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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01082068
Recruitment Status : Completed
First Posted : March 8, 2010
Last Update Posted : June 3, 2016
Information provided by (Responsible Party):

Brief Summary:

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 or disease Intervention/treatment Phase
Breast Cancer Drug: XL147 (SAR245408) Drug: XL765 (SAR245409) Drug: letrozole (Femara) Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 72 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : June 2010
Actual Primary Completion Date : April 2013
Actual Study Completion Date : April 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Letrozole

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: XL765 (SAR245409)
given orally twice daily as capsules

Drug: letrozole (Femara)
given orally once daily as tablets

Primary Outcome Measures :
  1. Safety and tolerability of XL147 and letrozole and XL765 and letrozole [ Time Frame: at weekly and bi-weekly study visits ]
  2. 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 ]
  3. In Phase 2, to evaluate progression-free survival at 3 months [ Time Frame: tumor assessments at Week 13 and every 8 weeks thereafter ]

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

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01082068

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Sponsors and Collaborators
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Study Director: Clinical Sciences & Operations Sanofi
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Responsible Party: Sanofi Identifier: NCT01082068    
Other Study ID Numbers: ARD11437
XL147-202 ( Other Identifier: (Other study code) )
First Posted: March 8, 2010    Key Record Dates
Last Update Posted: June 3, 2016
Last Verified: May 2016
Keywords provided by Sanofi:
HER2 negative
Hormone Receptor Positive
Breast Neoplasms
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs