First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M–mutant pediatric diffuse intrinsic pontine glioma: a case report

Matthew D. Hall Departments of Radiation Oncology,
Radiation Oncology,

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 MD, MBA
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Yazmin Odia Neurology, and

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 MD, MS
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Joshua E. Allen Oncoceutics, Philadelphia, Pennsylvania; and

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Rohinton Tarapore Oncoceutics, Philadelphia, Pennsylvania; and

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Ziad Khatib Pediatric Oncology, and

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Toba N. Niazi Pediatric Neurosurgery, Nicklaus Children’s Hospital, Miami, Florida;

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Doured Daghistani Oncology, Miami Cancer Institute; Departments of

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Lee Schalop Oncoceutics, Philadelphia, Pennsylvania; and

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Andrew S. Chi NYU Langone Medical Center and School of Medicine, New York, New York

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Wolfgang Oster Oncoceutics, Philadelphia, Pennsylvania; and

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Minesh P. Mehta Departments of Radiation Oncology,

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Diffuse intrinsic pontine gliomas (DIPGs) frequently harbor the histone H3 K27M mutation. Gliomas with this mutation commonly overexpress dopamine receptor (DR) D2 and suppress DRD5, leading to enhanced sensitivity to DRD2 antagonism. This study reports the first clinical experience with the DRD2/3 antagonist ONC201 as a potential targeted therapy for H3 K27M–mutant DIPG. One pediatric patient (a 10-year-old girl) with H3 K27M–mutant DIPG was enrolled in an investigator-initiated, IRB-approved compassionate-use study and began single-agent ONC201 treatment 1 month after completing radiotherapy. The study endpoints were clinical and radiographic response (primary) and toxicities (secondary).

The patient presented with House-Brackmann grade IV facial palsy and unilateral hearing loss. MRI demonstrated a 2.3 × 2.1 × 2.8–cm pontomedullary tumor. Stereotactic biopsy confirmed H3 K27M–mutated DIPG. The tumor was treated with radiotherapy, but 1 month after completion of that treatment, the tumor and neurological symptoms showed only minimal change, and ONC201 treatment was initiated as described above. The tumor volume sequentially decreased by 26%, 40%, and 44% over the next 6 months, and remained stable at 18 months. Ipsilateral hearing normalized and the facial palsy improved to House-Brackmann grade I by 4 months. After 1 year of ONC201 treatment, 2 new lesions were identified outside of the prior high-dose radiotherapy volume. The patient was treated with dexamethasone, bevacizumab, and additional focal radiotherapy to these new tumors. These tumors remained stable in size over the subsequent 6 months on MRI. To date, no adverse events have been observed or reported due to ONC201. The patient remains clinically improved as of the latest follow-up visit, 19 months after starting ONC201 and 22 months from diagnosis. This case supports further investigation of this novel agent targeting H3 K27M–mutated DIPG.

ABBREVIATIONS

DIPG = diffuse intrinsic pontine glioma; DR = dopamine receptor; IMRT = intensity-modulated radiotherapy; RECIST = Response Evaluation Criteria In Solid Tumors.

Diffuse intrinsic pontine gliomas (DIPGs) frequently harbor the histone H3 K27M mutation. Gliomas with this mutation commonly overexpress dopamine receptor (DR) D2 and suppress DRD5, leading to enhanced sensitivity to DRD2 antagonism. This study reports the first clinical experience with the DRD2/3 antagonist ONC201 as a potential targeted therapy for H3 K27M–mutant DIPG. One pediatric patient (a 10-year-old girl) with H3 K27M–mutant DIPG was enrolled in an investigator-initiated, IRB-approved compassionate-use study and began single-agent ONC201 treatment 1 month after completing radiotherapy. The study endpoints were clinical and radiographic response (primary) and toxicities (secondary).

The patient presented with House-Brackmann grade IV facial palsy and unilateral hearing loss. MRI demonstrated a 2.3 × 2.1 × 2.8–cm pontomedullary tumor. Stereotactic biopsy confirmed H3 K27M–mutated DIPG. The tumor was treated with radiotherapy, but 1 month after completion of that treatment, the tumor and neurological symptoms showed only minimal change, and ONC201 treatment was initiated as described above. The tumor volume sequentially decreased by 26%, 40%, and 44% over the next 6 months, and remained stable at 18 months. Ipsilateral hearing normalized and the facial palsy improved to House-Brackmann grade I by 4 months. After 1 year of ONC201 treatment, 2 new lesions were identified outside of the prior high-dose radiotherapy volume. The patient was treated with dexamethasone, bevacizumab, and additional focal radiotherapy to these new tumors. These tumors remained stable in size over the subsequent 6 months on MRI. To date, no adverse events have been observed or reported due to ONC201. The patient remains clinically improved as of the latest follow-up visit, 19 months after starting ONC201 and 22 months from diagnosis. This case supports further investigation of this novel agent targeting H3 K27M–mutated DIPG.

