Chooi Lee

Tumor Necrosis Factor α As a New Target for Renal Cell Carcinoma: Two Sequential Phase II Trials of Infliximab at Standard and High Dose

PURPOSE Tumor necrosis factor alpha (TNF-alpha) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti-TNF-alpha monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC. PATIENTS AND METHODS Patients progressing after cytokine therapy were treated with intravenous infliximab as follows: study 1 (19 patients), 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; study 2 (18 patients), 10 mg/kg at weeks 0, 2, and 6, and then every 4 weeks. Treatment continued until disease progression (PD). Response was assessed according to Response Evaluation Criteria in Solid Tumors. Plasma levels of TNF-alpha, CCL2, and interleukin-6 (IL-6) were measured before and during treatment. RESULTS TNF-alpha and its receptors were detected in malignant cells in RCC biopsies. In study 1, three patients (16%) achieved partial response (PR) and three patients (16%) achieved stable disease (SD). Median duration of response (PR + SD) was 7.7 months (range, 5.0 to 40.5+ months). In study 2, 11 patients (61%) achieved SD. Median duration of response was 6.2 months (range, 3.5 to 24+ months). One patient developed grade 3 hypersensitivity and another died as a result of pulmonary infection/sepsis. Enzyme-linked immunosorbent assay analysis of plasma revealed that higher levels of TNF-alpha at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-alpha, IL-6, and CCL2 and poor survival (< 12 months). CONCLUSION This is the first direct clinical evidence suggesting that TNF-alpha may be a therapeutic target in RCC. Plasma levels of TNF-alpha, IL-6, and CCL2 may have predictive and prognostic significance.

Phase I Study of MG98, an Oligonucleotide Antisense Inhibitor of Human DNA Methyltransferase 1, Given as a 7-Day Infusion in Patients with Advanced Solid Tumors

Purpose: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of MG98, an antisense oligonucleotide to DNA methyltransferase 1 (DNMT1), which has been shown to reduce CpG island methylation and allow reexpression of tumor suppressor genes in vitro. Experimental Design: In this phase I, open-label study, patients with advanced solid malignancies were treated with escalating doses of MG98 administered as a continuous i.v. infusion over 7 days repeated every 14 days. Cohorts of three patients, which could be expanded to six patients, were studied. The maximum tolerated dose was defined as the highest dose at which no more than 33% of subjects experienced dose-limiting toxicity. Pharmacokinetic and pharmacodynamic parameters of MG98 were also characterized. Results: Thirty-three patients were treated at doses of 100 to 250 mg/m2/d MG98. MG98 was well tolerated with mild fatigue and myalgia, dose-limiting toxicity was asymptomatic transaminitis, and the maximum tolerated dose was 200 mg/m2/d. One patient achieved a partial response and another prolonged disease stabilization. Plasma half-life of MG98 was short (2 hours), drug concentrations reaching a dose-dependent steady state during infusion with a volume of distribution equivalent to plasma volume. Suppression of DNMT1 expression was observed in 26 of 32 patients studied. Conclusions: MG98 was well tolerated with early evidence of clinical activity. Proof of mechanism was observed and measurement of DNMT1 expression in peripheral blood mononuclear cells may be useful in future phase II development.

A phase I study of the nitroimidazole hypoxia marker SR4554 using 19F magnetic resonance spectroscopy.

