 Exelixis regained full rights from Bristol-Myers Squibb (BMS) to develop and commercialize XL184, a small molecule orally available multi-kinase inhibitor targeting Met, VEGFr2, and Ret. Exelixis is developing the agent in medullary thyroid cancer in a phase III clinical trial, in glioblastoma multiforme (GBM), and potentially in some of the tumor types being evaluated in a phase I randomized discontinuation trial.
Based on discussions with the FDA, Pfizer decided to discontinue the commercial availability of Mylotarg (gemtuzumab ozogamicin for Injection) used for the treatment of relapsed CD33-positive acute myeloid leukemia (AML) in the USA and voluntarily withdraw the new drug application (NDA) for Mylotarg effective October 15, 2010. The decision is based on the fact that the drug, in combination with chemotherapy in a post approval clinical trial (protocol ID: SWOG-S0106; NCT00085709) in patients with previously untreated AML, did not improve survival compared with chemotherapy alone, and was also associated with higher toxicity.
Following a priority review, the FDA granted accelerated approval to Novartis' anticancer drug Tasigna (nilotinib) for the treatment of adult patients with newly diagnosed chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). Approval was based on results from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML Patients (ENESTnd) multicenter, randomized, open label phase III clinical trial (CAMN107A2303, EUDRACT 2007-000208-34) that compared the efficacy and safety of Tasigna versus Glivec/Gleevec (imatinib) in adult patients in this setting. In this trial Tasigna eliminated Bcr-Abl faster than Glivec, resulting in lower rates of cancer progression even as early as 12 months.
According to topline results from the phase II clinical trial (protocol ID: SHH4429g; NCT00636610) with GDC-0449, a Hedgehog (Hh) signaling pathway inhibitor, in combination with Avastin (bevacizumab) and FOLFOX or FOLFIRI chemotherapy as first line treatment in patients with metastatic colorectal cancer, the trial did not meet its primary endpoint of extending the time from randomization to disease progression or death in patients who were treated with GDC-0449 in addition to the current standard of care of bevacizumab and chemotherapy when compared to patients treated with only the current standard of care. GDC-0449 is under development by Genentech (USA), Chugai Pharmaceuticals (Japan), and Roche (ROW) under a collaborative agreement with Curis.
The FDA granted marketing authorization for sanofi-aventis' Jevtana (cabazitaxel) Injection in combination with prednisone for the treatment of patients with metastatic hormone-refractory prostate cancer (HRPC) previously treated with a docetaxel-containing treatment regimen. The drug was approved based on results from TROPIC, a phase III clinical trial (protocol ID: EFC6193; NCT00417079) involving 755 patients in which a statistically significant 30% (HR=0.70; p<0.0001) reduction in risk of death was observed in patients administered Jevtana in combination with prednisone compared with an active chemotherapy regimen consisting of a standard dose of mitoxantrone and prednisone; median OS was 15.1 months in the cabazitaxel combination arm versus 12.7 months in the mitoxantrone combination arm. Investigator-assessed tumor response rates by RECIST were 14.4% and 4.4% (p=0.0005) for cabazitaxel-treated and mitoxantrone-treated patients, respectively. There were no complete responses in either arm.
Merck Serono, a division of Merck KGaA, and its USA affiliate, EMD Serono, are resuming the Stimuvax (BLP25 liposome vaccine) clinical program in patients with non-small cell lung cancer (nsclc), which includes the phase III trials START and INSPIRE. The trial that remains on clinical hold by the FDA is the phase III STRIDE trial in advanced breast cancer. Merck KgaA has licensed Stimuvax from Oncothyreon.
According to positive results reported from a multicenter, global, randomized, double blind phase III clinical trial (protocol ID: MDX010-20; NCT00094653), treatment with ipilimumab significantly extended overall survival (OS) in patients with inoperable, previously treated metastatic melanoma. For the first time, a significant improvement in OS has been demonstrated in this setting in a large (n=676), randomized phase III clinical trial. Median OS was extended by 3.6 months to 3.7 months with ipilimumab compared to treatment with a gp100 vaccine (MDX-1327) as a control; 44% to 46% of patients treated with ipilimumab were alive at 1 year compared to 25% of patients treated with the gp100 vaccine. At 2 years, 22% to 24% of patients treated with ipilimumab were alive compared to 14% of patients treated with the gp100 vaccine. Bristol-Myers Squibb is in discussions with health authorities worldwide and expects to submit applications for regulatory approval of ipilimumab in advanced melanoma in 2010.