Diffuse intrinsic pontine glioma (DIPG) is a predominantly pediatric brain tumor; the median age of patients at initial presentation is 6 years. These tumors are essentially inoperable, with the exception of the dorsally exophytic component, which may be amenable to subtotal resection. The median overall survival is 8–9 months, and the 2-year survival rate is < 10%, a statistic that has not improved over the past 4 decades.10,18 Numerous clinical trials of radiation dose escalation, radiosensitizing agents, and cytotoxic and targeted drugs have consistently failed. The standard of care remains a 6-week course of non-curative focal radiotherapy, which rarely reverses the dense cranial nerve palsies that commonly occur in patients with these tumors.11

In recent years, a clonal heterozygous missense somatic mutation in H3F3A and other genes encoding histone H3 has been identified in 70%–85% of DIPGs. This mutation is also prevalent in other midline gliomas that commonly occur in children and young adults.6,13,23,25 In the 2016 WHO classification of brain tumors, diffuse midline gliomas that exhibit the H3 K27M mutation are now recognized as a distinct grade IV glioma category.17

In this paper, we present the case of a 10-year-old girl with a biopsy-proven H3 K27M–mutant DIPG who was treated with the dopamine receptor (DR) D2/3 (DRD2/3) antagonist ONC201 following completion of radiotherapy in an open-label compassionate-use study. The patient exhibited a dramatic radiographic response and a remarkably robust and sustained clinical response, with near-complete reversal of her grade IV facial palsy.

Study Medication: ONC201

ONC201 is a selective DRD2/3 antagonist that crosses the blood-brain barrier and exhibits p53-independent efficacy in preclinical models of high-grade glioma.1,2 DRD2, a G protein–coupled receptor that promotes tumor growth, has emerged as a therapeutic target for gliomas and other tumors that overexpress this molecule.16,22 Downstream of DRD2 antagonism, the mechanism of action of ONC201 involves the activation of the integrated stress response combined with inactivation of Akt/ERK and other pro-survival signaling pathways.2,9,14 ONC201 also depletes cancer stem cells in gliomas and other advanced cancers.21

Evaluation of H3 K27M–mutant gliomas has demonstrated increased levels of DRD2 expression and decreased levels of another tumor-inhibiting dopamine receptor, DRD5, compared to glioma cell lines without the H3 K27M mutation. Chi et al. demonstrated that patient-derived H3 K27M–mutant glioma cell lines are significantly more sensitive to ONC201 in vitro compared to cell lines from H3 wild-type and G34R gliomas.7

Results from a phase II clinical trial of oral ONC201 in adult patients with recurrent, bevacizumab-naïve glioblastoma have been reported.3 Among the 17 patients included in this study, only one, a 22-year-old woman with a thalamic tumor, harbored a biopsy-proven H3 K27M mutation. This patient developed a durable 96% regression of her tumor and remains on ONC201 after 23 months, providing initial clinical proof of activity in an adult case of a non-DIPG tumor carrying the same mutation as our patient’s tumor. These preclinical observations, early clinical experience with ONC201, and the presence of the H3 K27M mutation in our patient’s tumor prompted exploration of ONC201 following conventional radiotherapy.

Case Report

History and Presentation

This 10-year-old girl presented to the emergency department with a left facial palsy and left-sided hearing loss. She was treated empirically with corticosteroids and acyclovir for presumed Bell’s palsy without improvement. Within 2 weeks she developed progressive gait ataxia necessitating a second visit to the emergency department. MRI of the brain demonstrated a T2 hyperintense mass measuring 2.3 × 2.1 × 2.8 cm centered at the left pontomedullary junction, compressing and displacing the left middle cerebellar peduncle, with an exophytic component extending into the cerebellopontine cistern (Fig. 1A). There was minimal contrast enhancement. Dexamethasone treatment (4 mg, 2 times daily) was initiated, resulting in minimal improvement in her facial palsy.

FIG. 1.
FIG. 1.

