The aim of the phase Ib part is to estimate the MTD and/or identify the RP2D for the combination MEK162 and panitumumab, followed by a phase II part to assess the clinical efficacy and to further assess the safety of the combination in selected…
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Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase Ib: Incidence of Dose Limiting Toxicities in Cycle 1
Phase II: Outcome: Overall response rate (ORR) as per RECIST v1.1
Secondary outcome
Phase Ib and Phase II: Frequency and severity of AEs, SAEs, changes in
laboratory values, vital signs, and electrocardiograms
Phase Ib only: Objective Response Rate (ORR), Progression-free survival, (PFS),
duration of response
(DOR), disease control rate (DCR) as per RECIST v1.1
Phase II only: Progression-free survival, (PFS), duration of response (DOR),
disease control rate (DCR) as per RECIST v1.1
Background summary
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and
second leading cause of cancer death in the United States (US) and in the
European Union. In the last decade, substantial advances in the treatment of
metastatic colorectal cancer (mCRC) have resulted in an improvement in overall
survival (OS) This improvement has occurred with the addition of irinotecan,
oxaliplatin, bevacizumab, cetuximab, and panitumumab to the standard treatment
with 5-fluorouracil (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, panitumumab and cetuximab, 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, in
particular mutations of KRAS, play an important role in the progression of
colorectal cancer. KRAS mutations, which may be present in up to 40% of
patients with CRC, have emerged as important predictive markers of primary
resistance to anti-EGFR monoclonal antibodies resulting in limited treatment
options for metastatic CRC patients displaying KRAS mutations.
In patients with wild-type KRAS CRC, anti-EGFR monoclonal antibodies are an
important treatment option. However, resistance to anti-EGFR monoclonal
antibodies typically emerge after several months of treatment. The underlying
mechanism is not known, but recent data identified KRAS mutations as potential
and frequent drivers of acquired resistance to both anti-EGFR monoclonal
antibodies, panitumumab and cetuximab. The addition of MEK inhibitors to
anti-EGFR monoclonal antibodies may represent a rational strategy to overcome
resistance to anti-EGFR monoclonal antibodies. Preliminary activity for this
combination has been observed in a clinical trial (Deming 2012). These findings
show that co-targeting the EGFR and the downstream molecule MEK might emerge as
a potential therapeutic option for patients with mCRC who have progressed on
existing standard therapies.
Study objective
The aim of the phase Ib part is to estimate the MTD and/or identify the RP2D
for the combination MEK162 and panitumumab, followed by a phase II part to
assess the clinical efficacy and to further assess the safety of the
combination in selected patient populations.
Study design
This is a multi-center phase Ib/II study. The study has a dose escalation part
and a phase II part. Patients will be treated until progression of disease,
unacceptable toxicity develops, or withdrawal of informed consent, whichever
occurs first.
Cohorts of patients will be treated in the doseescaltion part with the
combination until the MTD/RP2D of the combination is identified.
Following MTD/RP2D declaration, additional patients will be enrolled in 4 phase
II arms.
Arm 1: mutant RAS mCRC patients who have not been pretreated with an EGFR
inhibitor (EGFRi), including EGFR tyrosine kinase inhibitor therapy and/or
anti-EGFR monoclonal antibody therapy.
Arm 2: mutant RAS mCRC patients who have been pretreated with anti-EGFR
monoclonal antibody therapy, but have not been pre-treated with EGFR tyrosine
kinase inhibitor therapy.
Arm 3 patients with WT RAS mCRC who have been pretreated with anti-EGFR
monoclonal antibody therapy, but have not been pretreated with EGFR tyrosine
kinase inhibitor therapy.
Arm 4: patients with WT RAS mCRC who have not been pretreated with an EGFRi,
including EGFR tyrosine kinase inhibitor therapy and/or anti-EGFR monoclonal
antibody
therapy.
Intervention
MEK162 tablet for oral use 15mg. Starting dose 45mg BID
Panitumumab intravenous infusion starting dose 6mg/kg Q2W
Study burden and risks
Side effects of the combination of MEK162 and panitumumab.
This combination has not been tested in humans before.
The main side effects of MEK162 (single agent) sofar are: rash or skin
irritation, diarrhea, fluid retention, increased creatine phosphokinase (that
may indicate muscle inflammation or damage), fatigue, nausea with or without
vomiting, changes in vision (such as blurred vision, seeing *floaters* or
swelling in or around the eye, constipation, dry mouth, dry skin,
stomatitis/mucositis, loss or reduction of appetite, hair loss, taste
alteration, high blood pressure, indigestion, muscle weakness, fever, anemia,
increase in the value of liver enzymes.
The main side effects of panitumumab are: infusion reactions , allergic
reactions , rash, dry skin, itchy skin,
anemia, hypokalemia, hypomagnesaemia, conjunctivitis, alopecia, stomatitis,
diarrhea, nausea, vomiting, abdominal pain, constipation, anorexia, decreased
weight, fatigue. Pyrexia, asthenia, peripheral edema, back pain, insomnia,
cough, dyspnea
The risks related to some study assessments as taking blood and imaging as
MUGA-scans and CT-scans.
Burden:
4 visits during Cycle 1 and 2, and 2 visits during the subsequent Cycles. Visit
duration 1-4 h.
Blooddraws at each visit (5 to 15 mL blood/each visit, depending on the
analysis that will be done).
ECG monitoring: weekly during Cycle 1, bi-weekly during Cycle 2 and once every
Cycle thereafter. Echocardiogram or MUGA-scan at screening and cycle 2 and
every 3rd cycle thereafter.
Walnut Street, 3200
Boulder CO 80301
US
Walnut Street, 3200
Boulder CO 80301
US
Listed location countries
Age
Inclusion criteria
1. Histological or cytological confirmation of mCRC
2. Progression on or following standard therapy or for whom no standard therapy exists.
3. Written documentation of WT RAS or somatic mutation in exon 2 (codons 12/13), 3 (codons 59/61) or 4 (codons 117/146) in either KRAS or NRAS in medical history.
4. Phase Ib only: Availability of a representative tumor sample at Screening/baseline (newly obtained or if not feasible, archival with a corresponding pathology report)
5. Phase II only: A newly obtained tumor sample must be collected to document the WT RAS or somatic mutation status (as described above) during the molecular pre-screening period at a local or a Novartis designated central laboratory. The tumor sample must be collected after the last anti-neoplastic treatment, and within 3 months prior to start of treatment on this study.
6. Evidence of measurable disease, as determined by RECIST v1.1.
7. ECOG performance status <= 2.
Exclusion criteria
1. Phase II arms 1 and 4 only: previous treatment with cetuximab, panitumumab, and/or other EGFR inhibitors
2. Previous treatment with MEK-inhibitors
3. History of severe infusion reactions to monoclonal antibodies.
4. Known hypersensitivity and/or contraindication to any of the study medications or their excipients
5. Symptomatic or untreated leptomeningeal disease.
6. Symptomatic brain metastasis.
7. History or current evidence of retinal disease or ophthalmopathy as assessed by ophthalmologic examination at baseline that would be considered a risk factor for CSR/RVO
8. History of keratitis or ulcerative keratitis.
9. Known acute or chronic pancreatitis.
10. Clinically significant cardiac disease including any of the following:
• Congestive heart failure (NYHA grade >= 2),
• Left ventricular ejection fraction (LVEF) < 45%
• Uncontrolled arterial hypertension (as defined > 140 (systolic) /100 (diastolic) mmHg
• 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
• Acute Myocardial Infarction (AMI) <= 3 months prior to starting study drug
• QTcF > 480 msec
11. Patients with any of the following laboratory values at Screening/baseline:
• Absolute neutrophil count (ANC) <1,500/mm3 [1.5 x 109/L]
• Platelets < 100,000/mm3 [100 x 109/L]
• Hemoglobin < 9.0 g/dL
• Serum creatinine >1.5 x ULN (upper limit of normal) or calculated or directly measured CrCl < 50% LLN (lower limit of normal)
• Serum total bilirubin >1.5 x ULN
• AST/SGOT or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present
• Magnesium < the lower limit of normal
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral MEK162.
13. Previous or concurrent malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and 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.
14. History of thromboembolic or cerebrovascular events within the last 6 months.
15. Patients who have received radiation therapy (that includes > 30% of the bone marrow reserve), chemotherapy, biological therapy (e.g., antibodies) within <= 4 weeks (6 weeks for nitrosourea, mitomycin-C), or who have been treated with continuous or intermittent small molecule therapeutics or investigational agents within 5 half-lives of the agent (or <= 4 weeks when half-life is unknown) prior to starting study drug or who have not recovered to grade <= 1 from the side effects of such therapy (except alopecia).
16. Any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery.
17. Known human immunodeficiency virus (HIV) infection.
18. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality
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 | EUCTR201300198618-NL |
| ClinicalTrials.gov | NCT01927341 |
| CCMO | NL46448.031.13 |