XL184 shows substantial activity in Patients with Previously Treated Glioblastoma Multiforme and Medullary Thyroid Cancer

Results from the ongoing phase II trial of XL184 demonstrates substantial activity in patients with previously treated progressive or recurrent glioblastoma multiforme (study XL184-201). Data of the ongoing trial was presented during the 45th annual meeting of the American Society of Clinical Oncology (ASCO). XL184 has exhibited dose-dependent tumor growth inhibition and tumor regression in a variety of tumor models, including breast cancer, colon cancer, medullary thyroid cancer , non-small cell lung cancer, and glioblastoma. Additional research now shows that treatment with XL184 at a dose of 175 mg PO qd results in potent inhibition of glioblastoma multiforme (GBM).

XL184 (BMS-907351) is a potent, orally administered, small molecule inhibitor of receptor tyrosine kinases. The compound also inhibits MET, a receptor tyrosine kinase that plays a key role in cellular proliferation, migration, and angiogenesis. MET is mutationally activated in some tumor types, such as hereditary and sporadic papillary renal cell carcinoma and some head and neck cancers. More frequently, MET is either over-expressed or activated in the absence of mutation in glioblastomas, breast carcinomas, some gastric cancers, and other solid tumors. MET amplification has been demonstrated in some NSCLCs.

VEGFR2 and RET
Overexpression of MET and vascular endothelial growth factor receptor-2 (VEGFR2), as well as the ligands which activate these receptors, has been shown to correlate with poor prognosis in glioblastoma multiforme, which is the most common and most aggressive form of brain tumor in humans, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors, and occurs in only 2–3 cases per 100,000 people in Europe and North America.

In addition, phosphorylated RET has been described in some cases of glioblastoma multiforme. Expression of VEGF has been observed in a variety of cancers and has been associated with prognostic significance. Targeting the VEGF receptor has been recognized as a potential anti-cancer strategy in multiple tumors. Dual targeting of MET and VEGFR2 blocks two of the major mechanisms tumors use to overcome hypoxia. Activated RET is involved in cell signaling cascades that regulate cell proliferation, migration, differentiation, and survival. RET is mutationally activated in papillary thyroid cancer (PTC) and in both familial and sporadic forms of medullary thyroid cancer (MTC).

Development of XL184
Exelixis Inc. (210 East Grand Avenue, P.O. Box 511, South San Francisco, CA 94083-0511 phone (650) 837-7000,fax (650) 837-8300), a biotechnology company focusing on the development of compounds targeting multiple receptor tyrosine kinases simultaneously as well as components of key components of downstream signaling pathways that play important roles in cancer and metabolic diseases, develops XL184 with Bristol-Myers Squibb Company (BMS), a global biopharmaceutical company.

The companies are currently conducting multiple clinical studies for XL184, in glioblastoma multiforme (GBM) and medullary thyroid cancer (MTC). John De Groot, MD, of The MD Anderson Cancer Center, and an investigator on the Phase 2 glioblastoma-trial, presented data during a poster session during the ASCO meeting.

The exploratory study evaluated the safety, tolerability and clinical activity of XL184 at a continuous daily dose of 175 mg in patients with previously treated glioblastoma multiforme. To date, 46 patients who make up the intent to treat (ITT) population have been enrolled in the trial, including 30 (65%) in first relapse and 16 (35%) in second or third relapse. Importantly, the trial did not exclude patients previously treated with an antiangiogenic agent.

The tumor response, as determined by an independent radiology facility (IRF), using MacDonald criteria were reported. By ITT analysis, 7 of 35 (20%) of the antiangiogenic naïve patients had a confirmed partial response. The overall rate of response in all patients, including the refractory population of previously treated patients with an antiangiogenic therapy, was 15%. The median duration of response by IRF was 2.9 months (range = 1.9-8.6 months). In an exploratory analysis, among 35 patients with at least one post baseline MRI scan, 12 (34%) had tumor shrinkage ≥50% as their best response as determined by investigator, including 1 patient who had received prior antiangiogenic therapy.

