T. Maughan

A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer : a Colorectal Clinical Oncology Group (CCOG) study

The purpose of this study was to evaluate the maximum tolerated dose (MTD) and recommended dose of oxaliplatin given synchronously with 5-fluorouracil (5FU), leucovorin (LV) and preoperative pelvic radiation for primary unresectable, locally advanced, rectal cancer. Preoperative pelvic radiotherapy using a three- or four-field technique and megavoltage photons comprised 45u2009Gy given in 25 fractions, 1.8u2009Gy per fraction, and delivered with escalating doses of oxaliplatin in combination with low-dose LV and 5FU. Chemotherapy was given synchronously with radiotherapy in weeks 1 and 5. Escalating doses of oxaliplatin (85, 130 and 150u2009mgu2009m−2) were given on days 2 and 30, followed by low-dose LV (20u2009mgu2009m−2) and 5FU (350u2009mgu2009m−2), both given on days 1–5 and 29–33. Surgery was performed 6–10 weeks later. The MTD was determined as the dose causing more than a third of patients to have a dose-limiting toxicity (DLT). Once the MTD was reached, a further 14 patients were treated at the dose level below the MTD. In all, 32 patients received oxaliplatin at the three dose levels, median age 60 years (range 31–79), 24 males and eight females. The MTD was reached at 150u2009mgu2009m−2 when four out of six patients experienced DLT. Dose-limiting grade 3 or 4 diarrhoea was reported in two out of six patients at 85u2009mgu2009m−2, 5 out of 20 at 130u2009mgu2009m−2 and four out of 6 at 150u2009mgu2009m−2. Grade 3 neuropathy was reported at 130u2009mgu2009m−2 (1 out of 20) and at 150u2009mgu2009m−2 (two out of six), and serious haematological toxicity was minimal; one grade 3 anaemia at 150u2009mgu2009m−2. In all, 28 out of 32 patients completed all treatments as planned; three had radiotherapy interrupted and three a chemotherapy dose reduction. Four patients did not proceed to surgery due to the presence of metastatic disease (two), unfitness (one) or patient refusal (one). Also, 28 patients underwent surgical resection. Histopathology demonstrated histopathological complete response (pCR) 2 out of 27 (7%), Tmic 3 out of 27 (11%), pCR+Tmic 5 out of 27 (19%), pT0–2 6 out of 27 (22%) and histologically confirmed clear circumferential resection margins in 22 out of 27 (81%). Dose-limiting toxicity with oxaliplatin is 150u2009mgu2009m−2 given days 2 and 30 when added to the described 5FU LV and 45u2009Gy radiation preoperatively. The acceptable toxicity and compliance at 130u2009mgu2009m−2 recommend testing this dose in future phase II studies. The tumour downstaging and complete resection rates are encouragingly high for this very locally advanced group.

Oxaliplatin/capecitabine vs oxaliplatin/infusional 5-FU in advanced colorectal cancer: the MRC COIN trial.

Background:COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC).Methods:Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment.Results:In total, 64% of 2397 patients received OxCap(±cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (±cetuximab) was associated with more mucositis and infection whereas OxCap(±cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50–80u2009mlu2009min−1 on OxCap(±cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function.Conclusions:Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50–80u2009mlu2009min−1 on both regimens require close toxicity monitoring.

A multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole)

The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

Changing the Paradigm—Multistage Multiarm Randomized Trials and Stratified Cancer Medicine

