Early clinical studies to explore candidate biomarkers in targeted cancer therapies

De afgelopen veertig jaar zijn chirurgie, radiotherapie en systeemtherapie de pijlers van kankerbehandeling geweest. Ondanks gestage uitbreiding van deze therapeutische mogelijkheden overlijdt nog steeds de he1ft van de kankerpatienten aan de gevolgen van gemetastaseerde ziekte. Dit is ten dele toe te schrijven aan het ontwikkelen van tumorcelresistentie tegen de toegediende systeemtherapie. Door een verbeterd inzicht in de tumorcelbiologie heeft de ontwikkeling van specifieke, doelgerichte medicijnen op grond van tumoreigenschappen zich de laatste jaren sterk uitgebreid. Tumorcellen die resistent zijn voor bijvoorbeeld chemotherapie hebben als gevolg van een defecte intrinsieke apoptoseroute een intrinsieke of verworven onvermogen om in apoptose te gaan. Deze resistentie zou potentieel omzeild kunnen worden door activatie van de extrinsieke apoptoseroute. De extrinsieke route wordt geactiveerd door het lichaamseigen Tumor Necrosis Factor (TNF) Related Apoptosis-Inducing Ligand (TRAil, of Apo2l). TRAIL kan aan vijf verschillende receptoren binden, maar induceert slechts apoptose na binding aan TRAIL-Rl (DR4) of TRAll-R2 (DRS). De andere drie receptoren, TRAll-R3 (DcRl), TRAIL-R4 (DcR2) en het oplosbare osteoprotegerine (OPG), fungeren als zogenaamde decoys. De ontdekking dat TRAil aileen apoptose in tumorcellen induceert en niet in de meeste normale cellen, maakt het een potentieel aantrekkelijk antikankermiddel. Vele preklinische studies hebben synergie laten zien indien TRAll-Rl/2 activerende stoffen worden gecombineerd met chemotherapie. Daarnaast worden veel chemotherapieresistente cellijnen en xenograftmodellen opnieuw gevoelig voor het betreffende chemotherapeuticum na toevoeging van recombinant humaan (rh) TRAil of een van de antilichamen gericht tegen de pro-apoptotische TRAIL-Rl/2. RhTRAll, dat aan aile TRAil receptoren bindt en monoclonale antilichamen die of TRAll-Rl of TRAIL-R2 binden, zijn inmiddels in fase 1 en fase 2 studies getest en lijken veilig te zijn. Een andere benadering om resultaten van oncologische behandelingen mogelijk te verbeteren, is het blokkeren van angiogenese, de vorming van nieuwe bloedvaten. Tumorcellen hebben een adequate bloedvatvoorziening nodig om voorzien te worden van voldoende zuurstof en voedingsstoffen. Hierdoor is de tumor in staat te groeien en te metastaseren

Targeting Trail Towards the Clinic

Tumor necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis upon binding to its death domain-containing transmembrane receptors. The preferential toxicity of TRAIL to cancer cells and the sparing of normal cells make it an ideal cancer therapeutic agent. TRAIL induces apoptosis via the extrinsic death receptor apoptotic pathway and activates the JNK, ERK, Akt and NF-kappa B signaling cascades. However, not all cancer cells are sensitive to TRAIL therapy. This may limit its efficacy in the clinic, although ways have already been identified to overcome resistance by combining TRAIL with chemotherapeutic and other biological agents. This review focuses on TRAIL receptor-targeting as anticancer therapy, the apoptotic signaling pathways induced by TRAIL receptors, the prognostic implications of TRAIL receptor expression and modulation by combination therapies. The mechanisms of TRAIL resistance and strategies to overcome drug resistance will also be addressed. Finally, the progress of TRAIL and DR4/DR5-specific agonistic antibodies in clinical trials and the development of new receptor-selective TRAIL variants are discussed including future directions for apoptosis inducing therapy.</p

Translating TRAIL-receptor targeting agents to the clinic

<p>The extrinsic apoptotic pathway can be activated by the endogenous ligand TRAIL (Tumor Necrosis Factor (TNE)-Related Apoptosis-Inducing Ligand) by binding to the death receptors TRAIL-R1 and TRAIL-R2 on the cell surface. This pathway is currently evaluated as an anticancer treatment strategy. Both recombinant human TRAIL and several agonistic antibodies against TRAIL-R1 and R2 have been studied in single agent and combination studies and proved to be safe and well tolerated. In this article, the clinical studies published to date will be reviewed. Also, future perspectives and biomarker studies for selecting patients that will benefit from these agents will be discussed. (C) 2012 Elsevier Ireland Ltd. All rights reserved.</p>

Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors

Purpose We evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, biologic activity, and antitumor efficacy of the DR5 antibody, LBY135 +/- capecitabine. Experimental design Escalating LBY135 was administered every 21 days, alone (Arm1) or with capecitabine (Arm2), to patients with advanced solid tumors. Results In Arm1 (n = 40), LBY135 (0.3-40 mg/kg) resulted in no dose-limiting toxicities (DLTs); adverse events (AEs) included fatigue, hypotension, abdominal pain, dyspnea, and nausea. Stable disease (SD) was observed in 21/38 (55.3 %) patients. In Arm2 (n = 33), LBY135 (1-40 mg/kg) plus capecitabine resulted in 3 DLTs (each grade 3): dehydration and mucosal inflammation (1 mg/kg), colitis (20 mg/kg), and diarrhea (40 mg/kg). AEs included fatigue, nausea, dyspnea, and vomiting. Partial response was observed in 2 patients (rectal and breast cancer) and SD in 12/27 (44.4 %) patients. Mean elimination half-life of LBY135 +/- capecitabine at saturation of clearance (a parts per thousand yen10 mg/kg) ranged between 146 h and 492 h. Immunogenicity was detected in 16/73 (22 %) patients, of which 6 patients experienced reduced LBY135 exposure with repeat dosing. M30/M65 levels were not predictive for LBY135 response. FDG-PET responses were not consistently associated with RECIST responses. Conclusions LBY135 was well tolerated up to 40 mg/kg, the maximal dose administered; no MTD for LBY135 +/- capecitabine was defined. Clearance was saturated at doses a parts per thousand yen10 mg/kg

Mapatumumab, a Fully Human Agonistic Monoclonal Antibody That Targets TRAIL-R1, in Combination with Gemcitabine and Cisplatin:a Phase I Study

Purpose: To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of mapatumumab, a fully human monoclonal antibody targeting tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with gemcitabine and cisplatin. Experimental Design: Patients with advanced solid tumors received gemcitabine 1,250 mg/m2 i.v. on days 1 and 8 and cisplatin 80 mg/m2 i.v. on day1 of each 21-day cycle. Escalating mapatumumab doses were administered i.v. every 21 days. Toxicity was evaluated and pharmacokinetic analysis of plasma mapatumumab, gemcitabine, 2-difluoro-2-deoxyuridine, and unbound and total platinum was done. TRAIL-R1 tumor expression was determined immunohistochemically. Results: Forty-nine patients received mapatumumab (1 mg/kg, n = 4; 3 mg/kg, n = 7; 10 mg/kg, n = 12; 20 mg/kg, n = 13; or 30 mg/kg, n = 13). A median of six cycles (range, 1-48) was administered. The adverse events most commonly observed reflect the toxicity profile of gemcitabine and cisplatin. Dose-limiting toxicities were seen in 3 of 12 patients at 10 mg/kg, consisting of grade 3 transaminitis, neutropenic fever, and grade 4 thrombocytopenia. At 20 mg/kg, 2 of 12 patients had dose-limiting toxicities, including grade 4 thrombocytopenia and grade 4 fatigue. The maximum tolerated dose was not reached. Pharmacokinetic interactions have not been observed. Twelve patients had a partial response, and 25 patients showed stable disease with a median duration of 6 months. Conclusions: Mapatumumab in combination with gemcitabine and cisplatin is safe and well tolerated at doses up to 30 mg/kg. Further studies on this combination are warranted

A Phase Ib Study of the VEGF Receptor Tyrosine Kinase Inhibitor Tivozanib and Modified FOLFOX-6 in Patients With Advanced Gastrointestinal Malignancies

Combining a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen with antiangiogenic therapy is a standard treatment option in advanced colorectal cancer. In this phase Ib study, safety, pharmacokinetics, and antitumor activity of tivozanib with mFOLFOX-6 were assessed. Tivozanib could be combined at its recommended dose Of 1.5 mg with mFOLFOX-6, demonstrating antitumor activity, A randomized study in advanced colorectal Cancer comparing bevacizumab and tivozanib with mFOLFOX-6 has been performed. Background: Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. Patients and Methods: Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. Results: Thirty patients were assigned to tivozanib 0.5 mg (n = 9); 1.0 mg (n = 3); or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8); fatigue (n = 8), and neutropenia (n = 6): MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. Conclusion: Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors