Daratumumab in Indian patients with relapsed and refractory multiple myeloma: a prospective, multicenter, phase IV study.

Aim: To assess the safety and effectiveness of daratumumab monotherapy in Indian patients with relapsed/refractory multiple myeloma. Methods: In this prospective, multicenter, phase IV study, patients (aged ≥18 years) received intravenous daratumumab (16 mg/kg) in six cycles. Safety was the primary end point. Results: Of the 139 patients included, 121 (87.1%) experienced ≥1 treatment-emergent adverse events (TEAEs; 53 [38.1%] drug-related), 32 (23%) had ≥1 serious TEAEs (five [3.6%] drug-related) and 16 (11.5%) deaths were reported (one death [0.7%] was drug-related). Overall response rate was 26.3%; 62.7% of patients had stable disease. Median time to first response and median progression-free survival were 5.2 and 5.9 months, respectively. Functional status and well-being were improved. Conclusion: Daratumumab showed an acceptable and expected safety profile with consistent efficacy, providing a novel therapeutic option for relapsed/refractory multiple myeloma management in India.

Daratumumab is a monoclonal antibody approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). This study evaluated the outcome of daratumumab single therapy in Indian patients who were not cured with other drugs used for the same disease. 139 adult patients were included in this study from 15 institutes across India. Daratumumab (16 mg/kg) was diluted with 500 or 1000 ml of saline solution and given slowly through the intravenous route 16-times within 6 months. The study examined whether the safety profile and benefits of daratumumab reported in Indian patients were similar to those reported in the RRMM populations of other countries. The study found that most of the adverse events were not severe and could be easily treated by the study physician. 16 patients died (one might have been due to daratumumab treatment). Daratumumab treatment provided life support and recovery benefits to many patients. Daratumumab single therapy provides an appropriate and acceptable safety profile with no new adverse events and consistent benefits in RRMM patients. Clinical Trial Registration: NCT03768960 (ClinicalTrials.gov), CTRI/2019/06/019546.

A Real-World Study of Safety, Immunogenicity and Efficacy of Bevacizumab in Patients With Solid Malignancies: A Phase IV, Post-Marketing Study in India.

Objective: The aim of this study was to evaluate the post-marketing safety, tolerability, immunogenicity and efficacy of Bevacizumab (manufactured by Hetero Biopharma) in a broader population of patients with solid tumors. Patients And Methods: This phase IV, prospective, multi-centric clinical study was carried out in Indian patients with solid malignancies (metastatic colorectal cancer, non-squamous non-small-cell lung cancer, metastatic renal cell carcinoma) treated with Bevacizumab between April 2018 and July 2019. This study included 203 patients from 16 tertiary care oncology centers across India for safety assessment, of which a subset of 115 patients who have consented were also evaluated for efficacy and immunogenicity. This study was prospectively registered in the Clinical Trial Registry of India (CTRI), and was commenced only after receiving approval from the competent authority (Central Drugs Standard Control Organization, CDSCO). Results: Out of the 203 enrolled patients, 121 (59.6%) patients reported 338 adverse events (AEs) during this study. Of 338 reported AEs, 14 serious adverse events (SAEs) were reported by 13 patients including 6 fatal SAEs, assessed as unrelated to the study medication and 7 non-fatal SAEs, 5 assessed as related, and 3 unrelated to Bevacizumab. Most AEs reported in this study (33.9%) were general disorders and administration site conditions, followed by gastrointestinal disorders (29.1%). The most frequently reported AEs were diarrhea (11.3%), asthenia (10.3%), headache (8.9%), pain (7.4%), vomiting (7.9%), and neutropenia (5.9%). At the end of the study, 2 (1.75%) of 69 patients reported antibodies to Bevacizumab without affecting safety and efficacy. However, at the end of 12 months, no patient had reported antibodies to Bevacizumab. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were reported in 18.3%, 22.6%, 9.6%, and 8.7% of patients, respectively. The overall response rate (CR + PR) was reported in 40.9% of patients at the end of the study. Disease control rate (DCR), also known as the clinical benefit rate (CBR) was reported in 50.4% of patients. Conclusions: Bevacizumab (Cizumab, Hetero Biopharma) was observed to be safe, well tolerated, lacking immunogenicity, and efficacious in the treatment of solid tumors. The findings of this phase IV study of Bevacizumab, primarily as a combination therapy regimen suggest its suitability and rationality for usage in multiple solid malignancies. Clinical Trial Registry Number: CTRI/2018/4/13371 [Registered on CTRI http://ctri.nic.in/Clinicaltrials/advsearch.php : 19/04/2018]; Trial Registered Prospectively.