Background:SR4554 is a fluorine-containing 2-nitroimidazole, designed as a hypoxia marker detectable with 19F magnetic resonance spectroscopy (MRS). In an initial phase I study of SR4554, nausea/vomiting was found to be dose-limiting, and 1400 mg m−2 was established as MTD. Preliminary MRS studies demonstrated some evidence of 19F retention in tumour. In this study we investigated higher doses of SR4554 and intratumoral localisation of the 19F MRS signal.Methods:Patients had tumours ⩾3 cm in diameter and ⩽4 cm deep. Measurements were performed using 1H/19F surface coils and localised 19F MRS acquisition. SR4554 was administered at 1400 mg m−2, with subsequent increase to 2600 mg m−2 using prophylactic metoclopramide. Spectra were obtained immediately post infusion (MRS no. 1), at 16 h (MRS no. 2) and 20 h (MRS no. 3), based on the SR4554 half-life of 3.5 h determined from a previous study. 19Fluorine retention index (%) was defined as (MRS no. 2/MRS no. 1)*100.Results:A total of 26 patients enrolled at: 1400 (n=16), 1800 (n=1), 2200 (n=1) and 2600 mg m−2 (n=8). SR4554 was well tolerated and toxicities were all ⩽grade 1; mean plasma elimination half-life was 3.7±0.9 h. SR4554 signal was seen on both unlocalised and localised MRS no. 1 in all patients. Localised 19F signals were detected at MRS no. 2 in 5 out of 9 patients and 4 out of 5 patients at MRS no. 3. The mean retention index in tumour was 13.6 (range 0.6–43.7) compared with 4.1 (range 0.6–7.3) for plasma samples taken at the same times (P=0.001) suggesting 19F retention in tumour and, therefore, the presence of hypoxia.Conclusion:We have demonstrated the feasibility of using 19F MRS with SR4554 as a potential method of detecting hypoxia. Certain patients showed evidence of 19F retention in tumour, supporting further development of this technique for detection of tumour hypoxia.

Randomized Phase II Study Comparing Thalidomide With Medroxyprogesterone Acetate in Patients With Metastatic Renal Cell Carcinoma

PURPOSE To investigate escalating doses of thalidomide compared with medroxyprogesterone in patients with metastatic renal cell carcinoma (RCC), who had either progressed after first-line immunotherapy or who were not suitable for immunotherapy. PATIENTS AND METHODS Thalidomide was started at 100 mg/d orally (PO) and escalated by 100 mg/d every 2 weeks to the maximum dose of 400 mg/d. Medroxyprogesterone was given at a fixed dose of 300 mg PO daily. RESULTS Sixty patients were entered (thalidomide:medroxyprogesterone = 29:31; median age, 59 [thalidomide], 60 [medroxyprogesterone]; No. of patients assessable for response, 22 [thalidomide], 26 [medroxyprogesterone]). In the thalidomide arm, there was no objective response seen. The best response was SD in three patients lasting 5+, 6+, and 12 months, respectively. All patients in the medroxyprogesterone arm progressed. There was no difference in overall survival between the two arms; median survival in the thalidomide arm was 8.2 months compared with 4.8 months in the medroxyprogesterone arm (P = .62). Hazard ratio was 0.88 (95% CI, 0.67 to 1.94). Median duration of treatment was 73 days (range, 14 to 364 days) in the thalidomide arm, and 84 days (range, 7 to 175 days) in the medroxyprogesterone arm. The high incidence of toxicity in the thalidomide arm, mainly somnolence, constipation, fatigue and paraesthesia, meant that only 30.8% of patients were able to tolerate the maximum dose of 400 mg/d of treatment. CONCLUSION Thalidomide is not superior to medroxyprogesterone acetate in patients with metastatic RCC. Its risk/benefit ratio does not favor its use in this patient population.

A randomised, open-label phase II trial of afatinib versus cetuximab in patients with metastatic colorectal cancer

PURPOSE This randomised phase II trial aimed to compare efficacy of the irreversible ErbB family blocker, afatinib, with cetuximab in patients with KRAS wild-type metastatic colorectal adenocarcinoma (mCRC) with progression following oxaliplatin- and irinotecan-based regimens. Efficacy in patients with KRAS mutations was also evaluated. PATIENTS AND METHODS Patients with KRAS wild-type tumours were randomised 2:1 to afatinib (40 mg/day, increasing to 50 mg/day if minimal toxicity) or cetuximab weekly (400 mg/m2 loading dose, then 250 mg/m2/week) according to number of previous chemotherapy lines. All patients with KRAS-mutated tumours received afatinib. Primary end-points were objective response (OR) for the wild-type group and disease control for the KRAS-mutated group. Secondary end-points were progression-free survival (PFS) and overall survival (OS). RESULTS Patients with KRAS wild-type tumours (n=50) received afatinib (n=36) or cetuximab (n=14). Unconfirmed and confirmed ORs were 3% and 0% for afatinib versus 20% and 13% for cetuximab (odds ratio: 0.122 [P=0.0735] and <0.001, respectively). Median PFS was 46.0 and 144.5 days for afatinib and cetuximab, respectively. Median OS was 355 days with afatinib but not reached for cetuximab. In the KRAS-mutated group (n=41), five (12%) patients achieved confirmed disease control (stable disease; P=0.6394 [comparison versus 10%]); no ORs were reported. Median PFS and OS were 41.0 and 173days, respectively. Most frequent treatment-related adverse events were diarrhoea and rash across groups. CONCLUSIONS The efficacy of afatinib was inferior to cetuximab in patients with KRAS wild-type mCRC. In patients with KRAS-mutated tumours, disease control was modest with afatinib. Afatinib had a manageable safety profile.

