Study of XL147 (SAR245408) or XL765 (SAR245409) in Combination With Letrozole in Subjects With Breast Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT01082068
First received: March 4, 2010
Last updated: April 9, 2013
Last verified: April 2013
  Purpose

Phase 1 of this study will evaluate the maximum tolerated dose (MTD) of XL147 when given in combination with letrozole (Femara) and of XL765 when given in combination with letrozole. After the MTD is established for each combination (Phase 2), subjects will be enrolled to evaluate the preliminary efficacy and safety of these combinations in subjects with breast cancer refractory to a non-steroidal aromatase inhibitor that is ER+/PGR+ and HER2-. Letrozole is used in the treatment of different types of breast cancer, but patients can develop resistance.

Upregulation of PI3K activity is one of the most common characteristics of human cancer cells, including breast tumor cells. Activation of PI3K results in stimulation of AKT and mTOR kinases, resulting in the promotion of tumor cell proliferation and survival. Preclinical and retrospective clinical data suggest that aberrant activation of the PI3K pathway may play a role in aromatase inhibitor resistance in patients with ER+, HER2- breast cancer. XL147 is a potent inhibitor of PI3K, and XL765 is a potent dual inhibitor of PI3K and mTOR; therefore either of these compounds in combination with letrozole warrants clinical investigation.


Condition Intervention Phase
Breast Cancer
Drug: XL147 (SAR245408)
Drug: XL765 (SAR245409)
Drug: letrozole (Femara)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1/2 Dose-Escalation Study of XL147 (SAR245408) or XL765 (SAR245409) in Combination With Letrozole in Subjects With Hormone Receptor-Positive and HER2-Negative Breast Cancer Refractory to a Nonsteroidal Aromatase Inhibitor

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Safety and tolerability of XL147 and letrozole and XL765 and letrozole [ Time Frame: at weekly and bi-weekly study visits ] [ Designated as safety issue: Yes ]
  • In Phase 1, to determine the maximum tolerated dose of XL147 in combination with letrozole and of XL765 in combination with letrozole [ Time Frame: assessed by weekly study visits ] [ Designated as safety issue: Yes ]
  • In Phase 2, to evaluate progression-free survival at 3 months [ Time Frame: tumor assessments at Week 13 and every 8 weeks thereafter ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • In Phase 2, to assess other clinical benefit and efficacy parameters [ Time Frame: tumor assessments at Week 13 and every 8 weeks thereafter ] [ Designated as safety issue: No ]
  • Pharmacokinetics and pharmacodynamics of XL147, XL765 and letrozole [ Time Frame: assessed every 2 weeks, then every 4 weeks ] [ Designated as safety issue: No ]

Enrollment: 72
Study Start Date: June 2010
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
XL147 (SAR245408) + letrozole
Drug: XL147 (SAR245408)
given orally once daily as tablets
Drug: letrozole (Femara)
given orally once daily as tablets
Experimental: Arm 2
XL765 + letrozole
Drug: XL765 (SAR245409)
given orally twice daily as capsules
Drug: letrozole (Femara)
given orally once daily as tablets

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The subject has histologically confirmed breast cancer that is ER+ and/or PGR+.
  • The subject's breast cancer is negative for HER2.
  • The subject has recurrent or metastatic breast cancer that is refractory to a nonsteroidal aromatase inhibitor and has either disease progression or disease recurrence.
  • Subjects previously treated with letrozole must be able to tolerate the approved dose and schedule of letrozole.
  • For subjects enrolled in Phase 2, either archival tumor samples must be available, or the subject must be willing to undergo a fresh biopsy.
  • In Phase 2, at least 30 subjects in each arm must have measurable disease
  • The subject is a postmenopausal female.
  • If a subject is currently receiving bisphosphonates, the subject must have received the bisphosphonates for at least 2 months before starting study treatment.
  • The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
  • The subject has adequate organ and marrow function.
  • The subject has no other diagnosis of malignancy or evidence of other malignancy for 2 years before screening for this study (except non-melanoma skin cancer or in situ carcinoma of the cervix).
  • The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.

Exclusion Criteria:

  • The subject has received prior treatment with a selective inhibitor of PI3K, AKT, and/or mTOR.
  • Certain restrictions on prior therapies apply.
  • The subject has not recovered from toxicity due to prior therapy to Grade ≤ 1 or to pre-therapy baseline.
  • The subject has untreated, symptomatic, or progressive brain metastases.
  • The subject has only non-measurable lesions, other than bone, skin, or chest wall metastasis
  • The subject has to start cytotoxic chemotherapy due to rapid progressive disease involving major organs.
  • The subject has prothrombin time/ International Normalized Ratio (PT/ INR) or partial thromboplastin time (PTT) test results at screening that are above 1.3 x the laboratory upper limit of normal.
  • The subject has uncontrolled significant intercurrent illness.
  • The subject has a baseline corrected QT interval (QTc) > 470 ms.
  • The subject has a diagnosis of uncontrolled diabetes mellitus.
  • The subject is known to be positive for the human immunodeficiency virus (HIV).
  • The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation(s).
  • The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01082068

Locations
United States, California
Investigational Site Number 1537
Los Angeles, California, United States, 90033
United States, Colorado
Investigational Site Number 1601
Denver, Colorado, United States, 80262
United States, Florida
Investigational Site Number 1238
Fort Meyers, Florida, United States, 33901
United States, Illinois
Investigational Site Number 1441
Chicago, Illinois, United States, 60611
United States, Massachusetts
Investigational Site Number 1138
Boston, Massachusetts, United States, 02115
United States, Michigan
Investigational Site Number 1331
Ann Arbor, Michigan, United States, 48109
Investigational Site Number 1330
Detroit, Michigan, United States, 48201
United States, Missouri
Investigational Site Number 5201
Columbia, Missouri, United States, 65201
United States, North Carolina
Investigational Site Number 1252
Durham, North Carolina, United States, 27710
United States, Tennessee
Investigational Site Number 1214
Nashville, Tennessee, United States, 37203
United States, Texas
Investigational Site Number 5246
El Paso, Texas, United States, 79915
France
Investigational Site Number 3321
Nantes Saint Herblain, France, 44805
Investigational Site Number 3324
Paris Cedex 05, France, 75231
Spain
Investigational Site Number 3415
Barcelona, Spain, 08035
Investigational Site Number 3419
Barcelona, Spain, 08036
Investigational Site Number 3413
Madrid, Spain, 28041
Investigational Site Number 3420
Madrid, Spain, 28050
Sponsors and Collaborators
Sanofi
Investigators
Study Director: Clinical Sciences & Operations Sanofi
  More Information

No publications provided

Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT01082068     History of Changes
Other Study ID Numbers: ARD11437, XL147-202
Study First Received: March 4, 2010
Last Updated: April 9, 2013
Health Authority: United States: Food and Drug Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Sanofi:
HER2 negative
Hormone Receptor Positive
Breast Neoplasms

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Letrozole
Aromatase Inhibitors
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 28, 2014