Breast Cancer
Conditions
Keywords
Breast Cancer, HER2 positive, adult-female, LBH589, HDAC inhibitor, panobinostat
Brief summary
The primary purpose of this study is to identify the maximum tolerated dose (MTD) of both intravenous and oral panobinostat plus trastuzumab. The study will evaluate safety and efficacy of the combination in adult female patients with HER2+ metastatic breast cancer
Detailed description
This phase Ib/IIa study was prematurely terminated due to lack of efficacy noted in 55 patients with HER2-positive MBC who had progressed on or following a trastuzumab-based therapy.
Interventions
DRUGPanobinostat
Participants received escalating doses of panobinostat until the maximum tolerated dose (MTD) was reached. The starting dose of panobinostat i.v. was 10mg/m\^2 at days 1 and 8 during a 21-day treatment cycle. The oral panobinostat starting dose was 20 mg twice weekly.
DRUGTrastuzumab
Fixed doses of trastuzumab were given in parallel with panobinostat. Trastuzumab i.v. was given weekly according to the instruction in the package insert.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria: * Age \> 18 year old * Confirmed HER2+ ve metastatic breast cancer * Prior treatment and progression on trastuzumab * Patients must have adequate laboratory values * Eastern Cooperative Oncology Group (ECOG) performance status of \<2 Key
Exclusion criteria
* Patients with active central nervous system (CNS) disease or brain metastases except those who have been previously treated and have been stable for at least 3 months. * Impaired heart function or clinically significant heart disease * Impairment of gastrointestinal (GI) function, or GI disease that may significantly alter the absorption of LBH589 * Ongoing diarrhea * Liver or renal disease with impaired hepatic or renal functions * Concomitant use of any anti-cancer therapy or certain drugs * Female patients who are pregnant or breast feeding * Patients not willing to use an effective method of birth control
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | day 21 | Safety data was reviewed to determine the DLTs. DLTs comprised adverse events (AEs) or abnormal laboratory values that occurred at any time and were assessed as clinically relevant and meeting any of the following criteria: considered to be related to the study treatment and unrelated to disease, disease progression, inter-current illness, or concomitant medications. Toxicities were assessed using the National Cancer Institute common terminology criteria for adverse events (NCI CTCAE), version 3.0. Disease related symptoms were not considered a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Best Overall Response | day 21 | Tumors were assessed according to Response Evaluation Criteria in Solid tumors (RECIST). Complete response (CR): disappearance of all lesions (i.e. all evidence of disease, not just the target lesions) determined by 2 observations not less than 4 weeks apart; Partial response (PR): \> 30% decrease in the sum of longest diameters of target lesions compared to baseline, with response or stable disease observed in non-target lesions, and no new lesions; Stable disease (SD): neither sufficient shrinkage to qualify for response or sufficient increase to qualify for progressive disease in target lesions, with response or stable disease observed in non-target lesions, and no new lesions; Progressive disease (PD): \> 20% increase in the sum of longest diameters of target lesions compared to smallest sum longest diameter recorded. In addition, the sum must also demonstrate an absolute increase of at least 5mm. |
Countries
Canada, France, Germany, Italy, United Kingdom, United States
Participant flow
Recruitment details
Eligible participants were allocated to dose escalation arm 1 (i.v. panobinostat) or arm 2 (oral panobinostat) according to a pre-determined sequence in the ratio 1:1. Each cohort consisted of newly enrolled participants. This study included a dose escalation phase to establish the maximum tolerated dose (MTD) and a dose expansion phase.
Participants by arm
| Arm | Count |
|---|---|
| Escalation: i.v. Arm - 10mg/m^2 10 mg/m\^2 i.v. was given on day 1 and day 8 of a 21 day cycle. | 7 |
| Escalation: i.v. Arm - 15mg/m^2 15 mg/m\^2 i.v. was given on day 1 and day 8 of a 21 day cycle. | 7 |
| Escalation/Expansion: i.v. Arm -20mg/m^2 20 mg/m\^2 i.v. was given on day 1 and day 8 of a 21 day cycle. | 21 |
| Oral Arm - Schedule A 20mg 20 mg was given twice weekly for two consecutive weeks as part of a 21-day treatment cycle. | 6 |
| Oral Arm - Schedule B 15mg 15 mg was given three times weekly for two consecutive weeks as part of a 21-day treatment cycle. | 12 |
| Oral Arm - Schedule B 20mg 20 mg was given three times weekly for two consecutive weeks as part of a 21-day treatment cycle. | 3 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Abnormal test procedure(s) | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Adverse Event | 2 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Disease progression | 5 | 7 | 15 | 5 | 11 | 3 |
| Overall Study | New cancer therapy | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 3 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Escalation: i.v. Arm - 10mg/m^2 | Escalation: i.v. Arm - 15mg/m^2 | Escalation/Expansion: i.v. Arm -20mg/m^2 | Oral Arm - Schedule A 20mg | Oral Arm - Schedule B 15mg | Oral Arm - Schedule B 20mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 58.0 Years | 49.0 Years | 57.0 Years | 54.5 Years | 53.5 Years | 47.0 Years | 53.0 Years |
| Sex/Gender, Customized Female | 7 Participants | 7 Participants | 21 Participants | 6 Participants | 12 Participants | 3 Participants | 56 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 7 / 7 | 21 / 21 | 6 / 6 | 12 / 12 | 3 / 3 |
| serious Total, serious adverse events | 3 / 7 | 1 / 7 | 5 / 21 | 3 / 6 | 2 / 12 | 1 / 3 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
Safety data was reviewed to determine the DLTs. DLTs comprised adverse events (AEs) or abnormal laboratory values that occurred at any time and were assessed as clinically relevant and meeting any of the following criteria: considered to be related to the study treatment and unrelated to disease, disease progression, inter-current illness, or concomitant medications. Toxicities were assessed using the National Cancer Institute common terminology criteria for adverse events (NCI CTCAE), version 3.0. Disease related symptoms were not considered a DLT.
Time frame: day 21
Population: The Maximum Tolerated Dose (MTD) determining set was used for this analysis. The MTD determining set consisted of all participants who either received sufficient study drug and had sufficient safety evaluations or discontinued due to unacceptable toxicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Escalation: i.v. Arm - 10mg/m^2 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Escalation: i.v. Arm - 15mg/m^2 | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Escalation/Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Oral Arm - Schedule A 20mg | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Oral Arm - Schedule B 15 mg | Number of Participants With Dose Limiting Toxicities (DLTs) | 3 Participants |
| Oral Arm - Schedule B 20mg | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
Secondary
Number of Participants With Best Overall Response
Tumors were assessed according to Response Evaluation Criteria in Solid tumors (RECIST). Complete response (CR): disappearance of all lesions (i.e. all evidence of disease, not just the target lesions) determined by 2 observations not less than 4 weeks apart; Partial response (PR): \> 30% decrease in the sum of longest diameters of target lesions compared to baseline, with response or stable disease observed in non-target lesions, and no new lesions; Stable disease (SD): neither sufficient shrinkage to qualify for response or sufficient increase to qualify for progressive disease in target lesions, with response or stable disease observed in non-target lesions, and no new lesions; Progressive disease (PD): \> 20% increase in the sum of longest diameters of target lesions compared to smallest sum longest diameter recorded. In addition, the sum must also demonstrate an absolute increase of at least 5mm.
Time frame: day 21
Population: The full analysis set was analyzed. The full analysis set included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Escalation: i.v. Arm - 10mg/m^2 | Number of Participants With Best Overall Response | Complete response | 0 Participants |
| Escalation: i.v. Arm - 10mg/m^2 | Number of Participants With Best Overall Response | Stable disease | 4 Participants |
| Escalation: i.v. Arm - 10mg/m^2 | Number of Participants With Best Overall Response | Partial response | 0 Participants |
| Escalation: i.v. Arm - 10mg/m^2 | Number of Participants With Best Overall Response | Progressive disease | 3 Participants |
| Escalation: i.v. Arm - 10mg/m^2 | Number of Participants With Best Overall Response | Unknown | 0 Participants |
| Escalation: i.v. Arm - 15mg/m^2 | Number of Participants With Best Overall Response | Unknown | 0 Participants |
| Escalation: i.v. Arm - 15mg/m^2 | Number of Participants With Best Overall Response | Stable disease | 1 Participants |
| Escalation: i.v. Arm - 15mg/m^2 | Number of Participants With Best Overall Response | Complete response | 0 Participants |
| Escalation: i.v. Arm - 15mg/m^2 | Number of Participants With Best Overall Response | Progressive disease | 6 Participants |
| Escalation: i.v. Arm - 15mg/m^2 | Number of Participants With Best Overall Response | Partial response | 0 Participants |
| Escalation/Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Complete response | 0 Participants |
| Escalation/Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Stable disease | 8 Participants |
| Escalation/Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Partial response | 1 Participants |
| Escalation/Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Unknown | 3 Participants |
| Escalation/Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Progressive disease | 9 Participants |
| Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Partial response | 0 Participants |
| Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Unknown | 1 Participants |
| Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Complete response | 0 Participants |
| Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Stable disease | 1 Participants |
| Expansion: i.v. Arm -20mg/m^2 | Number of Participants With Best Overall Response | Progressive disease | 4 Participants |
| Oral Arm - Schedule A 20mg | Number of Participants With Best Overall Response | Partial response | 0 Participants |
| Oral Arm - Schedule A 20mg | Number of Participants With Best Overall Response | Complete response | 0 Participants |
| Oral Arm - Schedule A 20mg | Number of Participants With Best Overall Response | Unknown | 2 Participants |
| Oral Arm - Schedule A 20mg | Number of Participants With Best Overall Response | Progressive disease | 7 Participants |
| Oral Arm - Schedule A 20mg | Number of Participants With Best Overall Response | Stable disease | 3 Participants |
| Oral Arm - Schedule B 15 mg | Number of Participants With Best Overall Response | Unknown | 0 Participants |
| Oral Arm - Schedule B 15 mg | Number of Participants With Best Overall Response | Stable disease | 0 Participants |
| Oral Arm - Schedule B 15 mg | Number of Participants With Best Overall Response | Partial response | 0 Participants |
| Oral Arm - Schedule B 15 mg | Number of Participants With Best Overall Response | Progressive disease | 3 Participants |
| Oral Arm - Schedule B 15 mg | Number of Participants With Best Overall Response | Complete response | 0 Participants |