Phase I Study of Nintedanib Incorporating Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Patients With Advanced Solid Tumors

BACKGROUND This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors. METHODS Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28. RESULTS Fifty-one patients received nintedanib 100-450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily. CONCLUSION Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.

A phase I study of a new nucleoside analogue, OSI-7836, using two administration schedules in patients with advanced solid malignancies

Purpose: To investigate the safety, tolerability, and pharmacokinetic profile of the novel nucleoside analogue OSI-7836 in patients with advanced solid malignancies. Experimental Design: OSI-7836 was initially given as a 60-minute i.v. infusion on day 1 every 21 days. In view of its dose-limiting toxicities, the administration time was amended to a 5-minute bolus, and subsequently, the schedule was amended to weekly for 4 weeks followed by a 2-week rest. Blood and urine samples were collected for pharmacokinetic studies. Analyses of cytokines and lymphocyte subsets were added later in the study to elucidate a mechanism for the severe fatigue and lymphocyte depletion observed in earlier patients. Results: Thirty patients received a total of 61 treatment cycles. Fatigue was the main dose-limiting toxicity. Maximum-tolerated dose was defined as 300 mg/m2 in the 60-minute infusion, (three times per week) schedule; 400 mg/m2 in the 5-minute bolus infusion, (three times per week) schedule; and 100 mg/m2 in the weekly schedule. Other common toxicities were nausea, vomiting, rash, fever, and a flu-like syndrome. There were no clinically significant hematologic toxicities. Following the initial dose, OSI-7836 was eliminated from plasma with a median (range) elimination half-life of 48.3 minutes (22.6-64.8 minutes). Lymphocyte subset analysis showed a significant drop in B cell counts, which persisted to day 14 and beyond. Cytokine analysis showed significant elevations of interleukin-6 and interleukin-10 in all patients who received ≥200 mg/m2 OSI-7836. Best response was disease stabilization in seven patients. Conclusion: OSI-7836 was associated with excessive fatigue, and despite changes in its schedule and duration of administration, we did not observe an improvement in its tolerability. Its potentially selective effect on B lymphocytes could be exploited in further studies in specific hematologic malignancies.

1248PA PHASE IB OPEN LABEL CLINICAL TRIAL OF CONTINUOUS ONCE DAILY ORAL AFATINIB (A) PLUS SIROLIMUS (S) IN PATIENTS (PTS) WITH EGFR MUTATION POSITIVE (EGFR M+) NSCLC AND/OR DISEASE PROGRESSION FOLLOWING PRIOR ERLOTINIB (E) OR GEFITINIB (G)