Cancer clinical trials have been the catalyst for many practice changing clinical advances in oncology [1, 2]. Increasingly, however, there is a realization that (a) the traditional drug discovery/drug development model is unsustainable [3]; (b) adult participation in cancer clinical trials is underwhelming, with recruitment rates sometimes as low as 5% [4]; and (c) in the era of targeted therapies, the classic drug A versus drug B strategy may no longer be fit for purpose [5], in many cases producing little or no incremental benefit when transformative improvement is what our patients need. Recognizing the limits of this traditional two arm approach (which frequently fails to demonstrate superiority after many years of effort [3]), Parmar et al. [6] have recently argued for a cultural shift in clinical trial methodology toward a multiarm design that can answer several clinical questions in the same time frame. We submit that this thesis also has important implications for biomarker-stratified clinical trials, in which evaluation of multiple novel therapies is often required, underpinned by precise biomarker-guided patient selection. n nIn metastatic colorectal cancer (mCRC), a more granular understanding of disease biology has fueled the development of a number of gene or pathway-targeted therapeutic approaches, increasing the armamentarium of drugs at our disposal to treat this aggressive malignancy. However, the design of clinical trials that incorporate these novel drugs in their appropriate genetic context is crucial. Recognizing and responding to this challenge, we propose a change in the clinical trial paradigm, eschewing the increasingly limited two-arm approach in favor of a more progressive multistage protocol that integrates one or more treatment comparisons against controls in each of several biomarker-selected subgroups within a single trial program. FOCUS4 is a population-enriched biomarker-stratified clinical trial program for first-line treatment of mCRC [7], designed to allow the efficacy and safety of multiple novel therapies to be assessed rapidly and efficiently in a single protocol, while also evaluating the effectiveness of a biomarker-guided stratified approach. n nFOCUS4 is a single trial design, in which each biomarker cohort is evaluated through a phase II/III enrichment approach. Putative biomarkers have already been identified for each treatment arm. In our initial staged analysis, the principle is that we first identify a positive effect, which then informs evaluation of both biomarker-positive and biomarker-negative patient groups. This enrichment approach allows refinement of the biomarker strategy as the program evolves—codevelopment of the companion diagnostic(s) and the different treatment arms is an important capability that is specifically built into our overarching trial design. FOCUS4 is also part of a recently funded Medical Research Council (MRC)–Cancer Research UK Stratified Medicine Program (Stratification in Colorectal Cancer [S-CORT]) [8]; one of the work streams specifically focuses on developing new molecular stratifiers for the FOCUS4 trial. n nThe design of FOCUS4 overcomes the inefficiencies and compromises inherent in most biomarker-stratified trials. The vast majority of mCRC patients are eligible for this trial, thus maximizing timely and efficient recruitment and ensuring the largest possible number of patients can benefit. An inclusive clinical trial design is also attractive to patients and patient advocacy groups, funding bodies, and pharmaceutical, biotechnology, and diagnostic companies. The trial design is flexible; currently, four molecularly defined cohorts are included with novel inhibitors selected for each biological subgroup: group A, BRAF mutant; group B, PI3 kinase mutant; group C, RAS mutant; and group D, all wild-type cohort (Fig. 1). n n n nFigure 1. n nStructure of FOCUS4 trail for advanced colorectal cancer. n n n nStatistical considerations are a key component of our innovative trial design [7, 9] and are indicated in detail in Table 1. A specific priority order has been established for allocating patients who could potentially fit into more than one biomarker cohort. This priority depends on, first, how closely the targeted agent appears to be linked to the biomarker (e.g., BRAF mutation and combined BRAF pathway inhibition for FOCUS4-A) and, second, on the size of the cohort. These prioritization decisions, like other aspects of the trial, also can be improved or refined during the course of the study based on developing biomarker evidence. When new developments (inevitable in this fast-moving field) are supported by an appropriate evidence base, other validated biomarkers, new cohorts, or other novel agents can be added (or substituted for ineffective treatment arms), all by amendment rather than by developing an entirely separate new trial. n n n nTable 1. n nEstimates of sample sizes for FOCUS4 trial n n n nThe BRAF mutant subgroup is an example of a cohort in which adding a multiarm comparison into the design is helpful, both to clarify underlying biology and to maximize therapeutic efficacy. BRAF inhibitor monotherapy is normally ineffective in mCRC, as escape signaling through the epidermal growth factor receptor (EGFR) occurs [10]. Downstream inhibition of mitogen-activated protein kinase kinase enzymes (MEKs) can reduce aberrant signal transduction. Thus, a multiarm trial design comparing BRAF tyrosine kinase (TK) inhibitor (BRAFi) + MEK inhibitor + EGFR monoclonal antibody (mAb) versus BRAFi + EGFR mAb versus placebo allows two relevant questions to be answered in parallel: (a) does combined targeting of the mutant BRAF TK plus its feedback signaling through EGFR improve progression-free survival in BRAF mutant mCRC, and (b) is the additional inhibition of downstream MEK essential or additive to this benefit? n nThe design of our trial promotes efficiency, significantly shortening the recruitment time and thus the overall trial duration. This allows novel therapies to be evaluated quickly, with a commensurate reduction in costs compared with multiple individual two-arm trials that test each novel therapy in isolation. More importantly, this approach increases the likelihood of therapeutic success, which is further enhanced by the biomarker-stratified design. Crucially, the multistage statistical design allows agents with insufficient activity to be reliably identified at an early stage (and potentially replaced), and the biomarker enrichment strategy used can be tested and validated in the later stages of the trial, together maximizing the ability to identify true clinical benefit. Repetitive tumor resampling is built into the trial to counter the effects of potential tumor heterogeneity n nOur increasing knowledge of the molecular taxonomy of cancer, informed by The Cancer Genome Atlas project and the International Cancer Genome Consortium, is fueling a number of biomarker-driven clinical trial initiatives, both specifically in colorectal cancer (e.g., SPECTAcolor [Screening Patients for Efficient Clinical Trial Access in Advanced Colorectal Cancer], which uses the European Organisation for Research and Treatment of Cancer SPECTA Biomarker screening platform [11], and MODUL [a biomarker-driven randomized clinical trial in mCRC] [12]) and more generally in multiple cancers (e.g., the National Cancer Institute’s Molecular Analysis for Therapy Choice [NCI-MATCH], which has approximately 20 arms, each addressing a particular molecular profile [13]). n nThe increasing fragmentation of clinically recognized diseases into multiple separate biologically defined subtypes threatens the current cornerstone of evidence-based medicine—the randomized controlled trial. Multiarm, multistage trials, such as STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial) [14], and the incorporation of biomarker stratification, such as in FOCUS4, emphasize the changing paradigm of clinical trial design, charting a course for the effective evaluation of novel therapies and the identification of the responsive patient subgroup(s) that maintains the rigor of a randomized controlled trial but allows its successful adaptation to the era of stratified medicine.

