Triple Negative Breast Neoplasms
Conditions
Keywords
PF-03084014, Notch Alterations
Brief summary
This study is designed to evaluate the preliminary anti-tumor activity and tolerability of PF-03084014 when administered as a single agent in the treatment of patients with advanced triple receptor-negative breast cancer (mTNBC) harboring genomic alterations in Notch receptors (NA+), and in a smaller subset of mTNBC patients whose tumor tests negative for genomic alterations in Notch receptors (NA-)
Interventions
DRUGPF-03084014
Tablet, 10 mg, twice a day.
Sponsors
Pfizer
Study design
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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. * 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
Exclusion criteria
* Known brain metastases. * Prior treatment with gamma secretase inhibitor or other Notch signaling inhibitor.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response (OR) Rate in Participants With Advanced Triple Receptor-Negative Breast Cancer (mTNBC) Harboring Activating Genomic Alterations in Notch Receptors (NA+) | Cycle 3 Day 1, Cycle 5 Day 1, and every 6 weeks for subsequent cycles ntil disease progression, patient refusal for further follow up, or start of another anti-cancer treatment, whichever occurred first. | OR status based on assessment of confirmed complete remission (CR) or confirmed partial remission (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR: Complete disappearance of all target lesions with the exception of nodal disease and all target nodes decreased to normal size (short axis less than \[\<\]10 millimeter \[mm\]). PR: Greater than or equal to (\>=)30% decrease under baseline of the sum of diameters of all target measurable lesions. OR=CR+PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) in Participants With NA+ or NA mTNBC | 2 years | The period from study entry until disease progression, death, whichever occurred first as per RECIST version 1.1. |
| Duration of Response (DR) in Participants With NA+ or NA mTNBC | 2 years | Time from the first documentation of objective tumor response to objective tumor progression or death due to any cause. DR was calculated for the subgroup of patients with a confirmed objective tumor response. Objective Progression (PD): 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm. |
| One-Year Survival Probability in Participants With NA+ or NA mTNBC | 1 year | Overall survival (OS) status (alive or not) at 1 year after study entry. The the survival probability at 1 year was summarized as a product limit estimator based on the Kaplan-Meier method to account for censored events. |
| Overall Survival (OS) in Participants With NA+ or NA mTNBC | 2 years | OS was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact. |
| Type of Notch Genomic Alterations in Participants With NA+ mTNBC | 2 years | Type of notch genomic alterations identified by NGS assay in patients with NA+ mTNBC |
| Pre-dose Serum Concentration (Ctrough) for PF-03084014 | Day 1 of Cycle 1, 2, 3, and 5 | — |
| Pharmacodynamic (PD) Effects of PF-03084014 in Tumor Specimens and Peripheral Blood | Day 1 of Cycle 1, 2, 3, and 5 | Original diagnostic tumor tissue or the most recent metastatic tumor (archival or de novo biopsy), plasma, and peripheral blood samples were collected for biomarker assessments of circulating analytes, immunohistochemistry for notch receptors expression, expression of notch pathway components and modulators, mutational analysis of pathway and disease associated genes. |
| OR Rate in Participants With mTNBC Whose Tumors Tested Negative for Eenomic Alterations in Notch Receptor (NA-) | Cycle 3 Day 1, Cycle 5 Day 1, and every 6 weeks for subsequent cycles ntil disease progression, patient refusal for further follow up, or start of another anti-cancer treatment, whichever occurred first. | OR status based on assessment of confirmed CR or confirmed PR according to RECIST 1.1. CR: Complete disappearance of all target lesions with the exception of nodal disease and all target nodes decreased to normal size (short axis \<10 mm). PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. OR=CR+PR. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | 2 years | An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were defined as all deaths, regardless of cause, from treatment start until 28 days after the last dose and non-fatal events occurring after treatment start regardless of cause, up until 28 days after the last dose or until start of new anti-cancer treatment, whichever was first. |
| Number of Participants With Treatment-Emergent AEs by CTCAE Grade | 2 years | An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. AEs were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
| Number of Participants With Laboratory Test (Hematology) Abnormalities | Day 1 of Cycles 1, 2, 3, 4, 5, and subsequent cycles. | Number of participants with CTCAE version 4.03 grade 1 to 4 hematological test abnormalities. |
| Number of Participants With Laboratory Test (Chemistry) Abnormalities | Day 1 and Day 15 of Cycles 1, 2, 3, 4, 5, and subsequent cycles up to Cycle 8 and Day 8 of Cycle 1 | Number of participants with CTCAE version 4.03 grade 1 to 4 chemistry test abnormalities |
| Number of Participants With Laboratory Test (Urinalysis) Abnormalities | Day 1 of Cycle 1 | Number of participants with CTCAE version 4.03 grade 1 to 4 urinalysis test abnormalities for urine protein. |
| Number of Notch Genomic Alterations in Participants With NA+ mTNBC | 2 years | Number of notch genomic alterations identified by NGS assay in patients with NA+ mTNBC |
