Study of Safety and Efficacy of INC280 and Cetuximab, in Adult c-MET Positive mCRC and HNSCC Patients After Progression on Cetuximab or Panitumumab Therapy

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Squamous Cell Carcinoma of Head and Neck (SCCHN), Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: INC280
* Drug: cetuximab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: c-MET positive mCRC and HNSCC<br>c-MET positive and K/NRAS WT mCRC and c-MET positive HNSCC patients | Drug: INC280<br> <br> Drug: cetuximab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLTs) | 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. | during Cycle 1 and up to 4 weeks from the time of study treatment start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Events (AEs)/Serious Adverse Events (SAEs) | To characterize the safety and tolerability of the INC280 and cetuximab combination as measured by the frequency of AEs/SAEs in patients treated with the combination of INC280 and cetuximab | During Cycle 1 Day 1 (C1D1) until treatment discontinuation for up to 2 years | 
| Overall Response Rate | To assess preliminary anti-tumor activity of the INC280 and cetuximab combination as measured by Overall Response Rate in patients treated with the combination of INC280 and cetuximab. The end of study was upon completion of the survival follow-up period of the last patient treated with the combination of INC280 and cetuximab. A treatment cycle was defined as 28 days with no scheduled break between cycles. | Every 8 weeks from cycle 1, day 1 until the end of study for up to 3 years | 
| Overall Survival | To assess additional clinical activity of the INC280 and cetuximab combination as measured by Overall Survival for patients in the expansion part of the study. The end of study was upon completion of the survival follow-up period of the last patient treated with the combination of INC280 and cetuximab. | Every 12 weeks until the end of study for up to 3 years | 
| Time versus plasma concentration profiles and basic PK parameters of INC280 | To characterize the PK profile of INC280 with cetuximab combination as measured by time versus plasma concentration profiles and basic PK parameters of INC280. A treatment cycle was defined as 28 days with no scheduled break between cycles. | during the first 4 Cycles of treatment or up to 16 weeks from the time of study treatment start | 
| Severity of Adverse Events (AEs)/Serious Adverse Events (SAEs) | To characterize the safety and tolerability of the INC280 and cetuximab combination as measured by severity of AEs/SAEs in patients treated with the combination of INC280 and cetuximab | From Cycle 1 Day 1 until treatment discontinuation for up to 2 years | 
| Frequency of dose treatment interruptions and reductions | To characterize the safety and tolerability of the INC280 and cetuximab combination as measured by the frequency of dose interruptions and dose reductions in patients treated with the combination of INC280 and cetuximab | From Cycle 1 Day 1 until treatment discontinuation for up to 2 years | 
| Progression Free Survival | To assess preliminary anti-tumor activity of the INC280 and cetuximab combination as measured by Progression Free Survival in patients treated with the combination of INC280 and cetuximab.The end of study was upon completion of the survival follow-up period of the last patient treated with the combination of INC280 and cetuximab. | Every 8 weeks from C1D1 until the end of study for up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SCCHN,, cancer, oral and nasal cavity, paranasal sinuses, pharynx, larynx, parotid glands, lympth nodes of neck, mucosal lining, epithelium, colon, large intestine, rectal cancer, INC280, c-MET inhibitor, cetuximab, metastatic colorectal cancer, head and neck, squamous cell carcinoma, resistance to cetuximab/panitumumab