Research-intensive cancer care in the NHS in the UK

In the late 1990 s, in response to poor national cancer survival figures, government monies were invested to enhance recruitment to clinical cancer research. Commencing with England in 2001 and then rolling out across all four countries, a network of clinical cancer research infrastructure was created, the new staff being linked to existing clinical care structures including multi-disciplinary teams. In parallel, a UK-wide co-ordination of cancer research funders driven by the virtual National Cancer Research Institute, combined to create a whole-system approach linking research funders, researchers and NHS clinicians all working to the same ends. Over the next 10 years, recruitment to clinical trials and other well-designed studies, increased 4-fold, reaching 17% of the incident cancer population, the highest national rate world-wide. The additional resources led to more studies opened, and more patients recruited across the country, for all types of cancers and irrespective of additional clinical research staff in some hospitals. In 2006, a co-ordinated decision was made to increasingly focus on randomized trials, leading to increased recruitment, without any fall-off in accrual to non-randomized and observational studies. The National Cancer Research Network has supported large successful trials which are changing clinical practice in many cancers.

Safety of capecitabine (X) compared to fluorouracil/leucovorin (5-FU/LV) for the adjuvant treatment of elderly colon cancer patients (pts)

3737 Background: The improved safety profile of the oral fluoropyrimidine X (Xeloda) versus bolus 5-FU/LV has been demonstrated in over 3000 pts in 3 large randomized trials in 1st line metastatic and adjuvant colon cancer (Twelves EJC 2002, Scheithauer Ann Oncol 2003). In addition, the safety advantage over 5-FU/LV in the adjuvant setting was maintained in older pts (≥65 years) and also in terms of less early severe toxicity with X. The median age of pts at diagnosis of colon cancer is increasing in developed countries. Therefore we examined whether there is enough evidence to support the safe use of X in an elderly population, i.e. pts 70 years and older.nnnMETHODSnWe performed retrospective analyses on the safety database of the X-ACT adjuvant colon cancer trial, which compared X (993 pts) to 5-FU/LV Mayo Clinic Regimen (974 pts) in Dukes C colon cancer pts. Adverse events (AEs) in the two arms were analyzed by age: <40, 41-69 and ≥70 years. P-values are not calculated due to the retrospective nature of analysis.nnnRESULTSnSufficient patient numbers enable comparisons between X and 5-FU/LV for the 41-69 age group (763 vs 738, not shown) and ≥70 group (186 vs 205, table), whereas there were few pts aged <40 (44 vs 31, not shown). [Figure: see text] Hyperbilirubinemia was minimal in both arms when graded by NCI CTCAE.nnnCONCLUSIONSnThe improved safety profile of X vs 5-FU/LV is not only maintained in pts over 65, but also in the elderly over 70 years of age. It would be of interest to compare this dataset to that of the INT 0089 trial (Mayo Clinic regimen vs Roswell Park weekly bolus regimen). Pending the final results of the X-ACT study, capecitabine could provide a convenient and effective new option for an aging population. Study sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. No significant financial relationships to disclose.

Tumour concentrations of flavone acetic acid (FAA) in human melanoma: comparison with mouse data