| 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. | Day 1 of Cycle 1, 2, 3, and 5 | Original diagnostic tumor tissue or the most recent metastatic tumor (archival or de novo biopsy), plasma, and peripheral blood samples were collected for biomarker assessments of circulating analytes, immunohistochemistry for notch receptors expression, expression of notch pathway components and modulators, mutational analysis of pathway and disease associated genes. |
Countries
Hungary, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-03084014 PF-03084014 at the starting dose of 150 mg twice daily (BID) (in the form of one 100-mg and one 50-mg tablet) was administered orally BID continuously in 21-day cycles until disease progression, patient refusal of further treatment, or unacceptable toxicity, whichever occurred first. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 1 |
| Overall Study | Global deterioration of health status | 1 |
| Overall Study | Objective progression or relapse | 10 |
| Overall Study | Other | 3 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | PF-03084014 |
|---|---|
| Age, Continuous | 57.4 years STANDARD_DEVIATION 12.1 |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 19 |
| serious Total, serious adverse events | 6 / 19 |
Outcome results
Primary
Objective Response (OR) Rate in Participants With Advanced Triple Receptor-Negative Breast Cancer (mTNBC) Harboring Activating Genomic Alterations in Notch Receptors (NA+)
OR status based on assessment of confirmed complete remission (CR) or confirmed partial remission (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR: Complete disappearance of all target lesions with the exception of nodal disease and all target nodes decreased to normal size (short axis less than \[\<\]10 millimeter \[mm\]). PR: Greater than or equal to (\>=)30% decrease under baseline of the sum of diameters of all target measurable lesions. OR=CR+PR.
Time frame: Cycle 3 Day 1, Cycle 5 Day 1, and every 6 weeks for subsequent cycles ntil disease progression, patient refusal for further follow up, or start of another anti-cancer treatment, whichever occurred first.
Population: Data for this outcome measure was not collected due to early termination of this study.
Secondary
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.
Original diagnostic tumor tissue or the most recent metastatic tumor (archival or de novo biopsy), plasma, and peripheral blood samples were collected for biomarker assessments of circulating analytes, immunohistochemistry for notch receptors expression, expression of notch pathway components and modulators, mutational analysis of pathway and disease associated genes.
Time frame: Day 1 of Cycle 1, 2, 3, and 5
Population: Due to study termination, no PD analyses were performed for this study.
Secondary
Duration of Response (DR) in Participants With NA+ or NA mTNBC
Time from the first documentation of objective tumor response to objective tumor progression or death due to any cause. DR was calculated for the subgroup of patients with a confirmed objective tumor response. Objective Progression (PD): 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.
Time frame: 2 years
Population: Data for this outcome measure was not collected due to early termination of this study.
Secondary
Number of Notch Genomic Alterations in Participants With NA+ mTNBC
Number of notch genomic alterations identified by NGS assay in patients with NA+ mTNBC
Time frame: 2 years
Population: Data for this outcome measure was not collected due to early termination of this study.
Secondary
Number of Participants With Laboratory Test (Chemistry) Abnormalities
Number of participants with CTCAE version 4.03 grade 1 to 4 chemistry test abnormalities
Time frame: Day 1 and Day 15 of Cycles 1, 2, 3, 4, 5, and subsequent cycles up to Cycle 8 and Day 8 of Cycle 1
Population: The safety analysis set included all enrolled participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Alanine aminotransferase | 5 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Alkaline phosphatase | 6 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Aspartate aminotransferase | 9 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Bilirubin (total) | 1 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Creatine kinase | 1 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Creatinine | 13 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Gamma glutamyl transferase | 1 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hypercalcemia | 3 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hyperglycemia | 13 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hyperkalemia | 3 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hypermagnesemia | 1 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hypernatremia | 0 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hypoalbuminemia | 8 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hypocalcemia | 4 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hypoglycemia | 1 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hypokalemia | 5 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hypomagnesemia | 3 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hyponatremia | 6 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Chemistry) Abnormalities | Hypophosphatemia | 14 participants |
Secondary
Number of Participants With Laboratory Test (Hematology) Abnormalities
Number of participants with CTCAE version 4.03 grade 1 to 4 hematological test abnormalities.
Time frame: Day 1 of Cycles 1, 2, 3, 4, 5, and subsequent cycles.
