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PD) of GSK2256098, a Focal Adhesion Kinase (FAK) Inhibitor, in Patients with Advanced Solid Tumors
Poster Session – Phase 0, I and II Tumor biospy were successful with more than 50% tumor cells in 36/50 pts (72%), and molecular profiling with sequencing and CGH were successful in all these patients. Clinical significant molecular alterations were found in 16/36 evaluable patients (44%). Somatic mutations were identified in 5/36 pts (14%), including mutations in PI3K, NRAS and FBXW7. Copy number alterations were identified in 14/36 pts (39%), including FGFR1 amplification, PTEN loss, MDM2 amplification... Based of this analysis, 14/50 pts (28%) were allocated to a specific targeted therapy in relationship with their molecular alteration. Conclusion: Our preliminary results suggest the operational feasibility of this approach: high interest for patients, significant yield of tumor biopsies and ad hoc molecular analysis, achievable timelines. High throughput molecular analysis is feasible in daily practice and may be used as a theranostic tool to identify molecular alterations in advanced cancer patients referred to a phase I Unit. Updated results concerning 9 months recruitment with a target accrual of 100 patients will be presented. 613 POSTER Pharmacokinetics/pharmacodynamics (PK/PD) of GSK2256098, a Focal Adhesion Kinase (FAK) Inhibitor, in Patients with Advanced Solid Tumors H. Gan1 , N. Nebot2 , J.C. Soria3 , H.T. Arkenau4 , S. Blagden5 , R. Plummer6 , M. Ranson7 , T.R.J. Evans8 , G. Zalcman9 , V. Peddareddigari11 , D. Gibson2 , S. Murray2 , J. Mazumdar11 , R. Fleming2 , K. Auger11 , M. Millward10 . 1 Austin-Ludwig Oncology Unit, Oncology, Melbourne, Australia; 2 GlaxoSmithKline, Oncology, Research Triangle Park, USA; 3 Institut Gustave Roussy, Medicine, Paris, France; 4 Sarah Cannon Research Institute, Oncology, London, United Kingdom; 5 Hammersmith Hospital, Oncology, London, United Kingdom; 6 Northern Centre for Cancer Care, Oncology, Newcastle, United Kingdom; 7 Christie Hospital, Oncology, Manchester, United Kingdom; 8 Beatson Institute for Cancer Research, Oncology, Glasgow, United Kingdom; 9 Caen University Hospital, Oncology, Caen, France; 10 Sir Charles Gairdner Hospital, Oncology, Perth, Australia; 11 GlaxoSmithKline, Collegeville, PA, USA: Background: FAK plays an important role in cancer invasion and metastasis. FAK and phospho-FAK (pFAK) are increased in advanced cancer and are correlated with poor prognosis. GSK2256098 is a potent and specific small molecule inhibitor of FAK. Xenograft studies have identified a target concentration for pFAK inhibition in tumor tissue of 500 ng/mL. Material and Methods: NCT01138033 is a first-time in cancer pts study to identify the maximum tolerated dose (MTD), safety, PK, PD, and clinical activity of GSK2256098 (J Clin Oncol 30, 2012; abstr 3000). Pts were administered GSK2256098 orally once daily on Day 1 then twice daily (BID) beginning on Day 2 with food. Serial PK samples were obtained over 24 h on Days 1 and 15. PD analysis included analysis of pFAK in pre- and postdose (Day 8−15) tumor tissue biopsies. Evaluation of Day 15 PK measures (Cmax, AUC(0−12h), and Ctrough) versus adverse events (AE) at any time during study were evaluated. Results: PK data were available from 55 pts at doses of 80 to 1500 mg BID on Day 1 & 15. GSK2256098 was rapidly absorbed with a Tmax of about 1.5 hour to 4 hours. At 1000 mg (MTD), the geometric mean half-life was 4.0 hours (25% CVb). The median (range) ratios of exposures at steady-state (Day 15) to single dose (Day 1) administration were 0.77 (0.51, 4.64) for AUC(0−12h) and 0.85 (0.33, 4.09) for Cmax. At MTD on Day 15, geometric mean Cmax, AUC(0−12h), and Ctrough were 6109 ng/mL, 25595 ng*hr/mL and 463 ng/mL respectively. Results of tumor pFAK levels were available in 6 individuals. PK/PD analysis showed that at systemic exposures for doses between 750 and 1500 mg BID, pFAK inhibition was near-maximal; in 5 of 6 pts, pFAK was 79−99% inhibited. Analysis of PD endpoints is ongoing with plans to explore lower dose cohorts. From preliminary analysis, it appears that there is a relationship between Day 15 AUC(0−12h) and nausea or vomiting at any time. Conclusions: Exposure of GSK2256098 at doses of 750–1500 mg BID results in near-maximal inhibition of pFAK levels in tumor tissue. Nausea or vomiting appear to be associated with drug exposures observed at the current MTD. Current data warrant investigation of lower doses to understand the exposure/PD and exposure/AE relationship to aid in selecting a regimen for further clinical evaluation.
