HER2+ Breast Cancer, Metastatic Breast Cancer
Conditions
Keywords
HER2, BKM120, PIK3, metastatic breast cancer, brain metastases, Herceptin, trastuzumab, capecitabine, open-label, maximum tolerated dose, Phase I/Phase ll
Brief summary
This study will assess the safety and efficacy of BKM120 in combination with trastuzumab in patients with relapsing HER2 overexpressing breast cancer who have previously failed trastuzumab. The study will further assess the safety and preliminary efficacy of BKM120 in combination with trastuzumab and capecitabine in patients with relapsing HER2 overexpressing breast cancer and brain metastases (BM) who have previously failed trastuzumab.
Interventions
DRUGCapecitabine
1000 mg/m2 twice a day from day 1 to Day 14 of a 21-day cycle.
DRUGBKM120
Buparlisib (BKM120) is the investigational drug. Burparlisib was supplied as 10 mg and 50 mg hard gelatin capsules. Buparlisib was dosed on a flat scale of mg/day and not adjusted to body weight or body surface area. Buparlisib capsules were packaged in high density polyethylene bottles with a plastic child resistant closure.
DRUGTrastuzumab
Trastuzumab was used in this study according to the local regulations in each participating country. A loading dose (4 mg/kg) of trastuzumab was administered (if required as assessed by the principal Investigator based on the timing of the last trastuzumab dose prior to enrollment) on Day -7 over 90 minutes, followed by weekly intravenous infusion of 2 mg/kg maintenance doses from Day 1 of Cycle 1 (over 30 minutes if the previous infusion was well tolerated).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* World Health Organization (WHO) Performance Status of ≤ 2 * Patients with HER2+ breast cancer by local laboratory testing (immunohistochemistry \[IHC\] 3+ staining or fluorescence in situ hybridization \[FISH\] confirmation for IHC 2+ and 1+) * Documented tumor resistance to trastuzumab: * Recurrence while on trastuzumab or within 12 months since the last infusion for patients who received trastuzumab as adjuvant treatment * Progression while on or within 4 weeks since the last infusion of trastuzumab for patients who received trastuzumab for metastatic disease. * Documented evidence of progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) on trastuzumab-based therapy defined as: * Phase Ib: at any time before study entry * Phase II: within 16 weeks before date of first dosing * Received at least 1 but no more than 4 prior anit-HER2 based regimens including at least 1 regimen containing trastuzumab (adjuvant or neo-adjuvant trastuzumab will be considered as one prior regimen). HER2 directed therapies are defined as comprising trastuzumab, lapatinib, and trastuzumab-DM1 (T-DM1) only. • Phase II only: trastuzumab, T-DM1 or lapatinib must be part of the most recent line of therapy * Previous lines of cytotoxic chemotherapy: * Phase Ib: no more than 4 lines of cytotoxic chemotherapy * Phase II: no more than 3 lines of cytotoxic chemotherapy Measurable disease: * Phase Ib: patient has at least one measurable lesion or non-measurable disease as defined per RECIST * Phase II: patient has at least one measureable lesion as defined per RECIST \|\| Specific Inclusion Criteria for patients in BM cohorts: * Patient has evidence of progressing brain metastases and/or new metastatic brain lesion(s) without leptomeningeal disease. * Patient has received prior WBRT and/or SRS at at \>28 and \>/= 14 days, respectively, prior to starting study drug and the patient must have recovered from the side effects of the therapy * WHO performance status of \</=1 * PT INR \</= 1.5 * Any number of prior HER2-directed and cytotoxic regimens, and the most recent line may be any type of anti-neoplastic therapy \|\|
Exclusion criteria
* Patients with untreated brain metastases * Patients with acute or chronic liver, renal disease or pancreatitis * Patients with any peripheral neuropathy ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 2 * Patients with a history of mood disorders or ≥ CTCAE grade 3 anxiety * Patient with clinical manifest diabetes mellitus or steroid-induced diabetes mellitus \|\| Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) - Phase l Only | cycle 1 - 28 days | Determination of the maximum tolerated dose (MTD) in the dose escalation part of the study was based upon the estimation of the probability of DLT in Cycle 1 in patients of the dose-determining set. |
| Overall Response Rate (ORR) - Phase ll | 18 months | Objective response rate (ORR) was defined as the rate of patients with best overall response (BOR) equal to complete response (CR) or partial response (PR) according to RECIST 1.0 from the Investigators review. Per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed of the disease status by imaging (i.e. CT/MRI): Complete Response (CR) = Disappearance of all tumor lesions; Partial Response (PR)= \>=30% shrinkage of lesions; Overall Response (OR) = patients with CR and PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll | 18 months | Disease control rate (DCR) = patients with complete response (CR), partial response (PR) or stable disease (SD) as per RECIST criteria. Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = disappearance of all tumor lesions; PR = \>=30% shrinkage of lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD); PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline. |
| Clinical Benefit Rate (CBR) - Phase l & ll | 18 months | CBR = patients with CR, PR or SD ≥ 24 weeks according to RECIST by the investigator. Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = Disappearance of all tumor lesions; PR= \>=30% shrinkage of lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline. |
| Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | 18 months | — |
Countries
Belgium, France, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
72 patients (pts) were enrolled: 18 in ph lb, 53 in ph ll, including 8 from ph lb, with 45 new pts in ph ll & 9 in the brain metastasis (BM) cohort. Of the 72 pts, 1 in ph lb & 3 in phase ll, did not receive Burparlisib, only Trastuzumab. Therefore, 68 patients (17 in ph l, 42 in ph ll, 9 in BM cohort) were treated with buparlisib + trastuzumab.
