The primary objective of this study is to demonstrate that SYD985 is superior to physician*s choice in prolonging progression-free survival (PFS) on the basis of the blinded independent central review of tumour assessment.The secondary objectives of…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is PFS based on blinded independent central
review (ICR) of tumour assessment according to RECIST 1.1. PFS is defined as
the time from the date of randomization to the date of first documented
ICR-assessed disease progression according to RECIST 1.1 or death due to any
cause (whichever occurs earlier).
Secondary outcome
- Overall Survival;
- Objective Response Rate on the basis of the blinded independent central
review;
- Investigator assessed PFS;
- Patient reported outcomes for health related quality of life;
Background summary
Results of the first-in-human Phase I study (SYD985.001) suggest that SYD985 is
efficacious and has an acceptable safety profile in heavily pre-treated
patients with HER2-positive locally advanced or metastatic breast cancer.
Part I of this Phase I study was a dose escalation study with patients with
solid tumors of any origin.
In this part 39 patients were enrolled and treated. For breast cancer patients
only (n=25), the objective response rate (ORR) was 36.0% (95% CI 18.0; 57.5),
with partial responses in 5 HER2- positive and 4 HER2-negative breast cancer
patients. The Kaplan Meier estimate of the median (95% CI) duration of
progression free survival (PFS) was 24.3 weeks for the breast cancer patients.
All but one HER2-positive breast cancer patients were pretreated with
trastuzumab and (ado-)trastuzumab emtansine. Therefore SYD985 represents a
reasonable treatment option for the intended patient population in this study.
Part II of the Phase I study is ongoing; expanded patient cohorts with specific
cancer types, including late-line HER2-positive locally advanced or metastatic
breast cancer, are being evaluated for safety and efficacy.
Study objective
The primary objective of this study is to demonstrate that SYD985 is superior
to physician*s choice in prolonging progression-free survival (PFS) on the
basis of the blinded independent central review of tumour assessment.
The secondary objectives of this study are to compare the two treatment groups
with respect to:
• Overall survival (OS);
• Objective response rate (ORR) on the basis of the blinded independent central
review;
• Investigator assessed PFS;
• Patient reported outcomes for health related quality of life;
• Safety and tolerability
Study design
This study is designed as a randomized, active-controlled, superiority study in
patients with unresectable locally advanced or metastatic HER2-positive breast
cancer. The patients should have had either progression during or after at
least two HER2-targeting treatment regimens for locally advanced or
metastatic disease or progression during or after (ado-)trastuzumab emtansine
treatment.
Eligible patients will be randomly assigned (2:1) to receive SYD985 or
physician*s choice treatment until disease progression, unacceptable toxicity
or study termination by the Sponsor. During treatment, patients will have to
visit the clinical site to assess efficacy, quality of life (QoL), and safety
using standardized criteria
Intervention
Investigational medicinal product (SYD985 - trastuzumab vc-seco-DUBA):
Patients in the investigational group will be treated every three weeks (Q3W)
with 1.2 mg/kg SYD985. SYD985 is an antibody-drug conjugate (ADC) comprised of
Synthon's HER2-targeting monoclonal IgG1 antibody trastuzumab (SYD977)
covalently bound to a linker-drug (SYD980). The linker-drug contains a
cleavable linker and the prodrug seco-duocarmycin-hydroxybenzamide-azaindole
(seco-DUBA, SYD978). The linker can be cleaved by proteases in the tumour at
the dipeptide valine-citrulline (vc) motif, which releases the active
DNA-alkylating toxin (DUBA, SYD986).
Drug product vials contain 80 mg sterile lyophilized SYD985 which should be
reconstituted prior to use with 8.0 mL sterile water for injection to yield a
solution of 10 mg/mL. SYD985 drug product vials should be stored at 2 to 8 °C
(36-46 °F) until use. The calculated amount of solution should be added to an
infusion bag containing 100 mL of 0.9% sodium chloride without other additives.
If reconstituted vials or the prepared infusion bag is not used immediately, it
can be stored at 2 to 8 °C (36-46 °F) for a maximum of 24 hours up to start of
infusion. SYD985 is to be administered intravenously over 60 minutes for the
first infusion, subsequent infusions can be given over 30 minutes.
Reference therapy: Treatment of physician*s choice:
Patients in the reference group will be treated with approved systemic therapy
administered as per local practice and according to the needs of each patient.
Investigators can choose between four pre-specified treatment regimens.
• Option 1: Lapatinib + Capecitabine
• Option 2: Trastuzumab + Capecitabine
• Option 3: Trastuzumab + Vinorelbine
• Option 4: Trastuzumab + Eribulin
Study burden and risks
Patients are asked to undergo procedures described in the tables on pages 7 - 9
of the study protocol. These procedures include physical and ophthalmological
examination, vital signs (blood pressure, heart rate, body temperature and
oxygen saturation), height/weight measurement, urine pregnancy tests (female;
childbearing patients) ECG, LEVF, CT or MRI of brain (per clinical indication),
whole body bone scan (per clinical indication), tumor assessment, blood draw,
ECOF performance status, complete questionnaires and or answer questions of
investigator or study team administration of study drug. Additionally, fertile
patients who are sexually active must consent to use an effective form of
contraception with their sexual partners throughout participation in the study.
Patients are also asked to inform their study doctor on their medication use
and change in health status.
