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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: XL147 (SAR245408); Drug: letrozole (Femara); Drug: XL765 (SAR245409)

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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: letrozole (Femara); given orally once daily as tablets; Drug: XL765 (SAR245409); given orally twice daily as capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability of XL147 and letrozole and XL765 and letrozole	at weekly and bi-weekly study visits
In Phase 1, to determine the maximum tolerated dose of XL147 in combination with letrozole and of XL765 in combination with letrozole	assessed by weekly study visits
In Phase 2, to evaluate progression-free survival at 3 months	tumor assessments at Week 13 and every 8 weeks thereafter

Secondary Outcome Measures

Outcome Measure	Time Frame
In Phase 2, to assess other clinical benefit and efficacy parameters	tumor assessments at Week 13 and every 8 weeks thereafter
Pharmacokinetics and pharmacodynamics of XL147, XL765 and letrozole	assessed every 2 weeks, then every 4 weeks

Collaborators and Investigators

• Sponsor: Sanofi

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: March 4, 2010
• First Submitted That Met QC Criteria: March 5, 2010
• First Posted (Estimate): March 8, 2010

Study Record Updates

• Last Update Posted (Estimate): June 3, 2016
• Last Update Submitted That Met QC Criteria: May 9, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: HER2 negative; Breast Neoplasms; Hormone Receptor Positive
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: ARD11437; XL147-202 (Other Identifier: (Other study code))