The primary purpose of the phase Ib part of this study is to determine the maximum tolerated dose(s) (MTD(s)) and/or recommended phase II dose (RP2D) in patients with BRAF mutant melanoma, and to delineate a clinical dose to be used in future…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary variabels:
Dose Limiting Toxicities, Ready for Phase 2 Dose, Overall Response Rate,
Progression Free Survival, Duration of Response.
Secondary outcome
Secundary variabels:
Adverse Events, Pharmacokinetics.
Background summary
Although clinical trials with selective BRAF and MEK inhibitors have shown
significant activity in patients with BRAF mutant melanoma, these patients
ultimately relapse and fail to respond to these therapies. Therefore, targeting
both the RAS/RAF/MEK/ERK pathway and the CCND1/CDK pathway downstream may
improve response and be an effective strategy to expand therapeutic options for
these patients with advanced melanoma that have very poor prognosis and
constitute a high unmet medical need.
The primary purpose of the phase Ib part of this study is to determine the
maximum tolerated dose(s) and/or recommended phase II dose of the combination
of LEE011 and LGX818 in patients with BRAF mutant melanoma. In the phase II
portion of the study, the combination will be evaluated in patients who have
not received prior BRAF inhibitors and in patients who have progressed on
previous treatment with BRAF inhibitors to gain preliminary evidence of
antitumor activity of LEE011 in combination with LGX818 in patients with BRAF
mutant melanoma.
LEE011 is a highly selective inhibitor of CDK4/6 which has shown in vitro and
in vivo activity in models of BRAF mutant melanoma both as single agent and in
combination with LGX818.
LGX818 is a highly potent and selective BRAF inhibitor, and preclinical data
suggest that LGX818 could lead to more sustained clinical responses in patients
with advanced and/or metastatic BRAF V600 mutant melanoma compared to other RAF
inhibitors. In the first in human study, LGX818 has demonstrated marked single
agent antitumor activity in patients with BRAF mutant melanoma who have not
received prior RAF inhibitors. However in patients resistant to prior BRAF
inhibitor therapy, the response to LGX818 is significantly less modest. Per the
data cutoff date of 30 September 2012, preliminary efficacy results in 24
patients* naïve to a previous BRAF inhibitor (BRAFi) treatment across all dose
levels evaluated show an ORR of 71% and DCR of 100%.
Based on pathway biology and preclinical data, the combination of LEE011 and
LGX818 has the potential to benefit patients with BRAF mutant melanoma. The
dual inhibition of MAPK and cell proliferation pathways could lead to enhanced
anti-tumor effect and overcome resistance to BRAF inhibition.
Since the single agent anti-tumor activity of LGX818 is comparable to other
BRAFi that are either approved or in clinical trials, treating BRAFi naïve
patients with LGX818 alone is deemed appropriate. This single agent anti-tumor
activity will be compared to that of the combination (LEE011 + LGX818) in the
BRAFi naïve patient population. Patients resistant to prior BRAF inhibitor
therapy will only receive the combination, as single agent activity of the
agents is either modest or unknown.
Study objective
The primary purpose of the phase Ib part of this study is to determine the
maximum tolerated dose(s) (MTD(s)) and/or recommended phase II dose (RP2D) in
patients with BRAF mutant melanoma, and to delineate a clinical dose to be used
in future studies. This study will also assess safety, tolerability, and PK. In
the phase II portion of the study, the combination will be evaluated in
patients who have not received prior BRAF inhibitors and in patients who have
failed BRAF inhibitors to gain preliminary evidence of antitumor activity of
LEE011 in combination with LGX818 in patients with BRAF mutant melanoma.
Study design
This is a multi-center, open-label, dose finding, Phase Ib dose escalation
study to estimate the MTD(s) and/or RP2D for the combination of LEE011 and
LGX818, followed by a Phase II study to assess the clinical efficacy and to
further evaluate the safety of the combination in patients with locally
advanced or metastatic BRAF mutant melanoma. Patients with documented mutations
in BRAF V600 will be included in both phases of the study. LEE011 will be
administered orally, once daily for 21 consecutive days followed by a 7-day
planned break (28-day cycle).