The FDA approved Amgen's Prolia (denosumab) for the treatment of postmenopausal women with osteoporosis at high risk for fracture.
The European Commission (EC) granted marketing authorization to Amgen's drug Prolia (denosumab) for the treatment of osteoporosis in postmenopausal women at increased risk of fractures, and for the treatment of bone loss associated with adrogen deprivation therapy (ADT) in men with nonmetastatic prostate cancer at increased risk of fractures. Prolia has been approved in all 27 European Union member states plus Norway, Iceland and Liechtenstein. The marketing authorization for Prolia is based on data from 6 phase III clinical trials, including two pivotal phase III trials with fracture endpoints in the osteoporosis and prostate cancer settings, in which subcutaneously administered Prolia (60 mg) every 6 months reduced the incidence of fractures and increased bone mineral density at all skeletal sites measured.
Novartis reported that the multicenter (n=168), international (n=22), open label, active control, parallel group, phase III clinical trial (protocol ID: CEPO906A2303; NCT00262990) that enrolled 829 patients with advanced epithelial ovarian, primary fallopian or primary peritoneal cancer refractory or resistant to platinum-based chemotherapy, who were randomized to either patupilone or Doxil (Centocor)/Caelyx (Merck), failed to meet its primary objective of a significant overall survival advantage compared to pegylated liposomal doxorubicin. Novartis does not plan to proceed with regulatory filings based on these data.
According to data reported by Genentech and Biogen Idec from the phase III PRIMA clinical trial (protocol ID: NCT00140582), continuing Rituxan (rituximab) treatment for two years in patients with previously untreated advanced follicular non-Hodgkin's lymphoma (NHL) who responded to initial treatment with Rituxan plus chemotherapy, doubles (hazard ratio=0.50) the likelihood of progression-free survival (PFS) compared to those who stopped treatment (p=<0.0001). After two years of follow-up, 82% of patients treated with Rituxan maintenance were in remission compared to 66% of patients who were not treated with the drug.
Based on clinical activity seen in the first stage of the phase II clinical trial (protocol ID: 9090-06 NCT01031225) with Synta Pharmaceuticals' HSP90 inhibitor STA-9090 in patients with advanced or metastatic non-small cell lung cancer (nsclc), the trial is advancing to its second stage. In 2 phase I clinical trials (protocol ID: 9090-01; NCT00688116 and 9090-02; NCT00687934), testing different dosing schedules in patients with advanced solid tumors, STA-9090 was well tolerated with preliminary signs of clinical activity.
Teva Pharmaceutical Industries initiated a multicenter, phase I/II clinical trial (protocol ID: RA-TL011-101; 2009-015702-18; NCT01123070) in February 2010, in Europe, to evaluate TL011, a biosimilar of rituximab, in severe active rheumatoid arthritis (RA). Trial objectives are to compare the pharmacokinetics (PK), and safety and tolerability of TL011 and MabThera in patients with RA.
According to final results presented by Wilex and IBA (Ion Beam Applications) from REDECT, a pivotal phase III registration trial (protocol ID: WX/20-001; NCT00606632), Redectane-based positron emission tomography (PET) significantly improved pre-surgical diagnosis in comparison to CT alone of patients suspected of having clear cell renal cell carcinoma (RCC) with a sensitivity of 86% (p</=0.002) and a specificity of 87% (p=0.057).
Rosetta Genomics' scientists, by sequencing small RNA (17-25 nt) from 23 breast, bladder, colon and lung tumor samples using high throughput sequencing, identified 49 novel microRNA, each one of which has the potential to be, alone or in combination with other miRNA, a diagnostic biomarker, response biomarker, or drug target. The expression of 10 novel small RNAs were further validated independently by microarray and RT-PCR in 31 different types of blood, and normal and tumor tissue samples. The company filed patent applications on each of these newly discovered miRNAs (Nucleic Acids Research 2009).
