A Phase Ib, Open-label, Multicenter, Dose Escalation and Expansion Study, to Evaluate the Safety, Pharmacokinetics and Activity of INC280 in Combination With Cetuximab in c-MET Positive CRC and HNSCC Patients Who Have Progressed After Anti-EGFR Monoclonal Antibody Therapy.
Trial Snapshot
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 13
- Locations
- 4
- Primary Endpoint
- Incidence of Dose Limiting Toxicities (DLTs)
Study Overview
Brief Summary
This was an open-label, phase Ib, multicenter clinical trial to determine the MTD/RDE of the orally administered c-MET inhibitor INC280 in combination with cetuximab. This combination was to be explored in c-MET positive mCRC and HNSCC patients whose disease progressed on cetuximab or panitumumab treatment. The dose escalation part was to be guided by a Bayesian Logistic Regression Model with overdose control. At MTD/RDE, additional mCRC and HNSCC patients who progressed on cetuximab or panitumumab treatment were to be enrolled in two expansion groups to further assess the anti-tumor activity and the safety and tolerability of the combination of INC280 and cetuximab. Patients were to receive INC280 on a continuous bid dosing regimen and cetuximab every week. A treatment cycle was defined as 28 days with no scheduled break between cycles.
The trial was terminated because of difficulties in identifying patients who met the eligibility criteria.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male or female aged ≥ 18 years
- •Metastatic colorectal cancer or head and neck squamous cell carcinoma
- •c-MET positive (defined by c-MET IHC intensity score +2 in ≥ 50% of tumor cells and MET gene copy number ≥ 5 by FISH or IHC intensity score +3 in ≥ 50% of tumor cells) and K/NRAS WT status for mCRC patients only
- •At least one previous line of treatment for the metastatic disease and the last treatment must have included cetuximab or panitumumab. Documentation of clinical benefit and subsequent progression on cetuximab or panitumumab as the most recent line of treatment is required for patients in the expansion part
- •Measurable disease as per RECIST v1.1
- •ECOG performance status ≤ 2
Exclusion Criteria
- •Prior treatment with c-MET/HGF inhibitors
- •History of severe reactions to cetuximab and/or panitumumab (except for G3 rash and G3 hypomagnesaemia)
- •History of acute or chronic pancreatitis
- •Active bleeding within 4 weeks prior to screening visit
- •Symptomatic brain metastases
- •Feeding tube dependence
- •Not adequate hematologic, renal and hepatic function
Arms & Interventions
c-MET positive mCRC and HNSCC
c-MET positive and K/NRAS WT mCRC and c-MET positive HNSCC patients
Intervention: INC280 (Drug)
c-MET positive mCRC and HNSCC
c-MET positive and K/NRAS WT mCRC and c-MET positive HNSCC patients
Intervention: cetuximab (Drug)
Outcomes
Primary Outcomes
Incidence of Dose Limiting Toxicities (DLTs)
Time Frame: during Cycle 1 and up to 4 weeks from the time of study treatment start
To estimate the MTD and/or RDE of INC280 in combination with cetuximab in c-MET positive mCRC and HNSCC patients as measured by the incidence of DLTs in Cycle 1. A treatment cycle was defined as 28 days with no scheduled break between cycles.
Secondary Outcomes
- Severity of Adverse Events (AEs)/Serious Adverse Events (SAEs)(From Cycle 1 Day 1 until treatment discontinuation for up to 2 years)
- Frequency of Adverse Events (AEs)/Serious Adverse Events (SAEs)(During Cycle 1 Day 1 (C1D1) until treatment discontinuation for up to 2 years)
- Overall Response Rate(Every 8 weeks from cycle 1, day 1 until the end of study for up to 3 years)
- Overall Survival(Every 12 weeks until the end of study for up to 3 years)
- Time versus plasma concentration profiles and basic PK parameters of INC280(during the first 4 Cycles of treatment or up to 16 weeks from the time of study treatment start)
- Frequency of dose treatment interruptions and reductions(From Cycle 1 Day 1 until treatment discontinuation for up to 2 years)
- Progression Free Survival(Every 8 weeks from C1D1 until the end of study for up to 3 years)