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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I Open Label Trial of Continuous Dosing With BIBW 2992 Combined With Paclitaxel and BIBW 2992 Combined With Paclitaxel and Bevacizumab, BIBW 2992 Combined With Carboplatin and BIBW 2992 Combined With Paclitaxel and Carboplatin in Patients With Advanced Solid Tumours

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: BIBW 2992
* Drug: Paclitaxel
* Drug: BIBW2992
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Bevacizumab
* Drug: BIBW 2992
* Drug: BIBW 2992


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients (patients) with a histologically confirmed diagnosis of malignancy that is now advanced, non-resectable and / or metastatic. Age 18 years old or older. Life expectancy of at least 3 months. Written informed consent that is consistent with ICH-GCP guidelines. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. Patients must have recovered from any previous surgery. Adequate organ function including the following: Cardiac left ventricular function with resting ejection fraction greater than or equal to 50% Absolute neutrophil count of greater than or equal to 1,500/microlitres; greater than 2000/microlitres for carboplatin Platelets greater than or equal to 100,000/microlitres Total bilirubin less than or equal to 1.5 mg/dl (<26 micromol /L, SI unit equivalent). AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal. Creatinine less than or equal to 1.5 mg/dl (less than or equal to 132 micromol per liter, SI unit equivalent). 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: Active infectious disease Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol 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. 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). Patients who require full-dose anticoagulation. 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. 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 Persistent Grade 2 or greater neurotoxicity / neuropathy from any cause. Patients on immunosuppressant therapy or with known HIV infection. 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. Participation in another clinical trial within the past 4 weeks before start of therapy or concomitantly with this trial. 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. Patients with known or suspected hypersensitivity to any of the trial drugs, their excipients or similar compounds. Patients unable to comply with the protocol. Active alcohol or drug abuse. Patients with known pre-existing interstitial lung disease Additional exclusion criteria for patients recruited to cohorts B: Patients with known or suspected hypersensitivity to bevacizumab, its excipients or Chinese hamster ovary cell products or other recombinant human or humanised antibodies. 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). Patients with intra-abdominal inflammation . 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. 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). 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)

