| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Metastatic Breast Cancer who have Progressed on a Previous Trastuzumab-Based Regimen |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives are:
• To evaluate the safety and tolerability of XL147 in combination with trastuzumab and in combination with
trastuzumab and paclitaxel.
• To determine the maximum tolerated dose (MTD) of XL147 when administered in combination with
trastuzumab and in combination with trastuzumab and paclitaxel (Phase 1).
• To estimate the efficacy endpoint of objective tumor response rate (ORR) in the study population and in
subpopulations based on the presence or absence of tumor PI3K pathway alterations (ie, molecular alterations
that directly affect the PI3K pathway: PIK3CA mutation/amplification and/or PTEN deficiency) (Phase 2). |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
• To estimate duration of response (DOR) and progression-free survival (PFS), including landmarks such as PFS
at 6 months (Phase 2).
• To assess the pharmacokinetics (PK) and pharmacodynamics of XL147 and trastuzumab when given in
combination, and of XL147, trastuzumab, and paclitaxel when given in combination. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject has pathologically and radiologically confirmed metastatic HER2 positive breast cancer (Stage IV
disease). The following restrictions to prior anti-cancer therapy apply:
a. Subjects must have received and progressed on at least one prior trastuzumab-containing regimen for
metastatic disease, or have received trastuzumab as adjuvant treatment and progressed within 1 year of their last
dose of trastuzumab.
b. Subjects must have received at least one prior taxane-containing regimen as adjuvant treatment or for
metastatic disease (Arm 2).
c. Subjects must have received no more than five prior cytotoxic chemotherapeutic regimens for MBC (Phase 2).
Note: consecutive re-treatment with the same regimen does count as one regimen.
NOTE: Drugs used to control bone pain and/or osteoporosis (eg, bisphosphonates) are allowed if started at least 2
months prior to screening activities or may be initiated during the course of the study with the agreement of the
sponsor.
2. 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) per RECIST Version 1.1.
NOTE: Bone lesions are not considered measurable by definition. Primary breast lesions are not considered
measurable if assessed only by physical examination.
3. The subjects enrolled in Phase 2 of both treatment arms must be willing to undergo a biopsy of the primary
tumor or a tumor metastasis at baseline, if tumor tissue is amenable to biopsy. Fresh tissue from this biopsy
must be in the possession of the participating site/institution, and designated for shipment to the sponsor or a
laboratory designated by the sponsor.
4. The subject’s primary tumor and/or metastatic lesion must overexpress HER2. Acceptable methods of
measurement of HER2 overexpression/amplification include immunohistochemical (IHC) based assessments and
fluorescence in situ hybridization (FISH). Tumors tested by IHC must be 3+ positive. Tumors tested by FISH
must have a ratio of HER2:CEP17 > 2.0.
5. The subject is ≥ 18 years old.
6. For subjects enrolled in Phase 2 of both treatment arms: at least fifteen (15) 4-10 micron tissue sections (≥
15 unstained slides [20 preferable], without cover slips) from archival or fresh tissue, or a tissue block of the
subject’s tumor should be identified, in the possession of the participating site/institution, and designated for
shipment to the sponsor or a laboratory designated by the sponsor.
• If, after the enrollment of the first 10 subjects in each arm, the incidence of molecular alterations directly
affecting the PI3K pathway in these 10 subjects in each arm is not between 40 and 60%, subject pre-selection
may be implemented and subsequent enrollment may be gated by alteration status to ensure that the frequency of
PI3K pathway alterations falls within the range of 40-60% for the study population in each arm.
7. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
8. The subject has organ and marrow function as follows:
a. Absolute neutrophil count (ANC) ≥ 1500/mm3.
b. Platelets ≥ 100,000/mm3.
c. Hemoglobin ≥ 9 g/dL.
d. Bilirubin ≤ 1.5 × the upper limit of normal (ULN).
e. Serum creatinine ≤ 1.5 × the ULN or calculated creatinine clearance ≥ 60 mL/min.
f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × the ULN if no liver
involvement, or ≤ 5 × the ULN with liver involvement.
9. 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.
10. Sexually active subjects must agree to use a medically-accepted barrier method of contraception (eg, barrier
methods, including male condom, female condom, or diaphragm with spermicidal gel) 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.
