FDA Panel Endorses Early Trials of Promising Anticancer Agents in Pediatric Patients

Members of the Pediatric Subcommittee of the FDA's Oncologic Drugs Advisory Committee voiced their support for new clinical trials examining promising cancer agents in pediatric patients.

Alberto S. Pappo, MD

Members of the Pediatric Subcommittee of the FDA’s Oncologic Drugs Advisory Committee (pedsODAC) voiced their support for new clinical trials examining promising cancer agents in pediatric patients.


During a 2-day meeting,1,2 the panel heard representatives from 5 pharmaceutical companies discuss ongoing or planned early stage pediatric trials exploring atezolizumab (Genentech), LOXO-101 (Loxo Oncology), entrectinib (Ignyta), venetoclax (AbbVie/Genentech), and tazemetostat (Epizyme). The panelists reacted favorably to the companies’ presentations, supporting each of the 5 pediatric development plans.The FDA granted the PD-L1 inhibitor atezolizumab (Tecentriq) an accelerated approval as a treatment for patients with locally advanced or metastatic urothelial carcinoma (mUC) whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.

The approval was based on data from the phase II IMvigor 210 study, in which atezolizumab had an overall response rate (ORR) of 14.8% in patients with locally advanced or mUC, regardless of PD-L1 expression. Among patients with PD-L1 expression ≥5%, ORR was 26%.

Several pediatric tumors have been observed to express PD-L1, including high-grade gliomas, rhabdomyosarcoma, lymphomas, soft tissue sarcomas, osteosarcoma, Ewing sarcoma, neuroblastoma, and Wilms tumor. Pediatric tumors have also been shown to have CD8+ tumor-infiltrating lymphocytes.

Through its iMATRIX trial platform, Genentech is collaborating with several pediatric oncology cooperatives to initiate clinical trials examining several potential treatments, including atezolizumab, in pediatric patients. The company’s current plan for atezolizumab in the pediatric setting consists of a nonclinical biomarker analysis and a clinical study.

The biomarker study is examining PD-L1 expression, the presence of CD8+ T cells, and other immune markers in 100 pediatrics tumor samples from patients with a variety of tumor types. The first clinical trial, study G029664, is accruing 40 to 100 pediatric and young adult patients aged <30 years with relapsed or refractory neuroblastoma, rhabdomyosarcoma, non- rhabdomyosarcoma soft tissue sarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, Hodgkin lymphoma, or non-Hodgkin lymphoma. Patients with other tumor types also have the potential to enroll.

The ongoing, open-label, multicenter single-arm study is designed to evaluate the safety and preliminary efficacy of atezolizumab in these patients. Most of the patients enrolled will have known PD-L1 expression; however, a limited number of patients who do not have documented PD-L1 expression will also be allowed to participate.

Patients <18 years of age will receive atezolizumab at 15 mg/kg (maximum 1200 mg) and patients aged ≥18 years will receive 1200 mg. The treatment will be administered every 3 weeks. After at least 10 patients for a specific tumor type have been treated and followed up for at least 6 months, Genentech will determine whether to enroll an expansion cohort with up to 40 patients. Depending on the results of an individual expansion cohort, the company will then decide whether to launch a second study to further examine atezolizumab in that tumor type.

“Overall, the committee feels that the study design is on target—it’s a classic phase I/II,” Alberto S. Pappo, MD, chairperson of pedsODAC, said when summarizing the panel’s response to the Genentech presentation.

Addressing the Genentech representative, Pappo added, “You should also consider combination studies, and those should be done relatively quickly once you’ve identified a dose and a subset of patients who may benefit from this drug. Also, there may not be a very clear correlation between histology and response in pediatric tumors, and therefore, you should explore immune competence, age, and other factors to better assess the reason for a response in these patients.”


Summarizing the committees’ thoughts on the use of PD-L1 inhibitors in pediatric patients, Pappo said, “Based on the data that have been presented, there are no unique toxicities seen in pediatric patients when using PD-L1 inhibitors and we believe that it’s reasonable to proceed with the development of the drug as you have explained it. We would very much appreciate better guidance on how to mitigate some of the side effects—specifically, when to introduce steroids to keep the patient on protocol."LOXO-101 is a highly selective oral inhibitor of the tropomyosin receptor kinase (TRK) family of neurotrophin receptors: TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes, respectively). In adult patients, LOXO-101 is currently being explored in a phase I dose escalation study in patients with advanced cancers (LOXO-TRK-14001) and a phase II basket trial in patients with NTRK fusion-positive tumors (LOXO-TRK-15002). The investigational agent is also part of the NCI-MATCH trial. A maximum-tolerated dose has not yet been determined.

