Sweden-based Isofol Medical has initiated their pivotal Phase III clinical trial, called the ISO-CC-007 study, for the treatment of first-line (initial) metastatic colorectal cancer (mCRC).

Arfolitixorin is a new drug candidate primarily developed to increase the efficacy of the cytotoxic agent 5?fluorouracil (5-FU) in the treatment of patients with advanced colorectal cancer and as a rescue drug after high-dose methotrexate treatment in osteosarcoma.

Rescue drug
The most common first-line therapeutic strategy for osteosarcoma is high-dose methotrexate in combination with cisplatin, ifosfamide, and doxorubicin. But despite its efficacy, high-dose methotrexate is associated with a number of serious adverse effects, including nephrotoxicity, mucositis, hepatotoxicity, pulmonary toxicity, and neurotoxicity.

Although leucovorin is widely co-administered to reduce the toxic effects of high-dose methotrexate, the therapy is still harmful to the patients, leading, in some patients to high-dose methotrexate-associated adverse effects such as mucositis and nephrotoxicity are associated with delayed clearance of methotrexate. Because of the potential of complications, high-dose methotrexate therapy requires rigorous pharmacokinetic monitoring and rescue with leucovorin.

Leucovorin vs. arfolitixorin
The key active metabolite in arfolitixorin, [6R]-5,10-methylene-tetrahydrofolate, is widely used folate-based drugs leucovorin and levoleucovorin. The investigational agent may be suitable for all patients regardless of their ability to activate folates to [6R]-5,10-methylenetetrahydrofolate, since arfolitixorin, unlike leucovorin and levoleucovorin, does not require metabolic activation to exert its effect.

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Unmet medical need
The expectation is that this novel, investigational agent may help in addressing the unmet need for effective new treatments for mCRC.

“We look forward to bringing arfolitixorin to all patients in need of an improved therapy for metastatic colorectal cancer, a devastating disease with minor therapeutic advancements in the first line treatment over the past 15 years,” said Anders Rabbe, chief executive officer of Isofol.

ISO-CC-007 study
Following completion of the Special Protocol Assessment (SPA) review by the U.S. Food and Drug Administration (FDA), Isofol has decided to move forward with the ISO-CC-007 study under the U.S. IND (Investigational New Drug) application without delay and discontinue the SPA process. This decision will not have any substantial impact on the clinical or regulatory processes of the pivotal Phase III clinical trial of arfolitixorin.

The Phase III clinical trial protocol for the IND meets the FDA?s requirements for safety and primary as well as secondary efficacy endpoints, overall response rate (ORR) and progression-free survival (PFS).

The primary endpoint for the Phase III study is objective response rate (ORR), and key secondary endpoint progression free survival (PFS). A dose level of 120 mg/m2 (approximately 200 mg for an adult male) will be used in the trial. Over 400 patients will be enrolled in ISO-CC-007 study which will be conducted in the U.S., Canada and Europe.

The study protocol has been submitted and first approvals have already been granted. Patient recruitment in the ISO-CC-007 study is therefore expected to start in December 2018.

Last Editorial Review: November 16, 2018

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