Flavone acetic acid (FAA) showed impressive effects against murine solid tumours but no activity in clinical studies. The mechanism of action in mice may involve damage to tumour vasculature or immunomodulation, and these effects may be species-specific. Alternatively, concentrations of FAA achieved in mouse tumours may be higher than in human tumours. It is important to resolve this issue since it raises important questions about the relevance of in vitro versus in vivo tumour screens and the development of FAA analogues. As part of a Cancer Research Campaign Phase II study of metastatic melanoma in which 8.4 g m-2 FAA was given as a 6 h infusion, six tumour biopsies were obtained from four patients. FAA tumour concentrations were determined by HPLC and compared with subcutaneous murine solid tumours within the same analytical laboratory. Tumour/plasma percentages (range 26-61%; mean +/- SD, 43.9 +/- 11.4%) were similar to those in mice, as was the area under the curve (AUC) extrapolated to infinity and the AUC above the putative activity threshold of 100 micrograms ml-1. We conclude that the exposure of drug-refractory human melanoma tissue to FAA was comparable to that of sensitive mouse tumours. This suggests that reduced penetration of FAA into human tumours is unlikely to explain the lack of antitumour activity observed in clinical studies and that differences in mechanism of action are predominant.

6006 ORAL Intermittent Chemotherapy (CT) Plus Continuous or Intermittent Cetuximab (C) in the First-line Treatment of Advanced Colorectal Cancer (aCRC): Results of the Two-arm Phase II Randomised MRC COIN-B Trial

536^ Background: COIN-B is a trial of intermittent chemotherapy (ICT) plus intermittent cetuximab (C) vs ICT plus continuous C in the first-line treatment of aCRC. It complements the COIN trial by investigating how C might safely and effectively be added to an ICT strategy.nnnMETHODSnPatients (pts) had measurable aCRC; no prior CT for metastases; WHO PS 0-2 and good organ function. Randomisation was: Arm D - continuous OxFU + weekly C for 12 wks then a planned break from all therapy; Arm E - OxFU + weekly C for 12 wks then weekly C. Upon RECIST progression on either arm, OxFU (or FU) plus C was restarted and continued until progression on maximal tolerated therapy. Prospective KRAS testing was introduced in May 2008. Primary outcome measure is Failure-Free Survival (FFS) at 10 months (mo) in KRAS-wt pts who had not progressed, died or failed the treatment strategy within 3 mo of randomisation. The trial was powered to differentiate between a desired 10-mo FFS rate of 50% and a minimum of 35%, in 136 pts (168 allowing for drop-outs). Secondary outcome measures included safety, overall survival (OS) and toxicity.nnnRESULTSn169 KRAS-wt pts were randomised 07/07 to 06/10, 77 arm D / 92 arm E. Median age 64 years (IQR 55-70); 92% PS 0-1. In Arms D and E respectively, 65 (84%) and 67 (73%) pts were eligible for the primary analysis; 10-mo FFS rates were 48% vs 54% (one-sided 95% confidence limit 37% and 43% respectively). Median FFS was 12.0 vs 13.7 mo respectively (IQR 6.1-20.3 and 8.6-23.2). Median OS was 20.1 vs 18.4 mo. First CFI length was 3.7 mo vs 5.1 mo (IQR 2.5-6.2 and 2.5-8.9). In pre-planned exploratory analysis, median time to progression/death after chemo break was 3.1 mo (IQR 2.1-8.1) in Arm D and 6.0 mo (IQR 2.9-10.9) in Arm E. Toxicity was similar and only 1 arm D pt had G 3 hypersensitivity following C reintroduction. Analyses by BRAF & NRAS (tested retrospectively) will be presented.nnnCONCLUSIONSnC was safely incorporated in 2 ICT strategies. Continuous C as maintenance was associated with a longer CFI and longer time to progression/death. This encouraging strategy of incorporating biological maintenance therapy needs validation in phase III trials.