Loxo Oncology, the company developing the agent, launched a phase I trial in December 2015 that is examining LOXO-101 in pediatric and young adult patients (aged 1 to 21) with locally advanced or metastatic solid tumors or primary CNS tumors that have progressed or are nonresponsive to available therapies or no standard therapy exists. Patients can also be enrolled if they are ≥ 1 month old and have infantile/ congenital fibrosarcoma with a documented NTRK fusion.

In the study, the dose of LOXO-101 for a patient is determined using a weight and age adjusted dose algorithm that approximates adult exposures achieved with a dose of 100 mg twice delay. The researchers hope to accrue 36 patients to determine the maximum-tolerated dose and then recruit an additional 30 to 60 patients for the dose expansion cohorts. Beyond the appropriate dose for further clinical analysis, the trial will examine the safety and antitumor activity of LOXO-101 in pediatric patients.

Tying together various committee members’ comments on LOXO-101, Pappo said, “The committee was impressed…we are extremely excited that you are bringing this agent to a very rare subgroup of pediatric tumors. One of the questions that the committee is struggling with is how to best define the optimal dose for this group of patients.”


Pappo added, “The committee feels that the safety profile of the drug appears to be very favorable. This protocol offers a unique opportunity to study not only the activity but the pharmacokinetics and short- and long-term toxicities of this drug in young patients…We also encourage you to keep looking at the long-term effects of this drug—specifically neurotoxicity.”The novel multikinase inhibitor entrectinib has demonstrated activity in adult patients with solid tumors harboring NTRK1/2/3, ROS1, or ALK rearrangements. The agent is currently being evaluated in 2 phase I studies (ALK-372-001 and STARTRK-1) and 1 phase II study (STARTRK-2) in adult patients with solid tumors.

Based on outcomes form the phase I studies, the BSA-based recommended phase II dose of entrectinib is 400 mg/m2 once daily and the fixed dose is 600 mg/daily.

Ignyta, the company developing entrectinib has recently launched the phase I/Ib study RXDX-101-03, which is exploring entrectinib in pediatric patients with relapsed/refractory solid tumors. The open-label, multicenter, dose-escalation trial involves 4 parts. Part A includes patients with relapsed/refractory solid tumors and part B includes patients with primary CNS tumors. Parts C and D will be expansion cohorts, with the part C cohort including patients with neuroblastoma and the part D cohort including patients other non-neuroblastoma, extracranial solid tumors harboring NTRK1/2/3, ROS1, or ALK gene rearrangements.

The trial is enrolling patients aged 2 to 22 years. The primary objectives are tumor response rates, safety, and determining the maximum-tolerated dose or recommended phase II dose for entrectinib in pediatric patients.

In part A of the study (estimated enrollment 6-30 patients) dosing of entrectinib will start at 250 mg/m2 and up to 4 dose quantities will be evaluated. The other 3 parts of the study will be initiated after the recommended phase II dose is determined in part A.

Panel member Brenda Weigel, MD, Developmental Therapeutics Chair of the Children's Oncology Group, discussed her thoughts on the promise of and differences between LOXO-101 and entrectinib.


“What we’ve heard about these 2 agents is that they’re not identical. [LOXO-101] is a much more selective TRK inhibitor and [entrectinib] has additional ALK targeting…so they may be different and they both may have a place, depending on the patient population. I think, at this point in time, to limit our options would be not prudent. It’s worth exploring both because I think they are fundamentally different drugs.”The BCL-2 inhibitor venetoclax has an accelerated approval from the FDA for the treatment of adult patients with chronic lymphocytic leukemia (CLL) who have a 17p deletion (del[17p]), following at least 1 prior therapy.

