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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Terminated

CT.gov ID

NCT02205398

Collaborator

(none)

Enrollment

Locations

Arm

29.8

Actual Duration (Months)

0.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of Head and Neck (SCCHN) Metastatic Colorectal Cancer	Drug: INC280 Drug: cetuximab	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

13 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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.

Actual Study Start Date :

Jul 28, 2014

Actual Primary Completion Date :

Jan 20, 2017

Actual Study Completion Date :

Jan 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: c-MET positive mCRC and HNSCC c-MET positive and K/NRAS WT mCRC and c-MET positive HNSCC patients	Drug: INC280 Drug: cetuximab

Arm

Intervention/Treatment

Experimental: c-MET positive mCRC and HNSCC

c-MET positive and K/NRAS WT mCRC and c-MET positive HNSCC patients

Drug: INC280

Drug: cetuximab

Outcome Measures

Primary Outcome Measures

Incidence of Dose Limiting Toxicities (DLTs) [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 Outcome Measures

Frequency of Adverse Events (AEs)/Serious Adverse Events (SAEs) [During Cycle 1 Day 1 (C1D1) until treatment discontinuation for up to 2 years]
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
Overall Response Rate [Every 8 weeks from cycle 1, day 1 until the end of study for up to 3 years]
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.
Overall Survival [Every 12 weeks until the end of study for up to 3 years]
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.
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]
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.
Severity of Adverse Events (AEs)/Serious Adverse Events (SAEs) [From Cycle 1 Day 1 until treatment discontinuation for up to 2 years]
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
Frequency of dose treatment interruptions and reductions [From Cycle 1 Day 1 until treatment discontinuation for up to 2 years]
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
Progression Free Survival [Every 8 weeks from C1D1 until the end of study for up to 3 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital Head & Neck	Boston	Massachusetts	United States	02114
2	Memorial Sloan Kettering MSKCC NY	New York	New York	United States	10017
3	University of Utah / Huntsman Cancer Institute Onc Dept	Salt Lake City	Utah	United States	84103
4	Novartis Investigative Site	Leuven		Belgium	3000
5	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1X6
6	Novartis Investigative Site	Lyon Cedex		France	69373
7	Novartis Investigative Site	Toulouse Cedex 9		France	31059
8	Novartis Investigative Site	Essen		Germany	45147
9	Novartis Investigative Site	Wuerzburg		Germany	97080
10	Novartis Investigative Site	Ancona	AN	Italy	60126
11	Novartis Investigative Site	Milano	MI	Italy	20162
12	Novartis Investigative Site	Barcelona	Catalunya	Spain	08003
13	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
14	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya	Spain	08907
15	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46010