The efficacy evaluable population was defined as patients having received at least 1 dose of XL184 and either had at least 1 post-baseline tumor assessment per investigator or failed to return for any tumor assessments because of death or clinical determination of progression. In the anti-angiogenic naïve population, 7 of 31 (23%) of efficacy evaluable patients had a confirmed partial response by IRF. The 6-month progression-free survival (PFS) rate in patients receiving no prior antiangiogenic therapy was 23%, with 10 patients censored for PFS at the time of analysis, and the median PFS interval was 3.6 months.

“These initial data from our ongoing glioblastoma multiforme (GBM) program are encouraging, and suggest that XL184 could have utility in this underserved indication,” said Michael M. Morrissey, Ph.D., president of research and development at Exelixis. “We believe that these data support continued evaluation of XL184 in patients with GBM, and we intend to enroll additional patients in this study to better assess the compound’s anti-tumor activity and safety profile in this difficult to treat patient population.”

As of January 6, 2009 all 46 patients were evaluated for safety. At least 1 post-baseline tumor assessment at 4 weeks was available for 26 pts. Of these, 17 pts had not received prior therapy with an anti-angiogenic agent, whereas 9 pts had received prior therapy with bevacizumab (n = 6), vandetanib (n = 2), or VEGF-TRAP (n = 1). Most adverse events were of Grade 1 or 2 severity. The most frequently occurring Grade 3 and Grade 4 adverse events were: fatigue (30%), alanine aminotransferase increase (9%), confusional state (9%), lipase increase (9%), lymphopenia (9%), convulsion (7%), headache (7%), and hypophosphatemia (7%). Adverse events of special interest were: hypertension (all incidences, 39%; Grade 3/4, 7%), palmar-plantar erythrodysesthesia (30%; 7%), bleeding events (28%; 9%), proteinuria (26%; 0%), pulmonary embolism (9%; 7%) and craniotomy wound dehiscence (4%; 2%).

In the study, 87% of patients had a dose interruption of XL184, median average daily dose was 122 mg/day. XL184 will be evaluated at a lower dose of 125 mg daily in order to provide continuous and sustained exposure to the drug in this previously treated glioblastoma population.

Other studies with XL184
Correlative tumor profiling and biomarker evaluation and vascular imaging data from this trial was also presented in two additional posters in the same poster session. Abstract 2048, entitled “Neurovascular imaging in GBM patients quantifies early physiologic changes after treatment with XL184, an inhibitor of multiple receptor tyrosine kinases: results from a Phase 2 study” was presented by Gregory Sorensen, MD, from the Massachusetts General Hospital, Boston, MA, and abstract 2049, entitled "Correlative tumor molecular profiling and plasma biomarker analysis in a phase 2 study of XL184 in patients with progressive or recurrent glioblastoma multiforme" was presented by Samuel DePrimo, PhD, Exelixis Inc, South San Francisco, CA.

Medullary Thyroid Cancer
The American Cancer Society estimates that Medullary Thyroid Cancer (MTC) accounts for aproximately5% of all thyroid cancers. Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation.

The disease occurs in sporadic and inherited forms (approximately 80% and 20% of MTC, respectively). Patients with the inherited form of medullary thyroid carcinoma (MTC) invariably have an activating mutation in RET in their germline DNA. Activating mutations in RET are also present in the tumor DNA of up to 50% of sporadic MTC patients with no familial history of thyroid cancer. MTC may metastasize to lymph nodes or other organs before it is ever diagnosed. Additionally, MTC does not take up radioactive iodine, which is commonly used to treat other types of thyroid cancers and to diagnose metastases. As a result, MTC is more difficult to treat than other thyroid cancers.

So far, there are no approved therapies for MTC; however, common treatments for MTC include surgery to remove malignant tissue, radiation therapy, and chemotherapy, all of which are associated with potential side effects, some of which may be long-term.

