PNOC014

20 evidence topics · 3 sources

Objective

Maximum tolerated or recommended phase 2 dose in children with recurrent MAPK-altered tumors

“The primary objective of this study was to determine the maximal tolerated dose (MTD) or recommended phase II dose (RP2D) of tovorafenib administered once every week to children and adolescents with radiographically recurrent or progressive MAPK pathway-activated tumors.” (opens the source at this quote in a new tab)

Location and study date

Treatment periods

“We treated nine eligible patients with primary CNS tumors at 280 (n = 3), 350 (n = 3), and 420 (n = 3) mg/m2 from February 2018 through November 2021.” (opens the source at this quote in a new tab)
“Patients were treated from June 2020 through November 2023.” (opens the source at this quote in a new tab)

Participating sites

No evidence found.

Registry record: sponsor, study status, and actual start and completion dates

Field	Registry record
Sponsor	“Karen D. Wright, MD”
Responsible party	“Karen D. Wright, MD, Dana-Farber Cancer Institute”
Study status	“Completed”
Study start (actual)	“2018-02-27”
Primary completion (actual)	“2025-12-31”
Study completion (actual)	“2025-12-31”
Last update posted	“2026-02-19”

Study design

Phase IA 3 + 3 escalation and phase IB subgroup-specific design

“The first phase (IA) followed a 3 + 3 design. Based on initial observed responses and pharmacokinetic data, the trial was modified to include phase IB using a subgroup-specific time to event (Sub-TITE) design to better determine dosing within two subgroups defined by body surface area (BSA ≤1.5 m2 and >1.5 m2).” (opens the source at this quote in a new tab)
“With that information, the decision was made to re-evaluate dosing in the context of BSA and exclude patients with NF1.” (opens the source at this quote in a new tab)

Eligibility criteria

Inclusion and exclusion criteria

“Eligible patients were between age 1 and 25 years with a confirmed diagnosis of radiographically recurrent or progressive CNS or solid tumors with associated activation of the MAPK pathway. Patients had to have received prior standard therapy.” (opens the source at this quote in a new tab)
“Exclusion criteria included patients having been treated with tovorafenib previously, receiving any other anticancer or experimental therapy, with unstable systemic diseases, pregnant or lactating, or having any condition that potentially hindered compliance with study protocol and the follow-up schedule.” (opens the source at this quote in a new tab)

Treatment

Dose levels and treatment duration

“Based on the adult oral RP2D of 350 mg/m2 given once every week (using a typical adult BSA of 1.7 m2), the starting dose for the phase IA study was 80% of the adult RP2D, which is 280 mg/m2.” (opens the source at this quote in a new tab)
“Patients received tovorafenib for 12 cycles from the time of study entry but could continue up to a total treatment period of 24 cycles. Patients progressing off therapy within 6 months could resume drug for an additional 12-24 cycles.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using dose-limiting toxicity as the primary endpoint

Primary endpoint, toxicity grading, and response assessment

“Toxicities were graded according to Common Terminology Criteria for Adverse Events version 5. Response was classified as complete response (CR), partial response (PR), or stable disease (SD).” (opens the source at this quote in a new tab)
“Magnetic resonance imaging or computed tomography depending on CNS or non-CNS tumor type, respectively, was assessed within 28 days of treatment start and at the end of every 2-3 cycles using RANO or RECIST criteria, as appropriate.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Bayesian subgroup-specific dose finding

“We used a modified Bayesian adaptive Sub-TITE design to allow separate determination of a MTD or RP2D in the two BSA subgroups, BSA ≤1.5 m2 and BSA >1.5 m2, starting at the prior tolerable dose of 420 mg/m2/dose once every week (Fig 1).” (opens the source at this quote in a new tab)
“For BSA ≤1.5 m2, the posterior mean toxicity probability that was closest to the 20% target toxicity rate was 0.19 at dose level 2.” (opens the source at this quote in a new tab)

Treated and evaluable participants

“We treated 44 eligible patients (phase IA: 9; phase IB: 35) with high-(n = 6) or low-grade (n = 38) tumors.” (opens the source at this quote in a new tab)
“For dose finding, 30 (n = 16 for BSA ≤1.5 m2; n = 14 for BSA >1.5 m2) of 35 patients were evaluable for the DLT observation period.” (opens the source at this quote in a new tab)
“Of the 35 eligible patients enrolled, 31 met evaluability criteria for objective response. Four patients did not complete cycle 1 of therapy and were unevaluable for response.” (opens the source at this quote in a new tab)

