Trial Finds Maximum Tolerable Dose for Combination Therapy for Metastatic Renal Cell Carcinoma Patients

A phase 1b clinical trial made up of a majority of Cleveland Clinic patients with metastatic renal cell carcinoma (mRCC) identified the maximum tolerable dose (MTD) for effective combination therapy using axitinib (AX) and crizotinib (CZ).

Both drugs are tyrosine kinase inhibitors (TKI). AX is a TKI of the vascular endothelial growth factor receptor (VEGFR) and CZ is a TKI of the mesenchymal-epithelial transition factor (c-MET).

The study — which was accepted for presentation at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago — is ongoing.

Two drugs, two separate pathways

AX, which works by inhibiting the formation of new blood vessels by cancer tumors, is standard treatment for mRCC, but patients typically develop resistance to it over time. Researchers involved in this trial wondered if combining it with CZ, which inhibits the c-MET pathway, a signaling route that when aberrantly activated can lead to the development of certain cancers, might overcome that resistance.

“Essentially we’re trying to come up with a better therapy by combining two drugs that work on two separate pathways,” says Dale Shepard, MD, PhD, Director of the Taussig Cancer Institute phase 1 clinical trials and sarcoma programs. “The thought is, if you just work on one pathway, the cell finds a way to get around that. If you block both, you might get a better response.”

Dose escalation phase finds tolerable, safe side effects

During the dose-escalation phase of the trial, 22 patients were treated with increased dosages:

• Five patients on AX 3 mg twice daily + CZ 200 mg twice daily
• Three patients on AX 3 mg twice daily + CZ 250 mg twice daily
• Four patients on AX 5 mg twice daily + CZ 200 mg twice daily
• Ten patients on AX 5 mg twice daily + CZ 250 mg twice daily

Patients received between one and 23 cycles of the drugs, with an average of four cycles. The majority, 68 percent, experienced some adverse effects — fatigue, nausea and diarrhea — but nothing life-threatening. One patient died due to disease progression.

“Those [side effects] are the standard toxicities that you would expect from these drugs independently,” says Dr. Shepard. “We got all the way with the highest dose, which is the standard dose for each drug, and we did not have any dose-limiting toxicities along the way. Essentially, this combination is very safe.”

Dose expansion phase shows combination exhibits anti-tumor effect

In the second phase, which is ongoing, Dr. Shepard and his colleagues divided patients into two cohorts: those with mRCC who were treatment naive and those with mRCC who had received one to two prior treatments.

So far, 15 patients — 11 in the first cohort and four in the second — have been treated with the MTD of AX 5 mg twice daily and CZ 250 mg twice daily. There has been one complete response (CR), three partial responses (PR) and four stable disease (SD) in 10 evaluable patients in the first cohort and one PR and two SD in the second cohort. Overall, 67 percent experienced side effects, most often nausea and diarrhea, and one patient died due to disease progression.

“That’s a pretty good response,” Dr. Shepard says. “Of those that were not previously treated, eight out of 10 had stable disease or better. In patients with mRCC, you can’t cure them, but if you can have people on a therapy that is keeping their disease from growing and they’re tolerating it well, that’s success.”

He cautioned that because the trial is not completed no firm conclusions can be drawn, but added that the fact that one patient had a CR indicates that combination therapies should not be ignored. “If you have a combination where you can get a complete response, you start thinking about the dual-pathway inhibitors and whether there are other pathways that could be inhibited.”