Activity of cabozantinib (XL184) in advanced ovarian cancer patients

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Activity of cabozantinib (XL184) in advanced ovarian cancer patients: Results from a phase II randomized discontinuation trial.

Sub-category: Ovarian Cancer

Category: Gynecologic Cancer

Meeting: 2011 ASCO Annual Meeting

Abstract No: 5008

Author(s): R. J. Buckanovich, R. Berger, A. Sella, B. I. Sikic, X. Shen, D. A. Ramies, D. C. Smith, I. B. Vergote; University of Michigan, Ann Arbor, MI; Sheba Medical Center, Tel HaShomer, Israel; Assaf Harofeh Medical Center, Zerifin, Israel; Stanford University School of Medicine, Stanford, CA; Exelixis, South San Francisco, CA; University Hospital Leuven, Leuven, Belgium

Abstract:

Background

Cabozantinib (Cabo) is an oral, potent inhibitor of MET and VEGFR2. MET over-expression has been observed in advanced ovarian cancer (OC). Anti-VEGF pathway agents have shown clinical benefit in pts w/ OC. Simultaneous targeting of the MET and VEGF signaling pathways with Cabo may therefore be a promising treatment strategy.

Methods

Epithelial OC pts with progressive measurable disease (mRECIST) received Cabo at 100 mg qd PO over a 12 wk Lead-in stage. Up to 2 prior regimens are allowed for platinum-resistant (R), and up to 3 prior regimens for platinum-sensitive (S) pts. Tumor response was assessed every 6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label Cabo, pts with SD were randomized to Cabo vs placebo, and pts with PD discontinued. Primary endpoint was ORR per mRECIST in the Lead-in stage, and progression free survival (PFS) in the randomized period. Accrual in any cohort could be halted for either high rates of ORR or PD.

Results

Accrual was halted at 68 pts based on an observed high rate of clinical activity. The median number of prior systemic treatments was 2. Most common related AEs ≥Grade 3 were hand-foot syndrome (10%), diarrhea (8%) and fatigue (4%). Dose reductions and permanent discontinuations for AEs occurred in 43% and 10% of pts, respectively. Of 51 pts evaluable for mRECIST RR at 12 wks, 28 are R, 17 are S, and 6 have unknown status. mRECIST RR at 12 wks: overall = 12/51(24%), R = 5/28(18%); S= 5/17(29%). Five additional PRs await confirmation. The overall DCR (PR+SD) at wk 12 is 58% (30/51). After a median f/u of 4 mos (range: 1 to 11 mos), the median duration of response and median PFS have not been reached. CA125 responses (assessed by GCIG criteria) in 40 pts with ≥1 post-baseline result: 7/40 (18%). Median maximum increase in hemoglobin (Hb) in anemic pts (Hb < 11 g/dL) was 1.9 g/dL (N=8 in pts w/ ≥ 6 wk f/u; range, 1.1-3.2 g/dL). All maximum Hb changes occurred w/in the first 12 wks. Randomization in this cohort was halted & pts unblinded due to observed efficacy.

Conclusions

Cabo exhibits clinical activity in ovarian cancer pts with advanced disease, regardless of prior platinum status, as reflected by high rates of response.

Citation: J Clin Oncol 29: 2011 (suppl; abstr 5008)

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They were looking for drugs to treat the inflammation seen in Crohn's disease and ulcerative colitis. They tested a compound called a PPAR-gamma modulator. It would never normally have been thought of as a cancer drug, or in fact a drug of any kind. They ran several tests and found the compound killed pretty much every epithelial tumor cell lines they have seen. Epithelial cells line organs such as the colon, and also make up skin.

They reported in the journal International Cancer Research that it killed colon tumors in mice without making the mice sick. The compound worked in much the same way as the taxane drugs, including Taxol, which were originally derived from Pacific yew trees. It targets part of the cell cytoskeleton called tubulin. Tubulin is used to build microtubules, which in turn make up the cell's structure.

Destroying it kills the cell, but cancer cells eventually evolve mechanisms to pump out the drugs that do this, a problem called resistance. Resistance to anti-tubulin therapies, like Taxol, is a huge problem in many cancers. They see this as another way to get to the tubulin. The PPAR-gamma compound does this in a different way from the taxanes, which might mean it could overcome the resistance that tumor cells often develop to chemotherapy.

Most of the drugs like Taxol affect the ability of tubulin to form into microtubules. This doesn't do that -- it causes the tubulin itself to disappear. They do not know why. They planned to do more safety tests in mice. As the compound is already patented, the team will probably have to design something slightly different to be able to patent it as a new drug.

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Taxol (paclitaxel) is a microtubule stabilising agent that destroys cancer cells by interfering with the cell cycle leading to apoptosis or cell death. Specifically, it interferes with the spindle microtubule dynamics within the cell that ensures the correct alignment of chromosome pairs before they pull apart and become segregated into two daughter cells. Similar to the strings on a puppet, microtubules need to be held at the correct tension for the chromosomes to align. Anything interfering with this process will ultimately cause cell death.