Population: The safety analysis set included all enrolled participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-03084014 | Number of Participants With Laboratory Test (Hematology) Abnormalities | Anemia | 12 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Hematology) Abnormalities | Lymphocyte count increased | 0 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Hematology) Abnormalities | Lymphopenia | 11 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Hematology) Abnormalities | Neutrophils (absolute) | 0 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Hematology) Abnormalities | Platelets | 3 participants |
| PF-03084014 | Number of Participants With Laboratory Test (Hematology) Abnormalities | White blood cells | 4 participants |
Secondary
Number of Participants With Laboratory Test (Urinalysis) Abnormalities
Number of participants with CTCAE version 4.03 grade 1 to 4 urinalysis test abnormalities for urine protein.
Time frame: Day 1 of Cycle 1
Population: The safety analysis set included all enrolled participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-03084014 | Number of Participants With Laboratory Test (Urinalysis) Abnormalities | 2 participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were defined as all deaths, regardless of cause, from treatment start until 28 days after the last dose and non-fatal events occurring after treatment start regardless of cause, up until 28 days after the last dose or until start of new anti-cancer treatment, whichever was first.
Time frame: 2 years
Population: The safety analysis set included all enrolled participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-03084014 | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Number of Participants with AEs | 18 participants |
| PF-03084014 | Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) | Number of Participants with SAEs | 6 participants |
Secondary
Number of Participants With Treatment-Emergent AEs by CTCAE Grade
An AE was any untoward medical occurrence without regard to causality in a participant who received study drug. AEs were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time frame: 2 years
Population: The safety analysis set included all enrolled participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PF-03084014 | Number of Participants With Treatment-Emergent AEs by CTCAE Grade | Any AEs, Grade 1 | 1 participants |
| PF-03084014 | Number of Participants With Treatment-Emergent AEs by CTCAE Grade | Any AEs, Grade 2 | 5 participants |
| PF-03084014 | Number of Participants With Treatment-Emergent AEs by CTCAE Grade | Any AEs, Grade 3 | 9 participants |
| PF-03084014 | Number of Participants With Treatment-Emergent AEs by CTCAE Grade | Any AEs, Grade 4 | 1 participants |
| PF-03084014 | Number of Participants With Treatment-Emergent AEs by CTCAE Grade | Any AEs, Grade 5 | 2 participants |
Secondary
One-Year Survival Probability in Participants With NA+ or NA mTNBC
Overall survival (OS) status (alive or not) at 1 year after study entry. The the survival probability at 1 year was summarized as a product limit estimator based on the Kaplan-Meier method to account for censored events.
Time frame: 1 year
Population: Data for this outcome measure was not collected due to early termination of this study.
Secondary
OR Rate in Participants With mTNBC Whose Tumors Tested Negative for Eenomic Alterations in Notch Receptor (NA-)
OR status based on assessment of confirmed CR or confirmed PR according to RECIST 1.1. CR: Complete disappearance of all target lesions with the exception of nodal disease and all target nodes decreased to normal size (short axis \<10 mm). PR: \>=30% decrease under baseline of the sum of diameters of all target measurable lesions. OR=CR+PR.
Time frame: Cycle 3 Day 1, Cycle 5 Day 1, and every 6 weeks for subsequent cycles ntil disease progression, patient refusal for further follow up, or start of another anti-cancer treatment, whichever occurred first.
Population: Data for this outcome measure was not collected due to early termination of this study.
Secondary
Overall Survival (OS) in Participants With NA+ or NA mTNBC
OS was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact.
Time frame: 2 years
Population: Data for this outcome measure was not collected due to early termination of this study.
Secondary
Pharmacodynamic (PD) Effects of PF-03084014 in Tumor Specimens and Peripheral Blood
Original diagnostic tumor tissue or the most recent metastatic tumor (archival or de novo biopsy), plasma, and peripheral blood samples were collected for biomarker assessments of circulating analytes, immunohistochemistry for notch receptors expression, expression of notch pathway components and modulators, mutational analysis of pathway and disease associated genes.
Time frame: Day 1 of Cycle 1, 2, 3, and 5
Population: Due to study termination, no PD analyses were performed for this study.
Secondary
Pre-dose Serum Concentration (Ctrough) for PF-03084014
Time frame: Day 1 of Cycle 1, 2, 3, and 5
Population: Due to study termination, no PK analyses were performed for this study.
Secondary
Progression-Free Survival (PFS) in Participants With NA+ or NA mTNBC
The period from study entry until disease progression, death, whichever occurred first as per RECIST version 1.1.
Time frame: 2 years
Population: Data for this outcome measure was not collected due to early termination of this study.
Secondary
Type of Notch Genomic Alterations in Participants With NA+ mTNBC
Type of notch genomic alterations identified by NGS assay in patients with NA+ mTNBC
Time frame: 2 years
Population: Data for this outcome measure was not collected due to early termination of this study.