Amgen submitted a Biologics License Application (BLA) to the FDA for denosumab (more), a subcutaneous RANK Ligand inhibitor. The BLA submission summarizes clinical experience from nearly 6,900 patients across 18 clinical trials, including approximately 5,700 patients with advanced cancer who were enrolled in three pivotal, phase III, head-to-head trials (protocol ID: 20050244; NCT00330759, 20050136; NCT00321464, and 20050103; NCT00321620) evaluating denosumab versus zoledronic acid (Zometa; Novartis). The FDA is currently reviewing denosumab under the trade name Prolia for conditions related to bone loss with a PDUFA action date of July 25, 2010.
Merck restructured its co-development and co-commercialization agreement with Ariad Pharmaceuticals for ridaforolimus (more) to an exclusive license agreement. Under the restructured agreement, Merck acquired full control of the development and worldwide commercialization of ridaforolimus. Ariad will receive a $50 million upfront fee and is eligible to receive milestone payments associated with regulatory filings and approvals of ridaforolimus in multiple cancer indications and achievement of significant sales thresholds. In lieu of the profit split on USA sales provided for in the previous agreement, Ariad will receive royalties on global net sales of ridaforolimus; all sales will be booked by Merck.
BioSante Pharmaceuticals, in a cooperative program with Johns Hopkins and the Prostate Cancer Foundation (PCF), reinitiated development of GVAX Prostate, planning a phase II clinical trial in the fourth quarter of 2010 at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, in patients with prostate cancer. Unlike Provenge that requires cells extracted from the patient to be processed ex vivo before reinfused in the same patient, GVAX is a non-patient-specific off-the-shelf vaccine. BioSante is funding the manufacturing of the vaccine, while the phase II clinical trial will be supported in part by the PCF; the OneInSix Foundation provided important start-up funding for this trial.
The FDA approved Dendreon's Provenge (sipuleucel-T), an autologous cellular immunotherapy, for the treatment of patients with asymptomatic or minimally symptomatic metastatic, castrate-resistant (hormone-refractory) prostate cancer. Approval is based on 3 phase III clinical trials involving 737 patients. In the pivotal multicenter, randomized, double blind, placebo-controlled phase III IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment) trial (protocol ID: D9902B; NCT00065442) that enrolled 512 patients, Provenge extended median survival beyond 2 years, for a median improvement of 4.1 months compared to the control group (25.8 months versus 21.7 months). Dendreon intends to make Provenge available through approximately 50 centers, all approved Provenge clinical trial sites, and expects to increase capacity over the next year.
Following a review by the independent Data Monitoring Committee (DMC), Pfizer discontinued the open label phase III clinical trial (protocol ID: A6181170; NCT00699374) in patients with advanced hepatocellular carcinoma (HCC) because of a higher incidence of serious adverse events (SAE) in the sunitinib (Sutent) arm compared to the sorafenib (Nexavar) arm and the fact that sunitinib was neither superior or non-inferior to sorafenib in terms of survival.
Genentech submitted a supplemental Biologics License Application (sBLA) to the FDA for Herceptin (trastuzumab) plus chemotherapy in patients with advanced, HEr2-positive adenocarcinoma of the stomach, including gastroesophageal junction cancer. The application is based on positive results from ToGA, an international phase III clinical trial (protocol ID: BO18255; NCT01041404) that enrolled 594 patients with locally advanced or metastatic HEr2-positive stomach cancer who were randomized to either Herceptin plus chemotherapy with either PO capecitabine (Xeloda; Roche) or IV 5-flourouracil (5-FU) and cisplatin or chemotherapy alone. Median overall survival (OS), the primary endpoint, was 13.8 months in those treated with Herceptin plus chemotherapy compared to 11.1 in those treated with chemotherapy alone for a hazard ratio (HR) of 0.74 (p=0.0046). A greater benefit was observed by the addition of Herceptin in 16% of patients with tumors overexpressing HEr2 (IHC3+ or IHC2+/FISH+). For these patients, OS was 16 months on average versus 11.8 months for patients treated with chemotherapy alone.
