The first patients have been dosed in a new Phase I dose-escalation clinical study to evaluate NKTR-102, Nektar Therapeutics’ lead oncology compound, in combination with 5-fluorouracil (5-FU)/leucovorin in refractory solid tumor cancers. The study is being conducted at University Hospitals Case Medical Center of the Case Comprehensive Cancer Center in Cleveland, Ohio.

NKTR-102, a novel topoisomerase I inhibitor-polymer conjugate compound, was invented by Nektar using its advanced polymer conjugate technology platform. NKTR-102 is designed to optimize the pharmacokinetic and pharmacodynamic profile of irinotecan by reducing peak concentrations of the active metabolite and extending drug half-life. In addition, the unique macromolecular structure of NKTR-102 targets tumor tissue through the EPR effect resulting in enhanced intratumoral drug concentrations as compared to normal tissues. Tumor exposure was increased four-fold with NKTR-102 in nonclinical tumor models as compared to irinotecan and was also associated with increased anti-tumor activity. [1]

Ongoing Studies

NKTR-102 is currently being studied in three separate tumor settings in Phase II development. In colorectal cancer, a 174-patient randomized Phase II/III study is currently enrolling to evaluate single-agent NKTR-102 compared to single-agent irinotecan in patients with second-line colorectal cancer with the KRAS gene mutation. In breast cancer, a 70-patient Phase II study of single-agent NKTR-102 in women with metastatic breast cancer has completed enrollment and is ongoing with a significant number of women still on treatment. In ovarian cancer, the company recently announced that it will be expanding its existing 71-patient study to evaluate single-agent NKTR-102 in an additional 50 women with platinum-resistant/refractory ovarian cancer. Phase III development planning for NKTR-102 is also underway in ovarian cancer.

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Development Milestone

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“The dosing of the first patients in this combination study marks another important milestone in the strategic development of NKTR-102,” said Lorianne Masuoka, M.D., Senior Vice President and Chief Medical Officer of Nektar. “The new Phase 1 study complements our continuing Phase 2 study in second-line colorectal cancer which is evaluating NKTR-102 as a single-agent as compared to irinotecan in patients possessing the KRAS gene mutation. Based upon the markedly enhanced activity of NKTR-102 over irinotecan in preclinical models of gastrointestinal cancer and its notable activity in Phase II clinical testing in breast and ovarian cancers, we believe NKTR-102 is a promising new anti-cancer agent that has the potential to provide an important treatment option for patients with the deadliest forms of colon and rectal cancers.”

NKTR-102 is a novel topoisomerase I inhibitor-polymer conjugate with a sustained exposure profile and a unique macromolecular structure that targets tumor tissue through the enhanced permeation and retention (EPR) effect. The Phase I study of NKTR-102 will assess the safety, pharmacokinetics and anti-tumor activity of this anti-cancer agent when given in combination with standard doses of 5-FU/leucovorin.

“The team at the Case Comprehensive Cancer Center is extremely excited to work with Nektar on the first clinical trial evaluating NKTR-102 in combination with 5-FU/leucovorin in cancer patients,” said Neal Meropol, M.D., Chief, Division of Hematology and Oncology, University Hospitals Case Medical Center & Case Western Reserve University, and Associate Director for Clinical Research at the Case Comprehensive Cancer Center.

The chemotherapy agent 5-FU is currently used as a part of a combination treatment regimen for colorectal cancer in combination with irinotecan, which is also known as the FOLFIRI regimen. In preclinical models of colorectal tumors, NKTR-102 in combination with 5-FU demonstrates superior tumor growth inhibition when compared to standard irinotecan in combination with 5-FU. Data from these studies of NKTR-102 will be presented at the upcoming ESMO Conference: 12th World Congress on Gastrointestinal Cancer in Barcelona, Spain on July 3, 2010 (Abstract P-0025: “Activity of NKTR-102 in nonclinical models of gastrointestinal cancers.”) .

Metastatic Colorectal Cancer

Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women in the U.S.[2] According to the American Cancer Society, nearly 150,000 new cases of colorectal cancer were diagnosed in the U.S. in 2009, and about 50,000 people will die annually of the disease. Worldwide, over 1.2 million people are diagnosed annually with colorectal cancer. [3] Most metastatic colorectal cancer patients have recurrence within two years and require retreatment with chemotherapy regimens. [4] The majority of metastatic colorectal cancer patients receive irinotecan-based regimens, primarily in combination with 5-FU/leucovorin.[5]

References:

[1] Eldon et. al. “NKTR-102, a novel PEGylated irinotecan conjugate, results in sustained tumor growth inhibition in mouse models of human colorectal and lung tumors that is associated with increased and sustained SN38 exposure.”AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, October 2007.
[2] American Cancer Society, “Colorectal Cancer Facts Figures 2008-2010“.
[3] GLOBOCAN, 2009.
[4] Decision Resources, 2009.
[5] Kantar Health, 2009.

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