A phase Ib dose-finding study of BYL719 plus everolimus and BYL719 plus everolimus plus exemestane in patients with advanced solid tumors, with dose-expansion cohorts in renal cell cancer (RCC), pancreatic neuroendocrine tumors (pNETs), and advanced breast cancer (BC) patients
- Conditions
- breastcancerpancreatic endocrine tumor10027655renal cell cancer
- Registration Number
- NL-OMON47387
- Lead Sponsor
- ovartis
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 10
1. Tumor tissue available for the analysis of PI3K signaling.
2. ECOG PS * 2 at time of screening
3. Adequate bone marrow and organ function:
*Absolute Neutrophil Count (ANC) * 1.5 x 109/L
*Platelets * 100 x 109/L
* Hemoglobin * 90 g/L or * 5,85 mmol/L
* INR * 2
* Serum creatinine * 1.5 x ULN
* Total serum bilirubin * 2.0 mg/dL
* AST and ALT * 2.5 x ULN (or * 5 x ULN if liver metastases are present)
* Fasting plasma glucose (FPG) * 140mg/dL or * 7.8 mmol/L
* Cholesterol (fasting) *300 mg/dL OR *7.75 mmol/L AND fasting triglycerides *2.5x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
Escalation phase:
4. Histologically/cytologically confirmed metastatic and/or recurrent solid tumor for whom no standard therapy exists ;Specific additional Inclusion criteria for the doublet combination * expansion phase
RCC patients* cohort:
a. Histologically/cytologically confirmed RCC
b. Prior treatment with cytokines is allowed. A maximum of two prior therapies with VEGF-targeting agents for advanced recurrent/metastatic disease is allowed ;pNET patients* cohort:
a. Histologically/cytologically confirmed well or moderately differentiated pNET
b. Patient may have received prior and/or concurrent long-acting somatostatin analogue therapy: ;mTOR inhibitor-pretreated patients* cohort: :
a. Histologically and/or cytologically confirmed solid malignancy that is metastatic and/or recurrent. Patient has progressed to a prior mTOR inhibitor. Patient who had discontinued prior mTOR inhibitor treatment due to non-tolerable toxicities is not eligible.;Specific additional inclusion criteria for the triplet combination - escalation and expansion phases
a. Histologically and/or cytologically confirmed diagnosis of BC
b. Radiologic evidence of inoperable locally advanced, or metastatic BC
c. HER2-negative BC (based on most recently analyzed biopsy)
d. Known HR-positive status (either estrogen or progesterone)
e. Patient is a postmenopausal woman.
f. Patient whose disease is refractory to previous letrozole or anastrozole (recurrence during or within 12 months after the end of adjuvant treatment or progression during or within 1 month after the end of treatment for advanced disease).
g. Up to two prior chemotherapy regimens for locally advanced or metastatic disease. ;Specific additional inclusion criterion for the triplet combination:
a. Patient has identified PIK3CA mutational status as determined by ctDNA by a Novartis designated laboratory.
b. Patient may have received up to one prior chemotherapy regimen for locally advanced or metastatic disease.
NOTE: Prior targeted therapy including CDK4/6 inhibitor is allowed ;Specific inclusion criteria at the time of the cross-over
a. Patient randomized to the alpelisib and exemestane combination who has a radiologically documented progressive disease
b. (ECOG Performance Status * 2
c. Toxicities < grade 3 while receiving alpelisib and exemestane
d. No residual toxicity related to alpelisib or exemestane > Grade 1 prior to initiating the triplet combination.
Dose-escalation and the dose-expansion phases
1. Patient has received previous treatment with a PI3K and/or AKT and/or mTOR inhibitor (e.g. sirolimus, temsirolimus, deforolimus). Note: Prior mTOR inhibitor treatment is allowed only in the expansion cohorts 3 and 5.
2. Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
3. Patient with primary central nervous system (CNS) tumor or CNS tumor involvement.
However, CNS metastasis are allowed under the following conditions:
a. 4 weeks from prior therapy completion (including radiation and/or surgery for CNS tumor) to starting the study treatment, and
b. Clinically stable with respect to the CNS tumor at the time of screening, and
c. Not receiving steroid therapy
4. Patient with diabetes mellitus, or documented steroid-induced diabetes mellitus
5. Patient has a history of another malignancy within 2 years prior to starting study treatment, except for cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix
6. Side effects (related to prior antineoplastic therapy) not recovered to grade 1 or better (except alopecia)
7. Several therapies including radiotherapy and surgery prior to start study treatment within specific timelines as described in the protocol section 5.3 (exclusion criteria 6 to 9)
8. Clinically significant cardiac disease or impaired cardiac function, such as:
a. Congestive heart failure New York Heart Association (NYHA) Grade * 2, left ventricular ejection fraction (LVEF) < 50%
b. History or current evidence of clinically significant cardiac arrhythmias, atrial fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, highgrade/ complete AV-blockage
c. Acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting), < 3 months prior to screening
d. QTcF > 480 msec on screening ECG
9. Any severe and/or uncontrolled medical condition (details specified in protocol section 5.3 exclusion criterion 11)
10. Use of medication with a known risk of prolonging the QT-interval or inducing Torsades de Pointes (TdP) Refer to protocol for details (Section 14.1, Table 14-3)
11. Use of medication known to be moderate or strong inhibitors or inducers of isoenzymes CYP34A or CYP2C8. Refer to protocol for details Refer to protocol (Section 14.1, Table 14-2);Specific inclusion criteria at the time of the cross-over
a. Patient randomized to the alpelisib and exemestane combination who has a radiologically documented progressive disease
b. Patient has ECOG PS * 2
c. Patient who experienced toxicities < grade 3 while receiving alpelisib and exemestane
d. Patient who has no residual toxicity related to alpelisib or exemestane > Grade 1 prior to initiating the triplet combination.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Dose escalation<br /><br>MTD and/or RDE of the doublet and triplet combination as measured by incidence<br /><br>of DLT (DLT rate at cycle 1).<br /><br><br /><br>Dose expansion<br /><br>Description of safety and tolerability of the doublet and triplet combination<br /><br>by cohort and then pooled for the doublet and triplet, as measured by type and<br /><br>severity of AEs according to NCI CTCAE v4.03, dose interruptions, reductions<br /><br>and dose intensity</p><br>
- Secondary Outcome Measures
Name Time Method