Breast Cancer
Conditions
Brief summary
The purpose of the study is to assess the benefit of panobinostat monotherapy given either orally or i.v. to women with HER2-positive locally recurrent or metastatic breast cancer
Interventions
DRUGPanobinostat - LBH589
Solution for infusion - 25mg/5ml
Sponsors
Translational Research in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent obtained prior to any study-related procedures * Women ≥ 18 years old * Patients with an ECOG performance status of ≤ 2 assessed within 2 weeks prior to randomization * Histologically or cytologically confirmed invasive breast carcinoma with locally recurrent or radiological evidence of metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent. * Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines * HER2-positive breast cancer patients by local laboratory testing * Prior trastuzumab-containing regimen (in neoadjuvant and/or adjuvant and/or metastatic settings) regardless of whether trastuzumab was given as monotherapy or in combination with chemotherapy. Any number of prior trastuzumab regimens is acceptable. Additional treatment with lapatinib after or before trastuzumab treatment is permitted, but not mandatory. * Radiological evidence of relapse or disease progression while on trastuzumab (or lapatinib) or within 12 months of the last dose of adjuvant trastuzumab. * Complete radiology and tumor assessment within 4 weeks prior to randomization: * Chest: Computed Tomography(CT) scan with intravenous contrast if the contrast is not medically contraindicated or Magnetic Resonance Imaging(MRI) * Abdomen: CT scan with intravenous and oral contrast if the contrast is not medically contraindicated or MRI * Brain: CT scan or MRI * Bone: Whole body Bone Scintigraphy * Up to 2 prior cytotoxic chemotherapy regimens, in addition to neo-adjuvant and adjuvant, for treatment of metastatic or locally recurrent breast cancer (including those cytotoxic chemotherapy treatments in combination with trastuzumab and/or lapatinib) * Patients must meet the following laboratory criteria within 2 weeks (14 days) prior to randomization: * Hematology * Neutrophil count of \> 1200/mm3 * Platelet count of \> 100,000/mm3 * Hemoglobin ≥ 90 g/L * Biochemistry * Aspartate aminotransferase/glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/glutamic pyruvic transaminase(ALT/SGPT) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if the transaminase elevation is due to disease involvement * Serum bilirubin ≤ 1.5 x ULN * Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 mL/min * Serum potassium, sodium, magnesium, phosphorus, total calcium (corrected for serum albumin) or ionized calcium within normal limits for the institution * Serum albumin ≥ Lower Limit of Normal(LLN) or 30g/L * Clinically euthyroid function (thyroid-stimulating hormone (TSH) and free T4). (Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism). * Left Ventricular Ejection Fraction(LVEF) assessment (2-D echocardiogram or Multiple Uptake Gated Acquisition Scan(MUGA) scan) performed within 6 weeks prior to randomization, showing a LVEF value \> 50% * Electrocardiogram performed within 1 week prior to randomization (details about findings on the Electrocardiogram that are not acceptable for participating in the study are reported in the
Exclusion criteria
section) * Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to randomization and agree to appropriate method of pregnancy prevention
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR). | At screening, every 2 cycles (i.e. 6 weeks) during the first 6 cycles, every 3 cycles (i.e. 9 weeks) during the subsequent cycles and at the End of Treatment (EOT) visit. After the EOT, the tumor assessments should be performed every 9 weeks. | The assessment of OR is based on the response of target lesion, of non-target lesion and on presence of new lesions (RECIST Criteria (V1.0)-assessed by CT scan spiral and bone scan) * CR:Disappearance of all target lesions * PR:\>=30% increase in the sum of the longest diameter (SLD),taking as reference the nadir SLD * Progressive Disease (PD):\>=20% increase in the SLD, taking as reference the nadir SLD, or the appearance of one or more new lesions * Stable Disease(SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the nadir SLD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Corrected QT Interval Fridericia's Formula (QTcF) | Panobinostat intra-venous (i.v.): All cycles pre-dose measurements. For cycles 1 and 2, post-dose measurements as well. / Panobinostat oral: Pre-dose and post-dose measurements for all cycles. Note: each cycle = 3 weeks | Prolonged QTcF: QTcF \>450 msec and increase of baseline on greater than or equal to 60 msec. |
Countries
United States
Participant flow
Recruitment details
Subjects were screened and enrolled at 28 sites in 4 countries (USA, Canada, France, Belgium).
