The latest update on XL184 (cabozantinib)

A new update was provided at the ASCO meeting today on progress from the Phase II clinical trial of XL184 (cabozantinib) in the treatment of men with metastatic, castration-resistant prostate cancer (mCRPC).

The trial enrolled men with mCRPC and with progressive measurable disease, all of whom were treated with cabozantinib at 100 mg/day for at least a 12-week lead-in stage. Treatment beyond 12 weeks was originally based on response at 12 weeks:

  • Patients who show at least a partial response at 12 weeks were continued on open-label cabozantinib.
  • Patients with stable disease at 12 weeks were randomized to cabozantinib or a placebo.
  • Patients with progressive disease at 12 weeks were discontinued.

Final responses were originally going to be assessed at 96 weeks on therapy.

Currently available data as reported by Hussain et al. at the American Society of Clinical Oncology annual meeting earlier this afternoon  are given below (and are more recent than the data provided in the abstract linked to above):

  • A total of 171 patients were enrolled .
  • The average (median) age of these patients was 68 years (range, 47 to 88 years).
  • 74/171 patients had received prior treatments for mCRPC (mostly docetaxel-based chemotherapy, but including some who had received abiraterone acetate or MDV3100).
  • 79/171 patients had at least a partial response to cabozantinib, and the randomization portion of the trial was suspended.
  • The single most common grade 3 adverse event was fatigue (in 16 percent of patients).
  • There were numerous other adverse effects and 51 percent of patients needed to have reductions in their dose of cabozantinib.
  • One patient died of possibly drug-related complications, but the reason for this death could not be confirmed as being drug-related.
  • There was a major complete or partial resolution of prostate cancer tumors to bone on bone scans in some patients
  • 74 percent of patients showed meaningful evidence of disease regression.

Additional detailed information is available in a media release from Exelixis.

This is a complicated trial, and the available data are still being analyzed to allow for appropriate determination of how best to proceed with the development of cabozantinib. However, what is clear is that:

  • Cabozantinib has significant clinical activity in men with mCRPC, regardless of whether they have received prior docetaxel-based chemotherapy or not.
  • This activity can be striking in men with mCPRC and with evident, symptomatic bone disease, as reflected by high rates of bone scan resolution and pain relief.

In giving this presentation, Dr. Hussain reported that additional Phase II clinical trials are now being started in selected groups of men with mCRPC. Whether it will be possible to initiate a randomized, double-blind, Phase III trial until some of the current questions have been resolved was not discussed. Nor was there any comment on the question of whether a slightly lower dose of cabozantinib might make it possible to limit the adverse reactions to the drug seen in this trial.

2 Responses

  1. This trial was a randomized discontinuation trial. Those patients who clearly benefited from the start (i.e., during the 12-week “run in” period) stayed on the drug. Those who had stable disease were randomized to drug/placebo. Those who clearly progressed were excluded from further participation This attempts to provide a placebo control and an open label on the same trial. Tricky.

  2. This type of adaptive trial design is becoming increasingly common. We are going to see a lot more Phase II trials of this type in coming years. What happened in this trial is that XL184 outperformed everyone’s expectations, so the “randomization” portion of this trial had to be rapidly abandoned.

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