Exelixis Inc., a biotechnology company committed to developing small molecule therapies for the treatment of cancer, has expanded the cabozantinib development programme under a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute’s Cancer Therapy Evaluation Programme (NCI-CTEP), with the approval of the initial programme of 12 proposed clinical trials under the agreement.

The CRADA provides for funding for as many as 20 active clinical trials each year for a five year period, which Exelixis believes will allow it to broadly expand the cabozantinib development programme in a cost-efficient manner. When initiated, these trials will substantially increase the number of indications and disease settings in which cabozantinib is being investigated and aid in prioritizing the next set of pivotal trials.

Cabozantinib is a potent, first-in-class, tyrosine kinase inhibitor that simultaneously targets the MET and VEGF signaling pathways. In clinical studies, cabozantinib has demonstrated a unique spectrum of anti-tumour activity in 12 out of 13 tumor types tested, with regression of metastatic or primary tumour lesions in soft tissue, visceral organs and the brain, resolution of bone lesions on bone scan, and substantial reductions in pain and narcotic use in patients with castration-resistant prostate cancer (CRPC). Exelixis initiated a rolling submission of a new drug application (NDA) for cabozantinib in medullary thyroid cancer in December 2011 based on the positive top-line results in the phase III EXAM trial announced in October 2011. The NDA submission is expected to be completed in the first half of this year. Cabozantinib is currently in phase III clinical development in CRPC.

Three groups of initial trials have been approved under the CRADA:

Trials to Prioritize Future Development. Four randomized phase II trials have the potential to demonstrate cabozantinib’s utility in disease settings where there is substantial unmet medical need. Trials are planned to be conducted in first line renal cell carcinoma, second line hepatocellular carcinoma, platinum-resistant or refractory ovarian cancer, and second line non-small cell lung cancer, all of which are settings in which cabozantinib has previously shown clinical activity. Additional non-randomized phase II trials in ocular melanoma and non-small cell lung cancer are expected to further expand the data sets from earlier studies which demonstrated the anti-tumour activity of cabozantinib in these settings. Results from this group of trials could aid in the prioritization of future phase III pivotal trials.

Signal Search Trials to Identify Indications for Further Study. Single arm phase II trials are planned to explore cabozantinib’s potential in additional tumor types, consisting of trials in endometrial cancer, bladder cancer and sarcoma. Positive results in these indications could lead to further study in randomized phase II or phase III studies.

Additional Trials. Phase I combination trials in additional tumor types are planned as well as a trial to evaluate cabozantinib in paediatric malignancies.

“In Exelixis-sponsored trials, cabozantinib has shown signs of tumour shrinkage in 12 of 13 tumour types studied, including medullary thyroid, prostate, breast, ovarian, and non-small cell lung cancer, melanoma, and hepatocellular carcinoma,” said Michael M Morrissey, PhD, president and chief executive officer of Exelixis. “Our CRADA with NCI-CTEP provides important support for evaluating the full potential of cabozantinib in these and other indications as we focus our internal resources on the late-stage development and potential commercialization of cabozantinib in thyroid and prostate cancers. We are grateful for the support of so many investigators in the oncology community and the staff at NCI-CTEP, and look forward to working with them to advance our understanding of the role that cabozantinib may play in improving outcomes for cancer patients.”

The proposed trials approved under the CRADA will be conducted under an investigational new drug application (IND) held by NCI-CTEP. Protocol development for each of the trials is expected to commence shortly and the first of these trials is anticipated to begin in approximately late 2012 or early 2013.

The CRADA between Exelixis and NCI-CTEP was established in November 2011 and covers up to twenty active clinical trials per year. The agreement reflects a major commitment by NCI-CTEP to support the full exploration of cabozantinib’s potential in a wide variety of cancers with substantial unmet medical need. The initial request for proposals from NCI investigators generated intense interest from the oncology community: Exelixis and NCI-CTEP personnel jointly reviewed more than 60 submissions to arrive at the final list of trials.

Cabozantinib is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumour cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumour types. MET is upregulated in many tumour types, thus facilitating tumour cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, antimetastatic and antiangiogenic effects, including: extensive apoptosis of malignant cells, decreased tumour invasiveness and metastasis, decreased tumor and endothelial cell proliferation, blockade of metastatic bone lesion progression and disruption of tumour vasculature.