Primary: To determine the maximum tolerated dose (MTD) and thus the recommended phase IIdose and schedule of single agent oral BGJ398 in patients with advanced solid tumors with FGFR1 or FGFR2 amplification or FGFR3 mutation.Secundary objectives* to…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence rate and category of Dose Limiting Toxicities
Secondary outcome
* Efficacy arm 4: Overall response Rate assessed by RECIST
* Safety: (Serious) Adverse drug reactions, changes in hematology and chemistry
values, specifically those associated with calcium/ phosphate homeostasis and
renal function; and assessments of physical examinations, vital signs and
electrocardiograms.
* PK: Time vs. concentration profiles, PK parameters of BGJ398 and known active
metabolite(s).
* PD: Pre- vs. post treatment serial changes in FGF23 plasma levels.
* Efficacy: Rate of objective tumor response and PFS assessed by investigator
per RECIST
Background summary
In 2002, 11 million new cancer cases and 7 million cancer deaths were estimated
worldwide
(Parkin et al., 2005). Solid malignancies are the most commonly diagnosed and
most
common causes of cancer death. Patients with advanced solid malignancies often
have limited therapeutic options beyond institutional standard of care. For
patients whose cancer has become refractory to all available treatments and who
have no further treatment options, there is a significant unmet therapeutic
need
Study objective
Primary: To determine the maximum tolerated dose (MTD) and thus the recommended
phase II
dose and schedule of single agent oral BGJ398 in patients with advanced solid
tumors with FGFR1 or FGFR2 amplification or FGFR3 mutation.
Secundary objectives
* to assess prelimanary anti-tumor activity of BGJ398 in expansion arm 4 in
patients with UCC with FGFR3 alterations
* To characterize the safety and tolerability of oral BGJ398 at the recommended
phase II dose
* To determine the pharmacokinetic profiles of oral BGJ398 including known
pharmacologically active metabolites BHS697 and BQR917.
* To evaluate the effect of BGJ398 on FGF23 plasma level.
* To assess any preliminary anti-tumor activity of BGJ398.
Study design
The study has been designed as a Phase IA dose-escalation trial including a MTD
dose expansion arm in patients with advanced solid tumors, in which oral BGJ398
will be administered once daily on a continuous schedule.
The initial dose level will be 5 mg /day. A minimum of 3 evaluable patients
will be treated per dose level.
Before a drug dosage can be declared to be the MTD, at least 6 patients will
have to be treated at this dose level for one at least 21 days. Once MTD has
been declared, the MTD cohort will be expanded to enroll a total of appr.20
patients with lung SCC and appr. 20 patients with other advanced solid tumors.
Intervention
BGJ398 as an oral formulation available as hard gelatin capsules. MTD = 125
mg/dag
Dosing schedule: continous dosing (arm 1 and 2) or 3 weeks on 1 week off (arm 3
and 4)
Study burden and risks
The main side effects and observations seen in laboratory studies with BGJ398
or potential side effects concluded from laboratory tests include the following:
* Elevation of some electrolytes: Phosphorus and calcium which potentially can
cause tissues calcifications in various body sites.
* Reduction of kidney function.
* Impaired intactness of the cornea
* Reproductive risks for both women and men. The risks to an unborn human fetus
or a nursing child from BGJ398 are not known.
Taking blood and tumorbiopsies may cause pain, bleeding, and/or bruising.
Patients will be exposed to radiation (CT-scan and X-rays). The radiation
exposure will not exceed the maximum ranges that are set within the Netherlands.
Ophthalmologic examinations: The patient will receive eyedrops in order to
dilate (expand) the pupils. Some lightsensitivity may be experienced for a few
hours after this examination. The dilating drops may also rarely cause
increased pressure in the eye, leading to nausea and pain.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. Patients with histologically/cytologically confirmed advanced solid tumors with FGFR1 or FGFR2 amplification or FGFR3 mutation, for which no further effective standard anticancer treatment exits. Patients with advanced solid tumors carrying any FGFR mutation or amplification identified locally may be enrolled
2. Measurable or non-measurable disease, for arm 4 measurable disease
3. * 18 years of age.
4. WHO performance status 0-2.
5. Adequate bone marrow function:
6. Adequate hepatic and renal function:
7. Calcium-phosphate homeostasis:
* Normal serum inorganic phosphorus (Pi).
* Normal serum total (t) and ionized (i) calcium (Ca).
8. Adequate cardiovascular function
* NYHA grade * 2.
* Ejection fraction * 50%.
* QTc interval * 470 msec.
* BP systolic in rest * 100 mmHg and * 150 mmHg.
* BP diastolic in rest * 100 mmHg.
* Heart rate in rest > 50/min and < 100/min.
9. Recovery from all adverse events of previous systemic anti-cancer therapies to Grade * 1 except for alopecia and stable neuropathy of Grade *2 which was induced by prior cancer treatment.
10. Contraception:
* Women of childbearing potential and men must use adequate contraceptive regimen during and for 3 months after the treatment period; women must have a negative pregnancy test and must not be nursing.
* For men must use adequate contraceptive regimen during and for 3 months after the treatment period.
Exclusion criteria
1. Prior treatment with FGFR-inhibitor or MEK-inhibitor with the exception of prior treatment with TKI258.
2. Patients with primary CNS tumor or CNS tumor involvement.
3. Patients with history and/or current evidence of endocrine alteration of calcium/phosphate
homeostasis
4. History and/or current evidence of ectopic mineralization/ calcification with the exception of calcified lymphnodes and asymptomatic coronary calcification.
5. Current evidence of corneal disorder/ keratopathy
6. Concomitant therapies that are known to prolong the QT interval and/or are associated with a risk of Torsades de Pointes < 7 days before the first dose; however amiodarone is not permitted <90 days before the first dose.
7. Medication or supplements to increase serum levels of phosphorus and/or calcium levels within 28 days before the first dose.
8. Active or unstable cardio/cerebro-vascular disease.
9. History or current evidence of cardiac arrhythmia and/or conduction abnormality CTCAE Grade * 1.
10. History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade * 3.
11. Chest x-ray/CT with evidence of lung calcifications with the exception of calcified
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 | EUCTR2009-010876-73-NL |
| ClinicalTrials.gov | NCT01004224 |
| CCMO | NL29778.031.09 |