The FDA approved OSI Pharmaceuticals' Tarceva (erlotinib) as maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer (nsclc) whose disease did not progress after four cycles of platinum-based first line chemotherapy. Approval was based on data from SATURN, a pivotal phase III clinical trial (protocol ID: BO18192; NCT00556712) in which Tarceva was administered as maintenance therapy immediately after first line chemotherapy. In SATURN, median OS was significantly improved by 23% with Tarceva compared to placebo (12.0 months versus 11.0 months) for a hazard ratio (HR) of 0.81, representing a 19% reduction in the risk of death (p=0.0088) and median PFS was improved by 41% with Tarceva compared to placebo (12.3 weeks versus 11.1 weeks) for an HR of 0.71, representing a 29% reduction in the risk of cancer progression or death (p<0.0001). Tarceva was also approved in the EU for this indication.
In a potentially landmark ruling, U.S. District Judge Robert Sweet of the Federal District Court for the Southern District of New York struck down Myriad Genetics' patents covering two genes, BRCA1 and BRCA2, linked to an increased risk of breast and ovarian cancer and other malignancies. The decision challenges the notion that patents may be issued on human genes, which are identical inside or outside the body (isolated DNA), and is expected to have broad implications for the biotechnology industry and medical research.
GenVec discontinued the PACT multicenter, randomized, active, and controlled phase III clinical trial comparing the standard of care with or without TNFerade in patients with locally advanced pancreatic cancer based on results of an interim analysis of overall survival (OS) that, according to the independent Data Safety Monitoring Board, indicate that the trial would not meet the goal of demonstrating persuasive evidence of clinical effectiveness that could form the basis for regulatory approval in the population chosen for evaluation.
Following a detailed analysis of primary and updated data from the phase III SPEAR trial of picoplatin in small cell lung cancer (sclc) and an evaluation of the ongoing New Drug Application (NDA) process with the FDA, Poniard Pharmaceuticals decided to suspend its efforts to obtain regulatory approval for picoplatin in sclc at this time.
Recently, numerous reports were presented regarding efforts to develop treatments for non-small cell lung cancer, one of the most challenging malignancies. There were a few positive news.
Abraxane, developed by Abraxis Oncology, was one of a few approved drugs or those in late stage of development, with positive results from phase III clinical trials in advanced non-small cell lung cancer (nsclc). The randomized, multicenter, registrational phase III clinical trial (protocol ID: CA031; NCT00540514) comparing Abraxane (protein-bound paclitaxel) with paclitaxel (Taxol; Bristol-Myers Squibb), both in combination with carboplatin, met its primary endpoint by demonstrating a significant improvement in overall response rate (ORR) with Abraxane compared to Taxol, in the first line treatment of patients with advanced nsclc, as assessed by independent radiologist review. Detailed results are to be presented at the 2010 meeting of ASCO.
Based on results from the SATURN trial, the European Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending approval of erlotinib (Tarceva) as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer (nsclc) with stable disease following 4 cycles of standard platinum-based first line chemotherapy. A final decision is expected from the European Commission within 45 days.
Several other drugs did not fare as well.
Merck Serono and its USA affiliate, EMD Serono, temporarily suspended the worldwide clinical development program for Stimuvax (BLP25 liposomal vaccine) as a result of a suspected unexpected serious adverse reaction (encephalitis) in a patient with multiple myeloma participating in an exploratory clinical trial. This decision was taken in alignment with the FDA's clinical hold placed on the IND application for Stimuvax. The suspension affects the phase III clinical program for Stimuvax, including the START and INSPIRE trials in non-small cell lung cancer (nsclc) and the STRIDE trial in breast cancer. Further recruitment of patients into all trials actively recruiting patients is suspended as well as ongoing treatment with Stimuvax in these trials.
According to results from the randomized phase II clinical trial (protocol ID: HGS1012-C1072; NCT00583830) combining mapatumumab (HGS-ETR1), under development by Human Genome Sciences, with paclitaxel and carboplatin as first line therapy in advanced non-small cell lung cancer (nsclc), there was no difference in disease response or progression-free survival (PFS) for the combination that included mapatumumab versus the control group; mapatumumab was well tolerated. Detailed results are to be presented at a future scientific meeting.
