S 81694 Plus Paclitaxel in Metastatic Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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Phase I/II Trial of S 81694 Administered Intravenously in Combination With Paclitaxel to Evaluate the Safety, Pharmacokinetic and Efficacy in Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer, Metastatic Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: Combination therapy (S81694 + paclitaxel) phase I
* Drug: Paclitaxel
* Drug: Combination therapy (S81694 + paclitaxel) phase II


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination therapy (S81694 + paclitaxel) phase I<br>Phase I: Single arm, non-randomized study in metastatic breast cancer patients. S81694 given intravenously every two weeks at different doses on D1 and D15 last for 28 days. The participants will also receive paclitaxel intravenously on D1, D8 and D15 last for 28 days. | Drug: Combination therapy (S81694 + paclitaxel) phase I<br>* Dose escalation S 81694 (IV); paclitaxel started at 80 mg/m²,(IV)<br>|
| Active Comparator: paclitaxel phase II<br>Phase II: Randomised phase II part , two-arm, in untreated metastatic triple negative breast cancer patients. Paclitaxel given intravenously on D1, D8, and D15 at 80 mg/m² during a 28-day cycle. | Drug: Paclitaxel<br>* Paclitaxel (IV) at 80 mg/m²/week<br>|
| Experimental: Combination therapy (S81694 + paclitaxel) phase II<br>Phase II: Randomised phase II part , two-arm, in untreated metastatic triple negative breast cancer patients. S 81694 given intravenously on D1 and D15 at recommended phase 2 dose (RP2D). Paclitaxel given intravenously on D1, D8, and D15 during a 28-day cycle. | Drug: Combination therapy (S81694 + paclitaxel) phase II<br>* S 81694 (IV) at RP2D; paclitaxel (IV) at 80 mg/m²/week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DLTs (dose-limiting toxicities) | Safety criterion - A DLT is defined as any toxicity attributable to S81694 or the combination that occurs before the end of Cycle 1 | Through study completion, an average of 4 years | 
| Safety and tolerability assessed by incidence of Adverse Events | Safety and tolerability criteria - Incidence of treatment-emergent adverse events (AEs) graded according to NCI CTCAE v4.03 | Through study completion, an average of 4 years | 
| Abnormalities in laboratory tests (haematology, blood biochemistry and urinalysis) | Safety and tolerability criteria disease progression according to RECIST v1.1 or death due to any cause | Through study completion, an average of 4 years | 
| Abnormalities in physical examination and performance status (ECG) (mm/s) | Safety and tolerability criteria | Through study completion, an average of 4 years | 
| Abnormalities in blood pressure (mmHg) | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment | Through study completion, an average of 4 years | 
| Abnormalities in heart rate (BPM (beat per minute)) | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment | Through study completion, an average of 4 years | 
| Abnormalities in body temperature (C°degree celsius) | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment | Through study completion, an average of 4 years | 
| Abnormalities in respiration rate (cycles per minute) | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment | Through study completion, an average of 4 years | 
| Abnormalities in body weight (Kg) | Safety and tolerability criteria - Treatment-emergent changes in physical examinations, ECOG performance status, at periodic intervals during the study and at End of Treatment | Through study completion, an average of 4 years | 
| Progression free survival (PFS) [based on Investigator review of the images according to RECIST 1.1] | 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. | Through study completion, an average of 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The PK (pharmacokinetic) profile of S 81694 and paclitaxel plasma concentration : Area under the plasma concentration-time curve (AUC) | Safety and tolerability criteria | Through study completion, an average of 3 years | 
| The PK profile of S 81694 and paclitaxel plasma concentration : Elimination half-life (T½) | Safety and tolerability criteria | Through study completion, an average of 3 years | 
| The PK profile of S 81694 and paclitaxel plasma concentration : Maximum plasma concentration (Cmax) | Safety and tolerability criteria | Through study completion, an average of 3 years | 
| The PK profile of S 81694 and paclitaxel plasma concentration : Minimum plasma concentration (Cmin) | Safety and tolerability criteria | Through study completion, an average of 3 years | 
| Overall Response Rate (ORR) [ based on Investigator review of the images according to RECIST 1.1] | Efficacy criterion | Through study completion, an average of 4 years | 
| Incidence of treatment-emergent adverse events (AEs) graded according to NCI CTCAE v4.03 | Safety criterion | Through study completion, an average of 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mps1, Mps1i, S81694, breast cancer, triple negative breast cancer, phase I, phase II