Axial FLAIR (upper row) and coronal T2-weighted (lower row) MR images illustrating the primary tumor in the left cerebellopontine angle at diagnosis (A), 1 month after radiotherapy (B), 6 months after beginning ONC201 (C), 12 months after beginning ONC201 (D), and 18 months after beginning ONC201 (E). Of note, the patient developed sites of tumor progression outside of the high-dose region 12 months after beginning ONC201.

Biopsy and Pathological Findings

Stereotactic biopsy by left posterior burr hole confirmed diffuse midline glioma, WHO grade IV, based on positive H3 K27M–mutant protein staining by immunohistochemistry and loss of nuclear expression of H3K27me3 (trimethylation of lysine 27) in tumor cells. Histopathologic examination demonstrated an infiltrative tumor with microvascular proliferation and high mitotic index (> 10 mitoses/10 high power fields), strong nuclear staining for OLIG2 and ATRX, and expression of p53. After biopsy, the patient’s facial palsy worsened to a House-Brackmann grade IV (see Fig. 2A).

FIG. 2.
FIG. 2.

Photographs of the patient obtained at diagnosis (A), after radiation therapy (B), 4 months after beginning ONC201 (C), 8 months after beginning ONC201 (D), and 18 months after beginning ONC201 (E) showing resolution of left facial palsy.

Radiotherapy

A month after initial diagnosis and 2 weeks after biopsy, intensity-modulated radiotherapy (IMRT; 59.4 Gy in 33 fractions) was initiated. IMRT was completed within 7 weeks with no improvement in the left-sided hearing loss, gait ataxia, or facial palsy. MRI performed 1 month following IMRT demonstrated no measureable change in tumor size.

Compassionate-Use Study of ONC201

Because of the lack of substantial response to radiotherapy, we designed an investigator-initiated, open-label compassionate-use study of ONC201 involving 1 pediatric patient in cooperation with Oncoceutics, which provided the study medication and regulatory support. The Miami Cancer Institute IRB and the FDA approved our single-patient compassionate-use protocol. The patient’s parents provided written informed consent, understanding that there was a mechanistic rationale for the use of the agent, but no prior clinically demonstrated activity in a pediatric case of DIPG.

History and physical examinations, a complete blood count, a comprehensive metabolic panel, evaluation of serum magnesium and phosphorus levels, and urinalysis were performed every 4 weeks. The patient and her family maintained a treatment diary of medications and symptoms, and the information was submitted to the primary investigator every 4 weeks.

Gadolinium-enhanced MRI and electrocardiography were performed at baseline and subsequently every 8 weeks. The MRI protocol included axial and sagittal T1-weighted images with coronal FLAIR, axial dual echo, coronal inversion recovery T2-weighted sequences, and gadolinium-enhanced axial, sagittal, and coronal T1-weighted sequences. The principal investigator (M.D.H.) measured the dimensions of the tumor at the centroid on the baseline examination and all surveillance MR images using the coronal T2-weighted series, since the tumor was predominantly nonenhancing, but hyperintense on T2-weighted images. The principal investigator delineated the tumor volume on each slice of the T2-weighted sequence in VelocityAI version 3.2.1 (Varian Medical Systems). This was repeated for each MRI study.

Pre-Treatment Evaluation

A pre–drug treatment baseline examination was performed 3 months after the initial MRI-based diagnosis. The findings were notable for stable to minimally improved grade IV facial palsy and unchanged left-sided hearing loss. On examination, the patient had clinically stable cerebellar dysmetria and gait ataxia. She had tapered off dexamethasone treatment by this time. As can be seen in Fig. 2B, she had a partial return of the left nasolabial fold compared to the baseline image, but she otherwise had stable House-Brackmann grade IV palsy. MRI demonstrated minimal change in the extent of enhancement and no significant change in the size of the tumor compared to baseline (Fig. 1B).

Initiation of ONC201 Treatment

Three months after initial presentation, and 1 month after radiotherapy, she began ONC201 treatment. She received a fixed, weekly oral dose of 500 mg, selected by body weight–based scaling of the recommended phase II dose established in adults.24

Clinical Improvement

After 2 months of therapy (5 months from initial diagnosis), the patient reported subjective improvement in her left-side hearing; her facial palsy remained House-Brackmann grade IV. After 4 months of therapy (7 months from initial diagnosis), near-complete resolution of her left facial palsy was observed, as can be seen in Fig. 1C, which demonstrates minimal flattening of the left corner of her mouth. She could now completely close her eye and reported no dryness or other symptoms—consistent with a House-Brackman grade I palsy. She reported normal hearing bilaterally and had no signs or symptoms of cerebellar dysmetria, ataxia, or gait disturbance. She discontinued lubricants for dry eye by 4 months on therapy. Figure 1D demonstrates her facial appearance after 8 months of ONC201 therapy (11 months from presentation).

