Cancer Treatment Today » Research in Oncology

TH-302

M Levin, MD — Tue, 18 Sep 2012 20:46:48 +0000

New drugs in development are initially referred to by letters and number. TH-302 is such a drug that is in clinical development. It is unique in that it is activated under hypoxic conditions, meaning that it works best in tissues that are not getting enough oxygen. Many cancers in the body outgrow their blood supply and are starved for oxygen. TH-302 exploits the activation of a nitroazole prodrug under hypoxic conditions by a process that generate a radical anion prodrug (RP). In the presence of oxygen (normoxia) the radical anion prodrug reacts rapidly with oxygen to generate the original prodrug and superoxide (SO). Under the low oxygen conditions of the hypoxic zones in tumors, however, the radical anion prodrug undergoes further irreversible reductions and goes thorugh other chemical steps, releasing the active drug and an azole derivative (AZ).

It is a promising drug. In March of 2012, European Commission has granted Orphan Drug Designation for TH-302. An international, randomized, controlled Phase 3 clinical trial was initiated in September 2011, and is being conducted in partnership with the Sarcoma Alliance for Research through Collaboration (SARC). The trial is designed to enroll 450 patients with metastatic or locally advanced unresectable soft tissue sarcoma.

With data from over 500 patients to date, TH-302 is currently being evaluated in a controlled Phase 2 clinical trial in patients with advanced pancreatic cancer. Results of phase I trials have been encouraging. University of Texas at San Antonio initiated a clinical trial of TH-302 in combination with bevacizumab in patients with recurrent high grade astrocytoma including glioblastoma.

Until more information is published and assessed, TH-302 remains an investigational agent but one with great promise.

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BMS-936558 (MDX-1106)

M Levin, MD — Fri, 24 Aug 2012 13:32:54 +0000

BMS-936558 is an antibody against PD-1, a protein involved in repressing the immune system. It activates the immune system and enables it to fight tumors. A well established approved drug, Yervoy blocks CTLA-4, another inhibitory protein expressed on immune cells and Yervoy and BMS-936558 belong to the same class of drugs. Both generate an anti-cancer immune response.

This very promising agent is in several trials for various diagnoses. For example, for renal cancer there is the Phase II trial of BMS-936558 (MDX-1106) in Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Tx and CA209-009 biolarker trial. There are also combination studies with various malignancies. It is a promising agent but still investigational.

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IMC-A12

M Levin, MD — Mon, 20 Aug 2012 20:07:45 +0000

It has gradually become clear that insight is involved in the cancer growth and regulation. Insulin Growth Factor Receptor(IGFR) is important in this process. IGF-IR blockaded by IMC-A12 results in rapid and profound growth inhibition of cancers of the breast, lung, colon, and pancreas, and many other cancers. Although promising single-agent activity has been observed, the most impressive effects of targeting the IGF-IR with IMC-A12 have been noted when this agent was combined with cytotoxic agents or other targeted therapeutics. So far, only a few preliminary human studies had been published, including in Ewing sarcoma. This drug may also have applications in auto-immune disorders. It remains an experimental drug.

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Anti-PD-1 Human Monoclonal Antibody MDX-1106 – pro

M Levin, MD — Mon, 20 Aug 2012 20:02:34 +0000

A now well established approach to cancer immunotherapy is using antibodies that are directed against substance (antigen) on a cancer cell surface. A fully human monoclonal antibody directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity. Put simply, it activates T cells and produces cell-mediated immune responses against tumor cells or pathogens. In vitro cytotoxicity and in vivo inhibition of growth can be restored by anti-PD-L1 antibodies or by genetic ablation of PD-1. First use in humans was published by Berger et al in 2008 and showed that a single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies. A more recent report in 2012 in the prestigious New England Journal of Medicine in 296 patients found cumulative response rates (all doses) of 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). On the other hand, Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. Ongoing studies should bring more clarity to how this agent can contribute to treating cancer.
Raanan Berger et al, Phase I Safety and Pharmacokinetic Study of CT-011, a Humanized Antibody Interacting with PD-1, in Patients with Advanced Hematologic Malignancies Clinical Cancer Research 14, 3044-3051, May 15, 2008.

Mohamed Elrefaei, Chris A. R. Baker, Norman G. Jones, David R. Bangsberg and Huyen Cao. Presence of Suppressor HIV-Specific CD8+ T Cells Is Associated with Increased PD-1 Expression on Effector CD8+ T Cells. The Journal of Immunology, 2008, 180: 7757-7763

Suzanne L. Topalian, M.D., F. Stephen Hodi, M.D., Julie R. Brahmer, M.D., Scott N. Gettinger, M.D., David C. Smith, M.D., David F. McDermott, M.D., John D. Powderly, M.D., Richard D. Carvajal, M.D., Jeffrey A. Sosman, M.D., Michael B. Atkins, M.D., Philip D. Leming, M.D., David R. Spigel, M.D., Scott J. Antonia, M.D., Ph.D., Leora Horn, M.D., Charles G. Drake, M.D., Ph.D., Drew M. Pardoll, M.D., Ph.D., Lieping Chen, M.D., Ph.D., William H. Sharfman, M.D., Robert A. Anders, M.D., Ph.D., Janis M. Taube, M.D., Tracee L. McMiller, M.S., Haiying Xu, B.A., Alan J. Korman, Ph.D., Maria Jure-Kunkel, Ph.D., Shruti Agrawal, Ph.D., Daniel McDonald, M.B.A., Georgia D. Kollia, Ph.D., Ashok Gupta, M.D., Ph.D., Jon M. Wigginton, M.D., and Mario Sznol, M.D.Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer N Engl J Med 2012; 366:2443-2454June 28, 2012

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Anti-PD-1 Human Monoclonal Antibody MDX-1106

M Levin, MD — Mon, 20 Aug 2012 19:59:10 +0000

A now well established approach to cancer immunotherapy is using antibodies that are directed against substance (antigen) on a cancer cell surface. A monoclonal antibody is a molecule that attaches to the cancer cell and causes changes within it or in immune cells around it, or it can carry a toxin or a radioactive material to the cancer cell. A fully human monoclonal antibody directed against the human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) it activates the immune T cells and induces cell-mediated immune responses against tumor. These antibodies can restore the immune efforts to kill cancer cells or to inhibit their growth. First use in humans was published by Berger et al in 2008 and showed that a single administration is safe and well tolerated in patients with advanced hematologic malignancies. A more recent report in 2012 in the prestigious New England Journal of Medicine in 296 patients found cumulative response rates (all doses) of 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). On the other hand, Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. Ongoing studies should bring more clarity to how this agent can contribute to treating cancer.

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Research in GE Junction Gastric Cancer

M Levin, MD — Mon, 13 Aug 2012 13:58:09 +0000

Gatrointestinal junction(GE) cancer (where esophagus and stomach meet) is a type of cancer that has similarities to both gastric and esophageal cancer. Since GE Junctions cancers that express HER turned out to respond well to Herceptin, there is great interest in targeting other molecules, such as the epidermal growth factor receptor, vascular endothelial growth factor receptor, and P13k/Akt/mTor pathway, as well as the insulin-like growth factor receptor, c-Met pathways, fibroblast growth factor receptor, and other pathways in this type of cancer. Much remains to be done before clinical therapies based on this concept become available and proven but there is much research activity. One study looking at a C-MET inhibitor is: MET111643 ,A Phase 2 Study of GSK1363089 (XL880) Administered Orally to Subjects with Metastatic Gastric Cancer.

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