S 81694 Plus Paclitaxel in Metastatic Breast Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer; Metastatic Triple Negative Breast Cancer
• Intervention / Treatment: Drug: Combination therapy (S81694 + paclitaxel) phase I; Drug: Paclitaxel; Drug: Combination therapy (S81694 + paclitaxel) phase II

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1000
    • Institut Jules Bordet Clinique Oncologie Médicale
  • Leuven, Belgium, 3000
    • UZ Leuven Campus Gasthuisberg Dept. of General Medical
• France
  • Saint Herblain, France, 44805
    • Institut de Cancérologie de l'Ouest site Saint Herblain
• Japan
  • Chiba, Japan, 2608717
    • Chiba cancer center Breast surgery
  • Osaka, Japan, 5418567
    • Osaka International Cancer Institute
• Netherlands
  • Rotterdam, Netherlands, 30145
    • Erasmus MC Section Clinical Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Combination therapy (S81694 + paclitaxel) phase I; 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; Dose escalation S 81694 (IV); paclitaxel started at 80 mg/m²,(IV)
ACTIVE_COMPARATOR: paclitaxel phase II; 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; Paclitaxel (IV) at 80 mg/m²/week
EXPERIMENTAL: Combination therapy (S81694 + paclitaxel) phase II; 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; S 81694 (IV) at RP2D; paclitaxel (IV) at 80 mg/m²/week

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier
• Collaborators: ADIR, a Servier Group company
• Investigators: Principal Investigator: Mario CAMPONE, Pr, Institut de Cancérologie de l'Ouest site Saint Herblain

Publications and helpful links

Helpful Links

• Results Summary
• Lay Summary

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 4, 2018
• Primary Completion (ACTUAL): June 8, 2020
• Study Completion (ACTUAL): June 8, 2020

Study Registration Dates

• First Submitted: December 13, 2017
• First Submitted That Met QC Criteria: January 25, 2018
• First Posted (ACTUAL): January 26, 2018

Study Record Updates

• Last Update Posted (ACTUAL): May 25, 2021
• Last Update Submitted That Met QC Criteria: May 20, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: breast cancer; phase I; phase II; triple negative breast cancer; Mps1; Mps1i; S81694
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel; Albumin-Bound Paclitaxel
• Other Study ID Numbers: CL1-81694-003; 2017-002459-27 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• IPD Sharing Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• IPD Sharing Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Study Data/Documents

1. Individual Participant Data Set
2. Study Protocol
3. Statistical Analysis Plan
4. Informed Consent Form
5. Clinical Study Report
6. study-level clinical trial data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No