Trial Exploring Afatinib (BIBW 2992) + Paclitaxel (Part A), Afatinib + Paclitaxel + Bevacizumab (Part B), Afatinib + Carboplatin (Part C) and Afatinib+ Paclitaxel +Carboplatin(Part D) in Patients With Advanced Solid Tumours
Condition: Neoplasms
Intervention: Paclitaxel; Carboplatin; BIBW 2992; Paclitaxel; BIBW2992; Paclitaxel; Carboplatin; Bevacizumab; BIBW 2992; BIBW 2992
Intervention description: Part A and B:80mg/m2 given on Day 1, 8 and 15 of 28 Day cycle.; AUC6 given on day 1 of 21 day cycle; Escalating dose cohorts; Part A and B:80mg/m2 given on Day 1, 8 and 15 of 28 Day cycle.; MTD dose of part A; 175mg/m2 given on Day 1 of 21 Day cycle; AUC6 given on day 1 of 21 day cycle; Escalating dose Cohorts - 5mg / kg, 7.5mg / kg and 10mg / kg given Day 1 and Day 15 of a 28 days cycle; Escalating dose cohorts; Escalating dose cohorts
Intervention MeSH terms: Paclitaxel; Albumin-Bound Paclitaxel; Bevacizumab; Carboplatin; Afatinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Masking: None (Open Label)
Enrollment: 83.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The main purpose of this study is to assess the optimum dose of the following medications
      when they are given together:

        -  BIBW 2992 and paclitaxel (Taxol)

        -  BIBW 2992 and paclitaxel and bevacizumab (Avastin)

        -  BIBW 2992 and carboplatin

        -  BIBW 2992 and paclitaxel and carboplatin The effect of the different drug combinations
           will also be assessed.
    

Eligibility criteria:

        Inclusion criteria:

          1. Male or female patients (patients) with a histologically confirmed diagnosis of
             malignancy that is now advanced, non-resectable and / or metastatic.

          2. Age 18 years old or older.

          3. Life expectancy of at least 3 months.

          4. Written informed consent that is consistent with ICH-GCP guidelines.

          5. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.

          6. Patients must have recovered from any previous surgery.

          7. Adequate organ function including the following:

          8. Cardiac left ventricular function with resting ejection fraction greater than or equal
             to 50%

          9. Absolute neutrophil count of greater than or equal to 1,500/microlitres; greater than
             2000/microlitres for carboplatin

         10. Platelets greater than or equal to 100,000/microlitres

         11. Total bilirubin less than or equal to 1.5 mg/dl (<26 micromol /L, SI unit equivalent).

         12. AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal.

         13. Creatinine less than or equal to 1.5 mg/dl (less than or equal to 132 micromol per
             liter, SI unit equivalent).

         14. Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control) for the duration of trial participation.
             Female patients with reproductive potential must have a negative serum pregnancy test
             within 7 days of trial enrolment. Breast feeding mothers will be excluded since these
             agents may be toxic to infants.

        Exclusion criteria:

          1. Active infectious disease

          2. Serious illness or concomitant non-oncological disease considered by the investigator
             to be incompatible with the protocol

          3. GI tract disease resulting in an inability to take oral medication or a requirement
             for IV alimentation, prior surgical procedures affecting absorption, or active peptic
             ulcer disease.

          4. Significant cardiovascular disease (a history of congestive heart failure requiring
             therapy, a need for anti-arrhythmic therapy for a ventricular arrhythmia, unstable
             angina pectoris or myocardial infarction within 6 months prior to trial entry).

          5. Patients who require full-dose anticoagulation.

          6. Patients not completely recovered from any therapy-related toxicities from previous
             chemo-, hormone-, immuno-, or radiotherapies to CTC less than or equal to Grade 1.
             Prior chemotherapy is allowed if completed at least 4 weeks prior to 1st trial
             treatment (6 weeks for mitomycin C or nitrosoureas) and the patient has recovered from
             the acute toxicities of that therapy.

          7. Patients with untreated or symptomatic brain metastases. Patients with treated,
             asymptomatic brain metastases are eligible if there has been no change in brain
             disease status for at least 8 weeks, no history of cerebral oedema or bleeding in the
             past 8 weeks and no requirement for steroids or anti-epileptic therapy

          8. Persistent Grade 2 or greater neurotoxicity / neuropathy from any cause.

          9. Patients on immunosuppressant therapy or with known HIV infection.

         10. Treatment with any of the following within 4 weeks of starting trial medication, or
             during the trial, is not permitted: chemo-, immuno-, radio- (small field palliative
             radiotherapy is allowed provided this does not represent clear disease progression),
             biological therapies (including trastuzumab), hormone therapy (excluding LHRH agonists
             in prostate cancer, or bisphosphonates), or treatment with other investigational
             drugs.

         11. Participation in another clinical trial within the past 4 weeks before start of
             therapy or concomitantly with this trial.

         12. Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2
             inhibiting drugs within the past 4 weeks before start of therapy or concomitantly with
             this trial.

         13. Patients with known or suspected hypersensitivity to any of the trial drugs, their
             excipients or similar compounds.

         14. Patients unable to comply with the protocol.

         15. Active alcohol or drug abuse.

         16. Patients with known pre-existing interstitial lung disease

             Additional exclusion criteria for patients recruited to cohorts B:

         17. Patients with known or suspected hypersensitivity to bevacizumab, its excipients or
             Chinese hamster ovary cell products or other recombinant human or humanised
             antibodies.

         18. Patients with brain metastases (a brain scan is not required unless the patient shows
             signs and symptoms of brain metastases and a brain scan is performed to rule out the
             presence of brain metastases).

         19. Patients with intra-abdominal inflammation .

         20. Major surgery within 4 weeks of starting treatment or any wound(s) deemed by the
             investigator to pose a significant risk to the patient in the event of delayed
             healing.

         21. Prior treatment with anthracycline and/or prior radiation to the chest wall ( patients
             in these categories will only be entered into the study where the investigator deems
             the benefit to the patient to outweigh the risk).

         22. Patients with any of the following conditions: significant hypertension, significant
             haemoptysis, known brian metastases, thrombotic or haemorrhagic disorders, INR greater
             than or equal to 1.5 abnormal PTT, therapeutic anti-coagulation, squamous non small
             cell lung cancer Additional exclusion criteria for patients recruited to cohorts C and
             D

               -  Patients with severe myelosuppression; i.e. absolute neutrophil count less than
                  2000/microlitres

               -  Patients with renal impairment (creatinine clearance less than 60ml per minute by
                  Cockcroft-Gault equation)