1. Nalley, Catlin

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The investigational drug tazemetostat shows early promise among children with relapsed or refractory malignant rhabdoid tumors, epithelioid sarcomas, or poorly differentiated chordomas with a particular genetic defect.


Data from a phase I study found the drug was well-tolerated with some objective and durable responses, according to results presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (Abstract A175).


"Malignant rhabdoid tumors and atypical teratoid rhabdoid tumors [ATRT; which occur in the brain] and other INI1-deficient tumors such as epithelioid sarcomas and poorly differentiated chordomas are extremely rare tumors in childhood," said Susan N. Chi, MD, Director of the Pediatric Brain Tumor Clinical Trials Program at the Dana-Farber Cancer Institute and Boston Children's Hospital, and Assistant Professor of Pediatrics at the Harvard Medical School. "However, children with these tumors have a poor prognosis despite conventional treatment regimens and, because of their rarity, there are no uniform treatment approaches."


INI1-Deficient Tumors

"INI1 is a gene that is uniquely mutated in these types of tumors," Chi noted. "And these tumors are highly malignant and very rare aggressive tumors of childhood. They include patients with malignant rhabdoid tumors (MRTs, ATRTs), epithelioid sarcoma, and poorly differentiated chordomas."


This mutation results in deficiencies in DNA transcription and cell proliferation, so cancer cells use an alternate pathway to enable uncontrolled cell proliferation, according to Chi. "The protein EZH2 is a component of this alternate pathway. Tazemetostat targets EZH2, thus inhibiting the proliferative activity of cancer cells.


"INI1-negative tumors are rare, aggressive, and they afflict children to the youngest of ages, particularly for kids with MRT and ATRT," Chi continued. "Children with MRTs and their central nervous system counterpart, ATRTs, have historically poor overall survival, and for the youngest of children especially those under the age of 3 the survival has historically been less than 20 percent."


Patients with epithelioid sarcoma, a soft tissue sarcoma that is often resistant to therapy, also has a poor survival rate. According to Chi, children with metastatic disease have a 1-year survival rate of less than 50 percent. Additionally, Chi noted, "Poorly differentiated chordomas are skull- and spine-based tumors and they have a high mortality rate of approximately 50 percent due to local and metastatic disease."


Study Details

This multicenter phase I study enrolled patients from 6 months to 21 years old with INI1-negative tumors, including rhabdoid tumors, epithelioid sarcomas, poorly differentiated chordoma, and synovial sarcoma.


"This is the first clinical trial for children testing this class of drugs," Chi noted. "The purpose of this study is to determine the highest dose tolerated, characterize the side effects of this drug in children, and assess the efficacy of this drug in select tumor types.


"This is a rolling 6 design which allows six subjects to be concurrently enrolled into each cohort," she explained during her presentation. Enrolled patients received one of the seven dose levels of tazemetostat as an oral suspension twice daily, according to researchers. Objective responses were assessed every 8 weeks.


At the time of presentation, 46 patients have been enrolled in the seven dose cohorts. When discussing patient demographics, Chi noted the young age of participants. "Our median age was quite young at 3 years old," she reported. "The majority of children (greater than 60%) had either ATRT or malignant rhabdoid tumors.


"All of the children had metastatic disease at the time of study entry and all of these patients were pretreated, the majority having 1-2 regimens prior to their enrollment," she continued. "Due to their aggressive nature, generally speaking, their regimens are very intense upfront."


Key Findings

Of the 46 patients treated so far, three-one with poorly differentiated chordoma, one with epithelioid sarcoma, and one with ATRT-had complete responses, and one patient with poorly differentiated chordoma had a partial response, according to investigators. "The patient with the longest complete response remains in remission after more than a year on study," Chi noted.


At the time of presentation, five of the 46 patients remain on tazemetostat and they all remain on doses above 520 mg/m2, researchers reported. "The children on this study experienced objective responses to this investigational drug that are durable at doses that appear to be well-tolerated," noted Chi, in a statement. "In fact, children have tolerated even higher doses than that in adults, thus demonstrating that children are not just 'little adults' from the standpoint of drug dosing."


In terms of safety, researchers found the treatment was well-tolerated. "There were fewer grade >=3 treatment emergent adverse events in the higher dose levels (>=520 mg/m2) versus those in a lower dose level (<520 mg/m2)," Chi said. "There was one DLT reported at 300 mg/m2 (grade 4 hypoxia and grade 3 dyspnea), but no other DLTs were noted in any other cohort.


"The most common side effects included vomiting, fatigue, and nausea, but overall it was a very well-tolerated medication," she continued. "These related AEs were not dose- or time-dependent, with the exception of asymptomatic hyperchloremia."


In addition, researchers performed pharmacokinetic studies at various time points, according to Chi. "Children achieved a mean steady-state AUC(0-12) increased in a dose-proportional fashion at doses >=520 mg/m2," she explained. "Mean steady-state AUC(0-12) was also four-fold greater as seen in the adults RP2D level of 800 mg BID. The mean AUC was lower at steady-state (day 15) relative to single dose (except at 1,200 mg/m2), consistent with induction of tazemetostat metabolism.


"When we looked at the pharmacodynamic relationship to the pharmacokinetic measurements, we were able to observe inhibition of H3K27M as measured by chromatin flow analysis on the pre- and post-dose levels of the peripheral blood in monocytes and granulocytes," Chi continued.


Based on the pharmacokinetic, pharmacodynamic, clinical safety, and efficacy results, Chi and her team established that the recommended phase II dose was 1,200 mg/m2 tazemetostat given twice daily.


"Tazemetostat was a single-agent generally well-tolerated in children and showed promising anti-tumor activity, including CRs in patients with INI1-negative," Chi noted. "Additionally, this efficacy result is consistent with that previously reported in the adult patients with INI1-negative tumors.


"We are encouraged by our findings that we may now have a novel agent that can be used to treat some of these very difficult-to-treat childhood cancers," she emphasized in a statement. "For the rarest of tumors, especially in pediatrics, where specific and singular mutations may be the driving trigger, advances in the treatment of these tumors may offer insight to other more common tumor types potentially in children or adults or both."


Continued Investigation

The study is currently in its dose expansion phase, according to Chi, which will include four cohorts based on tumor type: ATRT (Cohort 1), MRT and rhabdoid tumors of the kidney (Cohort 2), all other INI1-negative tumors (Cohort 3), and a tablet cohort of tumor types in cohorts 1-3 (Cohort 4).


"Tazemetostat is formulated as an oral liquid formulation and a very important consideration in pediatrics, especially in these young children who cannot swallow tablets," Chi explained. "Tazemetostat for the adults is formulated in a tablet, so we are also testing the tablet for children as well for the older group.


"While we are encouraged to see clinical activity in children, we should remember that large phase II/III studies will provide more definitive assessments of clinical activity for investigational drugs," Chi concluded.


Catlin Nalley is associate editor.