Primary objectives Phase Ib: To estimate the MTD and/or RP2D of LGX818 in combination with cetuximab ± BYL719. Incidence of dose-limiting toxicities (DLTs). Phase II: To compare the efficacy of the dual (LGX818, cetuximab) and triple (LGX818, BYL719…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence of DLTs, progression free survival
Secondary outcome
Incidence and severity of adverse events, pharmacokinetics, overall response
rate, duration of response, time to response, progression free survival and
overall survival.
Background summary
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and
second leading cause of cancer death in the EU and US. In 2009, an estimated
150,000 new cases and 50,000 deaths from CRC in the US have occurred. In the
last decade, substantial advances in the treatment of metastatic CRC (mCRC)
have resulted in an improvement in overall survival from 10-12 months to more
than 20 months. This has occurred with the addition of irinotecan, oxaliplatin,
bevacizumab, cetuximab, and panitumumab to the standard treatment with
5-FU/leucovorin. However, because many patients eventually develop resistance
to these agents, new agents to treat resistant tumors are an important area of
investigation.
The anti-EGFR monoclonal antibodies cetuximab and panitumumab were initially
evaluated as monotherapy in patients with EGFR-expressing tumors after they
became resistant to standard chemotherapy. Subsequent investigations discovered
that oncogenic activation of signaling pathways downstream of the EGFR, such as
mutations of KRAS and BRAF, play an important role in progression of CRC.
While the treatment of mCRC has improved significantly in patients whose tumors
express wild-type KRAS, recent data indicate that patients with wild-type KRAS
that also carry the BRAFV600E mutation have worse outcome, highlighting the
need for new therapies in this patient population. Evidence of clinical
activity of the selective BRAF inhibitor vemurafenib in patients with BRAF
mutant mCRC, supports that BRAF is a therapeutic target for this disease.
However, the clinical activity has been more modest than that observed in
patients with BRAF mutant melanoma, suggesting that additional factors may
modulate the response to BRAF inhibitor in mCRC.
Preclinical work has shown that BRAF inhibition causes a rapid feedback
activation of EGFR that supports continued proliferation of BRAF mutant CRC
tumor cells, and can be effectively prevented by the combination of vemurafenib
with anti-EGFR agents such as erlotinib or cetuximab. Activation of the
PI3K/AKT signaling pathway was also shown to confer resistance to vemurafenib
in BRAF mutant CRC cells. These reports suggest that both activation of EGFR
and aberrant PI3K pathway signaling may explain the limited therapeutic effect
of BRAF inhibitor monotherapy in patients with BRAF mutant mCRC.
The effect of combining the selective BRAF inhibitor LGX818 with the EGFR
inhibitor cetuximab or erlotinib, or the PI3Kα-specific inhibitor BYL719
resulted in a strong synergistic anti-tumor activity consistent with the recent
published reports. Furthermore, the results suggested that additional benefit
may be gained through the simultaneous combination of all three inhibitors.
The triple combination of LGX818, BYL719 and cetuximab effectively suppressed
both RAF/MEK/ERK and PI3K/AKT pathways, and inhibited proliferation to a
greater degree in vitro than did any of the dual combinations. These data
provide a strong rationale to evaluate the combination of LGX818 and cetuximab
± BYL719 in patients with BRAF mutant mCRC that have a poor clinical outcome,
and for whom no targeted therapeutic strategies are effective after failure of
standard chemotherapeutic regimens.
Study objective
Primary objectives
Phase Ib: To estimate the MTD and/or RP2D of LGX818 in combination with
cetuximab ± BYL719. Incidence of dose-limiting toxicities (DLTs).
Phase II: To compare the efficacy of the dual (LGX818, cetuximab) and triple
(LGX818, BYL719, cetuximab) combinations.
Secondary objectives: safety and tolerability, PK, tumor activity, gene
alterations/expression relevant to the RAF/MEK/ERK and EGFR/PI3K/AKT pathways
in tumor tissue
Study design
Open-label phase Ib dose escalation and randomized phase II study.
Approximately 124 patients.
Screening for KRAS wild-type and BRAF V600 mutation.
The aim of phase Ib (n~24) is to determine the MTD and/or RP2D of LGX818 in
combination with cetuximab (dual combination) and the MTD and/or RP2D of LGX818
in combination with BYL719 and cetuximab (triple combination). Cohorts of 3-6
patients. Cycle of 4 weeks.
Dose-escalation decision after 1 cycle.
After the MTD/RP2D of the dual combination has been determined, cohorts of
patients will be enrolled to be treated with the triple combination.
