INNO-206

Anthracyclines are a class of drugs that are among the most commonly used agents in the treatment of cancer. Doxorubicin, the first anthracycline to gain approval, has demonstrated efficacy in a wide variety of cancers including breast cancer, lung cancer, sarcomas, and lymphomas. However, doxorubicin is associated with side effects such as myelosuppression, gastrointestinal disorders, mucositis, stomatitis, cumulative cardiotoxicity and extravasation.

INNO-206 (formerly DOXO-EMCH) is a tumor-targeted doxorubicin conjugate. Specifically, it is the (6-Maleimidocaproyl) hydrazone of doxorubicin. Essentially, this chemical name describes doxorubicin (DOXO) attached to an acid sensitive linker (EMCH). We believe this novel agent has attributes that improve on native doxorubicin including reduction of adverse events, improvement in efficacy and the ability to reach the tumor more quickly. CytRx holds the exclusive worldwide rights to INNO-206.

The proposed mechanism of action is as follows:

• After administration, INNO-206 rapidly binds endogenous circulating albumin through the EMCH linker
• Circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including heart, bone marrow and gastrointestinal tract
• Once albumin-bound INNO-206 reaches the tumor, the acidic environment of the tumor causes cleavage of the acid sensitive linker
• Free doxorubicin is released at the site of the tumor

In preclinical models, INNO-206 was superior to doxorubicin with regard to ability to increase dosing, antitumor efficacy and safety. A Phase I study of INNO-206 that demonstrated safety and objective clinical responses in a variety of tumor types was completed in the beginning of 2006 and presented at the March 2006 Krebskongress meeting in Berlin. In this study, doses were administered at up to 4 times the standard dosing of doxorubicin without an increase in observed side effects over historically seen levels. Objective clinical responses were seen in patients with sarcoma, breast, and lung cancers.

CytRx completed a Phase 1b/2 clinical trial with INNO-206 in patients with advanced solid tumors, and will be presenting data from that trial at the ASCO conference in Chicago, Illinois in July, CytRx also has initiated a Phase 2b international clinical trial in patients with soft tissue sarcomas and recently initiated a Phase 2 trial for advanced pancreatic ductual adenocarcinomas. Of six patients who have completed four cycles with INNO-206 at the maximum tolerated dose in the Phase 1b/2 clinical trial, two patients have exhibited a partial tumor response (greater than 30% tumor shrinkage) and four patients have stable disease. Unexpectedly, a large, painful oral sarcoma that caused difficulty eating in one patient was greatly reduced following a single INNO-206 treatment. Common side effects reported to date from the Phase 1b/2 trial include low neutrophil (white blood cell) and platelet counts, minor mouth ulcers and mild nausea, which are expected side effects of doxorubicin.

In December 2011, CytRx initiated its international Phase 2b clinical trial to evaluate the preliminary efficacy and safety of INNO-206 as a first-line therapy in patients with soft tissue sarcoma who are ineligible for surgery. The Phase 2b clinical trial will provide the first direct clinical trial comparison of INNO-206 with native doxorubicin, which is dose-limited due to toxicity, as a first-line therapy.

The Phase 2b clinical trial with INNO-206 in patients with soft tissue sarcomas is an international trial under the direction of world-renowned expert in soft tissue sarcoma treatment Sant P. Chawla, M.D., F.R.A.C.P., Director of the Sarcoma Oncology Center in Santa Monica, Calif. Dr. Chawla also is acting as principal investigator for the Company's ongoing Phase 1b/2 clinical trial with INNO-206.

The Phase 2b clinical trial's primary objectives are to measure the progression-free survival, tumor response and overall survival of patients with advanced soft tissue sarcomas treated with INNO-206. This clinical trial also will assess the safety of INNO-206 compared to doxorubicin in this patient population through a number of indicators, including the frequency and severity of adverse events. The open-label trial will enroll 105 patients with metastatic, locally advanced or unresectable soft tissue sarcoma at approximately 30 study centers in the U.S., Hungary, Romania, Ukraine, Russia, India and Australia. Patients will be randomized into two groups with twice as many receiving INNO-206 as doxorubicin. Patients will be treated intravenously once every 21 days for up to eight consecutive cycles with INNO-206 administered drug at 350 mg/m2 (260 mg/m2 doxorubicin equivalents) and doxorubicin administered at 75 mg/m2 .

The Phase 2 clinical trial with INNO-206 in patients with pancreatic cancer will be conducted under the direction of Daniel Von Hoff, M.D., Physician-in-Chief and Distinguished Professor at the Translational Genomics Research Institute (TGEN) in Phoenix, and Director of the Cancer Center and Professor of Medicine at the University of Arizona. Dr. Von Hoff was a former member of the National Cancer Advisory Board and the FDA's Oncology Drug Advisory Committee, and former President of the American Association for Cancer Research. He currently heads the Pancreatic Cancer Dream Team, one of five Stand Up 2 Cancer teams comprised of renowned scientists working collaboratively on innovation, acceleration, targeted therapy and translational research in several major cancers.

That open-label Phase 2 clinical trial will enroll up to 27 patients at multiple clinical sites in the U.S. Trial patients will be treated with intravenously administered INNO-206 once every three weeks for up to eight cycles at a dose of 350 mg/m2 (the maximum tolerated dose established in two Phase 1b clinical trials, including the Phase 1b/2 trial currently being completed at the Sarcoma Oncology Center in Santa Monica, California). Trial patients will be evaluated for objective tumor response (measured by Response Evaluation Criteria in Solid Tumors or RECIST 1.1 criteria), with secondary endpoints including disease control (complete and partial responses, and stable disease at four months), as well as progression-free and overall survival.

INNO-206 has been granted orphan drug designation by the Office of Orphan Product Development of the U.S. Food and Drug Administration (FDA) for the treatment of patients with soft tissue sarcomas and pancreatic cancer.

Human Clinical Trials

A Safety and Maximum Tolerated Dose (MTD) Study of INNO-206 in Subjects With Advanced Solid Tumors is ongoing.

Click on the following link for current clinical trial information and eligibility criteria: clinicaltrials.gov