During 2008 annual meeting of the American Society of Clinical Oncology (ASCO) safety and clinical activity data were presented from an ongoing phase 1 trial of XL184 in 69 patients with various solid tumors, including 17 MTC patients evaluable for response. These data showed a disease control rate (percentage of patients with partial responses or prolonged stable disease greater than 3 months) of 100% in the evaluable MTC patients, with 53% of those patients (9 of 17) experiencing partial responses. In this trial, the median duration of partial responses and stable disease for patients with MTC had not yet been reached. Most of the MTC patients in the trial had previously failed other treatments, including tyrosine kinase inhibitors with anti-RET activity, including vandetanib (AstraZeneca, Zactima™, also known as ZD6474), sorafenib (Nexavar®, Bayer/Onyx), or motesanib (Amgen/Takeda) chemotherapeutic agents, immunotherapy, radioactive iodine, and radiotherapy. Patients are now recruited to participate in new and ongoing trials.

ASCO 2009 Abstracts

• De Groot JF, Prados M, Urquhart T, Robertson S, et al. A phase II study of XL184 in patients (pts) with progressive glioblastoma multiforme (GBM) in first or second relapse. J Clin Oncol 27:15s, 2009 (suppl; abstr 2047).
• Sorensen AG, Jenning D, Wang M, Andronesi O, Chen P, et al. Use of neurovascular imaging in GBM patients (pts) to quantify early physiologic changes after treatment with XL184, an inhibitor of multiple receptor tyrosine kinases: Results from a phase II study. J Clin Oncol 27:15s, 2009 (suppl; abstr 2048)\DePrimo S, Wu B, Huang S, Bautista R, Cancilla B, et al. Correlative tumor molecular profiling and plasma biomarker analysis in a phase II study of XL184 in patients with progressive or recurrent glioblastoma multiforme (GBM). J Clin Oncol 27:15s, 2009 (suppl; abstr 2049).
• Fox E, Widemann BC, Whitcomb PO, Aikin A, Dombi E, et al. Phase I/II trial of vandetanib in children and adolescents with hereditary medullary thyroid carcinoma. J Clin Oncol 27:15s, 2009 (suppl; abstr 10014).
• Carr L, Goulart B, Martins R, Keith E, Kell E, et al. Phase II trial of continuous dosing of sunitinib in advanced, FDG-PET avid, medullary thyroid carcinoma (MTC) and well-differentiated thyroid cancer (WDTC). J Clin Oncol 27:15s, 2009 (suppl; abstr 6056)

ASCO 2008 abstracts:

• Salgia R, Sherman S, Hong DS, Ng CS, Frye J, A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 3522). See Poster from EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics, in October 2008 in Geneva, Switzerland.

ASCO 2008 presentations:

• Ravi Salgia, MD, PhD Professor of Medicine, Director, Thoracic Oncology Research Program, University of Chicago Medical Center (Presenter). A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC). Abstract No: 3522

Clinical trials:

• Study of XL184 in Adults With Glioblastoma Multiforme (recruiting). The purpose of this study is to evaluate the objective response rate and 6-month progression-free survival rate of XL184 in subjects with recurrent or progressive glioblastoma multiforme. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. Contact: Exelixis Contact Line 1-866-939-4041.
• Phase III Efficacy Study of XL184 in Adults With Medullary Thyroid Cancer (recruiting). The purpose of this research study is to evaluate the progression-free survival (PFS) with XL184 as compared with placebo (an inactive substance) in subjects with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). Subjects will be randomized to receive XL184 or placebo in a 2:1 ratio. XL184 is an investigational drug that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. Contact: Exelixis Contact Line 1-866-939-4041 Stanford University School of Medicine, Primary contact: Ruth Lira, (650) 723-1367)
• Study of XL184 in Adults With Advanced Malignancies (ongoing, not recruiting) The purpose of this study is to determine the best and safest dose of XL184 administered orally. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration. To determine the highest safe dose, subjects will receive different amounts of the drug. The first group of subjects will receive the lowest dose of XL184. As long as no medically unacceptable side effects are noted, the dose will be increased for the next group. When the maximum tolerated dose (MTD) is reached, at least 20 subjects with Medullary Thyroid Cancer (MTC) will be enrolled to evaluate the effect of XL184 in this population.
• Study of XL184 in Adults With Glioblastoma Multiforme (recruiting) The purpose of this study is to evaluate the objective response rate and 6-month progression-free survival rate of XL184 in subjects with recurrent or progressive glioblastoma multiforme. XL184 is a new chemical entity that inhibits VEGFR2, MET and RET, kinases implicated in tumor formation, growth and migration.

