Part I (dose-escalation): to evaluate the safety of SYD985 and to determine the Maximum Tolerated Dose and Recommended Phase 2 DosePart II (expanded cohorts): to evaluate the Objective tumour Response Rate
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
locally advanced or metastatic solid tumours
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part I: incidence of Dose Limiting Toxicities and (serious) Adverse Events
Part II: ORR
Secondary outcome
- change in other safety parameters including vital signs and lab results
- preliminary efficacy endpoints including clinical benefit rate, Duration of
Response and Progression Free Survival
- PK parameters including Cmax, AUC and T1/2
- ORR
- Quality of Life
Background summary
HER2 plays an important role in tumorigenesis and tumour aggressiveness.
Overexpression or amplification of the HER2 receptor has been identified in a
variety of cancer types, including breast, gastric, bladder, pancreas,
endometrial, lung and prostate cancer. The main target population for the
currently available HER2-targeted therapies consists of patients with breast
cancer and metastatic gastric cancer. Even though patients with HER2 positive
cancer are treated with HER2-targeted drugs, the cancer progresses in many
cases.
The experimental drug SYD985 is an antibody-drug conjugate. The antibody
component of SYD985, i.e. trastuzumab, is similar to Herceptin and the antibody
component of Kadcyla. SYD985 differentiates from Kadcyla by having a cleavable
linker as opposed to an uncleavable linker in Kadcyla and by the different
'payload'. SYD985 has a DNA-alkylating cytotoxin (duocarmycin) whereas Kadcyla
carries a microtubule inhibitor (a maytansine derivate). Tubulin-interacting
agents mostly interfere with dividing cells, whereas DNA-alkylating agents are
less cell cycle specific and can also kill non-dividing cells present in
tumours. In addition, the duocarmycin is conjugated to the antibody as a
prodrug (not in the active form) and - once activated - has a very short
half-life, which is expected to limit systemic toxicity driven by systemic
exposure to the activated duocarmycin.
Results of in vitro and in vivo non-clinical pharmacology testing suggest that
SYD985 is a potent drug with considerable potency in comparison to other
HER2-targeting drugs. Based on the non-clinical data, it is expected that
SYD985 will be efficacious in patients with varying degrees of HER2 expression.
Study objective
Part I (dose-escalation): to evaluate the safety of SYD985 and to determine the
Maximum Tolerated Dose and Recommended Phase 2 Dose
Part II (expanded cohorts): to evaluate the Objective tumour Response Rate
Study design
This is the first-in-human study with SYD985. The study consists of two parts:
Part I is the dose-escalation phase and Part II is the expanded cohort phase.
Part I: Dose-escalation
Eligible patients will receive infusions of SYD985 every three weeks and will
be monitored for safety and the occurrence of dose-limiting toxicities (DLTs).
At least 3 patients will be enrolled at each dose level. Doses will be
increased in increments of 100% or less (see protocol). There will be no
further dose escalation once 2 or more patients out of 3 to 6 patients at a
certain dose level experience a DLT during the first treatment cycle (one cycle
is 21 days). The highest dose level at which not more than 1 out of 6 patients
experience a DLT will be the MTD. The RP2D will be determined based on all
available safety and pharmacokinetic data, and this dose will be administered
in Part II of the study. If considered needed, each dose level can be extended
with additional patients.
Part II: Expanded cohorts
This part of the study will consist of 4 cohorts (see the protocol for a
description for the cohorts). Approximately 10 to 16 patients will be enrolled
per cohort. Eligible patients will receive the RP2D of SYD985 as defined in
Part I.
All patients of both parts of the study will receive SYD985 infusions every
three weeks until disease progression or unacceptable toxicity.
A follow-up visit is planned 30 days after the treatment discontinuation visit.
In Part II, patients will be followed up further to assess disease progression
and overall survival every 3 months or until end of study data collection (1
June 2019).
Intervention
Investigational product: SYD985 will be administered every three weeks
(intravenous use).
Study burden and risks
Only patients who progressed on all standard treatments or for whom no standard
treatments are available will be eligible for this study. The mode of action
and the pre-clinical testing of SYD985 make it a promising anti-cancer drug in
the eligible study population. There is no guarantee that the individual
patient will have clinical benefit from the study treatment. However, this
study will learn us about the safety and efficacy of SYD985, and it might help
to treat future cancer patients. Possible risks for patients participating in
this study is the occurence of study drug-related side effects and risks from
study procedures (for a detailed description, please refer to the
Investigator's Brochure and the Study Protocol).
Microweg 22
Nijmegen 6545 CM
NL
Microweg 22
Nijmegen 6545 CM
NL
Listed location countries
Age
Inclusion criteria
1. Patient with histologically-confirmed, locally advanced or metastatic tumour
who has progressed on standard therapy or for whom no standard therapy exists,
whith the following restriction:
- Part I: solid tumours of any origin
- Part II: breast and gastric tumours, including adenocarcinomas of the
gastroesophageal junction, urothelial and endometrial tumours;
2. For Part II: HER2 tumour status as defined in the protocol
3. ECOG performance status <= 1
4. Life expectancy > 12 weeks
5. Adequate organ function
6. For Part II: measurable disease
7. For Part II only: Presence of a tumour lesion accessible for biopsy and
willingness to undergo a fresh tumour biopsy, unless biopsy material is
available from a metastatic lesion obtained not more than 6 months prior to
signing informed consent.
Exclusion criteria
1. Anthracycline treatment within 3 months and/or abnormal cardiac biomarker
values
2. Other anticancer therapy (except for LHRH agonists) within 4 weeks (6 weeks
for nitrosoureas and mitomycin C)
3. History of infusion-related reactions and/or hypersensitivity to
trastuzumab, trastuzumab emtansine
4. Severe, uncontrolled systemic disease
5. LVEF < 55%, or a history of absolut decrease in LVEF of >= 10% points to <
50% during previous treatment with trastuzumab or trastuzumab emtansine, or a
history of decrease in LVEF to < 40% during previous treatment with trastuzumab
or trastuzumab emtansine
6. History of clinically significant CV disease
7. Symptomatic brain metastases, or therapy for brain metastases (excluding PCI
and dexamethasone treatment with stable or decreasing daily dose) within 4
weeks
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 | EUCTR2014-001798-15-NL |
| ClinicalTrials.gov | NCT02277717 |
| CCMO | NL50221.091.14 |