11. Subjects of childbearing potential must have a negative pregnancy test at screening and enrollment. Subjects
of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who
have had any evidence of menses in the past 12 months with the exception of those who had prior hysterectomy,
oophorectomy or surgical sterilization). However, women who have been amenorrheic for ≥ 12 months are still
considered to be of childbearing potential if the amenorrhea is possibly due to any other cause including prior
chemotherapy, antiestrogens, or ovarian suppression. |
|
| E.4 | Principal exclusion criteria |
1. The subject has previously been treated with a selective inhibitor of PI3K and / or AKT.
2. The following restrictions on prior therapy apply:
a. Small molecule targeted (non-cytotoxic) inhibitors (including investigational kinase inhibitors) within 2
weeks or 5 half-lives of the compound or active metabolites, whichever is longer, before the first dose of study
treatment.
b.Radiation therapy within 2 weeks before the first dose of study treatment.
c. Hormonal therapy within 2 weeks before the first dose of study treatment.
d.Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) within 3 weeks, or nitrosoureas or
mitomycin C within 6 weeks before the first dose of study treatment.
e. Biologic therapy (including antibodies {other than trastuzumab}, immune modulators, cytokines) within 4
weeks before the first dose of study treatment. Note: There is no washout period required for trastuzumab.
f. Any other type of investigational agent within 4 weeks
g. Major surgery, or not recovered from major surgery, within 4 weeks before the first dose of study treatment.
3. The subject has not recovered from toxicity due to prior therapy to Grade ≤ 1 or to pre-therapy baseline. Grade 2 alopecia related to prior therapies will not affect the eligibility of the subject in Arm 1 and Arm 2. Grade 2 peripheral neuropathy will not affect the eligibility in Arm 1 but is an exclusion criterion for Arm 2.
4. The subject has untreated, symptomatic, or progressive brain metastases. Subjects must have no radiographic or other signs of progression in the brain for ≥1 month after completion of local therapy. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥4 weeks prior to first study treatment.
5. The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial thromboplastin time (PTT) test results at screening that are ≥ 1.3 x the laboratory ULN.
6. The subject has a diagnosis of uncontrolled diabetes mellitus (glycosylated hemoglobin A1C ≥ 8%) or has a fasting plasma glucose > 160 mg/dL
7. The subject has uncontrolled significant intercurrent illness including, but not limited to, ongoing or active infection requiring systemic treatment, or stroke within 3 months of screening.
8. The subject has uncontrolled hypertension (persistent values of ≥ 150 mm Hg systolic or 100 mm Hg diastolic despite anti hypertensive therapy); or significant cardiovascular disease, eg, ≥ New York Heart Association (NYHA) Class III congestive heart failure (CHF); or uncontrolled clinically significant atrial or ventricular cardiac arrhythmias; or any of the following in the past 6 months:
a. myocardial infarction
b. evidence of transmural infarction on ECG
c. unstable angina
d. coronary angioplasty
9. The subject has left ventricular ejection fraction (LVEF) ≤ 50% of the expected LVEF as documented by multiple-gated acquisition (MUGA) or echocardiogram (ECHO) performed within 28 days prior to the first dose of study drug.
10. The subject has a baseline corrected QT interval ≥ 460 ms.
11. The subject is currently receiving anticoagulation with therapeutic doses of warfarin (low-dose warfarin ≤ 1mg/day is permitted).
12. The subject is taking oral corticosteroids (equivalent to prednisone > 7.5 mg daily) chronically.
13. The subject is pregnant or breastfeeding.
14. The subject is known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at screening is not required).
15. 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.
16. The subject has a previously identified allergy or hypersensitivity or is intolerant to components of the study treatment formulation (XL147, trastuzumab (and paclitaxel for Arm 2)).
17. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• To evaluate the safety and tolerability of XL147 in combination with trastuzumab and in combination with trastuzumab and paclitaxel.
• To determine the MTD of XL147 when administered in combination with trastuzumab and in combination with trastuzumab and paclitaxel (Phase 1).
• To estimate the efficacy endpoint of objective tumor response rate (ORR) in the study population and in subpopulations based on the presence or absence of tumor PI3K pathway alterations (ie, molecular alterations that directly affect the PI3K pathway: PIK3CA mutation/ amplification and/or PTEN deficiency) (Phase 2).
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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