Rituximab biosimilar for the treatment of diffuse large B-cell lymphoma: a phase 3 randomized study in India.

PURPOSE: Very few studies have demonstrated the rituximab biosimilarity in terms of efficacy, safety, pharmacokinetics, pharmacodynamics, and immunogenicity in patients with diffuse large B-cell lymphoma (DLBCL) in India. Therefore, we compared the efficacy, safety, pharmacokinetic, pharmacodynamic, and immunogenicity of our biosimilar rituximab with the reference rituximab (Ristova, Roche products [India] Pvt. Ltd) in patients with DLBCL in India. METHODS: A phase 3, randomized, assessor-blind, parallel-group, two-arm study was conducted across 28 sites in India. A total of 153 newly diagnosed DLBCL patients were randomized to receive either biosimilar rituximab or reference rituximab. The study drugs were administered at a dose of 375 mg/m2 by intravenous infusion every 3 weeks for six cycles. The primary end point was objective response rate (ORR) at the end of Cycle 6. Secondary end points included: pharmacokinetic, pharmacodynamics, immunogenicity, and safety assessment. RESULTS: The ORR at the end of Cycle 6 was 82.14% in the biosimilar rituximab and 85.71% in the reference rituximab group. The risk difference (90% CIs) was - 3.57 (- 14.80, 7.66). It met the non-inferiority margin of - 20%. The pharmacokinetic and pharmacodynamic parameters were comparable between the two treatment groups. The incidence rate of immunogenicity was very low and similar in both the treatment groups. The safety profile of both the treatments was comparable with no major difference in terms of nature, frequency and severity of TEAEs. CONCLUSION: The study demonstrated the biosimilarity between the biosimilar rituximab and the reference rituximab. Our biosimilar rituximab could add to the cost-effective treatment alternatives for patients with DLBCL in India.

Gonadotropin-releasing hormone agonists in prostate cancer: A comparative review of efficacy and safety.

Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.

Afatinib alone and in combination with vinorelbine or paclitaxel, in patients with HER2-positive breast cancer who failed or progressed on prior trastuzumab and/or lapatinib (LUX-Breast 2): an open-label, multicenter, phase II trial.

PURPOSE: Resistance to HER2 (ErbB2)-targeted therapy may be mediated by other members of the ErbB family. We investigated the efficacy and safety of the irreversible ErbB family blocker, afatinib, alone as first-line therapy in the advanced setting and in combination with vinorelbine or paclitaxel for those who progressed on afatinib monotherapy, in female patients with metastatic breast cancer who had failed or progressed on prior HER2-targeted therapy in the early disease setting. METHODS: In this phase II, single-arm, two-part study (ClinicalTrials.gov: NCT01271725), patients in part A received afatinib 40 mg/day in 21-day cycles until disease progression or intolerable adverse events (AEs). Patients with progressive disease could then receive afatinib plus weekly vinorelbine 25 mg/m2 or paclitaxel 80 mg/m2 until disease progression or intolerable AEs (part B). The primary endpoint was confirmed objective response rate (RECIST v1.1). RESULTS: Eighty-seven patients were enrolled and 74 were treated in part A (median age: 51 years [range 27-76]; 31 [42%] estrogen receptor-positive, 26 [35%] progesterone receptor-positive). Of these, 39 (53%) patients went on to receive afatinib plus vinorelbine (13 patients) or paclitaxel (26 patients) in part B. Thirteen (18%) and 12 (31%) patients achieved an objective response in parts A and B, respectively. The most common treatment-related AEs with afatinib monotherapy (any/grade ≥ 3) were diarrhea (68%/8%) and rash (49%/4%). Combination therapy was generally well tolerated, with no additive toxicity observed. CONCLUSION: Afatinib treatment, alone or in combination with vinorelbine or paclitaxel, was associated with objective responses in ≥ 18% of patients with metastatic breast cancer for whom prior HER2-targeted therapy has failed. Treatment-related AEs were generally manageable, with few grade ≥ 3 AEs reported. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01271725, registered 1 July 2011.