In another setback in the search for a treatment for advanced non-small cell lung cancer (nsclc), Pfizer discontinued the phase III clinical trial (protocol ID: A4021018; NCT00673049), within the ADVIGO (ADVancing IGF-Ir in Oncology) program, examining the effects of figitumumab (CP-751,871) in combination with erlotinib (Tarceva; OSI Pharmaceuticals) as a second/third line treatment in patients with previously treated advanced non-adenocarcinoma nsclc. An independent Data Safety Monitoring Committee (DSMC) recommended the trial be stopped after concluding that the addition of figitumumab to erlotinib is unlikely to demonstrate a statistically significant improvement in the primary endpoint of overall survival (OS) compared to erlotinib alone in the trial population.
The primary endpoint of improvement in overall survival (OS) was not met in the pivotal phase III clinical trial with Novelos' NOV-002, in combination with first line chemotherapy, in advanced non-small cell lung cancer (nsclc). Detailed trial results are to be presented in an appropriate scientific venue later in 2010.
Incredibly, another phase III clinical trial in advanced non-small call lung cancer (nsclc) failed to meet its objective. Antisoma halted the ATTRACT-1 phase III clinical trial (protocol ID: CASA404A2301; NCT00662597) with ASA404 in previously untreated non-small cell lung cancer because, according to the planned interim analysis, continuation of the trial would be futile, as there is little or no prospect of demonstrating a survival benefit in this setting.
In March 2010, the FDA's Oncologic Drugs Advisory Committee (ODAC) panel voted unanimously that clinical trial data was not adequate to support approval of Cell Therapeutics' anticancer drug pixantrone (more) for the treatment of patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL). The FDA is expected to make a decision whether to approve pixantrone for this use by April 23, 2010.
According to top-line results of HORIZON III, a phase II/III clinical trial (protocol ID: D8480C00013; Eudract Number 2005-003440-66; NCT00384176) evaluating efficacy of AstraZeneca's Recentin (cediranib) compared with Avastin (bevacizumab), both in combination with chemotherapy, in patients with first line metastatic colorectal cancer (CRC), the trial did not meet the pre-specified criteria for the primary endpoint of the cediranib arm of non-inferiority in progression-free survival (PFS). Data are expected in the coming months from HORIZON II, the other phase III clinical trial (protocol ID: D8480C00051; EUDRACT No 2006-001194-14; NCT00399035), assessing the efficacy of cediranib combined with chemotherapy versus chemotherapy alone in metastatic CRC. Results from both trials will determine the clinical utility, if any, of cediranib in colorectal cancer and decisions regarding regulatory filing. Data from both of these trials will be submitted to a forthcoming medical meeting in the second half of 2010.
Abbott Laboratories agreed to acquire Facet Biotech for $27 per share in cash, a 67% premium to Facet's closing price of $16.21 per share. The deal is valued at ~$450 million ($722 million, less Facet's projected cash and marketable securities at closing of approximately $272 million). The deal follows the rejection by Facet shareholders of a bid worth $17.50 per share for the company offered by Biogen Idec in December 2010. Facet has 3 anticancer agents in clinical development.
After repeated offers to negotiate a deal, Astellas Pharma launched an unsolicited bid to acquire OSI Pharmaceuticals for $52 a share for a total of $3.5 billion. Upon OSI's rejection of the offer, Astellas sued OSI. OrbiMed, a major shareholder of OSI, suggested that a more equitable offer would value the company at $60 per share. OSI's revenues are derived from its anticancer drug erlotinib (Tarceva) marketed by Roche. OSI's oncology pipeline includes 3 drugs in clinical development.
Aveo Pharmaceuticals is planning an IPO of 7 million common shares at between $13 and $15 per share.
According to results from a phase III clinical trial (protocol ID: EFC6193; NCT00417079), dubbed TROPIC, presented at the Genitourinary Cancers Symposium sponsored by the American Society for Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO) and the Society of Urologic Oncology (SUO), the median overall survival of patients treated with sanofi-aventis' novel anticancer drug cabazitaxel (Jevtana) in combination with prednisone/prednisolone was 15.1 months compared to 12.7 months in the mitoxantrone with prednisone/prednisolone combination arm; median PFS was 2.8 months and 1.4 months, respectively. The company has initiated a rolling New Drug Application (NDA) submission to the FDA.
