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

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

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).

Inclusion criteria:

Part A only

1. Patients must have advanced malignant solid tumours that are metastatic or unresectable

2. At least one measurable or evaluable (non-measurable) lesion per RECIST 1.1 Part B only

3. Patients must have:

   1. measurable disease per RECIST 1.1

   2. 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

4. Age 18 years or older

5. Written informed consent that is consistent with ICH-GCP guidelines and local law.

6. Histological/Cytological confirmed diagnosis of malignant solid tumours (exclusion of sarcomas)

7. Advanced disease for whom standard treatment is ineffective or no longer effective

8. Recovered from previous therapy related AE to </= Grade 1 at the study entry (except, for stable sensory neuropathy </= Grade 2 and alopecia)

9. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.

10. 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:

1. Chemotherapy, biological therapy or investigational agents within 4 weeks prior to the start of study treatment.

2. 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)

3. Radiotherapy within 4 weeks prior to the start of study treatment, except as follows:

   1. Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to study treatment, and
   2. Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor prior to enrolling.

4. 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

5. Known hypersensitivity to afatinib or the excipients of any of the trial drugs

6. 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.

7. Female patients of childbearing potential who:

   1. are nursing or
   2. are pregnant or
   3. 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.

8. 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

9. 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.

10. Requiring treatment with any of the prohibited concomitant medications listed in the protocol that can not be stopped for the duration of trial participation

11. Known pre-existing interstitial lung disease

12. 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)

13. 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.

14. Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment.

15. Meningeal carcinomatosis

16. 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.

17. Any SPC listed contra-indications for cetuximab

18. Use of alcohol or drugs incompatible with patient participation in the study in the investigator's opinion.