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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02252211




Registration number
NCT02252211
Ethics application status
Date submitted
22/09/2014
Date registered
30/09/2014
Date last updated
1/03/2019

Titles & IDs
Public title
Safety and Bioimaging Trial of DS-8895a in Patients With Advanced EphA2 Positive Cancers
Scientific title
A Phase I Safety and Bioimaging Trial of DS-8895a in Patients With Advanced or Metastatic EphA2 Positive Cancers
Secondary ID [1] 0 0
LUD2014-002
Universal Trial Number (UTN)
Trial acronym
LUD2014-002
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Solid Tumor 0 0
Metastatic EphA2 Positive Cancer 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - DS-8895a 1 mg/kg
Treatment: Drugs - DS-8895a 3 mg/kg
Treatment: Drugs - DS-8895a 10 mg/kg

Experimental: DS-8895a - Patients received infusions with DS-8895a on Days 1, 8, 22, and 36. Infusions on Days 1 and 36 were trace labelled with ^89Zr (^89Zr-Df-DS-8895a). The Day 1 dose was 0.2 mg/kg, followed by subsequent doses calculated based on individual patient body weight and dosing cohort assignment.


Treatment: Drugs: DS-8895a 1 mg/kg
Patients received infusions with ^89Zr-Df-DS-8895a at a dose of 0.2 mg/kg on Day 1, DS-8895a at a dose of 1 mg/kg on Days 8 and 22, and ^89Zr-Df-DS-8895a at a dose of 1 mg/kg on Day 36. Patients who responded or had stable disease per RECIST version 1.1 at the Day 50 restaging may have continued to receive biweekly treatment with DS-8895a until disease progression.

Treatment: Drugs: DS-8895a 3 mg/kg
Patients received infusions with ^89Zr-Df-DS-8895a at a dose of 0.2 mg/kg on Day 1, DS-8895a at a dose of 3 mg/kg on Days 8 and 22, and ^89Zr-Df-DS-8895a at a dose of 3 mg/kg on Day 36. Patients who responded or had stable disease per RECIST version 1.1 at the Day 50 restaging may have continued to receive biweekly treatment with DS-8895a until disease progression.

