Primary:- To determine the MTD and/or a recommended phase II dose (RP2D) of BYL719 when administered orally in combination with imatinib 400 mg q.d.Secondary:- Assess the safety and tolerability profile of imatinib and BYL719 administered in…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Maximum Tolerated Dose and/or the Recommended Phase 2 Dose
Secondary outcome
Adverse effects, PK, disease progression
Background summary
More than 50% of patients with advanced GIST tumors has disease progression
after first line 1st treatment with imatinib. Sunitinib is available as 2nd
line treatment. However sunitinib has limitations due to adverse effects, such
as hypothyroidism and heart failure. In case imatinib and sunitinib have
failed, there is no accepted standard treatment available. Therefore BYL719 may
fulfill this medical need.
BYL719 is a small orally bioavailable class I *-selective PI3K inhibitor
belonging to the 2-aminothiazole class.
See also page 23 of the protocol: Study rationale and purpose.
Study objective
Primary:
- To determine the MTD and/or a recommended phase II dose (RP2D) of BYL719 when
administered orally in combination with imatinib 400 mg q.d.
Secondary:
- Assess the safety and tolerability profile of imatinib and BYL719
administered in combination.
- Evaluate the effect of BYL719 on steady-state PK of imatinib and the effect
of imiatinib on steady-state PK of BYL719
- Characterize the steady state and population PK profiles of imatinib and
BYL719 when administered in combination.
- Perform a preliminary assessment of the clinical activity of imatinib and
BYL719 combination treatment in patients with advanced GIST.
Study design
This open-label, phase Ib, dose-finding study in which safety and tolerability
of escalating doses of BYL719 in combination with imatinib administered at a
dose of 400mg q.d. in patients with metastatic and/or unresectable GIST, who
have failed prior therapy with imatinib and sunitinib, will be investigated.
The study will comprise 2 parts: a dose escalation part to establish the MTD
and/or RP2D and
a dose expansion part at the MTD or RP2D . The expected overall number of
recruited patients is in the range of 45 to 55, of which 8 in NL.
Intervention
Treatment with imatinib plus BYL719
Study burden and risks
Risk: adverse effects of (combination of) imatinib and BYL719. Tumor biopsy
Burden: Screening visit. Mono-therapy visit. Cycle 1: 4 visits. Cycle 2 and
above: 2 visits/cycle
Every visit: fasting for blood tests.
Physical examination
CT/MRI scan thorax/abdomen/pelvis (however same frequency as during regular
care).
ECG, MUGA scan or echocardiography
Blood draws every visit (3-4 mL per occasion)
Long hospital stays for PK measurements (0-8 en 24h post dose)
Pregnancy tests (if relevant)
Tumor biopsy: dose escalation patients at screening only if no archival tumor
is available. Dose expansion patients at screening and at end of study
(irrespective of availability of archival tumor tissue)
Raapopseweg 1
Arnhem 6834DP
NL
Raapopseweg 1
Arnhem 6834DP
NL
Listed location countries
Age
Inclusion criteria
1. Male or female patients * 18 years of age
2. WHO performance status of 0-2
3. Histologically confirmed diagnosis of GIST that is unresectable or metastatic
4. Available tissue specimen:
* Dose-escalation part: patients archival tumor tissue. Fresh if archival is unavailable.
* Dose-expansion part: patients archival tumor tissue plus fresh pre-treatment biopsy
5. Failed prior therapy with imatinib followed by sunitinib for the treatment of unresectable or metastatic GIST. Note the following specific criteria for the two parts of the trial:
- Dose escalation part: patients who failed prior therapy with imatinib and then have failed therapy with sunitinib. Treatment failure may be due to either disease progression on therapy (both imatinib aand sunitinib) or intolerance to therapy (sunitinib). Dose escalation part patients may have had additional lines of therapy than imatinib and sunitinib.
- Dose expansion part: patients must have documented disease progression on both imatinib and sunitinib. In addition, patients may have had up to 3 lines of prior therapy. Patients must have been treated with imatinib and must have been treated with sunitinib and then may have received one other line of therapy.
6. Radiological (CT/MRI) confirmation of disease progression (RECIST criteria) during prior therapy with imatinib and sunitinib will be required for patients entering the Dose Expansion part
7. At least one measurable lesion, as defined by RECIST version 1.1, will be required for
patients entering the Dose-expansion part.
Exclusion criteria
1. Previous treatment with PI3K inhibitors
2. Patient has active uncontrolled or symptomatic central nervous system (CNS) metastases
3. Patient with diabetes mellitus requiring insulin treatment and/or with clinical signs
4. Patient who has not recovered to grade 1 adverse events of imatinib and/or sunitinib
5. Patient has active cardiac disease or dysfunction, see protocol page 36
6. History of significant bleeding disorder unrelated to cancer
7. Patients who have not recovered from prior surgery
8. Patients who have received wide field radiotherapy within 4 weeks or limited field
radiation for palliation within 2 weeks
9. Patient is currently receiving chronic treatment with steroids, immunosuppressive agent, strong/moderate CYP3A4 inhibitors/inducers, warfarin, phenytoin, QT-prolongators or Torsade de Pointes inducers (see protocol for details and washout).
10. Pregnancy, lactation
11. Females of child-bearing potential and males not using safe contraception.
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 | EUCTR2012-003273-25-NL |
| ClinicalTrials.gov | NCT01735968 |
| CCMO | NL43135.058.13 |