Friday 9 November 2012 189 614 POSTER First-in-man Dose Escalation and Pharmacokinetic Study of CAP7.1, a Novel Etoposide Prodrug in Adults with Heavily Pretreated Solid Tumors 1 U. Keilholz1 , M. Knoedler1 , A. Schmittel1 , V. Kummerlen ¨ , K. Klinghammer1 , L. Rohde2 , P. Mehlitz2 , C. Gehringer2 , S. Joel3 , ¨ N. Utku4 . 1 Charite´ − Universitatsmedizin Berlin Campus Steglitz-Klinikum, Comprehensive Cancer Center, Berlin, Germany; 2 Charite´ − ¨ Universitatsmedizin Berlin Campus Virchow-Klinikum, Institut fur ¨ Med. Immunologie, Berlin, Germany; 3 Barts Cancer Institute, London, United 4 ¨ Kingdom; Charite´ − Universitatsmedizin Berlin Campus Virchow-Klinikum CellAct Pharma, institute fur ¨ med. immunologie, Berlin and Dortmund, Germany
CAP7.1 is a new chemical entity that releases etoposide in the presence of carboxylesterases, leading to higher intra-tumor etoposide (E) concentration than conventional E, improved safety and efficacy in animals including activity in E-resistant models. A phase I study in patients (pt) with heavily pretreated solid tumors was performed to define dose limiting toxicities (DLT), safety, recommended phase II dose (RP2D) and pharmacokinetics of CAP7.1. CAP7.1 was given i.v. day 1−5 in 3-week cycles (cy). Safety was assessed with CTCAE v 3.0, efficacy with RECIST 1.0. Dose escalation based on DLTs followed a 3+3 design and a modified Fibonacci schema. Nineteen pt were treated, in 4 successive dose levels: 45 (3 pt), 90 (3 pt), 150 (6 pt) and 200 (7 pt) mg/m2 /day ×5. Overall, 62 cy were administered (8 at 45, 10 at 90, 16 at 150 and 28 at 200 mg/m2 /day ×5). Non-hematological adverse events (AE) were mild or moderate. Most frequent AE were nausea, vomiting, fatigue and diarrhea (in 24, 17, 16, 9 pt respectively). Three pt presented DLTs including 1 febrile neutropenia (FN) at 150 mg, 1 sepsis and 1 FN at 200 mg/ m2 /d. G3−4 neutropenia in Cy1 occurred in 3 pt at 150 and in all pt at 200 mg/ m2 /d; uncomplicated g 3−4 thrombocytopenia occurred in 3/7 pt at 200 and in 1/6 at 150 mg/m2 /d. Plasma pharmacokinetic samples for evaluation of CAP7.1 and E levels were drawn on day 1−5 pre- and 15 minutes post- end of infusion (EOI); on day 1 samples were also taken 30 minutes prior to EOI and up to 10 hour after EOI. CAP7.1 was rapidly cleared (t1/2 = 30−45 min) whereas the mean t1/2 of E was 5.47, 8.23, 7.84 and 5.88 in dose levels 1−4, respectively. A pt with Merkel tumor and prior E achieved a partial response lasting 4 months (mo). Other 13/19 pt had stable disease (SD). At 200 mg/ m2 /d 4 pt had SD for 6 mo. Ten pt survived >6 months, with longest OS 25 mo (gallbladder carcinoma) and 20 mo (carcinoma of unknown origin). CAP7.1 presents manageable toxicity (mainly hematological) at dose levels 750–1000 mg/m2 /cycle, nearly a 2−3fold increase of conventional etoposide dose (360 mg/m2/cycle) without organ toxicity. Interestingly, CAP7.1 has no hematological toxicities at doses 360 mg/m2/cy used for E. Phase II studies are warranted and will include neoplasms known to be susceptible and resistant to E. 615 POSTER QTc Intervals as Inclusion/exclusion Criteria in Phase I Trial with Anticancer Agents: Vall d’Hebron Experience A. Delgado Colston1 , M. Banos ˜ 1 , M. Soria1 , A. Azaro1 , R. Dienstmann1 , G. Argiles1 , C. Cruz1 , J. Capdeville1 , J. Tabernero1 , J. Rodon1 . 