Adverse drug reactions: Possible adverse drug reactions are described in the
Investigator's Brochure. These side effects include nausea, flushing, shivering
fits, fever, trouble breathing, low blood pressure, rapid heartbeat, sudden
swelling of your face or tongue, or trouble swallowing during the infusion or
after the infusion on the first day of treatment. All possible adverse drug
reactions are described in the Investigator's Brochure. Adverse events while on
physician*s choice treatment are described in the Summary of Product
Characteristics and/or Package Insert of the respective treatments.
Risks related to study procedures:
• Blood sampling may cause bruising, fainting, and in rare cases infection.
• During computerized tomography scans (CT-scan) a minimal amount of radiation
is used which has no evident risks. The use of a contrast fluid given may lead
to itching, rash, hives or feeling warmth throughout the body. These are
usually self-limiting reactions that go away rather quickly. In rare cases a
more severe allergic reaction may occur.
• Echocardiogram will be done using ECHO or MUGA. There are no known risks from
an echocardiogram. The high-frequency sound waves used have not been shown to
have any harmful effects. For MUGA scans, allergic reactions to the radioactive
tracer are rare, but could occur. Most of the tracer will be eliminated from
the body within a day. The amount of exposure is small, and is equal to the
amount of radiation that the average person would be exposed to from the
environment in a period of 10 days. Occasionally, some soreness or swelling may
develop at the injection site.
• The MRI uses a magnetic field and radio waves.
• The slit lamp exam, and the electrocardiogram of the heart are standard
examinations and are not associated with any evident risks.
Results of the first-in-human Phase I study (SYD985.001) suggest that SYD985 is
efficacious and has an acceptable safety profile in heavily pre-treated
patients with HER2-positive locally advanced or metastatic breast cancer.
Microweg 22
Nijmegen 6545 CM
NL
Microweg 22
Nijmegen 6545 CM
NL
Listed location countries
Age
Inclusion criteria
1. Female patients, age = 18 years old at the time of signing informed consent;
2. Patients with histologically-confirmed, unresectable locally advanced or
metastatic breast cancer;
3. Patients should have had either progression during or after at least two
HER2-targeting treatment regimens for locally advanced or metastatic disease or
progression during or after (ado-)trastuzumab emtansine treatment for locally
advanced or metastatic disease;
4. HER2-positive tumour status according to the ASCO-CAP guidelines (defined as
a 3+ score on immunohistochemistry (IHC) and/or positive by in situ
hybridization (ISH)) confirmed by the central laboratory;
5. Patients must have measurable or non-measurable disease that is evaluable
per Response Evaluation Criteria for Solid Tumours (RECIST version 1.1).
Patients with bone-only sclerotic disease without a lytic component are not
eligible;
6. Eastern Cooperative Oncology Group (ECOG) performance status = 2;
7. Estimated life expectancy > 12 weeks at randomization;
8. Adequate organ function, evidenced by the following (local) laboratory
results:
- Absolute neutrophil count = 1.5 x 109 /L;
- Platelet count = 100 x 109 /L;
- Hemoglobin = 9.0 g/dL;
- Total bilirubin = 1.5 x the upper limit of normal (ULN);
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3.0x
ULN (or = 5.0x ULN in the presence of liver metastases);
- Serum creatinine = 1.5 x ULN;
9. For women of childbearing potential, two methods of effective contraception
must be used during the study and up to 6 months after last study treatment.
This is not required in case the patient or sole partner is surgically
sterilized or in case the patient truly abstains from sexual activity.
Exclusion criteria
1. Having been treated with:
a. SYD985 at any time;
b. Anthracycline treatment within 12 weeks prior to randomization;
c. Other anticancer therapy including chemotherapy, immunotherapy, or
investigational agents within 4 weeks prior to randomization;
d. Radiotherapy within 2 weeks prior to randomization;
e. Hormone therapy within 1 week prior to randomization; The patient must have
sufficiently recovered from any treatment-related toxicities to NCI CTCAE Grade
=1 (except for toxicities not considered a safety risk for the patient at the
investigator*s discretion);
2. History of infusion-related reactions and/or hypersensitivity to
trastuzumab, (ado-)trastuzumab emtansine or excipients of the study drug which
led to permanent discontinuation of the treatment;
3. History of keratitis;
4. Severe, uncontrolled systemic disease (e.g. clinically significant
cardiovascular, pulmonary, or metabolic disease) at screening;
5. Left ventricular ejection fraction (LVEF) < 50% as assessed by either
echocardiography or multigated acquisition (MUGA) scan at screening, or a
history of clinically significant decrease in LVEF during previous treatment
with trastuzumab or (ado-)trastuzumab emtansine leading to permanent
discontinuation of treatment;
6. Cardiac troponin value above the ULN (local laboratory) at screening;
7. History (within 6 months prior to randomization) of clinically significant
cardiovascular disease such as unstable angina, congestive heart failure (CHF),
myocardial infarction, uncontrolled hypertension, or cardiac arrhythmia
requiring medication;
8. Untreated brain metastases, symptomatic brain metastases, brain metastases
requiring steroids to manage symptoms, or treatment for brain metastases within
8 weeks prior to randomization. Patients with prior treatment of brain
metastases must have evidence of disease stability on baseline brain imaging as
compared to historical brain imaging;
9. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g.
bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis,
or evidence of active pneumonitis on screening chest CT scan.
10. Known active Hepatitis B or C infection;
11. Major surgery within 4 weeks prior to randomization;
12. Pregnancy or lactation;
13. Other condition, which in the opinion of the investigator, would compromise
the safety of the patient or the patient's ability to complete the study
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001994-18-NL |
| CCMO | NL62722.100.17 |