Phase II (n~100) will be performed with the highest well-tolerated dose of the
dual combination and the triple combination (randomized, 1:1).
Treatment until progression or unacceptable toxicity.
Follow-up for survival.
Intervention
Treatment with LGX818 in combination with cetuximab with or without BYL719.
Cetuximab will be administered intravenously. Startingdose: 400mg/m2 followed
by 250 mg/m2 weekly
LGX818 will be supplied as capsules for oral use of 10, 25, 50, and 100 mg
dosage strength and will be dosed on a flat scale of mg/day
BYL719 will be supplied as tablets for oral use of 10, 50, and 200 mg dosage
strength and will be dosed on a flat scale of mg/day
Study burden and risks
Risks: Adverse events of study medication LGX818 in combination with cetuximab
with or without BYL719. The combinations have not yet been tested in humans
before.
Burden:
Treatment courses of 4 weeks with weekly cetuximab infusions.
5 visits during courses 1-2 and 4 visits in the subsequent courses. Visit
duration 1-4 h. 3 visits of 8-10 h (PK sampling, for phase Ib only).
Weekly blood sampling during course 1 and bi-weekly thereafter. 3-40 ml of
blood/occasion.
Additional PK for participants to phase Ib (7-8 samples of 2,5 ml each).
ECGs: 1 (course 2 and thereafter) and 2 during course 1.
Echocardiogram or MUGA-scan at screening and end of treatment.
Eye assessments at screening and every 4 cycles.
Tumor evaluations at screening and every 6 weeks thereafter until disease
progression.
Tumor biopsy at screening (part II), during treatment and at disease
progression.
Follow-up for survival (phone call every 8 weeks).
Cambridge Park Drive 100
Cambridge MA 02140
US
Cambridge Park Drive 100
Cambridge MA 02140
US
Listed location countries
Age
Inclusion criteria
1. Histological or cytological proof of metastatic colorectal cancer (mCRC)
2. Progression after at least one prior standard of care regimen or be intolerant to irinotecan-based regimens
3. KRAS wild-type and BRAF V600E mutation, or any other BRAF V600 mutation
4. Phase II only: fresh tumor biopsy at baseline
5. Evidence of measurable disease, as determined by RECIST v1.1.
6. Life expectancy >= 3 months
7. ECOG performance status <= 2
Protocol amendment 4: Inclusion criteria 7: ECOG performance status <= 1
Exclusion criteria
1. Phase II only: previous treatment with cetuximab, panitumumab, other EGFR inhibitors, RAF-inhibitors, PI3K-inhibitors, and/or MEK-inhibitors
2. Symptomatic or untreated leptomeningeal disease
3. Symptomatic brain metastasis.
4. Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs or with fasting glucose >=7.8 mmol/L, history of clinically significant gestational diabetes mellitus or documented steroid-induced diabetes mellitus
5. Known acute or chronic pancreatitis
6. Clinically significant cardiac disease including any of the following:
Congestive heart failure requiring treatment (NYHA grade >= 2), LVEF < 45%), history or presence of clinically significant ventricular arrhythmias or atrial fibrillation, clinically significant resting bradycardia, unstable angina pectoris <= 3 months prior to starting study drug, Aacute Myocardial Infarction (AMI) <= 3 months prior to starting study drug, QTcF > 480 msec
7. Any of the following laboratory values at Screening/baseline:
•Absolute neutrophil count (ANC) <1.5 x 109/L
•Platelets < 100 x 109/L
•Hemoglobin < 5,58 mmol/L
•Serum creatinine >1.5 x ULN or Creatinin Clearance < 50% LLN (lower limit of normal)
•Serum total bilirubin >1.5 x ULN, except for patients with Gilbert*s syndrome, who may be included if total bilirubin is <= 3.0 x ULN and direct bilirubin is <= 1.5 x ULN
•AST/SGOT and/or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present
8. Impairment of gastrointestinal (GI) function or GI disease which may alter the absorption of LGX818
9. Previous or concurrent malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry.
10. Pregnant or nursing (lactating) women
11. History of thromboembolic or cerebrovascular events within the last 6 months, including transient ischemic attack, deep vein thrombosis, or pulmonary embolism.
12. Radiation therapy (> 30% of the bone marrow reserve), chemotherapy, biological therapy (e.g., antibodies) within <= 4 weeks
13. Any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery
14. Known human immunodeficiency virus (HIV) infection
15. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results
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 | EUCTR2012-002138-35-NL |
| ClinicalTrials.gov | NCT01719380 |
| CCMO | NL41787.031.12 |