Mesenteric leiomyosarcoma in a pregnant woman: A case report and review of literature.

We herein describe a case of primary leiomyosarcoma of descending mesocolon mesentery in a pregnant woman. A 31-year-old woman was referred to our clinic for the presence of a suspicious mass (solid heterogenous lesion with lobulated margins) detected during routine obstetric ultrasonography (USG), growing throughout her term. Imaging in her third trimester showed a considerable increase in the size of the mass and was suspected to be malignancy of uterine origin. Tru-cut biopsy performed post-partum indicated leiomyosarcoma. She underwent neoadjuvant chemotherapy with six cycles of dacarbazine and doxorubicin with partial response. Subsequently, she underwent surgery, and the tumor was found to be present in sigmoid colon mesentery extending in retroperitoneum involving 5 cm of ureter. The mass was resected along with part of the colon and ureter that was involved by disease. Patient had uneventful recovery post-surgery. Considering moderate response to chemotherapy and discussion in tumor board, she was not given adjuvant chemotherapy. At follow-up of 15 months, the patient is disease-free with a normal, healthy baby.

Substantial remission of prostate adenocarcinoma with dendritic cell therapy APCEDEN® in combination with chemotherapy.

Of the most prevalent solid tumors with advanced disease, prostate and ovarian cancer and non-small cell lung carcinoma have the fewest therapeutic options. Herein, we report the case of a 63-year-old male with metastatic prostate adenocarcinoma showing substantial remission post-administration of personalized dendritic cell-based vaccine APCEDEN® in combination with chemotherapeutic drug Mitoxantrone. Therapeutic response displayed an interesting clinical correlation validated by PET scan images showing decreased fluorodeoxyglucose (FDG) avidity in the prostate gland, reduced skeletal metastases further established by the drop in serum Prostate Specific Antigen (PSA) levels and expression of immune assessment markers (IFN-γ, Tregs, neutrophil lymphocyte ratio and platelet lymphocyte ratio). This case demonstrates the potential efficacy of dendritic cell immunotherapy, showing a potent antitumor activity by enhancing the host immune responses, and improving quality of life.

A phase 1b, multicenter, open-label, dose-finding study of eribulin in combination with carboplatin in advanced solid tumors and non-small cell lung cancer.

PURPOSE: This phase 1b study investigated the maximum tolerated dose (MTD; primary objective), safety, pharmacokinetics, and antitumor activity (secondary objectives) of eribulin combined with carboplatin in patients with solid tumors and, in particular, non-small cell lung cancer (NSCLC). METHODS: Two dose-escalation schemes were evaluated with carboplatin, at an area under the curve (AUC) of either 5 or 6 mg/mL·min. Eribulin, dose-escalated from 0.7 to 1.4 mg/m2 was administered 1 h before (Schedule A) or after (Schedule B) carboplatin as a 2-5-min bolus infusion on days 1 and 8 of a 21-day cycle. Following tolerability assessment, patients with NSCLC were recruited in an expansion cohort. RESULTS: The MTDs were eribulin 1.4 and 1.1 mg/m2 with carboplatin AUC 5 and AUC 6, respectively. The latter combination was used to treat NSCLC patients in the expansion cohort. Pharmacokinetics of eribulin and carboplatin were generally unaffected by administration sequence (i.e., administration of carboplatin did not significantly affect eribulin Cmax and AUC0-t and the converse was also observed). In the NSCLC cohort, the objective response rate was 27%. Median overall and progression-free survival durations were 12.1 and 4.2 months, respectively. No unexpected safety findings were observed. CONCLUSIONS: The combination of eribulin and carboplatin demonstrated antitumor activity; however, recent therapeutic advances may be more promising approaches for first-line treatment of NSCLC. Clinical trial registration NCT00268905.

A Randomized Phase 2 Study of ADXS11-001 Listeria monocytogenes-Listeriolysin O Immunotherapy With or Without Cisplatin in Treatment of Advanced Cervical Cancer.

