Palifosfamide belongs to a group of chemotherapy drugs called alkylating agents, which halt tumor growth by binding to cancer cell DNA and interfering with its function. Alkylating agents have demonstrated activity in a wide range of solid tumors and hematologic cancer. Palifosfamide was rationally designed to confer similar efficacy compared to in-class agents, with significantly improved tolerability.

Palifosfamide has shown promise as a treatment for cancers with increased levels of aldehyde dehydrogenase (ALDH), an enzyme though to confer cancer stem cell-like activity and therefore resistance to treatment, particularly treatment with alkylating agents. High levels of ALDH have also been associated with worse prognoses and poor clinical outcomes in cancer patients.

Clinical Status

Palifosfamide is currently being investigated in two Phase 3 studies.

Picasso 3 is an ongoing study evaluating palifosfamide in combination with doxorubicin for the front-line treatment of patients with metastatic soft tissue sarcoma (STS). PICASSO 3 has completed enrollment of approximately 424 patients at study sites worldwide. The primary endpoint of the study for accelerated approval is progression-free survival (PFS), the length of time a patient’s cancer does not grow or spread. The Company will announce topline results from this trial during the last week of March 2013.

ZIOPHARM is also currently enrolling patients in an adaptive Phase 3 trial, MATISSE, evaluating palifosfamide in combination with carboplatin and etoposide (PaCE) as a treatment for patients with extensive-stage small cell lung cancer (SCLC). The primary endpoint of the study is overall survival (OS), with PFS as a secondary endpoint.

ZIOPHARM is also developing an oral form of palifosfamide, for which an investigational new drug application has been accepted by the Food and Drug Administration.

For more information about the MATISSE and PICASSO 3 studies, as well as other palifosfamide trials, please visit clinicaltrials.gov.

About Soft Tissue Sarcomas (STS)

Soft tissue sarcomas (STS) are cancers of the body’s soft tissues, which connect, support and surround other body structures and include cartilage, muscle, fat, nerves, blood vessels as well as other connective tissues. While STS can occur anywhere in the body, the extremities, including the head, neck, arms and legs, are the most commonly affected parts of the body, accounting for approximately 50% of this type of cancer.

Worldwide, the prevalence of sarcoma is estimated at over 100,000 cases, with approximately 23,000 individuals being treated in the United States and Europe for front-line metastatic disease. Metastatic STS, which refers to the stage of disease where cancer has spread throughout the body, is deadly. Patients diagnosed with metastatic disease have median survival rates of approximately 8 to 12 months. No new therapies have been approved for front-line use in sarcoma in more than 20 years.

About Small Cell Lung Cancer (SCLC)

SCLC is almost exclusively associated with cigarette smoking and the majority of patients with extensive disease are treated front-line, but relapse with a very high mortality within one year. According to the American Cancer Society, approximately 15 percent of lung cancers are SCLC, or an incidence of approximately 33,400 patients yearly in the U.S. There is expected to be a substantially growing incidence worldwide, particularly in China, where the annual incidence is expected to grow to over 150,000 cases per year.

IL-12 Program

One approach to the treatment of cancer is to use the patient’s immune system to detect and destroy tumor cells. Interleukin-12 (IL-12) is a naturally occurring anticancer cytokine central to the initiation and regulation of cellular anti-cancer immune responses. Until now, the use of IL-12 as a cancer therapeutic has been limited, due to toxicities observed with its use as a recombinant protein.

ZIOPHARM is developing DNA therapeutics capable of producing IL-12 on demand within the body. For these DNA therapeutics, the production of IL-12 is controlled by an on/off biologic switch that is activated by an oral activator ligand called the RheoSwitch Therapeutic System®. RheoSwitch regulates the production of IL-12 expression to achieve a clinically active level of the therapy while limiting the broader system effects of the protein’s over-availability within the body.

• Ad-IL-12

  
  

  Ad-IL-12 is a DNA therapeutic which employs an adenoviral vector to deliver, directly into the patient’s cells, a gene which expresses IL-12. Within the cell, production of IL-12 is tightly regulated by the RheoSwitch Therapeutic System®. The safety and tolerability of Ad-IL-12 is currently being tested in a Phase 1 study in patients with unresectable Stage III or IV melanoma.

  
  

• DC-IL-12

  
  

  DC-IL-12 employs autologous (obtained from the patient) dendritic cells (immune cells) transduced with a gene which expresses IL-12. These dendritic cells are then returned to the patient, where production of IL-12 is tightly regulated by the RheoSwitch Therapeutic System®.

  
  

  A Phase 1b study testing DC-IL-12 as a treatment for patients with advanced melanoma found treatment to be well tolerated, and demonstrated a disease control rate (the percentage of patients who demonstrate a response to treatment) of 50%. Additionally, the study showed a correlation between immune response and positive patient outcomes.

Clinical Status

ZIOPHARM is currently testing AD-IL-12 and DC-IL-12 in Phase 1 trials in patients with advanced melanoma. For more information, please click visit clinicaltrials.gov.

Indibulin is a novel tubulin binding agent that interrupts the assembly of microtubules – the structural components of cell cytoskeletons, or scaffolding – to treat of a variety of solid cancers. Indibulin belongs to a class of agents that includes some of the most widely effective anti-cancer therapeutics available today, namely taxanes (paclitaxel and docetaxel) and Vinca alkaloids. Indibulin’s binding site is distinct from other in-class agents and is believed to address the challenge of neurotoxicity observed with other compounds. Preclinical studies showed a lack of neurotoxicity associated with indibulin, and results from a Phase 1 study in patients with advanced solid tumors found indibulin to be well tolerated.

Clinical Status

ZIOPHARM is currently testing indibulin in a Phase 1/2 trial in patients with metastatic breast cancer. For more information, please click visit clinicaltrials.gov.

About Metastatic Breast Cancer

Metastatic breast cancer, also known as Stage IV or advanced breast cancer, is the stage at which tumors have spread to other areas of the body. Approximately 49,000 new patients are diagnosed each year in the United States, approximately 25% of those with early-stage breast cancer develop the advanced, metastatic form of the disease. Currently, metastatic breast cancer is incurable, and only about 20% of people with this type of cancer are still alive five years after diagnosis.

Darinaparsin is a novel mitochondrial- and hedgehog-targeted agent (organic arsenic). Arsenic has been used to treat cancer for more than 2,000 years. Concepts of modern chemotherapy derive from early 20th century studies of arsenic when it was a mainstay of cancer chemotherapy. Unlike inorganic arsenic, preclinical and clinical studies of darinaparsin show little serious toxicities associated with organic arsenic. Further, aberrant hedgehog has been implicated in a number of cancers due to its association with the transformation of adult stem cells into cancer stem cells, a key target of broadly acting anti-cancer agents.

Clinical Status

Clinical studies investigating the anti-cancer activity of darinaparsin are currently ongoing in partnership with Solasia Pharma K.K.