Genentech reports that according to results from a phase III clinical trial, the addition of Avastin (bevacizumab) to a standard carboplatin and paclitaxel regimen followed by maintenance use with Avastin alone, increased progression-free survival (PFS) in women with previously untreated advanced ovarian cancer compared to chemotherapy alone. No details were provided. Data from the trial will be submitted for presentation at the American Society of Clinical Oncology (ASCO) annual meeting, June 4 to 8, 2010.
In the AVAGAST phase III clinical trial (protocol ID: AVF4200g; BO20904; NCT00548548) the addition of bevacizumab (Avastin) in a chemotherapy regimen consisting of capecitabine (Xeloda) or 5-FU, and cisplatin, did not extend survival of chemotherapy-naïve patients with inoperable, advanced or metastatic gastric cancer or esophageal junction cancer, compared to chemotherapy alone. Data from the trial will be submitted for presentation at the 2010 American Society of Clinical Oncology (ASCO) annual meeting.
ERYtech Pharma entered into a collaboration with investigators at M. D. Anderson Cancer Center to evaluate a biomarker useful in selecting patients with solid tumors likely to benefit from the company's anticancer drug Graspa.
A research study (Manuyakorn A, etal, JCO, 8 Feb 2010; epub ahead of print) of cellular levels of histone modifications, conducted by PrognosDx Health collaborators at the University of California Los Angeles (UCLA), identified subsets of patients with pancreatic cancer with distinct epigenetic phenotypes and clinical outcomes. Data was culled from a multicenter, randomized, 195-patient phase III clinical trial (RTOG-9704; E-R9704; SWOG-R9704; NCT00003216) conducted by the Radiation Therapy Oncology Group (RTOG), comparing adjuvant chemoradiation with gemcitabine versus 5-FU, and a 140-patient cohort with Stage I or II cancer from the UCLA Medical Center. Histone modifications may thus serve as novel, independent prognostic and predictive biomarkers in several tumor types, including prostate, kidney, lung, breast and ovarian cancer, with lower levels predicting significantly poorer survival. This is particularly true in pancreatic cancer and may predict response to chemotherapy.
The first patient was treated in a new phase II clinical trial of Genta's anticancer drug tesetaxel, a small molecule oral taxane, in advanced, inoperable or metastatic melanoma in the second line setting.
The pivotal, multicenter, international, randomized, double-blind phase III clinical trial (protocol ID: 20050103; NCT00321620) that compared Amgen's denosumab with zoledronic acid (Zometa; Novartis) in the treatment of bone metastases in 1,901 patients (mean age=71) with advanced, hormone-refractory prostate cancer (HRPC) met its primary and secondary endpoints.
Researchers at UCLA's Jonsson Comprehensive Cancer Center performed the first complete genomic sequencing of a brain cancer cell line. Sequencing of the extensively studied U87 cell line may lead to better ways of identifying drug targets and in developing in vitro tests to monitor patients to establish treatment results and brain cancer recurrence (news link). The study was published in PLOS Genetics.
The European Commission approved Roche's anticancer drug Herceptin (trastuzumab), in combination with chemotherapy incorporating a fluoropyrimidine and a platinum-based drug, for the treatment of patients with inoperable locally advanced, recurrent, and/or metastatic, HEr2-positive stomach cancer. The approval is based on the results from the international ToGA trial (protocol ID: BO18255; NCT01041404) according to which the overall survival of patients with tumors expressing high levels of HEr2 treated with Herceptin was 16 months compared to 11.8 months among those treated with chemotherapy alone.
St. Jude Children's Research Hospital and Washington University School of Medicine (St. Louis, MO) joined forces to decode the genomes of more than 600 children who have contributed tumor samples for this project. The St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project, estimated to cost $65 million over 3 years, is the largest investment to date aimed at understanding the genetic origins of childhood cancer. The project will sequence the entire genomes of both normal and cancer cells from each patient, comparing differences in the DNA to identify genetic errors that lead to cancer (news link). Additional news items are summarized in the News Module. |