ABSTRACT Aim: Preclinical data show that A, an irreversible ErbB family blocker, combined with an mTOR inhibitor such as S, may restore sensitivity in EGFR M+ NSCLC pts who progress after E/G. This trial was conducted to identify the maximum tolerated dose (MTD) of A + S. Methods: Pts with stage IIIB/IV NSCLC who failed ≥1 prior treatment, and whose tumour was EGFR M + , or negative/unknown, but had progressive disease after response or stable disease (SD) for ≥6 months on prior E/G were eligible. Pts received run-in treatment with sirolimus for 8 days before starting the combination therapy. Definition of MTD was initially based on dose-limiting toxicities (DLTs) in cycle (C) 1 (28 days) but with an amendment this was extended to C1 and 2. EGFR mutation was assessed (from blood and archival tumour) and PK sampling was performed. Tumour assessment was performed at week 4, 8, 12, then every 8 weeks. Results: 39 pts were treated: median age 61y (range: 32-81); male: 15; ECOG 0/1/2: 16/21/1; adeno/squamous/large cell carcinoma: 33/3/3. All had prior E/G; 32 had ≥1 prior chemotherapy. Median treatment duration: 103 days (range: 10-367). Pts were treated at 6 dose levels (A, mg/S, mg): 30/1 (n = 12), 40/1 (n = 3), 30/3 (n = 9), 30/5 (n = 9), 30/10 (n = 3), 40/5 (n = 3), with 30/1 defined as MTD. DLTs (C1 and 2) were seen in 12 pts (Table). The most frequent (≥20%, all grades) drug-related adverse events were: diarrhoea, mucositis, rash, asthenia, decreased appetite and nausea. The best response was partial response (PR) in 4 pts (2 at 30/5, 2 at 40/5); 23 had stable disease (SD) (median duration [days]: 105, range: 51-337). PK, tumour and blood mutation results will be presented. DLTs (grade [n]) by dose level 30/1 40/1 30/3 30/5 30/10 40/5 Diarrhoea – G3 (1) G3 (1) – G3 (2)* G3 (1) Mucositis – – G3 (1) G3 (2) G3 (1) G3 (2) Raised CPK – G4 (1) – – – – *1 pt had G3 diarrhoea, asthenia, anorexia and iliac fossa pain. Conclusions: A + S combination had limited tolerability in pts with EGFR M+ NSCLC progressing on E/G mainly due to overlapping DLTs of diarrhoea and mucositis. A 30 mg + S 1 mg was defined as MTD. PRs were observed at doses exceeding MTD; SD was observed at all doses. Disclosure: M. Majem: Membership on an advisory board for Roche, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb and Pfizer; N. Reguart: Membership on an advisory board for Roche, Lilly, Boehringer Ingelheim and Pfizer; C.P. Lee: Employee of Boehringer Ingelheim; S. Kraemer: Employee of Boehringer Ingelheim; D. Schnell: Employee of Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Abstract B281: Phase I study of two dosing schedules of BI 847325, an orally administered dual inhibitor of MEK and aurora kinase B, in patients with advanced solid tumors.