Imaging Assessment

Surveillance MRI demonstrated a consistent decrease in size of the primary tumor and absence of enhancement over the first 6 months of therapy with ONC201, consistent with a partial response according to the RECIST 1.1 (Response Evaluation Criteria In Solid Tumors version 1.1) guideline. The measured tumor volume sequentially decreased by 44% over the next 3 MRI studies. Table 1 illustrates the dimensions and volume of the primary tumor as measured in the VelocityAI software. Figure 2C demonstrates the residual tumor on MRI after 6 months on ONC201. As of this writing, no significant change was observed in the size of the primary tumor from month 6 to the most recent MRI study, 18 months after the initiation of ONC201 treatment.

TABLE 1.

Primary tumor dimensions, volumes, and percentage change during therapy

Months after DxImaging EventTumor Dimensions (cm)Tumor Size (cm3)Percentage ChangeMonths on Agent
0Post-op MRI2.3 × 2.1 × 2.85.83NA0
2Radiotherapy completed
3Post-RT MRI2.2 × 2.0 × 2.85.78−0.8%0
3ONC201 initiated
5Protocol MRI2.0 × 1.7 × 1.94.32−25.9%2
7Protocol MRI1.9 × 1.8 × 1.83.52−39.6%4
9Protocol MRI1.8 × 1.7 × 1.73.27−43.8%6
11Protocol MRI1.7 × 1.7 × 1.63.27−43.9%8
13Protocol MRI1.7 × 1.7 × 1.83.29−43.6%10
15Progression MRI1.7 × 2.1 × 2.03.53−39.5%12
17Protocol MRI1.7 × 1.8 × 2.03.42−41.3%14
19Protocol MRI1.7 × 1.7 × 2.03.24−44.4%16
21Protocol MRI1.7 × 1.8 × 2.03.32−44.8%18
22Last evaluation19

Dx = diagnosis; NA = not applicable; RT = radiotherapy.

Safety and Adverse Events

No treatment-related side effects were observed or reported since initiation of ONC201 treatment. No hematological, serum electrolyte, urinalysis, or electrocardiographic abnormalities have been observed.

Distant Failure

After 12 months on ONC201, the patient developed new right hemiparesis. MRI demonstrated that the primary tumor remained relatively stable in size (Fig. 2D), but there were new lesions in the thalamus and cerebellum located outside of the high-dose target volume from the first course of radiotherapy and consistent with tumor (Fig. 3A). Treatment with dexamethasone and bevacizumab was initiated, and the patient underwent another course of radiation therapy, with 39 Gy delivered in 13 fractions to these new tumors. Of note, the primary tumor was not re-treated. ONC201 treatment was continued. Subsequent imaging demonstrated stability in the size of the treated lesions.

FIG. 3.
FIG. 3.

A: MR images obtained after 12 months on therapy with ONC201, which demonstrated new lesions in the thalamus and cerebellum, which were outside of the high-dose region during the original course of radiotherapy. The lesions were treated with IMRT. B: MR images obtained 6 months after irradiation of the 2 new lesions. In both panels, the first and third images (reading from left to right) are axial FLAIR images and the second and fourth are coronal T2-weighted images.

Current Status

Presently, the patient continues to receive ONC201 therapy (for over 19 months as of this writing). She has again discontinued dexamethasone and takes no other medications except ONC201. She continues in school and participates in her normal activities at 22 months since diagnosis. Both the primary tumor (Fig. 1E) and the 2 new lesions (Fig. 3B) remain radiographically stable at the most recent follow-up, 7 months following her second course of radiotherapy.

Discussion

Diffuse intrinsic pontine glioma (DIPG) remains a uniformly lethal disease with no demonstrable improvements in outcome with any therapies to date.

