cancers. Invest New Drugs. 2022 Aug;40(4):747-755. doi: 10.1007/s10637-022-01237-3. Epub 2022 Apr 11.