Also read PubMed Abstracts:

• He H, Nilsson CL, Emmett MR, Ji Y, Marshall AG, Kroes RA, Moskal JR, Colman H, Lang FF, Conrad CA. Polar lipid remodeling and increased sulfatide expression are associated with the glioma therapeutic candidates, wild type p53 elevation and the topoisomerase-1 inhibitor, Irinotecan. Glycoconj J. 2009 Jun 26. [Epub ahead of print]
• Hottinger AF, Yoon H, Deangelis LM, Abrey LE. Neurological outcome of long-term glioblastoma survivors. J Neurooncol. 2009 Jun 26. [Epub ahead of print]
• Wong ML, Prawira A, Kaye AH, Hovens CM. Tumour angiogenesis: Its mechanism and therapeutic implications in malignant gliomas. J Clin Neurosci. 2009 Jun 23. [Epub ahead of print]
• Adamson C, Kanu OO, Mehta AI, Di C, Lin N, Mattox AK, Bigner DD. Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin Investig Drugs. 2009 Jun 26. [Epub ahead of print]
• Ye L, Santarpia L, Gagel RF. Targeted Therapy for Endocrine Cancer: The Medullary Thyroid Carcinoma Paradigm. Endocr Pract. 2009 Jun 22:1-24. [Epub ahead of print]
• Porterfield JR, Cassivi SD, Wigle DA, Shen KR, Nichols FC, Grant CS, Allen MS, Deschamps C. Thoracic metastasectomy for thyroid malignancies. Eur J Cardiothorac Surg. 2009 Jul;36(1):155-8.
• Cavalheiro BG, Junqueira CR, Brandão LG. Expression of membrane type 1 matrix metalloproteinase in medullary thyroid carcinoma: Prognostic implications. Head Neck. 2009 Jun 17. [Epub ahead of print]
• Kim JM, Chung KW, Kim SW, Choi SH, Min HS, et al. Spurious hypercalcitoninemia in patients with nodular thyroid disease induced by heterophilic antibodies. Head Neck. 2009 Jun 17. [Epub ahead of print]
• Machens A, Lorenz K, Dralle H. Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. J Intern Med. 2009 Jul;266(1):114-25.
• Santarpia L, Ye L, Gagel RF. Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma. J Intern Med. 2009 Jul;266(1):99-113.

More information (General):

• Cuccuru G, Lanzi C, Cassinelli G, Pratesi G, Tortoreto M, et al. Cellular Effects and Antitumor Activity of RET Inhibitor RPI-1 on MEN2A-Associated Medullary Thyroid Carcinoma. JNCI Journal of the National Cancer Institute 2004 96(13):1006-1014. Full Text Article.
• Glioblastoma Multiforme (GBM)
• Carcinomas of the Central and Peripheral nervous system: Glioblastoma multiforme (GBM) - overview.
• Medullary thyroid cancer (MTC)
• New York Thyroid Center (Columbia University Medical Center, Department of Surgery, New York, NY.): Medullary Thyroid Cancer.

Illustrations courtesy of the American Society of Clinical Oncology

New Drug Shows Promise in the Treatment of Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma

One of the largest prospective clinical trials in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), the PROPEL trial (Pralatrexate in patients with Relapsed Or refractory PEripheral T-cell Lymphoma), found that the investigational chemotherapy agent pralatrexate produces CR (complete responses or disappearance of all signs of cancer) in patients who had previously failed an average of three treatment regimens, including an autologous stem cell transplant for some patients.