OBJECTIVES: A global unmet medical need exists for effective treatments for persistent, recurrent, or metastatic cervical cancer, as patients have a short life expectancy. Recently, immunotherapies have shown promising survival benefits for patients with advanced forms of cancer. Axalimogene filolisbac (ADXS11-001), a Listeria monocytogenes immunotherapy with a broad effect on the immune system, is under investigation for treatment of human papillomavirus-associated cancers including cervical cancer. METHODS: This phase 2 study evaluated the safety and efficacy of ADXS11-001, administered with or without cisplatin, in patients with recurrent/refractory cervical cancer following prior chemotherapy and/or radiotherapy. A total of 109 patients were treated, and 69 were evaluable for tumor response at equal to or more than 3 months postbaseline. RESULTS: Median overall survival (OS) was comparable between treatment groups (ADXS11-001: 8.28 months; 95% confidence interval [CI], 5.85-10.5 months; ADXS11-001 + cisplatin: 8.78 months; 95% CI, 7.4-13.3 months). The 12- and 18-month milestone OS rates were 30.9% versus 38.9%, and 23.6% versus 25.9% for each group, respectively (34.9% and 24.8% combined). Median progression-free survival (6.10 vs 6.08 months) and the overall response rate (17.1% vs 14.7%) were similar for both groups. ADXS11-001 was generally well tolerated; adverse events were predominantly mild to moderate in severity and not related to treatment. More adverse events were reported in the combination group (429 vs 275). CONCLUSIONS: These promising safety and efficacy results, including the encouraging 12-month 34.9% combined OS rate, warrant further investigation of ADXS11-001 for treatment of recurrent/refractory cervical cancer.

Complete remission of rare adenocarcinoma of the oropharynx with APCEDEN® (dendritic cell-based vaccine): a case report.

APCEDEN ® is an autologous monocyte-derived dendritic cell-based immunotherapy. A 58-year-old man with adenocarcinoma of oropharynx shows complete remission after receiving APCEDEN ® in conjunction with Geftinib validated by reduction in size, whereas Gefitinib alone lead to disease progression.

A retrospective analysis comparing APCEDEN® dendritic cell immunotherapy with best supportive care in refractory cancer.

AIM: A retrospective survival benefit analysis of APCEDEN®, APAC BIOTECH Pvt Ltd 69, Jacranda Marg, DLF PHASE II, Gurugram, Haryana, India, an autologous dendritic cell-based product for management of refractory solid malignancies, was performed in comparison with a control group. METHODS: Subjects (retrospective data) whose survival data, geographical region, age, gender, ECOG performance status and stage of disease that could be matched with the treatment group were considered for analysis. RESULTS: The analysis suggests a significant survival benefit of 199 days for the APCEDEN therapy treatment group when compared with the control group (356 vs 157 days). The event-free survival time of APCEDEN therapy was 439 days in patients who demonstrated an objective response at first evaluation as per immune-related response criteria. CONCLUSION: APCEDEN demonstrated highly convincing survival benefits when compared with the control group.

Immune modulation by dendritic-cell-based cancer vaccines.

The interplay between host immunity and tumour cells has opened the possibility of targeting tumour cells by modulation of the human immune system. Cancer immunotherapy involves the treatment of a tumour by utilizing the recombinant human immune system components to target the pro-tumour microenvironment or by revitalizing the immune system with the ability to kill tumour cells by priming the immune cells with tumour antigens. In this review, current immunotherapy approaches to cancer with special focus on dendritic cell (DC)-based cancer vaccines are discussed. Some of the DC-based vaccines under clinical trials for various cancer types are highlighted. Establishing tumour immunity involves a plethora of immune components and pathways; hence, combining chemotherapy, radiation therapy and various arms of immunotherapy, after analysing the benefits of individual therapeutic agents, might be beneficial to the patient.

Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2) every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab-paclitaxel 260 mg/m(2) every 3 weeks. Statistically, significant differences were not observed in the PICN and nab-paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease.

Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study.

PURPOSE: This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. RESULTS: Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. CONCLUSION: Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.

Open-label, multi-center, non-randomized, single-arm study to evaluate the safety and efficacy of dendritic cell immunotherapy in patients with refractory solid malignancies, on supportive care.

