Metastatic Breast Cancer, Metastatic Triple Negative Breast Cancer
Conditions
Keywords
Mps1, Mps1i, S81694, breast cancer, triple negative breast cancer, phase I, phase II
Brief summary
The purpose of this study is to determine the safety profile, the maximum tolerated dose (MTD) and the associated dose-limiting toxicities (DLTs) of S 81694 in combination with paclitaxel in metastatic breast cancer (mBC) patients, and to investigate the antitumour activity of the combination in metastatic triple negative breast cancer (mTNBC) patients.
Interventions
DRUGCombination therapy (S81694 + paclitaxel) phase I
Dose escalation S 81694 (IV); paclitaxel started at 80 mg/m²,(IV)
DRUGPaclitaxel
Paclitaxel (IV) at 80 mg/m²/week
DRUGCombination therapy (S81694 + paclitaxel) phase II
S 81694 (IV) at RP2D; paclitaxel (IV) at 80 mg/m²/week
Sponsors
ADIR, a Servier Group company
Institut de Recherches Internationales Servier
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study will be conducted in two successive parts: * a dose escalation phase I part, which is a single arm, non-randomised and non-comparative study in patient with mBC * a randomised phase II part, which is a two-arm, randomised study at RP2D (recommended phase II dose), to evaluate the efficacy and the safety of S 81694 in combination with paclitaxel (experimental arm) versus paclitaxel alone (comparator arm) in untreated mTNBC
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For Phase I : * Histologically or cytologically confirmed metastatic breast cancer, refractory to any standard therapy or for which the standard therapy is considered unsuitable; * Patient must have at least one evaluable or measurable metastatic lesion (lesions as defined by revised Response Evaluation Criteria in Solid Tumors). For Phase II : * Histologically or cytologically confirmed advanced inoperable triple negative breast cancer with no prior anticancer therapy regimen in metastatic setting; * Patient with a minimum washout period of 12 months following previous taxane based adjuvant therapy; * Patient must have at least one measurable metastatic lesion. Ascites, pleural effusion, and bone metastases are not considered measurable; * Acceptance of pre-treatment metastatic biopsies for all patients and on-treatment metastatic biopsies in selected centres. For the whole study: * Male or female subjects aged ≥ 18 years old, or legal age of the majority in the country; * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; * Estimated life expectancy of at least 3 months; * Adequate haematological function based on the last assessment performed within 7 days prior to the first IMP (investigational medicinal product) administration; * Adequate renal function based on the last assessment performed within 7 days prior to the first IMP administration; * Adequate hepatic function based on the last assessment performed within 7 days prior to the first IMP administration; * Female participant of childbearing potential must have a negative pregnancy test (serum) within 7 days prior to the first day of test drug administration. Effective contraception both for female patients of childbearing potential and male patients with parteners of childbearing potential.
Exclusion criteria
* Other active malignancy within the last 3 years (except for basal cell carcinoma or a non-invasive/in situ cervical cancer or intra-mucosal gastro-intestinal cancers that were treated curatively); * Presence of grade ≥ 2 toxic effects (excluding alopecia) due to prior cancer therapy; * Known hypersensitivity to the IMP (S 81694 and paclitaxel) or their excipients; * Evidence of peripheral neuropathy of grade 2 or higher; * Participant previously received paclitaxel and discontinued due to toxicity related to paclitaxel; * Participant known as refractory to taxanes; * Any prior cancer therapy within 4 weeks or 5 half-life (whichever is the shorter) before the first IMP administration; * Participant with current, serious, uncontrolled infections; * Participant with brain metastasis or leptomeningeal metastasis (except patients with brain metastasis that have been stable post-radiation therapy and who are off steroids for \> 2 months); * History of cardiac disease; * Uncontrolled arterial hypertension; * Presence of risk factors for torsades de pointes (e.g. heart failure, hypokalaemia, family history of long QT syndrome); * Any clinically significant medical condition (e.g. organ dysfunction) or laboratory abnormality likely to jeopardize the patient's safety or to interfere with the conduct of the study, in the investigator's opinion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival (PFS) [based on Investigator review of the images according to RECIST 1.1] | Through study completion, an average of 4 years | Efficacy criterion - time from the date of first study drug intake until the date of the investigator-assessed disease progression or death due to any cause whichever occurs first. |
| Abnormalities in physical examination and performance status (ECG) (mm/s) | Through study completion, an average of 4 years | Safety and tolerability criteria |
| Abnormalities in blood pressure (mmHg) | Through study completion, an average of 4 years | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment |
| Abnormalities in heart rate (BPM (beat per minute)) | Through study completion, an average of 4 years | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment |
| Abnormalities in body temperature (C°degree celsius) | Through study completion, an average of 4 years | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment |
| Abnormalities in respiration rate (cycles per minute) | Through study completion, an average of 4 years | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment |
| Abnormalities in body weight (Kg) | Through study completion, an average of 4 years | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment |
| Incidence of DLTs (dose-limiting toxicities) | Through study completion, an average of 4 years | Safety criterion - A DLT is defined as any toxicity attributable to S81694 or the combination that occurs before the end of Cycle 1 |
| Safety and tolerability assessed by incidence of Adverse Events | Through study completion, an average of 4 years | Safety and tolerability criteria - Incidence of treatment-emergent adverse events (AEs) graded according to NCI CTCAE v4.03 |
| Abnormalities in laboratory tests (haematology, blood biochemistry and urinalysis) | Through study completion, an average of 4 years | Safety and tolerability criteria disease progression according to RECIST v1.1 or death due to any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The PK profile of S 81694 and paclitaxel plasma concentration : Elimination half-life (T½) | Through study completion, an average of 3 years | Safety and tolerability criteria |
| The PK profile of S 81694 and paclitaxel plasma concentration : Maximum plasma concentration (Cmax) | Through study completion, an average of 3 years | Safety and tolerability criteria |
| The PK profile of S 81694 and paclitaxel plasma concentration : Minimum plasma concentration (Cmin) | Through study completion, an average of 3 years | Safety and tolerability criteria |
| Overall Response Rate (ORR) [ based on Investigator review of the images according to RECIST 1.1] | Through study completion, an average of 4 years | Efficacy criterion |
| Incidence of treatment-emergent adverse events (AEs) graded according to NCI CTCAE v4.03 | Through study completion, an average of 4 years | Safety criterion |
| The PK (pharmacokinetic) profile of S 81694 and paclitaxel plasma concentration : Area under the plasma concentration-time curve (AUC) | Through study completion, an average of 3 years | Safety and tolerability criteria |
Countries
Belgium, France, Japan, Netherlands
Outcome results
None listed