Description of analysis sets

Toxicity and response-evaluable sets

“All 35 patients received at least one dose of tovorafenib and were evaluable for the toxicity analysis.” (opens the source at this quote in a new tab)
“Of the 31 evaluable patients, 30 patients had known response data from institutional imaging evaluation and 27 patients had known response data from central review imaging assessment using RANO criteria.” (opens the source at this quote in a new tab)

Results

Participant disposition

Deaths during follow-up

“Figure 2 highlights the swimmers plot for duration of follow-up, timing of PD, first response, and 5 deaths starting from study enrollment. All deaths were unrelated to treatment.” (opens the source at this quote in a new tab)

Baseline characteristics

Diagnoses and molecular alterations

“Pilocytic astrocytoma (n = 19) was the most common diagnosis; KIAA1549:BRAF fusion was the most common molecular alteration (n = 27).” (opens the source at this quote in a new tab)

Pediatric LGG population described in the FDA review

“The study enrolled 34 patients with pediatric LGG with an activating BRAF alteration, of which 29 patients harbored a RAF fusion (24/29 patients had the KIAA1549:BRAF fusion).” (opens the source at this quote in a new tab)

Efficacy results

Relapsed or recurrent pLGG and other MAPK-altered tumors: phase IA and IB responses

“Independent central radiology review by a single radiologist not involved in study conduct for the phase IA was notable for 2 complete response (CR), 3 partial response (PR), 2 stable disease (SD), and 2 median time to response of 10.5 weeks (range, 8-32 weeks).” (opens the source at this quote in a new tab)
“At approximately 5 years after completion of therapy, only 1 CR and 1 PR persist.” (opens the source at this quote in a new tab)
“For the 27 patients with centrally reviewed imaging, 25 (93%) were responders with CR/PR/SD. The median duration of response was 11.3 months (range, 0.03-35.4 months; Table 4). Of 10 patients treated at RP2D, 8 (80%) responders had median duration of response of 24.1 months (range, 11-35.4 months).” (opens the source at this quote in a new tab)

FDA consideration as confirmatory evidence

“In these 31 patients, 3 had a complete response and 10 had a partial response. The demonstration of responses in a heavily pre-treated patient population constitutes confirmatory evidence of the effectiveness of tovorafenib in the intended population.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

Dose-limiting toxicities and recommended phase 2 dose

“Phase IB included 6 DLTs: three in each BSA subgroup, all at 530 mg/m2/dose, all grade 3.” (opens the source at this quote in a new tab)
“Based on this information, the principal investigators chose 420 mg/m2/dose (dose level 1) for the RP2D in each BSA subgroup.” (opens the source at this quote in a new tab)

Common adverse events and laboratory abnormalities

“The most common adverse reactions (approximately 20%) were skin and subcutaneous disorders, which included rash and hair color changes, followed by GI disorders (10%), and blood and lymphatic system disorders (6%).” (opens the source at this quote in a new tab)
“The top three most common laboratory abnormalities were decreased phosphorus, increased creatinine phosphokinase, and increased AST. The most common grade 3 and 4 laboratory abnormality was low phosphorus.” (opens the source at this quote in a new tab)
“Three patients treated on phase IB experienced this event, with two grade 1 hemorrhages being deemed possibly related.” (opens the source at this quote in a new tab)

Growth suppression

“Eleven of 12 patients (92%) on drug for more than 6 months and not postpubertal experienced grade 3 growth suppression.” (opens the source at this quote in a new tab)
“For patients who received treatment for more than 6 months (n = 19), the average growth velocity was 0.94 cm/year (range: 0-3.6).” (opens the source at this quote in a new tab)
“Within the limits of our data, all patients except for one, for whom we do not have follow-up data to make the determination, recovered near-normal or normal growth rates within 12 months of drug discontinuation.” (opens the source at this quote in a new tab)

Study limitations

Summary: limitations of PNOC014

PNOC014 was a phase 1, nonrandomized, dose-finding study in 44 participants aged 1 to 25 years with recurrent or progressive MAPK pathway-altered tumors (38 low-grade and 6 high-grade tumors) at 15 US sites; it did not include treatment-naive participants. The design was changed mid-study from a 3 + 3 escalation to a Bayesian subgroup-specific design, and doses ranged from 280 to 530 mg/m2, so response data are pooled across dose levels. Responses were reported with stable disease counted as response (25 of 27 centrally reviewed participants, 93%), central and institutional assessments were discordant in 13 of 31 participants, and pharmacokinetic sampling in phase IB was disrupted by COVID-19 travel restrictions. The FDA stated that limited data from this study precluded its acceptance as a second adequate and well-controlled trial.

Authors’ discussion of heterogeneity of response

“We did not observe the same degree of response even among patients with the same genetic alteration.” (opens the source at this quote in a new tab)