MAIN OBJECTIVEDose escalation phase :- To determine the MTD and/or RDE of alpelisib (BYL719) in combination with everolimus, and the MTD and/or RDE of alpelisib in combination with everolimus and exemestaneDose expansion part:- To describe safety…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Dose escalation
MTD and/or RDE of the doublet and triplet combination as measured by incidence
of DLT (DLT rate at cycle 1).
Dose expansion
Description of safety and tolerability of the doublet and triplet combination
by cohort and then pooled for the doublet and triplet, as measured by type and
severity of AEs according to NCI CTCAE v4.03, dose interruptions, reductions
and dose intensity
Secondary outcome
Dose escalation
* Description of safety and tolerability of the doublet and triplet combination
as measured by type and severity of AEs according to NCI CTCAE v4.03, dose
interruptions, reductions and dose intensity.
* Evaluation of the effect of BYL719 on the pharmacokinetics of everolimus, as
measured by PK parameters (including but not limited to AUC0-tlast, AUC0-inf,
Cmax) of everolimus
* Characterization of the PK of BYL719, everolimus and exemestane when
administered together, as measured by summary statistics for PK.
Dose expansion
* Exploration of preliminary signs of efficacy of BYL719 and everolimus, and of
the triplet combination (BYL719, everolimus, and exemestane) in selected
patient populations by cohort, as measured by Progression free survival as per
RECIST v1.1.
* Evaluation of other antitumor activity parameters such as response rate,
clinical benefit rate, and duration of response by cohort, as measured by
Objective Response Clinical Benefit and Duration of Response (DoR) as per
RECIST v1.1.
Background summary
PI3Ks are lipid kinases that are important in controlling signaling pathways
involved in cell proliferation, motility, cell death and cell invasion. The
deregulation of the PI3K signaling pathway is implicated in many human cancers.
BYL719 is an oral class I *-specific PI3K inhibitor that is currently in an
early stage of clinical development in solid tumors. Everolimus is a derivative
of rapamycin that acts as a signal transduction mTOR inhibitor. Exemestane is
an irreversible steroidal aromatase inactivator.
Treatment with mTOR inhibitors has proven efficacious both in advanced RCC and
pNET; and recent clinical evidence demonstrates that the addition of everolimus
to exemestane results in a statistically significant and clinically meaningful
improvement in clinical outcome in HR-positive HER2-negative BC. However,
resistance to mTORC1 inhibition occurs and lack of response and/or progression
to mTOR inhibitors is seen in the clinical setting.
Preclinical evidence suggests that the phosphorylation status of AKT can be a
determinant of resistance to mTORC1 inhibition. BYL719 has the potential of
inhibiting pAKT. Conversely, persistent mTORC1 activation (mediated by
phosphoS6) may limit BYL719 sensitivity. Combined mTORC1 inhibition with
everolimus and p110 alpha blockade with BYL719 has proven to be synergistic in
preclinical models.
In the current study, the combination of BYL719 and everolimus will be firstly
evaluated.
Then, and once the MTD of the doublet is established, the combination of BYL719
with everolimus and exemestane will be assessed separately in post-menopausal
HR-positive
HER2-negative advanced BC patients.
Study objective
MAIN OBJECTIVE
Dose escalation phase :
- To determine the MTD and/or RDE of alpelisib (BYL719) in combination with
everolimus, and the MTD and/or RDE of alpelisib in combination with everolimus
and exemestane
Dose expansion part:
- To describe safety and tolerability of the doublet and triplet combination
SECONDARY OBJECTIVES
Dose escalation:
- Describe safety and tolerability of the doublet and triplet combination
- Evaluate whether alpelisib (BYL719) affects the PK of everolimus and
determine the magnitude of the interaction
- Characterize the PK of alpelisib, BZG791 and everolimus; and of alpelisib,
BZG791, everolimus and exemestane when administered together
Dose expansion part
Key secondary (Triplet expansion)
- Assess the anti-tumor activity of the triplet combination in the PIK3CA
mutant and non-mutant BC cohorts and of the doublet combination in the PIK3CA
mutant BC cohort.
OTHER SECONDARY
Triplet only
- Assess the added value of everolimus to the combination alpelisib and
exemestane on the anti-tumor activity in the PIK3CA mutant BC cohort
- Evaluate other antitumor activity parameters
Doublet expansion
- Explore preliminary signs of efficacy of alpelisib and everolimus, and of the
triplet combination in selected patient populations by cohort
- Evaluate other antitumor activity parameters
Study design
A multi-center, open-label, dose escalation phase Ib study combining BYL719 and
everolimus and BYL719, everolimus and exemestane in patients with advanced
solid tumors followed by dose-expansion cohorts in renal cell cancer,
pancreatic neuroendocrine tumors, and advanced breast cancer patients.
After determination of the MTD of the triplet, 80 additional post-menopausal
women with HR-positive HER2-negative advanced BC will be included according to
their ctDNA PIK3CA status.
Based on the ctDNA PIK3CA status, these patients will be assigned to the
following cohorts:
1) PIK3CA mutant BC (n=60); these patients will be randomized at 2:1 to one of
the following treatment arms:
- Alpelisib, everolimus and exemestane (n=40); or
- Alpelisib and exemestane (n=20);
Randomization will be stratified according to the presence of visceral disease.
Presence of visceral disease includes pulmonary, hepatic, pleural and
peritoneal involvement
2) PIK3CA non-mutant BC (n=20) will receive alpelisib, everolimus and
exemestane.
The PIK3CA mutational status will neither be communicated to the investigators
nor to the patients.
Intervention
Doublet combination
BYL719 plus everolimus once daily
Triplet combination:
BYL719, everolimus plus exemestane once daily
BYL719 is oral medication
Study burden and risks
Compared to regular treatment, more, and more often, tests and exams will take
place. For the patient*s safety more ECGs will be made, more and more often
blood will be drawn and the patient will have to visit the hospital more
often. Additional ophthalmological and heart exams (echocardiogram or
MUGA-scan) will be performed. In an optional extra biomarker study, 2 extra
biopsies will be taken. To better assess the effect on the tumor, CT- or
MRI-scans will be performed more often. Generally, the duration of the visits
to the hospital will extend from 1 to 4 hours, because of the extra tests and
exams done. On the days extensive blood sampling for pharmacokinetics will take
place, a visit will last for about 9 hours. The frequency of the several tests
is further described in attachment B of the patient information.
Risks are possible side effects of study medicine, and those from the tests the
patient is asked to do. The risks are further described in attachments D and E
of the patient information.
There may be risks and inconveniences related to the assessments e.g. frequent
blood draws, biopsies and radiologic evaluations.
Side effects of everolimus and exemestaan can be found in the SmPC.
Side effects of the combination of everolimus + BYL719 and everolimus (see
patientinformation)
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
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.
Exclusion criteria
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR201300198618-NL |
| ClinicalTrials.gov | NCT02077933 |
| CCMO | NL48012.031.14 |