Primary: To estimate the MTD or RDE and preferred dosing schedule of LJM716 when administered in combination with trastuzumab in patients with HER2 overexpressing metastatic breast cancer or gastric cancer.Secondary: Safety and tolerability, PK, PD…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence of dose-limiting toxicities.
Secondary outcome
Adverse events, PK parameters, post-treatment change from baseline in pHER3
levels in tumor and skin, PK/PD, Overall Response Rate, Progression Free
Survival and Duration of Response, antibodies against LJM716.
Background summary
HER3 plays a major role in ErbB driven tumors and is likely to limit the
clinical effectiveness of ErbB targeted therapeutics. The HER2/HER3 signaling
complex is a potent activator of PI3K signal transduction in HER2 amplified
cancers. Consequently, dual inhibition of both HER2 and HER3 is expected to
more effectively inhibit HER2/ HER3 driven signaling in HER2 over -expressing
metastatic breast cancer (MBC) or gastric cancer. Furthermore, since
inappropriate HER3 signaling is speculated to be a mechanism of trastuzumab
resistance, effective HER3 inhibition may restore response to trastuzumab.
LJM716 is a fully-human monoclonal antibody that binds specifically to human
HER3. A potential clinical use for LJM716 is in combination with trastuzumab to
inhibit growth and/or initiate destruction of HER2 amplified cancer cells
dependent upon the HER2/ HER3 signaling pathway. Preclinical in vitro and in
vivo data indicates that LJM716 synergizes with trastuzumab in models of HER2
over-expressing cancer, highlighting the potential benefit of combining LJM716
with trastuzumab in the clinic.
The purpose of the dose escalation part of this study is to estimate the
maximum tolerable dose (MTD) or a lower recommended dose for expansion (RDE) to
use for further testing in patients with HER2 overexpressing MBC or gastic
cancer who have progressed after up to 2 (gastric) or 3 (breastcancer) prior
anti- HER2 based regimens. The expansion part will further characterize the
safety and tolerability profile of the MTD/RDE of LJM716 in combination with
trastuzumab.
Study objective
Primary: To estimate the MTD or RDE and preferred dosing schedule of LJM716
when administered in combination with trastuzumab in patients with HER2
overexpressing metastatic breast cancer or gastric cancer.
Secondary: Safety and tolerability, PK, PD in tumor tissue and skin, PK/PD,
preliminary anti-tumor activity, anti-LJM716 antibodies.
Study design
Multicenter open-label, dose-escalation phase I study.
LJM716 will be administered weekly intravenously in combination with weekly
I.V. trastuzumab 2 mg/kg.
Dose-escalation: at least 15 patients in subsequent cohorts. Starting dose
LJM716 3 mg/kg. Until MTD or RDE.
When MTD/RDE has been reached: expansion part with at least 20 Breast cancer
patients and 20 gastric cancer patient (LJM716 in MTD/RDE).
Cycle of 28 days. Treatment in principle until disease progression or
unacceptable toxicity.
Intervention
Treatment with LJM716 in combination with trastuzumab.
Study burden and risks
Risk: Adverse events of study medication.
Burden: Study duration in principle until disease progression or unacceptable
toxicity. Weekly visits for evaluation and I.V. administration of LJM716 and
trastuzumab.
Extra visits during cycle 1 and 3: 7x in total.
Physical examination every 4 weeks.
Blood tests 4x during cycle 1 and 2, 2x during the following cycles. Amount:
125-150 mL during cycle 1-3, thereafter 15-25 ml per cycle.
PK blood draws (2 mL): 1 sample 4x during cycle 1 and 3, 1x during other
cycles. On day 1 of cycle 1 and 3: 4-5 samples in 2-8 h.
Urine test during screening and start cycle 1.
Pregnancy test every 4 weeks.
ECG every 4 weeks.
Echocardiography every 12 weeks.
CT/MRI every 8 weeks.
Skin biopsy: day 1 cycle 1-2.
Tumor biopsy day 1 cycle 1.
Optional:
* Remaining blood/tissue stored for 15 years for future testing.
* Skin biopsy at the start of cycle 3.
* Tumor biopsy at the start of cycle 3.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. Patients (>18yr) with histologically or cytologically confirmed diagnosis of breast cancer, or patients with documented cytologically or histologically confirmed gastric adenocarcinoma or gastroesophageal junction adenocarcinoma. Patients must have metastatic or locally advanced-unresectable disease.
2. an Eastern Cooperative Oncology Group (ECOG) performance status of * 2.
3. At least one prior trastuzumab-containing regimen.
4. Metastatic breast cancer patients must have received a minimum of 1 and a maximum of 3 prior anti-HER2-based regimens, with documented progression on the most recent regimen which must contain trastuzumab or lapatinib
5. Gastric cancer patients must have received a minimum of 1 and a maximum of 2 prior anti-HER2-based regimens, with documented progression on the most recent regimen which must contain trastuzumab.
During the dose expansion part of the study:
6. Baseline tumor tissue must be obtained by biopsy
7. In dose expansion only, patients must have measurable disease as defined by RECIST v1.1 (at least one lesion * 10 mm in at least one dimension when assessed by CT or MRI, or a cutaneous lesion with clearly defined margins that measures * 10 mm in at least one dimension)
Exclusion criteria
* Untreated and/or symptomatic CNS metastasis (see protocol page 32 for exceptions).
* No archival tumor sample available or tumor sample readily obtainable.
* Prior anti-HER3 treatment.
* Patients who have received systemic antineoplastic therapy or any investigational therapy within 4-6 weeks (see protocol page 32 for details).
* Major surgery within 28 days before study treatment.
* Radiotherapy within 2 weeks prior to the first dose of study treatment except localized radiation therapy for symptomatic bone metastasis.
* Active infection requiring systemic therapy within 10 days before study treatment.
* Known history of HIV or active infection with hepatitis B or C virus.
* Impaired cardiac function (see protocol page 32-33 for details).
* Pregnancy, lactation, inadequate contraception.
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 | EUCTR2011-004881-13-NL |
| ClinicalTrials.gov | NCT01602406 |
| CCMO | NL40912.031.12 |