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Pharmaceuticals, Inc. BI Trial No.: 1200.2 Page 3 12 January 2007 17 March 2004 to 09 February 2012 Title of study: Investigator: A Phase I open-label dose escalation study of once-daily oral treatment with for 21 days in patients with advanced solid tumors Study centers: Multicenter study, cf. Appendix 16.1.4 Publication (reference): Clinical phase: Objectives: Methodology: Stopfer P, Schaefer HG, Amelsberg A, Huisman H, Eskens F, Gietema JA, Briscoe J, Lewis N, Cohen RB, Marshall J, Verweij J,. Pharmacokinetic results from two phase I dose escalation studies of once daily oral treatment with BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with advanced solid tumors. AACR-NCI-EORTC Int Conf 'Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications', Philadelphia, 14-18 Nov 2005 2005 Abstr. B172 (R06-4114). Marshall JL, Lewis NL, Amelsberg A, Briscoe J, Hwang J, Malik S, Cohen R,. A phase I dose escalation study of, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a 3 week on 1 week off schedule in patients with advanced solid tumors. AACR-NCI-EORTC Int Conf 'Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications', Philadelphia, 14-18 Nov 2005 Clin Cancer Res 2005;11(23)(Suppl):168 Abstr B161 (R06-4110). Stopfer P, Schaefer HG, Amelsberg A, Huisman H, Eskens F, Gietema JA, Briscoe J, Lewis N, Cohen RB, Marshall J, Verweij J,. Pharmacokinetic results from two phase I dose escalation studies of once daily oral treatment with BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with advanced solid tumors. AACR-NCI-EORTC Int Conf 'Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications', Philadelphia, 14-18 Nov 2005 2005 Abstr. B172 (P06-07602). I The primary objective was the assessment of safety of as assessed by the maximum tolerated dose (MTD). Secondary objectives were collection of overall safety data, antitumor efficacy data, as well as the determination of pharmacokinetics and the pharmacodynamic modulation of biomarkers by. Open-label, dose escalation study
Pharmaceuticals, Inc. BI Trial No.: 1200.2 Page 4 12 January 2007 17 March 2004 to 09 February 2012 No. of subjects: planned: enrolled: 54 entered: 45 actual: enrolled: 49 entered: 43 Treatment A: 10 mg entered: 3 treated: 3 analyzed (for primary endpoint): Treatment B: 20 mg entered: 6 treated: 6 analyzed (for primary endpoint): Treatment C: 40 mg entered: 8 treated: 8 analyzed (for primary endpoint): Treatment D: 55 mg entered: 20 treated: 20 analyzed (for primary endpoint): Treatment E: 65 mg entered: 6 treated: 6 analyzed (for primary endpoint) Diagnosis and main criteria for inclusion: Test product: Test product: dose: mode of admin.: batch no.: Patients with a confirmed diagnosis of a malignant solid tumor refractory or not amenable to standard therapies, preferably patients with breast, colorectal or prostate cancer. tablets Starting dose of 10 mg /day once daily, followed by dose escalation Oral B030902, B040108, B040806 (5 mg); B030905, B040109, B040111 (20 mg) Duration of treatment: Continuous daily dosing for 21 days followed by 7 days off, repeated courses (administration for 21 consecutive days followed by 7 days off ) in the absence of clinical disease progression. Reference therapy: NA dose: mode of admin.: batch no.:
Pharmaceuticals, Inc. BI Trial No.: 1200.2 Page 5 12 January 2007 17 March 2004 to 09 February 2012 Criteria for evaluation: Efficacy: Safety: Statistical methods: SUMMARY CONCLUSIONS: Efficacy results: Pharmacokinetic and pharmacodynamic parameters (biomarker modulation in skin and tumor biopsies). Objective tumor response (based on RECIST). Adverse events (AEs) according to common terminology criteria (CTC), laboratory evaluations, patient performance, cardiac left ventricular function, ECG Descriptive statistics of the patient population as well as for pharmacokinetic determinations. Adverse Events were analyzed for first treatment period as well as for all treatment periods combined. Overall, the patient population was consistent with a general Phase I population. The most frequent tumors were colorectal, breast, pancreatic, ovarian, thyroid, esophageal, prostate, and lung cancer. Tumors were evaluated according to RECIST criteria in 39 patients. All patients had at least one prior treatment while most of the patients (84.6%) had three or more prior therapies. Almost 72% of patients with measurable disease had three or more prior chemotherapies. No patient experienced a confirmed objective response. One patient with squamous cell carcinoma of the skin experienced a transient PR with progression at a repeat assessment two treatment cycles later. One patient experienced tumor shrinkage by 13%, which was maintained and the patient entered the roll-over trial.