Background: BI 847325 is an orally bioavailable, potent and selective dual inhibitor of MEK and aurora kinase B. Preclinical studies showed efficacy in a range of xenograft models including tumors with BRAF and KRAS mutation. Materials and Methods: Patients with advanced, unresectable or metastatic solid malignancies were enrolled into two treatment schedules in a Phase I, first-in-human, dose-escalation study: once a day, D1-14 of a 21-day cycle (Arm A); once a day, D1-5, repeated every week (Arm B; 1 cycle=3 weeks). All patients underwent pharmacokinetic sampling. The following pre- and post-treatment samples were collected: skin biopsies to measure phosphorylated histone H3 (pHH3) by Western blot analysis and immunohistochemistry (IHC) as a marker of Aurora kinase inhibition; and peripheral blood mononuclear cells (PBMC) to measure phosphorylated ERK level (by ELISA) as a marker of MEK inhibition. KRAS, BRAF, and NRAS mutation status was determined from patients’ archival tumor material. Results: A total of 69 patients (47 in Arm A, 22 in Arm B) were treated at two centers (male/female = 33/36, median age: 57 [range: 26-78]; ECOG performance status: 0/1: 18/51). Median number of courses administered was two (range: 1-12). Patients were treated at 11 dose levels in Arm A (6-160 mg/d) and 8 dose levels in Arm B (6-180 mg/d). The maximum tolerated dose (MTD) was exceeded at 160 mg in Arm A and at 180 mg in Arm B. MTD was defined as 120 mg and 150 mg in Arms A and B, respectively. The most frequent (≥10%) treatment-related adverse events (AEs) were: fatigue (36%), diarrhea (35%), nausea (20%), vomiting (17%), neutropenia (16%), anemia (16%), and decreased appetite (15%). Dose-limiting toxicities in the first cycle, observed in 9 patients, included: neutropenia/febrile neutropenia (n=6), diarrhea (n=2), vomiting (n=2), thrombocytopenia (n=1), troponin I elevation (n=1), increased fatigue (n=1), decreased appetite (n=1), and hypokalaemia (n=1). Dose-limiting neutropenia and diarrhea were seen at higher dose levels and were the main DLTs observed. Among 56 evaluable patients, 1 patient (esophageal SCC, received 160 mg in Arm A) had a partial response, and 7 patients had stable disease which lasted >4 cycles. Nine tumors harbored a KRAS mutation and one had a BRAF V600 mutation: 1 patient with KRAS-mutated thymus cancer was on treatment for 12 cycles, 1 patient with KRAS-mutated rectal carcinoma was on treatment for 6 cycles. Cmax and AUC increased with dose in a greater than linear fashion particularly at the higher dose levels. Mean terminal half life ranged from 4–17 hours with high interpatient variability. Analyses of skin biopsies for pHH3 and PBMC for pERK will be presented. Conclusions: BI 847325 showed an acceptable safety profile; dose-limiting neutropenia was the most common high grade AE observed; 120 mg and 150 mg were defined as the MTD for Arms A and B, respectively. One patient experienced a PR, and 7 had stable disease lasting >4 cycles. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B281. Citation Format: Philippe Aftimos, Herlinde Dumez, Ahmad Awada, Maureen Billiet, Amelie Deleporte, Katrien De Block, Jo Costermans, Marie-Anne Meeus, Rainer-Georg Goeldner, David Schnell, Chooi Lee, Patrick Schoffski. Phase I study of two dosing schedules of BI 847325, an orally administered dual inhibitor of MEK and aurora kinase B, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B281.

A phase Ib trial of continuous once-daily oral afatinib plus sirolimus in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer and/or disease progression following prior erlotinib or gefitinib

OBJECTIVES Dysregulation of the downstream PI3K/AKT/mTOR signaling pathway is a proposed mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We investigated safety and antitumor activity of afatinib plus sirolimus as a potential combination to reverse acquired resistance to EGFR-TKIs in a phase IB trial in patients with EGFR mutation-positive non-small-cell lung cancer (EGFR mut NSCLC) and/or disease progression following prior erlotinib/gefitinib. MATERIALS AND METHODS Patients with EGFR mut NSCLC and/or disease progression following at least prior erlotinib/gefitinib were included in the trial. The primary endpoint was incidence of dose-limiting toxicities (DLT) to determine the maximum tolerated dose (MTD). Four initial dose cohorts were proposed to evaluate DLTs. Other endpoints included tumor response, safety, progression-free survival (PFS) and pharmacokinetics. RESULTS Thirty-nine patients received afatinib and sirolimus. Additional dose cohorts were added since the second cohort (afatinib 40mg/day and sirolimus 5mg/day) was considered to have excessive toxicity. All patients experienced adverse events (AE) [grade 3: 66.7%; serious AE: 56.4%]. The most frequent AEs were diarrhea (94.9%), mucosal inflammation (64.1%), asthenia (53.8%) and rash (53.8%). Discontinuations and dose reduction due to AEs occurred in 23.1% and 25.6% of patients. MTD was determined as afatinib 30mg and sirolimus 1mg. Responses were observed in 5 patients (12.8%) [2 (5.1%) with confirmed partial response (PR); 3 (7.7%) with unconfirmed PR], and stable disease in 18 patients (46.2%). Four of the 5 responses were at doses above MTD. PFS at 6 months was estimated in 33.3% (median PFS 3.4 months). Pharmacokinetic parameters of afatinib and sirolimus were similar after single administration or in combination. CONCLUSION The combination of afatinib and sirolimus showed lower responses than expected. Together with increased AEs and poor tolerability, this precludes clinical use and further clinical development of this combination. No pharmacokinetic interactions were observed. CLINICALTRIALS. GOV IDENTIFIER NCT00993499.