The FDA approval was primarily based on data from the phase II M13-982 study, in which venetoclax elicited responses in nearly 80% of patients with relapsed/refractory del(17p) CLL. The Vysis CLL FISH probe kit was also approved as a companion diagnostic to venetoclax for detection of the del(17p).

Venetoclax also has an FDA breakthrough therapy designation for potential use in combination with a hypomethylating agent for patients with acute myeloid leukemia, and has demonstrated preliminary clinical activity in adult patients with non-Hodgkin Lymphoma, including Diffuse Large B-Cell Lymphoma.

The rationale for testing venetoclax in pediatric tumors was based on preclinical activity in mouse xenograft models, tumors with high levels of BCL-2 expressed, and preliminary clinical findings in adult tumor types that occur in children. The most appropriate tumor types in which to investigate venetoclax in pediatric patients were determined to be acute lymphocytic leukemia (ALL), non-Hodgkin Lymphoma, and neuroblastoma.

Venetoclax is not currently being studied in pediatric patients. AbbVie/Genentech’s proposed phase I study discussed at the ODAC meeting would accrue approximately 150 patients with relapsed/refractory acute myeloid leukemia (AML), ALL, non-Hodgkin lymphoma, or neuroblastoma. The trial would include a dose escalation phase, followed by a cohort expansion phase.

Doses would be adjusted by age and weight to match the equivalent adult target dose of 400 mg or 800 mg. In the second phase, each cohort would initially enroll 8 patients and at least 1 patient must respond to continue that cohort’s enrollment. Up to 17 more patients can be enrolled if antitumor activity is observed, with additional enrollment allowed as necessary.

Following a 21-day dose-limiting toxicity period, patients with the following responses would be allowed to receive a combination regimen of venetoclax with chemotherapy: complete remission and unable to receive stem cell transplant; partial remission and no sign of additional response at second response assessment; stable disease after 3 assessments in the AML and ALL cohorts, and 2 assessments in the non-Hodgkin lymphoma and neuroblastoma cohorts; or progressive disease.


The specific chemotherapies paired with venetoclax in each cohort will be low-dose cytarabine in the AML group, dexamethasone and vincristine (imatinib if Philadelphia chromosome positive) in the ALL arm, rituximab in the non-Hodgkin lymphoma cohort, and cyclophosphamide in the neuroblastoma group.The EZH2 inhibitor tazemetostat is currently being examined in 3 ongoing studies in adult patients and 1 ongoing trial in pediatric patients. The disease types in the adult trials are non-Hodgkin lymphoma, mesothelioma, and solid tumors.

Based on the initial dose-escalation trial of tazemetostat, the recommended phase 2 dose is 800 mg orally twice daily. Also in this early research, 4 objective responses, including 1 complete response, were observed in patients with INI1- and SMARCA4-negative cancers.

It has been hypothesized that EZH2 inhibition with tazemetostat will be an effective treatment in patients with INI1 or SMARCA4 mutations or deletions. INI1 deletions have been observed in multiple malignancies, including malignant rhabdoid tumors, which can occur in the brain (atypical teratoid rhabdoid tumor [ATRT]), kidney, soft tissues, and solid organs.

An ongoing phase I escalation safety and tolerability study is examining tazemetostat in 24 patients with relapsed/refractory INI1-negative tumors or synovial sarcoma. The trial will also include 3 expansion cohorts.

The primary endpoint of the escalation phase is to determine the maximum tolerated dose with oral tazemetostat when delivered twice daily. The primary objective of the expansion cohort phase is objective response rate of tazemetostat in pediatric patients with relapsed/refractory with atypical teratoid rhabdoid tumor (ATRT; Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), and INI1-negative tumors or synovial sarcoma (Cohort 3).

Epizyme will also participate in the multicenter Pediatric MATCH trial, which is being sponsored by the NCI. The trial, which is expected to launch sometime this year, is examining targeted agents in children with advanced tumors who have limited options. Tazemetostat is scheduled to be 1 of the first investigational therapies tested in the study, according to Epizyme.


  1. US Food and Drug Administration. FDA Briefing Document: Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC): June 28, 2016. http://1.usa.gov/296iko8. Accessed June 29, 2016.
  2. US Food and Drug Administration. FDA Briefing Document: Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC): June 29, 2016. http://1.usa.gov/29bcKQR. Accessed June 29, 2016.