Pre-assignment details
Primary outcome measure for BM cohort was MTD/RP2D which was not reached/established due to premature termination of the study. Objective Response Rate (ORR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR) & Progression Free Survival (PFS)were not calculated for the BM cohort either.
Participants by arm
| Arm | Count |
|---|---|
| Phase Ib - 50 mg Patients in the phase Ib dose escalation cohort who received 50 mg of buparlisib - investigational drug | 5 |
| Phase Ib - 100mg Patients in the phase Ib dose escalation cohort who received 100 mg of buparlisib - investigational drug | 12 |
| Phase II - 100mg Patients in the phase II only expansion cohort who received 100 mg of buparlisib - investigational drug | 42 |
| BM Cohort - 80mg Patients in the BM cohort who received 80 mg of buparlisib - investigational drug | 3 |
| BM Cohort - 100mg Patients in the BM cohort who received 100 mg of buparlisib - investigational drug | 6 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| BM Cohort | Adverse Event | 0 | 0 | 0 | 0 | 1 |
| BM Cohort | Disease progression | 0 | 0 | 0 | 3 | 4 |
| BM Cohort | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
| Phase lb | Adverse Event | 0 | 1 | 0 | 0 | 0 |
| Phase lb | Disease Progression | 4 | 9 | 0 | 0 | 0 |
| Phase lb | Withdrawal by Subject | 1 | 2 | 0 | 0 | 0 |
| Phase ll | Adverse Event | 0 | 0 | 10 | 0 | 0 |
| Phase ll | Death | 0 | 0 | 2 | 0 | 0 |
| Phase ll | Disease progression | 0 | 0 | 35 | 0 | 0 |
| Phase ll | Withdrawal by Subject | 0 | 0 | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase Ib - 50 mg | Phase Ib - 100mg | Phase II - 100mg | BM Cohort - 80mg | BM Cohort - 100mg | Total |
|---|---|---|---|---|---|---|
| Age, Customized <65 years | 5 Participants | 11 Participants | 35 Participants | 3 Participants | 6 Participants | 60 Participants |
| Age, Customized >=65 years | 0 Participants | 1 Participants | 7 Participants | 0 Participants | 0 Participants | 8 Participants |
| Female: Child bearing potential Able to bear children | 2 Participants | 3 Participants | 8 Participants | 1 Participants | 1 Participants | 15 Participants |
| Female: Child bearing potential Post-menopausal | 3 Participants | 8 Participants | 31 Participants | 2 Participants | 4 Participants | 48 Participants |
| Female: Child bearing potential Premenarche | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Female: Child bearing potential Sterile - of child bearing age | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 42 Participants | 3 Participants | 6 Participants | 68 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 12 / 12 | 50 / 50 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 2 / 5 | 2 / 12 | 17 / 50 | 2 / 3 | 4 / 6 |
Outcome results
Primary
Dose Limiting Toxicity (DLT) - Phase l Only
Determination of the maximum tolerated dose (MTD) in the dose escalation part of the study was based upon the estimation of the probability of DLT in Cycle 1 in patients of the dose-determining set.