Taxol-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. Unlike other tubulin targeted drugs such as colchicine that inhibit microtubule assembly, however, Taxol stabilizes the microtubule polymer and protects it from disassembly. The inability of the chromosomes to achieve a metaphase spindle configuration leads to a mitotic block in which there is prolonged activation of the mitotic checkpoint with the subsequent triggering of apoptosis or slippage back into the G1-phase of the cell cycle without cell division.

The ability of Taxol to inhibit spindle function is generally attributed to its suppression of microtubule dynamics, but recent studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. At the higher antimitotic concentrations, Taxol appears to act by suppressing microtubule detachment from centrosomes, a process normally activated during mitosis. The binding site for Taxol has been shown to reside on the beta-tubulin subunit.

In other words, Taxol gumms up the innards (microtubules) of all rapidly dividing cells (good cells and bad cells). When microtubules get gummed up, the tumor cell commits suicide. A report in the journal International Cancer Research stated that taxane drugs, including Taxol, targets part of the cell cytoskeleton called the tubulin. Tubulin is used to build microtubules, which in turn make up the cell's structure. Destroying it kills the cell, but cancer cells eventually evolve mechanisms to pump out the drugs that do this (resistance). Resistance to anti-tubulin therapies, like Taxol, is a huge problem in many cancers.

It's like a gasoline engine in an automobile. Say the motor is running and for some reason the key in the ignition is broken/jammed and you cannot shut the engine off, and you cannot open the bonnet to cut ignition wires to stop the engine. So the only other way is to pour sugar into the gasoline tank until the motor gummies up and stops running. Now, you shut off the engine the best way you possibly could because of the restrictions. However, while cutting ignition wires would save the engine for another day (replace just the wires), by placing sugar into the gas tank you virtually destroyed the engine, unless you can completely overhaul it.

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Brito D. A., Yang Z., Rieder C. L. (2008). "Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied". J. Cell Biol. 182 (4): 623–9. doi:10.1083/jcb.200805072. PMC 2518701. PMID 18710927.

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Ganguly A, Yang H, Cabral F, Paclitaxel-dependent cell lines reveal a novel drug activity.Mol Cancer Ther. 2010 Nov;9(11):2914-23. Epub 2010 Oct 26.

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The investigational drug cabozantinib is showing promise against several types of advanced cancer, and may also reduce or eliminate bone metastases (cancer that has spread to the bone) in some patients. These results will be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

Metastatic cancer refers to cancer that has spread to distant sites in the body. Several types of cancer—including cancers of the prostate, lung, and breast—have a tendency to spread to the bone. Bone metastases can lead to serious problems such as fracture and spinal cord compression, and may require treatment with surgery or radiation therapy.

Cabozantinib is an investigational drug that targets two proteins—MET and VEGFR2—that play a role in the development and progression of many types of cancer.

To evaluate cabozantinib in the treatment of advanced cancer, researchers conducted a Phase II clinical trial among 398 patients. The nine types of cancer included in the study were breast, stomach/gastroesophageal junction, non-small cell lung, ovarian, pancreatic, hormone-refractory prostate, small cell lung, liver, and melanoma. At the start of the study, 39% of the patients had bone metastases.

Patients were initially treated with 12 weeks of cabozantinib. After 12 weeks, patients who had a partial response to treatment (a reduction in detectable cancer) remained on cabozantinib, patients with stable disease (no significant change in the cancer) were randomly assigned to either continue with cabozantinib or to take a placebo, and patients with progressive (worsening) cancer were withdrawn from the study.

By week 12, 9% of patients responded to treatment.

For some types of cancer, cabozantinib produced high disease control rates (defined as either a reduction in cancer or stable disease). The disease control rates were 76% for liver cancer, 71% for prostate cancer, and 58% for ovarian cancer.

Among the 68 patients with bone metastases, 59 had partial or complete disappearance of the cancer on bone scans, often accompanied by significant pain relief. A majority of these patients had hormone-refractory prostate cancer, but patients with breast cancer and melanoma also experience a disappearance of bone metastases. The researchers had not expected this result.

The most common side effects were fatigue and hand-foot syndrome (pain, swelling, numbness, tingling, or redness of the hands or feet).

In a prepared statement, the lead author of the study noted “Cabozantinib appears to have significant effects on several treatment-resistant tumors, as well as impressive effects on bone metastases. In addition, these effects are associated with rapid improvement in pain, a reduction in opiate narcotic requirements and improvement in anemia. The implications of these results are very exciting—it is unusual to find a targeted therapy, absent of a molecular mutation in tumors, that works in bony disease and has this activity.”

Reference: Gordon MS, Vogelzang NJ, Schoffski P et al. Cabozantinib (XL184) has activity in both soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) w/ advanced solid tumors. Paper presented at: 2011 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, IL. Abstract 3010.