Pharmaceuticals, Inc. BI Trial No.: 1200.2 Page 6 12 January 2007 17 March 2004 to 09 February 2012 Safety results: Forty-three patients were treated at doses of 10, 20, 40, 55, and 65 mg. Gastrointestinal disorders (mainly diarrhea, nausea, vomiting and stomatitis,) and skin adverse events (mainly rash, pruritus, mucosal inflammation and dry skin) were the most frequently reported drug-related AEs. The single most frequently reported AE related to trial medication was diarrhea (65.1%). It generally commenced within 1 week of start of trial medication but occasionally occurred only in later treatment courses when lower doses were administered. The onset of skin-related events is later than that of diarrhea (mainly in the second week of treatment). The incidence of stomatitis appears to dose-related. In Treatment Period 1 (TP1) there appears to be a relationship between the incidence of drug-related diarrhea and the dose of. This relationship was not maintained when all treatment periods were analyzed together. Events of epistaxis were seen at a higher frequency than expected. A similar finding has been made in the 1200.1 study (administration of for 2 weeks followed by a 2 week drug-free period in repeated cycles). Epistaxis was mostly observed at higher dose levels. Severity of epistaxis was always low (CTC Grade 1), and the duration was generally brief. Supportive treatment was not required. A correlation between epistaxis or other bleeding events and coagulation parameters (especially PT, PTT) was not found. Most patients did not exhibit significant changes in liver enzymes over the conduct of this study. For the smaller number of patients demonstrating more pronounced elevations in transaminases, the events were primarily observed after discontinuation of during the post-treatment period. The most likely interpretation for these increases in liver transaminases was a progression of the underlying disease (either primary liver carcinoma or liver metastases from colorectal or breast cancer disease). A number of patients experienced a pronounced decline in previously elevated transaminases. Other clinically relevant changes in a limited number of patients were reversible increase in serum creatinine, hyponatremia, and hypokalemia. Some of these changes were associated with the occurrence of diarrhea and/or vomiting. Decreases in body weight may have been associated with gastrointestinal AEs but may also have been related to the course of the patient s disease. There was some reversible decline in hemoglobin, which may have been the result of multiple blood draws. There have been occasional changes in lymphocyte counts without a clear cause. Similar changes have also been seen in animal studies. Coagulation parameters changed in some patients and did not appear to be correlated with bleeding events. A correlation of changes in coagulation with the treatment seemed unlikely.
Pharmaceuticals, Inc. BI Trial No.: 1200.2 Page 7 12 January 2007 17 March 2004 to 09 February 2012 There was no decrease in LVEF to CTC Grade 2 during the conduct of study observed. No important changes in vital signs and ECGs were noted. A trend toward increasing severity of AEs with increasing dose was observed, which seemed to be relevant for cases of diarrhea and rash. The incidence of drug-related AEs seemed to increase when patients receive more than one course of treatment with. Fifteen patients (34.9%) experienced one or more SAEs. There were 10 deaths, two during screening period, three during the treatment period and five in the post-treatment period. A total of 5 patients died due to disease progression. None of these cases were considered to be related to the trial medication. Seven patients discontinued from the trial as a result of AEs. In total, 11 patients developed DLT in TP1. The most common DLT event was diarrhea (5 patients). This protocol defined the MTD based on DLT events reported during TP1 of the dose-escalation phase of this trial. While DLT events were observed in 3/6 (50%) patients in the 65 mg cohort, only one DLT event was observed in the initial group of 6 patients at 55 mg. According to the protocol, 55 mg was the MTD group to be further evaluated in an expansion cohort. During the conduct of the expansion cohort, an additional 6 patients developed DLT events exceeding a pre-set limit in the protocol. The further enrolment into this dose cohort was discontinued. An expansion cohort below 55 mg was not evaluated. For Phase II clinical trials a daily dose below 55 mg (e.g., 40 mg) should be evaluated. It may be considered to aggressively treat diarrhea or to prescribe antidiarrheal medication prophylactically. In general, AEs observed in this trial were consistent with the safety profile of other EGFR inhibitors, although the rate of epistaxis has been higher.
Pharmaceuticals, Inc. BI Trial No.: 1200.2 Page 8 12 January 2007 17 March 2004 to 09 February 2012 Pharmacokinetics: exhibited similar disposition kinetics after both single and multiple administrations and could be described by at-least biexponential disposition kinetics. After oral administration of, maximum plasma concentrations were mostly detected between 2-5 hours post-drug administration. Generally, maximum plasma concentrations and exposure increased with increasing doses after single administration and at steady state. For, all PK parameters displayed moderate to high variability in all treatment cohorts, both after single dose and at steady state, but this was within the expected range for an orally administered anti-cancer drug in the first Phase I dose finding study. The gmean terminal half-life following oral administration of ranged between 20 hours and 43 hours. However, the terminal half-life determination for was more reliable on Day 21 of TP1. Therefore, the terminal half-life of is likely in the range of 35 hours to 43 hours. Pharmacodynamics: A relatively high apparent total body clearance and volume of distribution for was determined. The values obtained for total body clearance and volume of distribution should be treated with caution as the absolute bioavailability of in humans is unknown. Steady state was reached, at latest, within 8 days after the first administration of. The gmean accumulation ratios based on Cmax values were between 1.36 and 2.35. Based on AUC values gmean accumulation ratio values were approximately 1.81 to 3.07. treatment significantly reduced the proliferation rate of epidermal keratinocytes, with a concordant increase in epidermal keratinocyte differentiation. Furthermore, there might be a correlation between the clinically used treatment doses and the level of inhibition of epidermal keratinocyte proliferation and the accompanied induction of epidermal keratinocyte differentiation. No significant changes in any of the other studied biomarkers were observed.
Pharmaceuticals, Inc. BI Trial No.: 1200.2 Page 9 12 January 2007 17 March 2004 to 09 February 2012 Conclusions: In summary, has an AE profile that is consistent with other EGFR and EGFR / HER2 inhibitors. The MTD is 55 mg once daily, although a lower dose (e.g., 40 mg/day) may be used in subsequent trials in a schedule with 21 days on treatment followed by a 7 day drug-free period in repeated cycles. Preliminary signs of clinical efficacy, with tumor shrinkage and one transient partial response, have been observed. At 16 weeks of treatment, the Kaplan-Meier estimate was that 25.2% of patients at the MTD were alive and free of disease progression. This compares favorably to other compounds evaluated in Phase I settings. The PK profile is acceptable and skin biopsies have shown a pharmacodynamic modulation of epidermal keratinocytes as expected from a drug inhibiting the EGFR inhibitor. Based on the findings in this trial, the further evaluation of in clinical trials is warranted.