Time frame: cycle 1 - 28 days
Population: The Dose-determining set (DDS) for the determination of the MTD consisted of all patients from the safety set in the dose escalation phase who had met the minimum safety evaluation requirements and the minimum exposure criterion or had experienced DLT during Cycle 1 and were discontinued. MTD analysis was done only on the phase lb group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib - 50 mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - grade 2 | 0 Participants |
| Phase Ib - 50 mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary system orgran class (SOC) PT - grade 1 | 0 Participants |
| Phase Ib - 50 mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT (asthenia) - grade 3 | 0 Participants |
| Phase Ib - 50 mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - grade 4 | 0 Participants |
| Phase Ib - 50 mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - missing | 0 Participants |
| Phase Ib - 50 mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT (somatits/diarrhea) - grade 3 | 0 Participants |
| Phase Ib - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - missing | 0 Participants |
| Phase Ib - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary system orgran class (SOC) PT - grade 1 | 0 Participants |
| Phase Ib - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - grade 2 | 0 Participants |
| Phase Ib - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT (somatits/diarrhea) - grade 3 | 0 Participants |
| Phase Ib - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - grade 4 | 0 Participants |
| Phase Ib - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT (asthenia) - grade 3 | 1 Participants |
| BM Cohort - 80mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - missing | 0 Participants |
| BM Cohort - 80mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT (asthenia) - grade 3 | 0 Participants |
| BM Cohort - 80mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - grade 2 | 0 Participants |
| BM Cohort - 80mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT (somatits/diarrhea) - grade 3 | 0 Participants |
| BM Cohort - 80mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary system orgran class (SOC) PT - grade 1 | 0 Participants |
| BM Cohort - 80mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - grade 4 | 0 Participants |
| BM Cohort - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary system orgran class (SOC) PT - grade 1 | 0 Participants |
| BM Cohort - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - grade 2 | 0 Participants |
| BM Cohort - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT (somatits/diarrhea) - grade 3 | 1 Participants |
| BM Cohort - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT (asthenia) - grade 3 | 0 Participants |
| BM Cohort - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - grade 4 | 0 Participants |
| BM Cohort - 100mg | Dose Limiting Toxicity (DLT) - Phase l Only | Primary SOC PT - missing | 0 Participants |
Primary
Overall Response Rate (ORR) - Phase ll
Objective response rate (ORR) was defined as the rate of patients with best overall response (BOR) equal to complete response (CR) or partial response (PR) according to RECIST 1.0 from the Investigators review. Per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed of the disease status by imaging (i.e. CT/MRI): Complete Response (CR) = Disappearance of all tumor lesions; Partial Response (PR)= \>=30% shrinkage of lesions; Overall Response (OR) = patients with CR and PR.
Time frame: 18 months
Population: The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II - 100mg | Overall Response Rate (ORR) - Phase ll | 5 Participants |
Secondary
Clinical Benefit Rate (CBR) - Phase l & ll
CBR = patients with CR, PR or SD ≥ 24 weeks according to RECIST by the investigator. Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = Disappearance of all tumor lesions; PR= \>=30% shrinkage of lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
Time frame: 18 months
Population: The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib).~CBR analysis was not done for the BM cohort population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib - 50 mg | Clinical Benefit Rate (CBR) - Phase l & ll | Phase l | 0 Participants |
| Phase Ib - 50 mg | Clinical Benefit Rate (CBR) - Phase l & ll | Phase ll | 0 Participants |
| Phase Ib - 100mg | Clinical Benefit Rate (CBR) - Phase l & ll | Phase l | 3 Participants |
| Phase Ib - 100mg | Clinical Benefit Rate (CBR) - Phase l & ll | Phase ll | 0 Participants |
| Phase II - 100mg | Clinical Benefit Rate (CBR) - Phase l & ll | Phase l | 0 Participants |
| Phase II - 100mg | Clinical Benefit Rate (CBR) - Phase l & ll | Phase ll | 7 Participants |
Secondary
Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll
Disease control rate (DCR) = patients with complete response (CR), partial response (PR) or stable disease (SD) as per RECIST criteria. Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 assessed the disease status by imaging (i.e. CT/MRI): CR = disappearance of all tumor lesions; PR = \>=30% shrinkage of lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD); PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
Time frame: 18 months
Population: The full analysis set (FAS) consisted of all patients who received at least one dose of study drug (buparlisib).~CBR analysis was not done for the BM cohort population. DCR analysis was not done for the BM cohort population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib - 50 mg | Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll | Phase l | 1 Participants |
| Phase Ib - 50 mg | Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll | Phase ll | 0 Participants |
| Phase Ib - 100mg | Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll | Phase ll | 0 Participants |
| Phase Ib - 100mg | Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll | Phase l | 7 Participants |
| Phase II - 100mg | Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll | Phase ll | 25 Participants |
| Phase II - 100mg | Disease Control Rate (DCR) Based on Investigator Assessment- Phase l & ll | Phase l | 0 Participants |
Secondary
Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll
Time frame: 18 months
Population: FAS consisted of all patients who received at least 1 dose of study drug (buparlisib). PFS analysis was not done for the BM cohort population. MTD/RP2D was not established due to premature termination of the study. In the phase ll portion of the study, PFS was analyzed only in patients with known PIK3 status, thus only 26/50 patients were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase Ib - 50 mg | Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | Phase ll: PIK3CA wildtype (n =18) | NA Months |
| Phase Ib - 50 mg | Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | Phase l | 1.7 Months |
| Phase Ib - 50 mg | Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | Phase ll: PIK3CA mutated (n =8) | NA Months |
| Phase Ib - 100mg | Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | Phase ll: PIK3CA wildtype (n =18) | NA Months |
| Phase Ib - 100mg | Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | Phase l | 3.3 Months |
| Phase Ib - 100mg | Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | Phase ll: PIK3CA mutated (n =8) | NA Months |
| Phase II - 100mg | Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | Phase l | NA Months |
| Phase II - 100mg | Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | Phase ll: PIK3CA mutated (n =8) | 1.8 Months |
| Phase II - 100mg | Progression Free Survival (PFS) - Based on Investigator Review Using Kaplan Meier - Phase l & ll | Phase ll: PIK3CA wildtype (n =18) | 1.7 Months |