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Study of XL147 (SAR245408) in Combination With Trastuzumab or Paclitaxel and Trastuzumab in Subjects With Metastatic Breast Cancer Who Have Progressed on a Previous Trastuzumab-based Regimen

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.
ClinicalTrials.gov Identifier: NCT01042925
Recruitment Status : Completed
First Posted : January 6, 2010
Last Update Posted : June 3, 2016
Information provided by (Responsible Party):

Study Description
Brief Summary:

Phase 1 of this study will evaluate the maximum tolerated dose (MTD) of XL147 when given in combination with trastuzumab (Herceptin) and in combination with trastuzumab and paclitaxel. 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 metastatic HER2 positive breast cancer. Both trastuzumab and paclitaxel are used in the treatment of metastatic breast cancer (MBC), but patients can develop resistance.

The link between PI3K mutations and trastuzumab resistance has been seen in breast cancer patients. This suggests that inhibitors of the PI3K/PTEN pathway may have the potential to restore sensitivity to trastuzumab. Similarly, introduction of activated mutant forms of PI3K has been shown to transform and confer paclitaxel resistance to immortalized breast epithelial cells. XL147 is a potent and selective inhibitor of PI3K and inhibits phosphorylation of multiple downstream components of PI3K/PTEN signaling. Therefore, XL147 may have utility in the treatment of trastuzumab resistant/refractory and HER2-positive MBC when administered in combination with trastuzumab alone or with trastuzumab and paclitaxel.

Condition or disease Intervention/treatment Phase
Breast Cancer Breast Neoplasms Drug: XL147 (SAR245408) Biological: trastuzumab Drug: paclitaxel Phase 1 Phase 2

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of XL147 (SAR245408) Administered in Combination With Trastuzumab or Paclitaxel and Trastuzumab in Subjects With Metastatic Breast Cancer Who Have Progressed on a Previous Trastuzumab-Based Regimen
Study Start Date : February 2010
Primary Completion Date : December 2012
Study Completion Date : December 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Arm 1
XL147 in combination with trastuzumab
Drug: XL147 (SAR245408)
administered orally once daily as tablet(s)
Biological: trastuzumab
administered by IV once every 3 weeks
Other Name: Herceptin
Experimental: Arm 2
XL147 in combination with trastuzumab and paclitaxel
Drug: XL147 (SAR245408)
administered orally once daily as tablet(s)
Biological: trastuzumab
administered by IV once every 3 weeks
Other Name: Herceptin
Drug: paclitaxel
administered by IV once every week

Outcome Measures

Primary Outcome Measures :
  1. Safety and tolerability of XL147 in combination with trastuzumab and in combination with trastuzumab and paclitaxel [ Time Frame: safety assessments at weekly study visits ]
  2. In Phase 1, the maximum tolerated dose (MTD) of XL147 when administered in combination with trastuzumab and in combination with trastuzumab and paclitaxel [ Time Frame: assessed by weekly study visits ]
  3. In Phase 2, objective tumor response [ Time Frame: every 6 weeks ]

Secondary Outcome Measures :
  1. Duration of response and progression-free survival (Phase 2) [ Time Frame: every 6 weeks ]
  2. Pharmacokinetics and pharmacodynamics of XL147 and trastuzumab when given in combination, and of XL147, trastuzumab, and paclitaxel when given in combination [ Time Frame: assessed weekly, then every 3 weeks ]

Eligibility Criteria

Information from the National Library of Medicine

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

Inclusion Criteria:

  • The subject has pathologically and radiologically confirmed metastatic HER2 positive breast cancer (Stage IV disease). Subjects must have received and progressed on at least one prior trastuzumab-containing regimen for metastatic disease. For subjects in Arm 2, they must also have received at least one prior taxane-containing regimen.
  • The subject has at least one lesion that is not within a previously radiated field and measurable on computerized tomography (CT) or magnetic resonance imaging scan (MRI)
  • The subjects enrolled in Phase 2 must be willing to undergo a biopsy of the primary tumor or a tumor metastasis at baseline, if tumor tissue is amenable to biopsy
  • The subject's primary tumor and/or metastatic lesion must overexpress HER2
  • For subjects enrolled in Phase 2: samples from archival or fresh tissue, or a tissue block of the subject's tumor.
  • The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
  • The subject has adequate organ and marrow function
  • The subject is capable of understanding the informed consent and complying with the protocol and has signed the informed consent document prior to any study-specific screening procedures or evaluations being performed.
  • Sexually active subjects must agree to use a medically-accepted barrier method of contraception during the course of the study and for 3 months following discontinuation of study treatments. For subjects using oral contraceptives, a barrier method must be used in addition to the oral contraceptive
  • Subjects of childbearing potential must have a negative pregnancy test at screening and enrollment

Exclusion Criteria:

  • The subject has previously been treated with a selective inhibitor of PI3K and / or AKT
  • 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. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥4 weeks prior to first study treatment
  • The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial thromboplastin time (PTT) test results at screening that are ≥ 1.3 times above the laboratory upper limit of normal
  • The subject has a diagnosis of uncontrolled diabetes mellitus
  • The subject has uncontrolled significant intercurrent illness
  • The subject has uncontrolled hypertension or other clinically significant cardiovascular disease
  • The subject has left ventricular ejection fraction (LVEF) ≤ 50%
  • The subject has a baseline corrected QT interval ≥ 460 ms
  • The subject is currently receiving anticoagulation with therapeutic doses of warfarin (low-dose warfarin ≤ 1mg/day is permitted)
  • The subject is pregnant or breastfeeding
  • The subject is known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at screening is not required)
  • The subject has any other diagnosis of malignancy or evidence of malignancy (except non-melanoma skin cancer, in situ carcinoma of the cervix) within 2 years prior to screening for this study
  • The subject has a previously identified allergy or hypersensitivity or is intolerant to components of any of the study treatment formulations
  • The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
Contacts and Locations

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 ClinicalTrials.gov identifier (NCT number): NCT01042925

United States, California
Investigational Site Number 1537
Los Angeles, California, United States, 90033
United States, Florida
Investigational Site Number 1238
Fort Meyers, Florida, United States, 33901
United States, Massachusetts
Investigational Site Number 1138
Boston, Massachusetts, United States, 02115
United States, Michigan
Investigational Site Number 1330
Detroit, Michigan, United States, 48201
United States, New York
Investigational Site Number 1151
Bronx, New York, United States, 10467
Investigational Site Number 1150
New York, New York, United States, 10032
United States, Tennessee
Investigational Site Number 1214
Nashville, Tennessee, United States, 37203
Investigational Site Number 1246
Nashville, Tennessee, United States, 37232
Investigational Site Number 3413
Madrid, Spain, 28041
Sponsors and Collaborators
Study Director: Clinical Sciences & Operations Sanofi
More Information

Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT01042925     History of Changes
Other Study ID Numbers: ARD11439
XL147-203 ( Other Identifier: (other study code) )
First Posted: January 6, 2010    Key Record Dates
Last Update Posted: June 3, 2016
Last Verified: May 2016

Keywords provided by Sanofi:
HER2 positive breast cancer
breast cancer
breast tumors
human mammary carcinoma

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action