The identification of the H3 K27M mutation has reignited enthusiasm for targeted therapies for diffuse midline gliomas expressing this mutation, but until recently no agent was known to target this mutation. Lysine 27, located in the conserved N-terminal tail of histone H3, is a component of the nucleosome and is responsible for broad epigenetic regulation of gene expression or silencing through its acetylation or methylation, respectively. The H3 K27M mutation often co-occurs with mutations in TP53, PDGFR, or ACVR1 and is mutually exclusive to mutations conferring a more favorable prognosis, including IDH mutation and 1p/19q co-deletion.5,26 Gene silencing occurs through trimethylation of H3 K27 by the polycomb repressor complex 2 (PRC2) that is catalytically inhibited by H3 K27M.4,12,15 This leads to hyperacetylation of the remaining wild-type histone H3 variants and enhanced oncogenic transcription associated with heterotypic H3 K27M/H3 K27–acetylated nucleosome. Prior efforts to target this epigenetic aberrancy have focused on the HDAC inhibitor panobinostat,8 inhibition of EZH2,19 and inhibition of CDK7 or BRD4,20 which have proven effective in preclinical models. Clinical trials examining novel targeted therapies for DIPG, including panobinostat, WEE1 inhibitors, and other novel agents, are ongoing (NCT02717455; NCT01922076; and NCT03696355).

Here, we describe the mechanism of action of ONC201 as a potential targeted therapy for H3 K27M–mutant DIPG. On therapy, our patient derived a clinically significant radiographic response, near-complete resolution of her grade IV facial palsy (which has not been evidenced following standard therapies to date), hearing normalization, and reversal of ataxic gait. The clinical and radiographic response was sustained for more than 1 year on therapy. The patient developed out-of-field failure and received a second course of radiation therapy directed at these 2 new lesions while continuing ONC201 at 22 months since diagnosis.

This report is clearly limited, as it describes only a single-patient experience. Although radiographic responses by RECIST are uncommon in DIPG, the response and disease course observed in this case may be related to radiotherapy alone or other factors. Distant failure is infrequently observed in DIPG, but this finding has been increasingly observed in patients with H3 K27M–mutant gliomas in ongoing clinical investigations of ONC201. The significance of this finding, whether it may be due to increased imaging surveillance or may reflect a change in patterns of failure in this population, and its implications remain uncertain. However, given the lack of any meaningful established therapies for this disease, and with an identifiable mutation underlying a molecular mechanism of action, these results support the ongoing clinical investigation of ONC201 for the treatment of H3 K27M–mutant gliomas to examine the safety profile and efficacy of this agent (NCT03416530; NCT03295396; and NCT02525692).

Disclosures

J.E.A., R.T., L.S., and W.O. have ownership/employment relationships with Oncoceutics, which developed ONC201. M.P.M. serves on the Board of Directors of Oncoceutics (with stock options).

Author Contributions

Conception and design: Hall, Odia, Allen, Daghistani, Schalop, Chi, Oster, Mehta. Acquisition of data: Hall, Tarapore, Khatib, Niazi. Analysis and interpretation of data: Hall, Odia, Allen, Tarapore, Khatib, Niazi, Daghistani, Chi, Oster, Mehta. Drafting the article: Hall, Odia, Allen, Tarapore, Mehta. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Hall. Statistical analysis: Hall, Odia, Allen. Administrative/technical/material support: Hall, Allen, Tarapore, Niazi, Schalop, Oster. Study supervision: Hall, Khatib, Daghistani, Mehta.

Supplemental Information

Previous Presentations

Portions of this work were presented in abstract form as proceedings at the 18th International Symposium on Pediatric Neuro-Oncology (ISPNO) in Denver, Colorado, on July 2, 2018.

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  • Axial FLAIR (upper row) and coronal T2-weighted (lower row) MR images illustrating the primary tumor in the left cerebellopontine angle at diagnosis (A), 1 month after radiotherapy (B), 6 months after beginning ONC201 (C), 12 months after beginning ONC201 (D), and 18 months after beginning ONC201 (E). Of note, the patient developed sites of tumor progression outside of the high-dose region 12 months after beginning ONC201.

  • Photographs of the patient obtained at diagnosis (A), after radiation therapy (B), 4 months after beginning ONC201 (C), 8 months after beginning ONC201 (D), and 18 months after beginning ONC201 (E) showing resolution of left facial palsy.

  • A: MR images obtained after 12 months on therapy with ONC201, which demonstrated new lesions in the thalamus and cerebellum, which were outside of the high-dose region during the original course of radiotherapy. The lesions were treated with IMRT. B: MR images obtained 6 months after irradiation of the 2 new lesions. In both panels, the first and third images (reading from left to right) are axial FLAIR images and the second and fourth are coronal T2-weighted images.

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