locally advanced, recurrent and metastatic breast cancer. MedDRA version: 14.1 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: TYVERB
Pharmaceutical Form: Coated tablet
INN or Proposed INN: LAPATINIB
CAS Number: 231277-92-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-
P
Sponsors
Institut Paoli-Calmettes
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Female or male patients = 18 years 2. WHO performance status = 1 3. Locally advanced, recurrent or metastatic, histologically confirmed HER2 positive (IHC 3+ or FISH positive) breast cancer after failure of trastuzumab treatment. Failure of trastuzumab treatment is defined as documented tumor progression as per RECIST 1.1 criteria: - while on trastuzumab or within 4 weeks since the last infusion of trastuzumab for metastatic disease - within 12 months of the last infusion for patients who received trastuzumab as adjuvant or neoadjuvant treatment 4. For the phase II part, progression on trastuzumab must have occurred within 16 weeks before entering this trial. 5. The patients should not have received more than 3 lines of anti-HER2 therapy. No more than 3 previous lines of chemotherapy in the metastatic disease setting are allowed in the phase II part and no more than 4 chemotherapy regimens for the dose escalation part. 6. For the phase II part, activation of PI3K/AKT pathway detected according to one at least of the following criteria : - PTEN negative by IHC - Somatic mutations (exons 9 and 20) of PIK3CA and/or - Overexpression of phospho-AKT by IHC 7. The patient is capable of understanding and complying with the protocol and has signed the informed consent document 8. Patients must have the following laboratory values: - Absolute Neutrophil Count (ANC) = 1.0 x 10^9/L - Hemoglobin (Hb) = 9 g/dL (transfusion is allowed to be given to patients so they may reach this inclusion requirement prior to trial entry) - Platelets (Plt) = 100 x 10^9/L - Potassium within normal limits - Total calcium (corrected for serum albumin) within normal limits (patients actively using biphosphonate for malignant hypercalcemia control are not allowed to enter the trial) - Magnesium = the lower limit of normal - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = ULN or = 3.0 x ULN if liver metastases are present - Serum bilirubin within normal range (or = 1.5 x ULN if liver metastases are present; or total bilirubin = 3.0 x ULN with direct bilirubin within normal range in patients with well documented Gilbert Syndrome) - Serum creatinine = 1.5 x ULN or 24-hour clearance = 50 mL/min - Serum amylase = ULN - Serum lipase = ULN - Fasting plasma glucose (FPG) = 120 mg/dL or = 6.7 mmol/L - Negative serum pregnancy test within = one week before first dose for child-bearing potential women and for women 50% (MUGA or ECHO) 12. Affiliation to social security Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Previous treatment with lapatinib, neratinib or a PI3K inhibitor 2. Patients with untreated brain metastases. However, patients with asymptomatic metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (incl. radiation and/or surgery), is clinically stable with respect to the tumor at the time of study entry and if their signs and symptoms are well controlled with chronic therapy with low dose of corticosteroids 3. Patients with acute or chronic liver, renal disease or pancreatitis 4. Patients with any peripheral neuropathy = CTCAE grade 2 5. Patient has any of the following mood disorders as judged by the Investigator or a Psychiatrist, or meets the cut-off score of = 10 in the PHQ-9 or a cut-off of = 15 in the GAD-7 mood scale, respectively, or selects a positive response of ‘1, 2, or 3’ to question number 9 regarding potential for suicidal thoughts ideation in the PHQ-9 (independent of the total score of the PHQ-9) - Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others) - = CTCAE grade 3 anxiety 6. Patients with diarrhea = CTCAE grade 2 7. Patient has active cardiac disease including any of the following: - Left Ventricular Ejection Fraction (LVEF) 480 msec on screening ECG (using the QTcF formula) - Angina pectoris that requires the use of anti-anginal medication - Ventricular arrhythmias except for benign premature ventricular contractions - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication - Conduction abnormality requiring a pacemaker - Valvular disease with documented compromise in cardiac function - Symptomatic pericarditis 8. Patient has a history of cardiac dysfunction including any of the following; - Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function - History of documented congestive heart failure (New York Heart Association functional classification III-IV) - Documented cardiomyopathy - Other clinically significant heart disease such uncontrolled hypertension (please refer to WHO-ISH guidelines) 9. Patient has poorly controlled diabetes mellitus (HbA1c > 8 %) 10. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection, chronic pancreatitis, active chronic hepatitis) that could cause unacceptable safety risks or compromise compliance with the protocol 11. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Patients with unresolved diarrhea will be excluded as previously indicated. FOR CRITERIA 12 TO 23 SEE PROTOCOL.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase Ib part: To determine the maximum-tolerated dose (MTD) of BKM120 when administered orally in combination with daily lapatinib to adult patients trastumuzab-resistant HER2+ locally advanced, recurrent and metastatic breast cancer. Phase II part: To determine the efficacy of daily BKM120 in combination with daily lapatinib as measured by objective response rate (ORR), defined by complete response (CR) or partial response (PR) of target and non target lesions according to RECIST V1.1., in patients with activation of PI3K/AKT pathway detected according to one at least of the following criterias, measured on primary or metastatic tissue: PTEN negative by IHC and/or somatic mutations (exons 9 and 20) of PIK3CA and/or Overexpression of phospho-AKT by IHC. ;Secondary Objective: - To evaluate safety and tolerability of the combination - To evaluate clinical benefit (CB defined as complete response (CR) + partial response (PR) + Stable disease (SD) > 6 months) - To assess progression-free survival (PFS) - To determine pharmacokinetics profile of oral BKM120 in combination with orally lapatinib and to monitor exposure to lapatinib ;Primary end point(s): When objective response is reached | — |
Countries
France
Contacts
Public ContactDr Dominique GENRE
Institut Paoli-Calmettes
Outcome results
None listed