Taking Cabazitaxel into Childhood Cancers
Taxol (paclitaxel) and related taxane drugs are widely used chemotherapies against solid tumor types in adults. However, taxanes do not generally enter the brain and so they are not effective against brain tumors. Furthermore, for reasons that are still unclear, taxanes are not effective in treating solid tumors in children. Now a new taxane, cabazitaxel, may solve both problems and is entering the first test in pediatric cancers, including brain tumors. “We are first establishing the safety of cabazitaxel in children, and we hope within one year to begin a phase II trial to see if cabazitaxel can benefit patients who have recurrent solid tumors,” explains Peter Manley, MD (DFCI), the principal investigator of the current phase I dose escalation trial. The trial is open and accruing patients.
Rationale for Cabazitaxel
Cabazitaxel has a mechanism of action similar to the older taxanes, which work by disrupting the function of microtubules and inhibiting mitosis, or cell division. Taxanes contain compounds from yew (Taxus) trees, but cabazitaxel is a 'fine-tuned' semi-synthetic derivative of such a compound that may be more effective than older formulations. Importantly, tumor cells that are resistant to the older taxanes succumbed to cabazitaxel, so it may be beneficial in recurrent tumors.
Preclinical evidence in animal studies indicates that the new drug can cross the blood brain barrier. This barrier protects the brain from harmful toxins, but it can also prevent many therapeutic compounds from reaching brain tumors. “We hope this drug will show as much therapeutic activity in the human brain as it does in other adult solid tumors,” says Manley, who is a pediatric neuro-oncologist. “Altogether these were compelling reasons to design the pediatric cabazitaxel study to include brain cancer patients too.”
Study Objective and Design
The study objective is to determine the maximum tolerated dose (MTD) of cabazitaxel for patients with any recurrent solid tumor, including brain tumors. The dose escalation trial, which follows a 3-plus-3 design, is open to patients age 5 to 18. After establishing the maximum safe dose, a safety expansion will enroll an additional ten patients age 2 to 18, of which at least four patients must be as young as 2. The objective for the safety expansion is to gather more empirical evidence about the drug’s safety in preparation for a phase II trial to determine whether cabazitaxel is effective at treating solid tumors and can improve survival.
Patients will receive a dose based on their body surface area (meter squared or m2). For the first round, three patients will receive 20 milligrams/m2, which is 80% of the approved adult dose. If these patients tolerate the dose, the next three patients to enter will receive a higher dose. The dose will escalate at 5 mg/m2 up to a limit of 40 mg/m2. The pediatric dose could be higher than the adult dose because children may metabolize drugs faster. At any dose level, if two out of three patients experience significant toxicity, the MTD will drop down a level, and the safety expansion will proceed at that dose. The drug will be administered intravenously one day every three weeks.
It Takes A Consortium
Because of the rarity of childhood cancers, the trial is running at ten institutions as part of POETIC, or the Pediatric Oncology Experimental Therapeutics Investigators Consortium, so that investigators can accrue enough patients – up to 40 – to complete the study quickly. Manley, who is the principal investigator for the entire study, says, “We’re very excited because we haven’t used taxanes at all in treating brain tumors. And for children, we hope it will be a well tolerated therapy that can also prevent relapse, and in some cases even provide a cure.”
Phase I Trial
Title: Cabazitaxel in Pediatric Patients With Refractory Solid Tumors Including Central Nervous System Tumors
Principal Investigator: Peter Manley, MD (DFCI)
NIH Trial Number: NCT01751308
DF/HCC Protocol Number: 12-441
More Information: The trial is open and recruiting patients. For information on ClinicalTrials.gov, go to clinicaltrials.gov/show/NCT01751308
— Cathryn Delude