Peripheral T-cell lymphoma or PTCL is a biologically diverse group of blood cancers that account for 1 in 100 cases of non-Hodgkin's lymphoma (NHL) in the United States. The disease is more common in adults than in children, and it affects slightly more men than women. The average five-year survival is approximately 25 percent.

Dr. Owen A. O'Connor MD, PhD, the Principal Investigator of the PROPEL trial and the Director of the Lymphoid Development and Malignancy Program and Chief of the Lymphoma Service at the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Hospital/Columbia University Medical Center, and Associate Professor of Medicine at Columbia University College of Physicians and Surgeons, who presented the results of the trial during the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, explained: ‘Presently, there are no FDA-approved treatments for patients with PTCL, either in the first-line or relapsed or refractory setting. This underscores the need for new therapies to treat this challenging disease. Pralatrexate has the potential to play a clinically meaningful role in the treatment of these patients.’

Pralatrexate, a novel targeted antifolate, is in the same class of drugs as methotrexate, a chemotherapy drug that has been available for several decades, but it is far more potent. The new drug is a designed to accumulate in high concentrations in tumor cells, inhibiting DNA synthesis.

Based on preclinical studies, pralatrexate is thought to selectively enter cells expressing RFC-1, a protein that is over expressed on cancer cells compared to normal cells. Once inside cancer cells, pralatrexate is efficiently polyglutamylated, which leads to high intracellular drug retention. Polyglutamylated pralatrexate essentially becomes ‘trapped’ inside cancer cells, making it less susceptible to efflux-based drug resistance. Acting on the folate pathway by ‘mimicking folic acid,’ pralatrexate interferes with DNA synthesis and triggers cancer cell death. Researchers believe that pralatrexate has the potential to be delivered as a single agent or in combination therapy regimens.

A total of 115 patients were enrolled into this phase II, single-arm, non-randomized, open-label study and received weekly intraveneous infusions of pralatrexate (30 mg/m2) for seven weeks. All patients also received vitamin B12 and folic acid throughout the study in order to prevent potential side effects of the pralatrexate. The primary endpoint of the study was the objective response rate (ORR), including all patients who had some response of their disease to therapy. Secondary endpoints included duration of response, progression-free survival, and overall survival.

Interim data of the first 65 evaluable patients showed that 29 percent of patients responded to treatment, with 11 percent experiencing a complete response and 18 percent experiencing a partial response. The most common severe (grade 3 and 4) side effects associated with pralatrexate were thrombocytopenia (31 percent), mucositis (14 percent), anemia (12 percent), and neutropenia (11 percent).

Orphan drug status and Fast-track approval
This is the first promising treatment to be developed in years and based on the promising results of this and previous studies the US Food and Drug Administration granting orphan drug statusand a fast-track approval process to pralatrexate for T-cell lymphoma.

Commenting on the PROPEL trial, Dr Owen O'Connor concluded: ‘This [ ..] trial demonstrate that pralatrexate produced durable, complete responses in heavily pre-treated patients.’

Allos Therapeutics Inc., the maker of the drug, will submit a NDA for pralatrexate for the treatment of patients with relapsed or refractory PTCL to the FDA once the Phase II data has been fully reviewed. This is expected sometime in the first half of 2009.

Pralatrexate was developed by a team of researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) and the Southern Research Institute, including Dr. O'Connor, while at MSKCC. Dr. O'Connor and his colleagues identified the unique activity of pralatrexate in patients with lymphoma. Dr. O'Connor has continued to study pralatrexate at NewYork-Presbyterian/Columbia, now focusing on determining how the drug works in T-cell lymphoma, and on how best to combine it with other drugs to improve the treatment of patient with hematologic cancers.