LGX818 will be administered orally, once daily on a continuous dosing schedule
(28-day cycle). Patients will be treated until progression of disease,
unacceptable toxicity develops, or withdrawal of informed consent, whichever
occurs first.
Continued treatment beyond progression of disease will be allowed under
specific circumstances.
Intervention
Treatment with LEE011 and LGX818 or LGX818 alone.
Study burden and risks
Risks: Adverse Events of the trial medication
Burden:
Cycle of 4 weeks (LGX818) and 3 weeks (LEE011) with 2 oral treatments.
6 visits during cycle 1, 3 visits during cycle 2 and 2 visits the next cycles.
Duration 1-8 (phase Ib) or 1-4 (phase II) hour.
4 times taking blood samples during cycle 1, 2 times during cycle 2 and one
time during the next cycles.15 ml blood/time.
Extra PK: phase Ib 2 sessions of 8 hour (6 samples of 2.5 mL), phase II: 2
sessions of 4 hour (4 samples).
4 times ECG during cycle 1, 2 times during cycle 2 and one time during the next
cycles.
Echocardiogram or MUGA-scan at screening and at end of treatment.
Skin test (routine research) cycle 3, 5, 7 etcetera.
Eye examinations: visual acuity, visual field, slit lamp examination,
intraocular pressure (IOP) and dilated funduscopy at screening and every 4
cycles thereafter.
Tumor evaluations at screening:
• Phase Ib, phase II (only BRAF inhibitor naive patients): archival tumor
sample; fresh tumor biopsy if no or insufficient archival tumor material
• Phase II (resistant against previous BRAF inhibitor): archival tumor sample
of direct after tumor progression of under last BRAF; fresh tumor biopsy if no
or insufficient archival tumor material is available of that moment.
At stop of trial treatment without progression, the patient will be controlled
every 2 months on progression (CT/MRI) until new treatment.
Follow-up for survival (every 3 months, only phase II).
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. Adult with histologically confirmed diagnosis of locally advanced or metastatic melanoma along with written documentation of any BRAF V600 mutation.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.
3. Patients must have evidence of evaluable and/or measurable disease, by RECIST v1.1.
4. A representative tumor sample is available for molecular testing
5. A sufficient interval must have elapsed, Cytotoxic chemotherapy >= 2 weeks, biologic therapy >= 4 weeks.
6. A negative serum βHCG test <= 72 hours before starting study treatment for premenopausal women and for women < 1 years after the onset of menopause
Exclusion criteria
1. Symptomatic brain metastases. Asymptomatic stable metastases are allowed.
2. Symptomatic or untreated leptomeningeal disease.
3. Patients with the abnormal laboratory values during screening, please check protocol for specific info: ANC, Hgb, platelets, serum creatine, serum total bilirubine, ASAT and ALAT
4. Impairment of gastro-intestinal function /GI disease that may significantly alter the absorption
5. In the phase II BRAFi naïve arms (1a/b), prior exposure to CDK4/6 inhibitor
6. Impaired cardiac function or clinically significant cardiac diseases, including any of the following: LVEF <= 45%, QTcF >450 ms for males and >470 ms for females.
7. Patients who are currently receiving treatment QTc prolongators
8. History of thromboembolic or cerebrovascular events within the last 6 months,
9. Patients with concurrent severe and/or uncontrolled concurrent medical conditions
10. Previous or concurrent malignancy.
11. Major surgery < 2 weeks before starting study treatment
12. Patients unwilling or unable to comply with the protocol
13. Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C
14. Pregnant or nursing (lactating) women
15. Women of child-bearing potential, unless highly effective methods of contraception or post-menopausal. Sexually active male must use a condom during intercourse
Design
Recruitment
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 | EUCTR2012-004551-36-NL |
| ClinicalTrials.gov | NCT01777776 |
| CCMO | NL43491.041.13 |