BACKGROUND AIMS: A phase II clinical trial of an autologous dendritic cell (DC) formulation for the management of refractory solid malignant tumors was conducted across six sites in India with an objective to study safety and efficacy. METHODS: A total of 51 patients with refractory cancer (either sex) with life expectancy ≥3 months, Eastern Cooperative Oncology Group score ≤2, available tumor tissue and adequate organ and bone marrow function were recruited. Monocytes obtained by leukapheresis, differentiated into DCs by cytokines and primed with autologous tumor lysate (fresh tissue biopsy or paraffin block). On the 8th day, mature DCs were analyzed for expression of CD40, CD80, CD83, CD86, DC205 and DC209. The treatment regime consisted of six doses (intravenous) over 14 weeks with 2 post-treatment follow-up visits, 6 weeks apart. Safety was assessed at all visits and responses were evaluated on days 58, 100 and 184 or at end of the study. RESULTS: A total of 38 patients were evaluated for safety and efficacy. One adverse event classified as possibly related was an episode of rigors or chills with mild pyrexia during one infusion. Objective response rate by Response Evaluation Criteria In Solid Tumors was 28.9% (11/38) and immune-related response criteria was 42.1% (16/38); 90% confidence interval for objective response rate was (17.2, 43.3) and (28.5, 56.7) by Response Evaluation Criteria In Solid Tumors and immune-related response criteria, respectively. The median time to treatment progression was >9 weeks. Median overall survival was 397 days. An increase in the expression of interferon-γ was not significant. CONCLUSIONS: Therapy was safe. The responses, time to treatment progression and survival are encouraging for patients with aggressive refractory disease.

A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer.

BACKGROUND: We conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer. METHODS: Patients were randomised to paclitaxel (90mg/m(2), weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ≤ 0.82 (1-sided α=0.14) after 120 events supporting a treatment effect. FINDINGS: Patients were randomised in India (n=170), the United States (n=52) and Brazil (n=15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR)=0.788; 95% confidence interval (CI), 0.558-1.112; P=0.1715 [1-sided P=0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR=0.674; 95% CI 0.465-0.975; P=0.0343) and improved overall response (67% versus 54%; P=0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR=1.022; 95% CI 0.715-1.461; P=0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm. INTERPRETATION: The addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.

The ACT-ONE trial, a multicentre, randomised, double-blind, placebo-controlled, dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design.

AIMS: Cachexia, the wasting disorder associated with a wide range of serious illnesses including cancer, is a major cause of morbidity and mortality. There is currently no widely approved therapeutic agent for treating or preventing cancer-associated cachexia. Colorectal cancer and non-small cell lung cancer have relatively high incidences of cachexia, approximately 28% and 34%, respectively. Neurohormonal overactivity has been implicated in the genesis and progression of cachexia and beta receptor antagonism has been proposed as a potential therapy. MT-102, a novel anabolic/catabolic transforming agent, has a multi-functional effect upon three potential pharmacological targets in cancer cachexia, namely reduced catabolism through non-selective ß-blockade, reduced fatigue, and thermogenesis through central 5-HT1a antagonism and increased anabolism through partial ß-2 receptor agonism. METHODS: At least 132 male and female patients, aged between 25 and 80 years with a confirmed diagnosis of late-stage non-small cell lung cancer or colorectal cancer, with cachexia will be randomised to either one of the two MT-102 doses or placebo in a 3:1:2 ratio (MT-102 10 mg BD(-1)/MT-102 2.5 mg BD/placebo). Patients will continue on study treatment for maximally 16 weeks. The primary endpoint, to be analysed by assigned treatment group, will be body weight change over 16 weeks. For this endpoint, the study has 85% power (0.05% significance level) to detect per 4-week period a mean change of -0.8 kg in the placebo group and 0 kg in the high-dose MT-102 arm. The first patient was randomised in February 2011 and patient recruitment is expected to continue until mid-2012. PERSPECTIVE: The ACT-ONE trial is designed to test whether the anabolic/catabolic transforming agent MT-102 will positively impact on the rate of change of body weight in cancer cachexia, thereby evaluating a novel therapeutic strategy in this hitherto poorly treatable condition. A separate ACT-TWO trial will recruit patients who complete the ACT-ONE trial and remain on randomised double-blind medication. Participants in ACT-TWO will be followed for an additional period with a separate primary endpoint.