Clinical trial NCT00809133: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2008-12-17
Enrollment: 83
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: TREATMENT

Brief 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)

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs) in the First Cycle for the Determination of the Maximum Tolerated Dose (MTD)
timeFrame: Cycle 1: 21 days (part C and D) or 28 days (part A and B)
measure: Maximum Tolerated Dose (MTD)
timeFrame: Cycle 1: 21 days (part C and D) or 28 days (part A and B)
Secondary outcomes:
measure: Incidence and Intensity of AEs According to the Maximum Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade
timeFrame: From first drug administration until the end of treatment cycle 1; 21 days (part C and D) or 28 days (part A and B)
measure: Part A: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15
timeFrame: Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.
measure: Part A: Afatinib Cmax,ss on Day 15
timeFrame: Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.
measure: 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
timeFrame: 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.
measure: Part A: Paclitaxel Cmax on Day 1 and Day 15
timeFrame: 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.
measure: Part B: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State on Day 15
timeFrame: 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.
measure: Part B: Afatinib Cmax,ss on Day 15
timeFrame: Day 15: -0:05 (hh:mm), 0:00, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00 and 24:00.
measure: 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
timeFrame: 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.
measure: Part B: Paclitaxel Cmax on Day 1 and Day 15
timeFrame: 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.
measure: Part B: Bevacizumab Plasma Concentration
timeFrame: 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.
measure: Part C: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State in Cycle 2
timeFrame: 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.
measure: Part C: Afatinib Cmax,ss in Cycle 2
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Part C: Carboplatin Cmax in Cycle 1 and Cycle 2
timeFrame: 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
measure: Part D: AUCt,ss: Area Under the Concentration-Time Curve of Afatinib in Plasma at Steady State.
timeFrame: 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.
measure: Part D: Afatinib Cmax,ss
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Part D: Paclitaxel Cmax in Cycle 1 and 2
timeFrame: 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
measure: 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
timeFrame: 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
measure: Part D: Carboplatin Cmax in Cycle 1 and 2
timeFrame: 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.
measure: Objective Tumour Response (Unconfirmed)
timeFrame: From first drug administration until the last trial drug administration, up to 1156 days.
measure: Objective Tumour Response (Confirmed)
timeFrame: From first drug administration until the last trial drug administration, up to 1156 days.
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: 1200.12.4402 Boehringer Ingelheim Investigational Site
city: Sutton
country: United Kingdom
facility: 1200.12.4401 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: O'Brien MER, Sarker D, Bhosle J, Thillai K, Yap TA, Uttenreuther-Fischer M, Pemberton K, Jin X, Wiebe S, de Bono J, Spicer J. A phase I study to assess afatinib in combination with carboplatin or with carboplatin plus paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2018 Nov;82(5):757-766. doi: 10.1007/s00280-018-3661-1. Epub 2018 Aug 7.
citation: Suder A, Ang JE, Kyle F, Harris D, Rudman S, Kristeleit R, Solca F, Uttenreuther-Fischer M, Pemberton K, Pelling K, Schnell D, de Bono J, Spicer J. A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours. Eur J Cancer. 2015 Nov;51(16):2275-84. doi: 10.1016/j.ejca.2015.07.041. Epub 2015 Aug 18.