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>BIBW2992 + Paclitaxel | Drug: BIBW 2992<br>* Escalating dose cohorts<br>Drug: Paclitaxel<br>* Part A and B:80mg/m2 given on Day 1, 8 and 15 of 28 Day cycle.<br>|
| Experimental: Part B<br>BIBW2992 + Paclitaxel + Bevacizumab | Drug: Paclitaxel<br>* Part A and B:80mg/m2 given on Day 1, 8 and 15 of 28 Day cycle.<br>Drug: BIBW2992<br>* MTD dose of part A<br>Drug: Bevacizumab<br>* Escalating dose Cohorts - 5mg / kg, 7.5mg / kg and 10mg / kg given Day 1 and Day 15 of a 28 days cycle<br>|
| Experimental: Part C<br>BIBW2992 + Carboplatin | Drug: Carboplatin<br>* AUC6 given on day 1 of 21 day cycle<br>Drug: BIBW 2992<br>* Escalating dose cohorts<br>|
| Experimental: Part D<br>BIBW2992 +Paclitaxel + Carboplatin | Drug: Carboplatin<br>* AUC6 given on day 1 of 21 day cycle<br>Drug: Paclitaxel<br>* 175mg/m2 given on Day 1 of 21 Day cycle<br>Drug: BIBW 2992<br>* Escalating dose cohorts<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD) | Dose limiting toxicity (DLT) was defined as an Adverse Event (AE) or laboratory abnormality considered as related to study treatment. | Cycle 1: 21 days (part C and D) or 28 days (part A and B) | 
| Maximum Tolerated Dose (MTD) | The MTD of afatinib in selected combination treatments was defined as the highest dose at which no more than 1 out of 6 patients experienced DLTs during the first treatment cycle, i.e. the highest dose with a DLT incidence ≤17%. The MTD was determined separately for Afatinib in combination with Paclitaxel (part A), Afatinib in combination with Paclitaxel and Bevacizumab (part B), Afatinib and Carboplatin (part C), and Afatinib in combination with Paclitaxel and Carboplatin (part D). In part C, dose escalation was not continued beyond the dose level A40C6, due to safety and pharmacokinetic considerations and upon mutual agreement between the investigators and the sponsor. Formally, no MTD was determined, however a recommended phase II dose was determined and is presented here. 0=not maximum tolerated dose, 1=is maximum tolerated dose Note, the depicted order of treatment groups is driven by dose level, not by the actual dosing steps. | Cycle 1: 21 days (part C and D) or 28 days (part A and B) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Intensity of AEs According to the Maximum Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade | Incidence and Intensity of AEs (Adverse Events) graded according to the maximum CTCAE (Common Toxicity Criteria for Adverse Events) grade based on the number of patients with AEs with CTCAE Grade 1-5. | From first drug administration until the end of treatment cycle 1; 21 days (part C and D) or 28 days (part A and B) | 
| Part A: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15 | Area under the concentration-time curve of Afatinib in plasma at steady state. | Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00. | 
| Part A: Afatinib Cmax,ss on Day 15 | Maximum measured concentration of Afatinib in plasma at steady state. | Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00. | 
| Part A: AUC0-24: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From Zero Extrapolated to 24 Hours on Day 1 and Day 15 | AUC0-24: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 24 hours. | Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. | 
| Part A: Paclitaxel Cmax on Day 1 and Day 15 | Maximum measured concentration of Paclitaxel in plasma. | Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. | 
| Part B: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15 | Area under the concentration-time curve of Afatinib in plasma at steady state. | Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. There were no analyzable patients for Part B: A30P80B5 (Afatinib + Paclitaxel + Bevacizumab. | 
| Part B: Afatinib Cmax,ss on Day 15 | Maximum measured concentration of Afatinib in plasma at steady state. | Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00. | 
| Part B: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours on Day 1 and Day 15 | AUC0-24: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 24 hours. | Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. | 
| Part B: Paclitaxel Cmax on Day 1 and Day 15 | Maximum measured concentration of Paclitaxel in plasma. | Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. | 
| Part B: Bevacizumab Plasma Concentration | Bevacizumab plasma concentration after infusion of Bevacizumab 5mg/kg after end of 1st and 2nd infusion in Cycle 1. | Day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 24:00. | 
| Part C: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State in Cycle 2 | AUCt,ss: Area under the concentration-time curve of Afatinib in plasma at steady state. | Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00. | 
| Part C: Afatinib Cmax,ss in Cycle 2 | Maximum measured concentration of Afatinib in plasma at steady state. | Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00. | 
| Part C: Area Under the Concentration-Time Curve of Carboplatin in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours in Cycle 1 and Cycle 2 | AUC0-24: Area under the concentration-time curve of Carboplatin in plasma over the time interval from zero extrapolated to 24 hours. | Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00. | 
| Part C: Carboplatin Cmax in Cycle 1 and Cycle 2 | Maximum measured concentration of Carboplatin in plasma. | Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 24:00 | 
| Part D: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State. | AUCt,ss: Area under the concentration-time curve of Afatinib at steady state. | Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00. | 
| Part D: Afatinib Cmax,ss | Maximum measured concentration of Afatinib in plasma at steady state. | Cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00. | 
| Part D: Area Under the Concentration-Time Curve of Paclitaxel in Plasma Over the Time Interval From 0 Extrapolated Upto 23 Hours in Cycle 1 and Cycle 2 | AUC0-23: Area under the concentration-time curve of Paclitaxel in plasma over the time interval from zero extrapolated to 23 hours. | Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 23:00. | 
| Part D: Paclitaxel Cmax in Cycle 1 and 2 | Maximum measured concentration of Paclitaxel in plasma. | Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00 | 
| Part D: Area Under the Concentration-Time Curve of Carboplatin in Plasma Over the Time Interval From 0 Extrapolated Upto 24 Hours in Cycle 1 and Cycle 2 | AUC0-24: Area under the concentration-time curve of Carboplatin in plasma over the time interval from zero extrapolated to 24 hours. | Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00 | 
| Part D: Carboplatin Cmax in Cycle 1 and 2 | Maximum measured concentration of Carboplatin in plasma. | Cycle 1, day 1 and cycle 2, day 1: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00 and 24:00. | 
| Objective Tumour Response (Unconfirmed) | Number of subjects with objective tumour response (unconfirmed). Objective Response (OR) was defined as Complete Response (CR) or Partial Response (PR). | From first drug administration until the last trial drug administration, up to 1156 days. | 
| Objective Tumour Response (Confirmed) | Number of subjects with confirmed objective tumour response. Objective Response (OR) was defined as Complete Response (CR) or Partial Response (PR). Objective response was to be confirmed by a second tumour assessment at least 4 weeks after the assessment of CR or PR. | From first drug administration until the last trial drug administration, up to 1156 days. |