‘We are very excited by these results. If approved, the launch of pralatrexate will represent a first to market opportunity for Allos,' said Paul L. Berns, President and Chief Executive Officer of Allos. 'And we would like to extend our appreciation to the patients who participated in the PROPEL trial, as well as to their families, for helping us to identify a potential new treatment option for this disease.’

Other Pralatrexate studies
During the 50th Annual Meeting of the American Society of Hematology results from two other pralatrexate studies were presented as posters. One poster reported interim data from a Phase 1 trial of pralatrexate as a single agent in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL). The second poster reports interim data from a Phase 1/2a trial of pralatrexate in combination with gemcitabine in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma.

The first poster (Pralatrexate is Active in Cutaneous T-Cell Lymphoma: Preliminary Results of a Multi-center Dose-finding Trial; abstract 1569) presented interim data from an ongoing Phase 1 trial of pralatrexate in patients with relapsed or refractory CTCL.

Dr Steven Horwitz, M.D., Assistant Attending Physician, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, the Principal Investigator of the study and his team presented the data which included 24 patients, with 22 evaluable patients who completed at least one cycle of treatment at doses ranging from 10-30 mg/m(2) as part of a weekly schedule for two or three weeks followed by one week of rest. Responses were observed in 12 of 22 evaluable patients (55%), including one complete response and 11 partial responses. Patients received a median of four prior systemic therapies. The most common adverse event was mucosal inflammation, with Grade 1/2 mucosal inflammation observed in 11 of 24 patients and Grade 3 mucosal inflammation observed in 4 of 24 patients. There was no Grade 4 mucosal inflammation and no thrombocytopenia above Grade 1. Up to 56 evaluable patients will be enrolled in the study with the objective of determining the optimal dose and schedule for pralatrexate in this patient population.

The second poster (A Phase 1/2a Open-label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies’; abstract 1570) presented interim data from an ongoing Phase 1/2a open-label, multi-center study of pralatrexate in combination with gemcitabine in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma. This data included 27 patients, 22 of whom were evaluable for response. Patients have been enrolled in eight cohorts with different doses and schedules. Partial responses were observed in 6 of 22 evaluable patients, including five patients on a sequential dosing schedule and one patient on a same-day dosing schedule. Patients received a median of three prior systemic regimens. The most common adverse event was thrombocytopenia, with Grade 3 observed in four patients and Grade 4 observed in seven patients. The maximum tolerated dose for the sequential dosing schedule was established as 10 mg/m(2) of pralatrexate followed by 300 mg/m(2) of gemcitabine, once every two weeks. Enrollment in the trial is ongoing to determine the maximum tolerated dose for the same same-day dosing schedule.

For more information, read

• Owen A. O’Connor OA, Pro B, Pinter-Brown L, Popplewell L, et al. PROPEL: A Multi-Center Phase 2 Open-Label Study of Pralatrexate (PDX) with Vitamin B12 and Folic Acid Supplementation in Patients with Replapsed or Refractory Peripheral T-Cell Lymphoma. (Oral Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #261

Other abstracts:

• Horwitz SM, Duvic M,Kim Y,Zain JM, et al. Pralatrexate (PDX) IS Active in Cutaneous T-Cell Lymphoma: Preliminary Results of a Multi-Center Dose-Finding Trial. (Poster Session) Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #1569
• Horwitz SM, Vose JM, Advani R, Sankhala K, et el. A Phase 1/2A Open-Label Study of Pralatrexate and Gemcitabine in Patients with Relapsed or Refractory Lymphoproliferative Malignancies. (Poster Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #1570

Also read PubMed Abstracts:

• Toner LE, Vrhovac R, Smith EA, et al. The schedule-dependent effects of the novel antifolatepralatrexate and gemcitabine are superior to methotrexate and cytarabine in models of human non-Hodgkin's lymphoma. Clin Cancer Res 2006;12(3):924-932.
• O'Connor OA, Hamlin PA, Gerecitano J, et al. Pralatrexate (PDX) produces durable complete remissions in patients with chemotherapy resistant precursor and peripheral T-cell lymphomas: results of the MSKCC Phase I/II experience. (Abstract 400). Presented at The American Society of Hematology's 48th Annual Meeting. Blood 2006;108(11):122a-3a.
• O'Connor O, Hamlin P, Neylon E, et al. Early phase experience with pralatrexate (10-propargyl-10-deazaaminopterin [PDX]), a novel antifolate with high affinity for the reduced folate carrier, in patients with chemotherapy refractory lymphoproliferative malignancies. (Abstract 461). Eur J Cancer 2006;4(Suppl 12):141.
• O'Connor OA. Pralatrexate: an emerging new agent with activity in T-cell lymphomas. Curr Opin Oncol 2006;18(6):591-597.
• Krug LM, Heelan RT, Kris MG, et al. Phase II Trial of Pralatrexate (10-Propargyl-10-deazaaminopterin, PDX) in Patients with Unresectable Malignant Pleural Mesothelioma. J Thorac Oncol 2007;2(4):317-320.
• Azzoli CG, Krug LM, Gomez J, et al. A phase 1 study of pralatrexate in combination withPaclitaxel or docetaxel in patients with advanced solid tumors. Clin Cancer Res2007;13(9):2692-8.
• O'Connor OA, Hamlin PA, Portlock C, et al. Pralatrexate, a novel class of antifol with highaffinity for the reduced folate carrier-type 1, produces marked complete and durableremissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. British Journal of Haematology 2007;139(3):425-428.
• Izbicka E, Diaz A, Campos D, et al. Differential activity and potential mechanism of action of pralatrexate (PDX) methotrexate, and pemetrexed (Alimta) in human cancer models in vivo and in vitro (abstract A135). Proceedings of AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications October 22-26, 2007:108.
• James LP, Azzoli CG, Krug LM, et al. Phase I study of the antifolate pralatrexate given with vitamin B12 and folic acid supplementation in patients with advanced non-small cell lung cancer (NSCLC) (abstract A143). Proceedings of AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications October 22-26, 2007:111.
• O'Connor OA, Hamlin PA, Portlock C, et al. A Phase '2-1-2' study of two different doses and schedules of pralatrexate, a high affinity substrate for the reduced folate carrier (RFC-1), in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies (abstract C85). Proceedings of AACR-NCI-EORTC International Conference Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications October 22- 26, 2007:283.
• Leitenberger JJ, Berthelot CN, Polder KD, et al. CD4+ CD56+ hematodermic/plasmacytoid dendritic cell tumor with response to pralatrexate. J Am Acad Dermatol 2008;58(3):480-4.
• Damaj BB. In vitro and in vivo effects of pralatrexate (PDX) on the survival and growth of the A549 non-small cell lung cancer cell line. (Abstract 2298). American Association for Cancer Research (AACR) 2008 Annual Meeting; 2008 14-18 Apr 2008 San Diego, CA; 2008.
• O'Connor OA-, Hamlin P, Moskowitz C, et al. Pralatrexate (PDX) produces a high and durable complete response rate in patients with chemotherapy resistant T-cell lymphomas. (Abstract 138). Ann Oncol (ESMO Conference Proceedings) 2008;19(4):iv128.
• Horwitz S, Duvic M, Kim Y, et al. Low dose pralatrexate (PDX) is active in cutaneous T-celllymphoma: Preliminary results of a multi-center dosse finding trial. (abstract 261). Ann Oncol (ESMO Conference Proceedings) 2008;19(4):iv162.
  O'Connor OA. New drugs for the treatment of T-cell lymphoma. (abstract 134). Ann Oncol (ESMO Conference Proceedings) 2008;19(4):iv127.
• Molina JR. Pralatrexate, a dihydrofolate reductase inhibitor for the potential treatment ofseveral malignancies. IDrugs 2008;11(7):508-21
  

Clinical trials:

Study of Pralatrexate With Vitamin B12 and Folic Acid in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma. Allos Therapeutics, ClinicalTrials.gov Identifier: NCT00364923