Trial of Afatinib (BIBW 2992) + Cetuximab in Advanced Solid Tumours

Study Overview
=================
Brief Summary
-----------------
The trial is divided in two parts, Part A and Part B. Part A will involve dose-finding of dose-limiting toxicity (DLT) and MTD in patients with advanced solid tumours. Part B will involve expansion of the MTD to 3 cohorts including non-small cell lung cancer squamous histology, recurrent/ metastatic squamous cell carcinoma of head and neck and other advanced solid tumours (except sarcomas).

Official Title
-----------------
A Phase Ib Dose Escalation Study of Afatinib in Combination With Cetuximab in Patients With Advanced Solid Tumours

Conditions
-----------------
Neoplasms

Intervention / Treatment
-----------------
* Drug: Cetuximab( erbitux®)
* Drug: Afatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Part A only Patients must have advanced malignant solid tumours that are metastatic or unresectable At least one measurable or evaluable (non-measurable) lesion per RECIST 1.1 Part B only Patients must have: measurable disease per RECIST 1.1 diagnosis of one of the following Advanced Non-Small Cell Lung Cancer -Squamous Histology (NSCLC-SQ) with no more than 2 lines of chemotherapy for advanced/metastatic disease ( prior EGFR directed treatment is permitted) or Recurrent/Metastatic Squamous Cell Carcinoma of Head and Neck (R/M SCCHN) no more than 2 lines of chemotherapy for advanced disease and no more than 1 line of prior cetuximab permitted. or Other malignant solid tumours except sarcomas (for metastatic colorectal cancer, only wild type KRAS are permitted) Part A and B Age 18 years or older Written informed consent that is consistent with ICH-GCP guidelines and local law. Histological/Cytological confirmed diagnosis of malignant solid tumours (exclusion of sarcomas) Advanced disease for whom standard treatment is ineffective or no longer effective Recovered from previous therapy related AE to </= Grade 1 at the study entry (except, for stable sensory neuropathy </= Grade 2 and alopecia) Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. Adequate organ function as defined by the following criteria: LVEF >50% or within institutional values Absolute neutrophil count (ANC) >1500/ mm3 Platelet count >75.000/ mm3 Estimated creatinine clearance > 45ml/ min Total bilirubin<1.5 times upper limit of institutional normal Aspartate amino transferase (AST) or alanine amino transferase (ALT) <3 x upper limit of institutional normal (ULN) (if related to liver metastases< 5xULN) Exclusion criteria: Chemotherapy, biological therapy or investigational agents within 4 weeks prior to the start of study treatment. Hormonal anti-cancer treatment within 2 weeks prior to the start of study treatment (continued use of anti-androgens and/or gonadorelin analogues [LHRH] is permitted) Radiotherapy within 4 weeks prior to the start of study treatment, except as follows: Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to study treatment, and Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor prior to enrolling. Major surgery (as judged by the investigator) within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study Known hypersensitivity to afatinib or the excipients of any of the trial drugs History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator. Myocardial infarction within 6 months prior start treatment. Female patients of childbearing potential who: are nursing or are pregnant or are not using an acceptable method of birth control or do not plan to continue using this method throughout the study and/or do not agree to submit to pregnancy testing required by this protocol. Any history of or concomitant condition that, in the opinion of the Investigator, would compromise the patient's ability to comply with the study or interfere with the evaluation of the efficacy and safety of the test drug Previous or concomitant malignancies at other sites, except effectively treated non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or effectively treated malignancy that has been in remission for more than 3 years and is considered to be cured. Requiring treatment with any of the prohibited concomitant medications listed in the protocol that can not be stopped for the duration of trial participation Known pre-existing interstitial lung disease Any history or presence of poorly controlled gastrointestinal disorders that could affect the absorption of the study drug (e.g. Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) Active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV carrier. Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment. Meningeal carcinomatosis Patients with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids or have been on stable dose of corticosteroids for at least 4 weeks before starting study treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment. Any SPC listed contra-indications for cetuximab Use of alcohol or drugs incompatible with patient participation in the study in the investigator's opinion.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: combination arm<br>Patients to receive afatinib once daily plus weekly cetuximab infusion | Drug: Cetuximab( erbitux®)<br>* once per week<br>Drug: Afatinib<br>* once per day<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of Afatinib in Combination With Cetuximab Based on the Number of Patients With DLTs During the First Treatment Cycle (Afatinib). | Maximum Tolerated Dose (MTD) of Afatinib in combination with cetuximab based on the number of patients with dose limiting toxicity (DLT) during the first treatment cycle (Dose escalation part). The MTD is defined as the highest dose level at which less than 33% of the patients experience DLT in first treatment cycle. | First 21 days treatment cycle | 
| Dose Limiting Toxicities During Cycle 1 | Number of Patients With Dose Limiting Toxicity (DLT) Occurring during Cycle 1. The following drug related AEs qualified as DLT: 1) CTCAE Grade ≥2 decrease in cardiac left ventricular function 2) CTCAE Grade 2 diarrhoea lasting for ≥7 days, despite appropriate use of standard antidiarrheal therapy based on Protocol Amendment 1 dated 22 Oct 2013 3) CTCAE Grade ≥3 diarrhoea despite appropriate use of standard anti-diarrheal therapy for at least 2 days. 4) CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days 5) CTCAE Grade ≥3 rash despite standard medical management. 6) CTCAE Grade ≥3 fatigue lasting more than 7 days. 7) All other AEs of CTCAE Grade ≥3 (except alopecia and allergic reaction) that led to an interruption of afatinib and/or cetuximab dosing for more than 14 days until recovery to baseline or Grade 1, whichever was higher. 8) CTCAE Grade 4 hypomagnesemia or Grade 3 hypomagnesemia with clinically-significant sequelae | First 21-day treatment cycle | 
| MTD of Afatinib in Combination With Cetuximab Based on the Number of Patients With DLTs During the First Treatment Cycle (Cetuximab). | Maximum Tolerated Dose (MTD) of Afatinib in combination with cetuximab based on the number of patients with DLTs during the first treatment cycle (Dose escalation part). | First treatment cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities During All Treatment Cycles | Number of patients with DLT occuring during all treatment cycle is presented | All treatment cycle (each treatment cycle of 21 days) | 
| Recommended Phase II Dose Based on the Number of Patients With Dose Limiting Toxicity Events (Cetuximab) | MTD was deemed the recommended Phase II dose based on the number of patients with dose limiting toxicity events at all treatment cycles. | All treatment cycle (each treatment cycle of 21 days) | 
| Best Overall Response | Best overall response (according to RECIST version 1.1) was defined as the best response recorded at any time from the first administration of afatinib or cetuximab to the End of Treatment (EOT). As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. | Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 19 months | 
| Objective Response | Objective response was defined as the proportion of patients with measurable disease having at least a best overall response of complete response (CR) or partial response (PR), according to RECIST version 1.1. As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. | Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 19 months | 
| Disease Control Rate | For patients with measurable disease, disease control was defined as the proportion of patients having at least a best overall response of CR, PR or stable disease (SD). As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression | Post baseline tumour-imaging was performed at every 6 weeks (in the week preceding the start of Cycles 3, 5, 7, 9, 11, etc.) until EOT; up to 19 months | 
| Recommended Phase II Dose Based on the Number of Patients With Dose Limiting Toxicity Events (Afatinib) | MTD was deemed the recommended Phase II dose based on the number of patients with dose limiting toxicity events at all treatment cycles. | All treatment cycle (each treatment cycle of 21 days) |