The primary objective of the study is to determine the MTD (maximum tolerated dose) and/or RDE (recommended dose for expansion) of BGJ398 in combination with BYL719.The secondary objectives are to characterize the safety and tolerability of BGJ398…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the study, MTD and/or RDE, is measured by incidence of
DLTs in cycle 1.
Secondary outcome
* Incidence and severity of adverse events and serious adverse events, changes
in laboratory values, electrocardiograms and vital signs. Dose interruptions,
reductions and dose intensity.
* Time vs. concentration profiles, derived PK parameters of BGJ398 and BYL719
and known active metabolites.
* Overall response rate (ORR; CR+PR) assessed by investigators per RECIST and
progression free survival.
Background summary
The study of molecular pathways involved in the pathogenesis of malignancy has
led to the development of drugs that selectively act on those targets. Most
solid tumors have complicated molecular profiles with a number of genetic
aberrations. It may be preferable in these cases to treat with combinations of
agents directed at multiple oncogenic targets in order to enhance anti-tumor
activity and potentially prevent emergence of resistance.
PI3Ks are important in controlling signaling pathways involved in cell
proliferation, motility, cell death, and invasion. There is substantial
evidence in many tumors that the PI3K signaling pathway is dysregulated or
constitutively activated. This is thought to be a critical step in mediating
the transforming potential and growth stimulating activity of various
oncogenes, contributing to the onset and growth of solid and hematologic tumors
in patients. PIK3CA is one of the most commonly mutated genes and mutations
occur at high frequency in many human cancer types including breast, gastric,
and lung cancer.
Several lines of evidence support the involvement of FGFRs in human cancer,
where genetic alterations leading to abnormal activation and/or deregulated
expression have been found in diverse tumor types, such as breast cancer, lung
squamous cell carcinomas (SCC) and hepatocellular carcinoma.
BGJ398 is an orally bio-available, selective pan FGFR kinase inhibitor that has
demonstrated anti-tumor activity in preclinical, in vitro, and in-vivo tumor
models harboring FGFR genetic alterations. A first-in-human trial is ongoing to
determine the maximum tolerated dose (MTD) and/or recommended dose for
expansion (RDE) of monotherapy BGJ398 in patients whose tumors harbor FGFR
genetic alterations.
BYL719 is an oral class I *-specific PI3K inhibitor that inhibits strongly the
PI3K* isoform (p110* and p110* mutations). BYL719 is being investigated as a
single agent and as a combination agent in several studies. As a single agent,
doses up to 450 mg once daily have been administered to cancer patients. The
MTD is 400 mg once daily.
The rationale for the combination of a FGFR inhibitor with a PI3K inhibitor in
patients whose tumors demonstrate PIK3CA mutations derives from three
observations. First, activating mutations in the PIK3CA gene were found to
frequently co-occur with amplification of the FGFR1 gene in breast cancer.
Second, sensitivity of PIK3CA mutant breast cancer-derived cell lines to the
PI3K inhibitor BYL719 was abrogated by FGF-ligand mediated activation of one or
more of the FGFRs. Lastly, synergy has been observed between BYL719 and BGJ398
in endometrial and bladder cancer models that carry mutation or dysregulation
of both the PI3K and FGFR signals.
Study objective
The primary objective of the study is to determine the MTD (maximum tolerated
dose) and/or RDE (recommended dose for expansion) of BGJ398 in combination with
BYL719.
The secondary objectives are to characterize the safety and tolerability of
BGJ398 in combination with BYL719, to determine the single and multiple dose PK
profiles of the investigational drugs in combination and to assess any
preliminary antitumor activity of the combination.
An exploratory objective is to assess markers that may correlate with
prediction of response and/or resistance.
Study design
The MTD and/or RDE of the combination of oral BGJ398 with oral BYL719 will be
determined in this multi-center, open-label phase Ib dose escalation trial.
Upon identification of the MTD or RDE, an expansion part will be opened to
patient enrollment to further characterize the safety, PK, and pharmacodynamics
(PD) of the combination.
The escalation part will enroll approximately 15 patients with advanced solid
cancers with PIK3CA mutations.
Intervention
BGJ398 in combination with BYL719.
Oral administration for both drugs.
BGJ398 administration schedule: once daily (3 weeks on/ 1 week off medication).
Starting dose BGJ398 is 20mg/day (dose escalation part).
BYL719 adminstartion schedule once daily continuous
Starting dose BYL719 is 300mg/day (dose escalation part).
Study burden and risks
The patient may receive no direct benefit from being in this study. The patient
needs to go to the hospital more often and will undergo more tests such as ECG,
echocardiogram or MUGA, eye exams, more (frequent) blood sampling and imaging
scans. The visits may take more time (1-8 hours). Other disadvantages are the
inconveniences of the several tests such as extra blood sampling, eye exams and
biopsy.
The study medication may cause side effects.
The risks of treating humans with the combination of BGJ398 and BYL719 are not
known.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
* Histologically/cytologically confirmed advanced or metastatic solid tumors who have failed standard therapy or for whom no effective standard anticancer therapy exists ;* Documented PIK3CA mutations in all patients in dose escalation and expansion with or without documented genetic alterations in FGFR depending upon dose expansion cohort (either local or central determination);* Measurable disease defined by RECIST v1.1 ;* ECOG performance status of *2
Exclusion criteria
* Prior PI3Ki or selective FGFR inhibitor treatment (for patients enrolled to expansion part) ;* Ongoing grade 2 or greater sequelae from previous systemic anti-cancer therapies, except for:
alopecia and stable neuropathy of * grade 2 ;* History and/or current evidence of tissue calcification;* Patients with diabetes mellitus requiring insulin treatment or with fasting glucose * 140 mg/dL / 7.8 mmol/L, ;* Known acute or chronic pancreatitis;* Treatment with chronic systemic corticosteroids * 2 weeks prior to starting study drug,
* Impairment of gastrointestinal tract function or GI disease that may significantly alter the absorption of BGJ398 or BYL719;* History and/or current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis etc;* Confirmed evidence of corneal or retinal disorder;* Treatment with agents that are known strong inducers or inhibitors CYP3A4 are prohibited. ;* Insufficient bone marrow function:
-ANC <1,000/mm3 [1.0 x 109/L]
-Platelets < 75,000/mm3 [75 x 109/L]
-Hemoglobin < 9.0 g/dL;* Insufficient hepatic and renal function
-Total bilirubin > 1.5x ULN
-AST/SGOT or ALT/SGPT > 3x ULN (AST or ALT > 5x ULN in the presence of liver metastases)
-Serum creatinine > ULN
-Calculated or measured creatinine clearance < 75% LLN;* Calcium-phosphate homeostasis
-Inorganic phosphorus outside of normal limits
-Total and ionized serum calcium outside of normal limits;* Clinically significant cardiac disease including any of the following:
- Congestive heart failure requiring treatment (NYHA grade * 2),
- LVEF < 50% (MUGA or ECHO),
- History or presence of clinically significant ventricular arrhythmias, atrial fibrillation, resting bradycardia, or conduction abnormality,
- Unstable angina pectoris or acute myocardial infarction * 3 months prior to starting study drug,
- QTcF > 450 msec, history of congenital long QT syndrome
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 | EUCTR2013-001018-14-NL |
| ClinicalTrials.gov | NCT01928459 |
| CCMO | NL47080.031.13 |