1 Vall d’Hebron, Molecular Therapeutics Research Unit of Cancer, Barcelona, Spain Introduction: QTc values on electrocardiogram (ECG) can potentially influence eligibility in Phase 1 trials of anticancer agents. Few guidelines are available for cardiac risk assessment during development of an oncology drug. This limitation has led to very strict inclusion/exclusion criteria regarding QTc values and many cancer patients may be inappropriately ineligible for Phase 1 trial of promising new agents. Methods: We performed a retrospective analysis of the screening ECGs (corrected QT intervals according to Bazett and Fridericia formulae) of 268 patients potentially eligible for Phase 1 trials at the Molecular Therapeutics Research Unit of Vall d’Hebron Hospital in 2011. The following clinical parameters were assessed: gender, cardiac risk factors, and chronic diseases indicating treatment with agents with potential risk of QTc prolongation. We also reviewed the QTc eligibility criteria of 46 Phase 1 clinical trials available during the same period. Results: In total, 52.3% were female, 23.1% were taking medication to control hypertension, 14.2% dyslipidemia, 7.5% diabetes, 6.8% ischemia cardiac disease and 6% depressive syndrome. Mean (range) corrected QTc interval was 427.3 ms (362–557) and 410.5 ms (340–520) according to Bazett and Fridericia, respectively. No patient was excluded from Phase 1 trial based QTc criteria. Three trials (6.5%) excluded patients with QTc intervals <450 ms, 9 (19.5%) if QTc intervals were <470 ms and 21 (46%) did not mention QTc values as inclusion/exclusion criteria. If the strictest
Friday 9 November 2012 189 614 POSTER First-in-man Dose Escalation and Pharmacokinetic Study of CAP7.1, a Novel Etoposide Prodrug in Adults with Heavily Pretreated Solid Tumors 1 U. Keilholz1 , M. Knoedler1 , A. Schmittel1 , V. Kummerlen ¨ , K. Klinghammer1 , L. Rohde2 , P. Mehlitz2 , C. Gehringer2 , S. Joel3 , ¨ N. Utku4 . 1 Charite´ − Universitatsmedizin Berlin Campus Steglitz-Klinikum, Comprehensive Cancer Center, Berlin, Germany; 2 Charite´ − ¨ Universitatsmedizin Berlin Campus Virchow-Klinikum, Institut fur ¨ Med. Immunologie, Berlin, Germany; 3 Barts Cancer Institute, London, United 4 ¨ Kingdom; Charite´ − Universitatsmedizin Berlin Campus Virchow-Klinikum CellAct Pharma, institute fur ¨ med. immunologie, Berlin and Dortmund, Germany
CAP7.1 is a new chemical entity that releases etoposide in the presence of carboxylesterases, leading to higher intra-tumor etoposide (E) concentration than conventional E, improved safety and efficacy in animals including activity in E-resistant models. A phase I study in patients (pt) with heavily pretreated solid tumors was performed to define dose limiting toxicities (DLT), safety, recommended phase II dose (RP2D) and pharmacokinetics of CAP7.1. CAP7.1 was given i.v. day 1−5 in 3-week cycles (cy). Safety was assessed with CTCAE v 3.0, efficacy with RECIST 1.0. Dose escalation based on DLTs followed a 3+3 design and a modified Fibonacci schema. Nineteen pt were treated, in 4 successive dose levels: 45 (3 pt), 90 (3 pt), 150 (6 pt) and 200 (7 pt) mg/m2 /day ×5. Overall, 62 cy were administered (8 at 45, 10 at 90, 16 at 150 and 28 at 200 mg/m2 /day ×5). Non-hematological adverse events (AE) were