THE COMBINATION OF MULTIPLE DOSES OF ETANIDAZOLE AND PIMONIDAZOLE IN 48 PATIENTS - A TOXICITY AND PHARMACOKINETIC STUDY

The two radiosensitizers etanidazole and pimonidazole, currently in clinical phase 3 trials, have different toxicities. The former produces a peripheral neuropathy after cumulative doses and the latter presents an accurate but transient central nervous system syndrome after each dose. A strategy for improving on the maximum radiosensitization achievable using either drug alone, has been investigated in the study reported in this paper. Escalating doses of the two drugs were given together to determine toxicity up to a maximum of 15 doses of 2.0 g/m2 etanidazole and 0.75 g/m2 pimonidazole/dose. 25 neuropathies were seen in the total of 48 patients (48%). This included 6 grade 2 neuropathies (12.5%) or 15% of those receiving 9 or more infusions. There were no significant correlations between the incidence of neuropathy and various dose and AUC parameters for the 31 patients receiving 10 or more infusions. However, in the selected group of 26 patients planned to receive multiple doses of etanidazole at 2 g/m2/dose with pimonidazole at 0.75 g/m2, significant correlations were seen with the cumulative dose, with single and cumulative AUCs for pimonidazole and also for the cumulative dose and the cumulative AUC for etanidazole, but not its single AUC. In the light of these observations and the recent reports of higher peripheral neuropathy rates than previously reported in studies in the USA, it is concluded that it is not possible at this time to determine whether there is toxicity interaction between the two drugs. There remains the possibility that, on the basis of the combined drug dosage achieved, an increased therapeutic efficacy can be reached with either drug alone.

Combining Oncolytic Adenovirus with Radiation—A Paradigm for the Future of Radiosensitization

Oncolytic viruses and radiotherapy represent two diverse areas of cancer therapy, utilizing quite different treatment modalities and with non-overlapping cytotoxicity profiles. It is, therefore, an intriguing possibility to consider that oncolytic (“cancer-killing”) viruses may act as cancer-selective radiosensitizers, enhancing the therapeutic consequences of radiation treatment on tumors while exerting minimal effects on normal tissue. There is a solid mechanistic basis for this potential synergy, with many viruses having developed strategies to inhibit cellular DNA repair pathways in order to protect themselves, during genome replication, from unwanted interference by cell processes that are normally triggered by DNA damage. Exploiting these abilities to inhibit cellular DNA repair following damage by therapeutic irradiation may well augment the anticancer potency of the approach. In this review, we focus on oncolytic adenovirus, the most widely developed and best understood oncolytic virus, and explore its various mechanisms for modulating cellular DNA repair pathways. The most obvious effects of the various adenovirus serotypes are to interfere with activity of the MRE11-Rad50-Nbs1 complex, temporally one of the first sensors of double-stranded DNA damage, and inhibition of DNA ligase IV, a central repair enzyme for healing double-stranded breaks by non-homologous end joining (NHEJ). There have been several preclinical and clinical studies of this approach and we assess the current state of progress. In addition, oncolytic viruses provide the option to promote a localized proinflammatory response, both by mediating immunogenic death of cancer cells by oncosis and also by encoding and expressing proinflammatory biologics within the tumor microenvironment. Both of these approaches provide exciting potential to augment the known immunological consequences of radiotherapy, aiming to develop systems capable of creating a systemic anticancer immune response following localized tumor treatment.