Participants by arm
| Arm | Count |
|---|---|
| Panobinostat Intra-venous (i.v.) | 2 |
| Panobinostat Oral | 2 |
| Total | 4 |
Baseline characteristics
| Characteristic | Panobinostat Intra-venous (i.v.) | Panobinostat Oral | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Continuous | 48.1 years STANDARD_DEVIATION 20.8 | 59.0 years STANDARD_DEVIATION 11.5 | 53.5 years STANDARD_DEVIATION 15.1 |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS 0 (Fully active) | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS 1 (Restricted in physically strenuous activity) | 1 Participants | 2 Participants | 3 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS 2 (Ambulatory and capable of all selfcare) | 1 Participants | 0 Participants | 1 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS 3 (Capable of only limited selfcare) | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS 4 (Completely disabled) | 0 Participants | 0 Participants | 0 Participants |
| Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS 5 (Dead) | 0 Participants | 0 Participants | 0 Participants |
| Number of lines of prior chemotherapy in metastatic setting 1 line of prior chemotherapy | 0 Participants | 2 Participants | 2 Participants |
| Number of lines of prior chemotherapy in metastatic setting 2 lines of prior chemotherapy | 1 Participants | 0 Participants | 1 Participants |
| Number of lines of prior chemotherapy in metastatic setting 3 lines of prior chemotherapy | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 1 / 2 | 0 / 2 |
Outcome results
Primary
Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR).
The assessment of OR is based on the response of target lesion, of non-target lesion and on presence of new lesions (RECIST Criteria (V1.0)-assessed by CT scan spiral and bone scan) * CR:Disappearance of all target lesions * PR:\>=30% increase in the sum of the longest diameter (SLD),taking as reference the nadir SLD * Progressive Disease (PD):\>=20% increase in the SLD, taking as reference the nadir SLD, or the appearance of one or more new lesions * Stable Disease(SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the nadir SLD
Time frame: At screening, every 2 cycles (i.e. 6 weeks) during the first 6 cycles, every 3 cycles (i.e. 9 weeks) during the subsequent cycles and at the End of Treatment (EOT) visit. After the EOT, the tumor assessments should be performed every 9 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panobinostat Intra-venous (i.v.) | Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR). | Progressive Disease (PD) | 2 participants |
| Panobinostat Intra-venous (i.v.) | Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR). | Stable Disease (SD) | 0 participants |
| Panobinostat Intra-venous (i.v.) | Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR). | Complete Response (CR) | 0 participants |
| Panobinostat Intra-venous (i.v.) | Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR). | Partial Reponse (PR) | 0 participants |
| Panobinostat Oral | Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR). | Partial Reponse (PR) | 0 participants |
| Panobinostat Oral | Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR). | Progressive Disease (PD) | 1 participants |
| Panobinostat Oral | Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR). | Complete Response (CR) | 0 participants |
| Panobinostat Oral | Overall Response (OR) Rate (as Determined by the Investigator): the Number of Patients Assigned to a Treatment Arm With a Confirmed Best Response of Complete Response(CR) or Partial Response (PR). | Stable Disease (SD) | 1 participants |
Secondary
Corrected QT Interval Fridericia's Formula (QTcF)
Prolonged QTcF: QTcF \>450 msec and increase of baseline on greater than or equal to 60 msec.
Time frame: Panobinostat intra-venous (i.v.): All cycles pre-dose measurements. For cycles 1 and 2, post-dose measurements as well. / Panobinostat oral: Pre-dose and post-dose measurements for all cycles. Note: each cycle = 3 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Panobinostat Intra-venous (i.v.) | Corrected QT Interval Fridericia's Formula (QTcF) | Electrocardiogram QT normal | 1 participants |
| Panobinostat Intra-venous (i.v.) | Corrected QT Interval Fridericia's Formula (QTcF) | Electrocardiogram QT prolonged | 1 participants |
| Panobinostat Oral | Corrected QT Interval Fridericia's Formula (QTcF) | Electrocardiogram QT normal | 2 participants |
| Panobinostat Oral | Corrected QT Interval Fridericia's Formula (QTcF) | Electrocardiogram QT prolonged | 0 participants |