mild or moderate. Most frequent AE were nausea, vomiting, fatigue and diarrhea (in 24, 17, 16, 9 pt respectively). Three pt presented DLTs including 1 febrile neutropenia (FN) at 150 mg, 1 sepsis and 1 FN at 200 mg/ m2 /d. G3−4 neutropenia in Cy1 occurred in 3 pt at 150 and in all pt at 200 mg/ m2 /d; uncomplicated g 3−4 thrombocytopenia occurred in 3/7 pt at 200 and in 1/6 at 150 mg/m2 /d. Plasma pharmacokinetic samples for evaluation of CAP7.1 and E levels were drawn on day 1−5 pre- and 15 minutes post- end of infusion (EOI); on day 1 samples were also taken 30 minutes prior to EOI and up to 10 hour after EOI. CAP7.1 was rapidly cleared (t1/2 = 30−45 min) whereas the mean t1/2 of E was 5.47, 8.23, 7.84 and 5.88 in dose levels 1−4, respectively. A pt with Merkel tumor and prior E achieved a partial response lasting 4 months (mo). Other 13/19 pt had stable disease (SD). At 200 mg/ m2 /d 4 pt had SD for 6 mo. Ten pt survived >6 months, with longest OS 25 mo (gallbladder carcinoma) and 20 mo (carcinoma of unknown origin). CAP7.1 presents manageable toxicity (mainly hematological) at dose levels 750–1000 mg/m2 /cycle, nearly a 2−3fold increase of conventional etoposide dose (360 mg/m2/cycle) without organ toxicity. Interestingly, CAP7.1 has no hematological toxicities at doses 360 mg/m2/cy used for E. Phase II studies are warranted and will include neoplasms known to be susceptible and resistant to E. 615 POSTER QTc Intervals as Inclusion/exclusion Criteria in Phase I Trial with Anticancer Agents: Vall d’Hebron Experience A. Delgado Colston1 , M. Banos ˜ 1 , M. Soria1 , A. Azaro1 , R. Dienstmann1 , G. Argiles1 , C. Cruz1 , J. Capdeville1 , J. Tabernero1 , J. Rodon1 . 1 Vall d’Hebron, Molecular Therapeutics Research Unit of Cancer, Barcelona, Spain Introduction: QTc values on electrocardiogram (ECG) can potentially influence eligibility in Phase 1 trials of anticancer agents. Few guidelines are available for cardiac risk assessment during development of an oncology drug. This limitation has led to very strict inclusion/exclusion criteria regarding QTc values and many cancer patients may be inappropriately ineligible for Phase 1 trial of promising new agents. Methods: We performed a retrospective analysis of the screening ECGs (corrected QT intervals according to Bazett and Fridericia formulae) of 268 patients potentially eligible for Phase 1 trials at the Molecular Therapeutics Research Unit of Vall d’Hebron Hospital in 2011. The following clinical parameters were assessed: gender, cardiac risk factors, and chronic diseases indicating treatment with agents with potential risk of QTc prolongation. We also reviewed the QTc eligibility criteria of 46 Phase 1 clinical trials available during the same period. Results: In total, 52.3% were female, 23.1% were taking medication to control hypertension, 14.2% dyslipidemia, 7.5% diabetes, 6.8% ischemia cardiac disease and 6% depressive syndrome. Mean (range) corrected QTc interval was 427.3 ms (362–557) and 410.5 ms (340–520) according to Bazett and Fridericia, respectively. No patient was excluded from Phase 1 trial based QTc criteria. Three trials (6.5%) excluded patients with QTc intervals <450 ms, 9 (19.5%) if QTc intervals were <470 ms and 21 (46%) did not mention QTc values as inclusion/exclusion criteria. If the strictest