A phase Ib / II randomized study of BI 836845 in combination with exemestane and everolimus versus exemestane and everolimus alone in women with locally advanced or metastatic breast cancer.With following objectives:Phase Ib part: To determine the…
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 endpoint of the phase 2 part of the study is progression free
survival (PFS), which is defined as the duration of time from the date of C1V1
until the date of the first objective tumor progression or death due to any
cause.
Secondary outcome
1. Time to progression (TTP), defined as the duration of time from the date of
C1V1 until the date of the first objective tumor progression
2. Objective response (OR), defined as complete response (CR) or partial
response (PR)
3. Time to objective response
4. Duration of objective response
5. Clinical benefit (CB), defined as best overall response of complete response
(CR) or partial response (PR), or stable disease (SD) *6 months, or
Non-CR/Non-PD for *6 months
6. Duration of clinical benefit
Background summary
Breast cancer is the most common malignancy in women worldwide and is currently
the second leading cause of cancer-related death in women. This high mortality
rate reflects the limited effectiveness of current therapeutic options,
particularly in patients with advanced disease.
Despite recent progress by the introduction of mTOR targeted treatments,
hormone-positive advanced or metastatic breast cancer still has a dismal
prognosis with a median PFS (Progression Free Survival) of less than one year
and almost all patients eventually succumb to their disease.
Early evaluations of ongoing clinical trials of anti-IGF/IGF-1R agents
including BI 836845, as monotherapy, and pharmacodynamic studies of BI 836845
in neoplastic cell lines, indicate the possibility of disease stabilization or
tumor response in patients with advanced and otherwise incurable cancers.
Study objective
A phase Ib / II randomized study of BI 836845 in combination with exemestane
and everolimus versus exemestane and everolimus alone in women with locally
advanced or metastatic breast cancer.
With following objectives:
Phase Ib part: To determine the maximum tolerated dose (MTD) and recommended
phase II dose of BI 836845 in combination with exemestane and everolimus in
women with HR+/HER2- locally advanced or metastatic breast cancer
Phase II part: To evaluate the anti-tumor activity of BI 836845 in combination
with exemestane and everolimus versus exemestane and everolimus alone in women
with HR+/HER2- locally advanced or metastatic breast cancer
In addition, safety will be assessed.
Also pharmacokinetics (PK), pharmacogenomics and biomarkers will be explored in
both Phase I and Phase II part.
Study design
A Phase Ib / II randomized, open-label, multicenter international study in two
parts:
* Phase I - single arm, dose escalation with BI 836845 + everolimus + exemestane
* Phase II - two arms, randomized, parallel design, arm 1: everolimus +
exemestane arm 2: BI 836845 + everolimus + exemestane
Eligible patients will be randomly assigned in a 1:1 manner in one of the
treatment groups. Each arm will enroll approximately 75 patients (total of
approximately 150 patients). Randomization will be stratified by visceral
involvement (yes vs. no). Visceral refers to lung, liver, brains, pleural and
peritoneal metastases.
Intervention
Phase I part:
Initially a *3+3* dose finding study will be performed to determine the Maximum
Tolerated Dose (MTD), Recommended Phase II dose (RP2D) and pharmacokinetics of
BI 836845, everolimus and exemestane in women with HR+/HER2- advanced breast
cancer. The RP2D will be determined based on MTD in combination with totality
of the safety data.
Patients participating in the Phase I part will be concluded for the study
participation after the completion of the follow-up visit.
Phase II part:
Once the RP2D is determined, an open-label, two-arm randomized phase II study
will commence to further assess the anti-tumor activity of
BI 836845 in combination with exemestane and everolimus in women with HR+/HER2-
locally advanced or metastatic breast cancer.
Arm 1 (control arm): Once daily everolimus 10 mg plus once daily exemestane 25
mg orally
Arm 2 (experimental arm): Once daily exemestane 25mg orally, once daily
everolimus orally and BI836845 is administered intravenously weekly. The
treatment dose of everolimus and BI 836845 will be that of the RP2D from the
Phase I part of the study.
Patients will receive continuous daily treatment of everolimus plus exemestane
with or without weekly infusions of BI 836845 until progression, intolerable
adverse events or other reason necessitating withdrawal. The treatment will be
administered as courses of 28 days.
Study burden and risks
Based on the assumption as described in question E2 that the mean duration of
the study for the patient will be 10 cycles, the patient will undergo:
- Physical examination: phase 1 + phase 2: 13x
- Weight, blood pressure, pulse and temperature: phase 1: 17x; phase 2: 16x
- ECG: phase 1: 12x; phase 2: 10x
- Safety labs: phase 1: 17x; phase 2: 15x
- blood samples for PK or biomarkers: phase 1: 37x; phase 2, arm 1: 4x; phase
2, arm 2: 19x
- urine sample: phase 1 + phase 2: 2x
- handing in medication diary: only phase 1: 5x
- bone scan and CT chest, abdomen and pelvis and imaging of other suspected
sites of disease: phase 1 + phase 2: 5x
- Intravenous administration of BI 836845: only for phase 1 and phase2, arm 2:
40x
Comeniusstraat 6
Alkmaar 1817 MS
NL
Comeniusstraat 6
Alkmaar 1817 MS
NL
Listed location countries
Age
Inclusion criteria
- Histologically-confirmed locally advanced or metastatic breast cancer not deemed amenable to curative surgery or curative radiation therapy
- Tumors are positive for estrogen-receptor (ER) and/or progesterone receptor (PgR). Tumors must be negative for HER2 per local lab testing.
- Postmenopausal women
- Objective evidence of recurrence or progression on or after the last systemic therapy prior to the study entry
- Disease refractory to non-steroidal aromatase inhibitors (letrozole and/or anastrozole)
- ECOG<<=2
- Patients must have a measurable lesion according to RECIST version 1.1 or bone
lesion only: lytic or mixed (lytic + sclerotic) in the absence of measurable lesions
Exclusion criteria
-Previous treatment with agents targeting on IGF pathway, PI3K signaling pathway, protein kinase B (AKT), or mTOR pathways (sirolimus, temsirolimus, etc.)
-Prior treatment with exemestane
-History of another primary malignancy within 5 years, with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer
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 |
|---|---|
| Other | Clinical trials.gov (NCT02123823); www.clinicaltrialsregister.eu (1280.4) |
| EudraCT | EUCTR2013-001110-15-NL |
| CCMO | NL45357.068.14 |