Treatment: Drugs: DS-8895a 10 mg/kg
Patients were to receive infusions with ^89Zr-Df-DS-8895a at a dose of 0.2 mg/kg on Day 1, DS-8895a at a dose of 10 mg/kg on Days 8 and 22, and ^89Zr-Df-DS-8895a at a dose of 10 mg/kg on Day 36. Patients who responded or had stable disease per RECIST version 1.1 at the Day 50 restaging may have continued to receive biweekly treatment with DS-8895a until disease progression.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Patients With Treatment-emergent Adverse Events - Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through the study period.
Timepoint [1] 0 0
Continuously for up to 58 weeks
Secondary outcome [1] 0 0
Number of Patients With Tumor Uptake of ^89Zr-Df-DS-8895a - The biodistribution and tumor uptake of ^89Zr-Df-DS-8895a was determined based on qualitative analysis of whole body positron emission tomography (PET)/computed tomography (CT) images. PET imaging was performed following the ^89Zr-Df-DS-8895a infusions on Day 1 (Days 1, 4/5, and 7/8) and Day 36 (Days 36, 39/40 and 42/43). Qualitative parameters assessed included tumor uptake of reference lesions (scored on a 0-3 point scale: none, low, med, high). The reference lesions were initially identified on fluorodeoxyglucose (FDG) PET scans with a score of 3 for [18F]-fluorodeoxyglucose uptake. The summary table presents the maximum reference lesion ^89Zr-Df-DS-8895a uptake score reported for individual patients.
Timepoint [1] 0 0
Up to Day 43
Secondary outcome [2] 0 0
Number of Patients With Best Overall Tumor Response - Tumor responses were evaluated using computed tomography and categorized according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1) at Screening (up to 21 days before the first dose of study drug), on Day 50, and approximately every 6 weeks thereafter for patients who received continued study dosing. Per RECIST, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): = 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): = 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria.
Timepoint [2] 0 0
Up to 58 weeks
Secondary outcome [3] 0 0
Mean Area Under the Serum Concentration Curve of ^89Zr-Df-DS-8895a Following the First Infusion - The pharmacokinetics (PK) of ^89Zr-Df-DS-8895a were calculated based on data from gamma counting of serum samples. Serum samples for gamma counting were drawn on Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion), Day 2 (24 hours post-infusion), Day 4/5 (anytime), Day 36 (pre-infusion, and 5 minutes, 1, 2, and 4 hours post infusion), Day 37 (24 hours post-infusion), Day 39/40 (anytime), Day 42/43 (anytime), and Day 50 (anytime). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [3] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [4] 0 0
Mean Volume of Distribution at Steady State of ^89Zr-Df-DS-8895a Following the First Infusion - The PK of ^89Zr-Df-DS-8895a was calculated based on data from gamma counting of serum samples. Serum samples for gamma counting were drawn on Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion), Day 2 (24 hours post-infusion), Day 4/5 (anytime), Day 36 (pre-infusion, and 5 minutes, 1, 2, and 4 hours post infusion), Day 37 (24 hours post-infusion), Day 39/40 (anytime), Day 42/43 (anytime), and Day 50 (anytime). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [4] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [5] 0 0
Mean Total Serum Clearance of ^89Zr-Df-DS-8895a Following the First Infusion - The PK of ^89Zr-Df-DS-8895a was calculated based on data from gamma counting of serum samples. Serum samples for gamma counting were drawn on Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion), Day 2 (24 hours post-infusion), Day 4/5 (anytime), Day 36 (pre-infusion, and 5 minutes, 1, 2, and 4 hours post infusion), Day 37 (24 hours post-infusion), Day 39/40 (anytime), Day 42/43 (anytime), and Day 50 (anytime). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [5] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [6] 0 0
Mean Maximum Serum Concentration of ^89Zr-Df-DS-8895a Following the First Infusion - The PK of ^89Zr-Df-DS-8895a was calculated based on data from gamma counting of serum samples. Serum samples for gamma counting were drawn on Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion), Day 2 (24 hours post-infusion), Day 4/5 (anytime), Day 36 (pre-infusion, and 5 minutes, 1, 2, and 4 hours post infusion), Day 37 (24 hours post-infusion), Day 39/40 (anytime), Day 42/43 (anytime), and Day 50 (anytime). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [6] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [7] 0 0
Mean Elimination Half-life of ^89Zr-Df-DS-8895a Following the First Infusion - The PK of ^89Zr-Df-DS-8895a was calculated based on data from gamma counting of serum samples. Serum samples for gamma counting were drawn on Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion), Day 2 (24 hours post-infusion), Day 4/5 (anytime), Day 36 (pre-infusion, and 5 minutes, 1, 2, and 4 hours post infusion), Day 37 (24 hours post-infusion), Day 39/40 (anytime), Day 42/43 (anytime), and Day 50 (anytime). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [7] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [8] 0 0
Mean Area Under the Serum Concentration Curve of DS-8895a Following the First Infusion - The PK of DS-8895a was calculated based on data from enzyme-linked immunosorbent assay (ELISA) of serum samples. Serum samples for ELISA were drawn at the same times as for gamma counting with the addition of Day 8 (pre- and 0 to 30 minutes post-infusion), Day 9 (anytime), and Day 22 (pre- and 0 to 30 minutes post-infusion). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [8] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [9] 0 0
Mean Volume of Distribution at Steady State of DS-8895a Following the First Infusion - The PK of DS-8895a was calculated based on data from enzyme-linked immunosorbent assay (ELISA) of serum samples. Serum samples for ELISA were drawn at the same times as for gamma counting with the addition of Day 8 (pre- and 0 to 30 minutes post-infusion), Day 9 (anytime), and Day 22 (pre- and 0 to 30 minutes post-infusion). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [9] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [10] 0 0
Mean Total Serum Clearance of DS-8895a Following the First Infusion - The PK of DS-8895a was calculated based on data from enzyme-linked immunosorbent assay (ELISA) of serum samples. Serum samples for ELISA were drawn at the same times as for gamma counting with the addition of Day 8 (pre- and 0 to 30 minutes post-infusion), Day 9 (anytime), and Day 22 (pre- and 0 to 30 minutes post-infusion). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [10] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [11] 0 0
Mean Maximum Serum Concentration of DS-8895a Following the First Infusion - The PK of DS-8895a was calculated based on data from enzyme-linked immunosorbent assay (ELISA) of serum samples. Serum samples for ELISA were drawn at the same times as for gamma counting with the addition of Day 8 (pre- and 0 to 30 minutes post-infusion), Day 9 (anytime), and Day 22 (pre- and 0 to 30 minutes post-infusion). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [11] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [12] 0 0
Mean Elimination Half-life of DS-8895a Following the First Infusion - The PK of DS-8895a was calculated based on data from enzyme-linked immunosorbent assay (ELISA) of serum samples. Serum samples for ELISA were drawn at the same times as for gamma counting with the addition of Day 8 (pre- and 0 to 30 minutes post-infusion), Day 9 (anytime), and Day 22 (pre- and 0 to 30 minutes post-infusion). For Cycle 2 onward, blood samples for PK were taken at pre- and 0 to 30 minutes post-infusion on Days 1, 15, and 29.
Timepoint [12] 0 0
Cycle 1 Day 1 (pre-infusion and 5 minutes, 1, 2, and 4 hours post-infusion)
Secondary outcome [13] 0 0
Number of Patients With Pharmacodynamic (Metabolic) Response - The pharmacodynamic (metabolic) response of DS-8895a was assessed by ^18F-FDG PET at Screening, Day 29, and Day 50. Tumor metabolism response was evaluated as the difference in standardized uptake values between the pre- and post-treatment FDG PET scans. The measurement of [18F]-FDG uptake for tumor metabolic response monitoring was performed according to the European Organization for Research and Treatment of Cancer (EORTC) PET response criteria (Young et al. Eur J Cancer 1999;35:1773-82).
Timepoint [13] 0 0
Day 29 and Day 50
Secondary outcome [14] 0 0
Number of Patients With Human Anti-Human Antibody Positivity - Blood samples to detect human anti-human antibody (HAHA) formation were collected on Days 1 (pre-infusion [within 7 days of Day 1 dose] and post-infusion), 8, 22, 36 (pre-infusion), and 50 (anytime). For Cycle 2 onward, HAHA samples were collected on Day 1 (pre-infusion) and at the end of the study (anytime). HAHA samples were analyzed using ELISA and were categorized as either positive or negative for a HAHA response. HAHA positivity indicates that a patient has developed an antibody response.
Timepoint [14] 0 0
Up to 43 Weeks

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Austin Health - Heidelberg
Recruitment postcode(s) [1] 0 0
3084 - Heidelberg

Funding & Sponsors
Primary sponsor type
Other
Name
Ludwig Institute for Cancer Research
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Daiichi Sankyo Co., Ltd.
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Austin Health
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02252211
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Andrew Scott, MD
Address 0 0
Austin Health, Melbourne, Australia
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications