| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ADVANCED TRIPLE-NEGATIVE BREAST CANCER WITH OR WITHOUT GENOMIC ALTERATIONS IN NOTCH RECEPTORS |
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| E.1.1.1 | Medical condition in easily understood language |
| ADVANCED TRIPLE-NEGATIVE BREAST CANCER WITH OR WITHOUT GENOMIC ALTERATIONS IN NOTCH RECEPTORS |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
| •To estimate the objective response rate (ORR) of PF-03084014 when given as a single agent in the treatment of patients with advanced TNBC harboring genomic alterations in Notch receptors (NA+). |
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| E.2.2 | Secondary objectives of the trial |
•To estimate the ORR of PF-03084014 when given as a single agent in the treatment of patients with advanced TNBC whose tumor tests negative for genomic alterations in Notch receptors (NA-);
•To evaluate progression-free survival (PFS), duration of response (DR), one year survival probability, and overall survival (OS) on PF-03084014 treatment in patients with NA+ or NA- mTNBC;
•To determine the performance of the proposed NGS assay in indentifying patients with NA+ or NA- mTNBC;
•To determine steady state serum concentrations of PF-03084014;
•To characterize the pharmacodynamic effects of PF-03084014 in tumor specimens and peripheral blood;
•To characterize alterations in genes, proteins, and ribonucleic acids (RNAs) relevant to the Notch signaling pathway, to TNBC biology, and to sensitivity/resistance to PF-03084014 in tumor specimens and peripheral blood;
•To evaluate the overall safety profile of PF-03084014.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Histological or cytological diagnosis of triple negative breast cancer (TNBC) with evidence of a) metastatic or b) locally recurrent advanced disease that is not amenable to resection or radiotherapy with curative intent.
•For France: Histological diagnosis of triple negative breast cancer (TNBC) with evidence of a) metastatic or b) locally recurrent advanced disease that is not amenable to resection or radiotherapy with curative intent.
•In all patients, documentation of ER/PR-negative status and HER2/neu receptor- negative status (ie, by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) [where approved] negative or immunohistochemistry (IHC) 0 or +1) on archival biopsy.
2.De novo or previously treated advanced disease in patients whose tumors are NA + provided they have no impending vital organ compromise (visceral).
•For France and Germany: previously treated with 1 or more prior therapies for advanced disease in patients whose tumors are NA +.
3.Previously treated with 1 or more prior therapies for advanced disease in patients whose tumors are NA-.
•For France and Germany: Patients whose tumors are NA- are excluded from enrollment.
4.At least one measurable tumor lesion as defined by RECIST version 1.1.
5.Availability of an original diagnostic tumor tissue or the most recent metastatic tumor biopsies (archival biopsy or de novo biopsy) and a peripheral blood sample for Notch receptors genomic profiling:
•In at least 28 patients, detectable genomic alteration in Notch 1, 2, 3, or 4 receptor in original diagnostic tumor tissue or the most recent metastatic tumor biopsies (archival biopsy or de novo biopsy) as defined by a CLIA-certified NGS assay; presence of Notch 1, 2, 3, or 4 receptor activating alterations must be confirmed by comparison to the germline status, as detected in the peripheral blood sample;
•In at least 20 patients, no detectable genomic alteration in Notch 1, 2, 3, or 4 receptor in original diagnostic tumor tissue or the most recent metastatic tumor biopsies (archival biopsy or de novo biopsy) as defined by a CLIA-certified NGS assay.
6.Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2.
7.Female, age ≥ 18 years.
8.Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1 except for those AEs not constituting a safety risk by Investigator judgment.
9.Adequate Bone Marrow Function, including:
•Absolute Neutrophil Count (ANC) ≥1,500/μL or ≥1.5 x 1 000 000 000/L;
•Platelets ≥100,000/μL or ≥100 x 1 000 000 000/L;
•Hemoglobin ≥9 g/dL.
10.Adequate Renal Function, including:
•Serum creatinine ≤1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥60 mL/min as calculated using the method standard for the institution.
11.Adequate Liver Function, including:
•Total serum bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome;
•Aspartate and Alanine Aminotransferase (AST and ALT) ≤2.5 x ULN; ≤5.0 x ULN if there is metastatic liver disease;
•Alkaline phosphatase ≤2.5 x ULN; (≤5 x ULN in case of bone metastasis).
12.Serum/urine pregnancy test (for patients of childbearing potential) negative at screening.
13.Patients of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and for at least 28 days after the last dose of assigned treatment.
Patients who are not of childbearing potential (ie, meet at least 1 of the following criteria):
•Have undergone a documented hysterectomy and/or bilateral oophorectomy;
•Have medically confirmed ovarian failure; or
•Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal women.
14.Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
15.Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other procedures.
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| E.4 | Principal exclusion criteria |
1.Known brain metastases.
2.Major surgery within 4 weeks of study entry.
3.Radiation therapy within 4 weeks of study entry; a previously irradiated lesion is non-measurable unless it has progressed since completion of radiation treatment.
4.Systemic anti cancer therapies within 2 weeks of study entry.
5.Prior treatment with gamma secretase inhibitor or other Notch signaling inhibitor.
6.Participation in other studies involving investigational drug(s) (Phases 1-4) within 2 weeks before the current study begins and/or during study participation.
7.Current use or anticipated need for treatment with other anti-cancer drugs.
8.Known malabsorption syndrome or other condition that may impair absorption of PF 03084014 (eg, gastric bypass or lap band).
9.Active and clinically significant bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
10.Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism.
11.QTc interval >470 msec (mean of triplicate electrocardiogram (ECG) readings).
12.Diagnosis of any second malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or adequately treated carcinoma in situ of the cervix.
13.Pregnant or breastfeeding patients.
14.Current use or anticipated need for food or drugs that are strong/moderate CYP3A4/5 inhibitors, including their administration within 7 days prior to study entry. Refer to Appendix 3 and Appendix 4 for a list of strong and moderate inhibitors.
15.Current use or anticipated need for food or drugs that are strong CYP3A4/5 inducers, including their administration within 7 days prior to study entry. Refer to Appendix 5 for a list of strong inducers.
16.Current use or anticipated need for treatment with oral anti vitamin K agents or other oral anti coagulants. Treatment with therapeutic doses of low-molecular weight heparin is allowed.
17.Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees directly involved in the conduct of the study.
18.Other severe acute or chronic medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Objective response (OR) as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 in patients with NA+ mTNBC. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please see the protocol for the timepoints. |
|
| E.5.2 | Secondary end point(s) |
•OR as assessed using the Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 in patients with NA mTNBC;
•Progression-free survival (PFS) in patients with NA+ or NA mTNBC;
•Duration of response (DR) in patients with NA+ or NA mTNBC;
•One-year survival probability in patients with NA+ or NA mTNBC;
•Overall survival (OS) in patients with NA+ or NA mTNBC;
•Type and number of Notch genomic alterations identified by NGS assay in patients with NA+ mTNBC;
•PF-03084014 serum Ctrough levels;
•Pharmacodynamic effects of PF-03084014 in tumor specimens and peripheral blood;
•Alterations in genes, proteins, and RNAs relevant to the Notch signaling pathway, to TNBC biology, and to sensitivity/resistance to PF-03084014 in tumor specimens and peripheral blood;
•Adverse Events as characterized by type, frequency, severity [as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, timing, seriousness and relationship to study therapy];
•Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 4.03) and timing.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please see the protocol for the timepoints. |
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| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | No |
| 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 |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
| United Kingdom |
| United States |
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| 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
|
End of trial in a Member State of the European Union is defined as the time at which it is deemed that a sufficient number of patients have been recruited and completed the study as stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application in the Member State.
End of trial in all other participating Countries is defined as last patient last visit (LPLV). |
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| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 30 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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