Lay Summary

This proposal is designed to help support a novel international clinical trial for children with the highly morbid brain tumor, Adamantinomatous Craniopharyngioma (ACP). 

ACP is a solid/cystic tumor that originates in the sellar/suprasellar region at the base of the brain, adjacent to critical structures for vision, hormone balance, and basic body functions (including metabolism, weight control and concentration). Therapy has depended heavily on surgery and radiation for over 50 years. This paradigm has been associated with the lowest quality of life scores of any pediatric brain tumor. No biologically-guided anti-tumor therapies have been established for ACP, largely based on a lack of preclinical models and resultant absence of candidate therapies for clinical trials. Recently, however, basic research has identified potential therapeutic vulnerabilities and available candidate anti-tumor therapies. Pilot clinical experience with these agents supports their efficacy against ACP. To determine if these therapies are truly efficacious, we designed 2 parallel novel multicenter international clinical trials, which will be offered through the CONNECT Consortium. This proposal, and its companion, request support for the administration of these trials, to supplement funding that has been negotiated with industry. 

This trial (which is paired with a parallel trial) hypothesizes that single-agent binimetinib (a selective small molecule inhibitor of MEK) will be safe and effective at inducing tumor response in children with residual ACP. Children from age 1-25 years who have tumor that can be identified on MRI will be eligible. Patients will fall into 1 of 2 groups: those who have previously been treated with radiation therapy and those who have not. These groups will be enrolled and followed separately because the response of tumor after radiation may differ from that of tumor that has not been exposed to radiation. In addition, the patient population that has received radiation is likely to differ from that who has not. Each group will include up to 19 patients. Therapy will be delivered intravenously once every 2 weeks, for up to 2 years. This is in accordance with the regimen that has been well established in children with other illnesses who receive tocilizumab. It is also the regimen that has been used in our patients with ACP who have been treated on a small pilot trial at Children’s Hospital Colorado and on a compassionate use basis at multiple institutions in the US and Europe. 

Personnel

Todd C. Hankinson: Study Chair

Dr. Hankinson is professor and head of pediatric neurosurgery at Children’s Hospital Colorado/University of Colorado. He established and leads Advancing Treatment for Pediatric Craniopharyngioma (ATPC), a North American consortium dedicated to ACP research. He has developed multiple local, national and international collaborations and a record of external funding. His laboratory contributed to the initial data indicating that MEK inhibition may have benefit against ACP, which was led by the laboratory of Dr. Juan Pedro Martinez-Barbera. Dr. Martinez-Barbera is a close collaborator of Dr. Hankinson and is based at a CONNECT institution, University College London/Great Ormond Street Hospital. Together with Dr. Dorris and the CONNECT team, Dr. Hankinson developed the clinical trial protocol in this proposal. 

Kathleen Dorris: Co-Investigator

Dr. Dorris is an Associate Professor of Pediatrics at University of Colorado School of Medicine.  She is the Clinical Lead for the Neuro-Oncology group at Children’s Hospital Colorado.  She has extensive training and experience with clinical trial design, activation and conduct and has a Master of Science degree in Clinical Research. She collaborates with laboratory-based researchers to pursue the most rational molecular targets in the context of early phase clinical trials. She is the CHCO Site Principal Investigator (PI) for the Pediatric Brain Tumor Consortium (PBTC) and CONNECT Consortium.

COllaborative Network for NEuro-oncology Clinical Trials (CONNECT)

Established in 2018, CONNECT is an international collaborative network that fills a critical gap between Phase I and Phase II/III trials by conducting smaller, scientifically rational trials that demonstrate the safety and feasibility of novel agents and therapeutic modalities for children with high-risk brain tumors.

The CONNECT Operations staff of 8 brings over 50 years of clinical trial experience in protocol coordination and trial design, regulatory, study management and biostatistics. Based at Nationwide Children’s Hospital, the consortium has 3 trials that are open or recently completed, and is funded by support from the FDA, industry and philanthropy. 

ACP does not fall into CONNECT’s typical portfolio of tumors with high short term mortality rates. The unique combination of clinical and biological data, absence of available trials, and CONNECT member sites (Colorado and University College London) leading basic science research in ACP led to this trial having high priority with the group, which has enthusiastically developed the protocol that this proposal will support. 

Executive Summary

Hypothesis: Systemically delivered single-agent binimetinib will be safe and effective at inducing tumor response in a multicenter, international cohort of children with residual ACP

Goals:

Primary Aims:

1. Following treatment with systemic binimetinib, a sustained (>8 weeks) objective response rate [minor response (MR) + partial response (PR) + complete response (CR)] will be identified in at least 35% of patients with recurrent/progressive previously irradiated Adamantinomatous Craniopharyngioma (ACP) (Stratum 1).

2.  Following treatment with systemic binimetinib, a sustained (>8 weeks) objective response rate (MR + PR + CR) will be identified in at least 35% of patients with residual, unresectable, recurrent or progressive Adamantinomatous Craniopharyngioma (ACP) (Stratum 2).

Secondary Aims:

1. In children with recurrent or refractory ACP, toxicity associated with binimetinib will be similar to that which has been established in other pediatric populations. Less than 10% of patients will be removed from study due to medication related toxicity. 

2. One-year progression-free survival rates for patients with ACP who are treated with binimetinib single-agent therapy following progression after radiation (Stratum 1) will be determined.

3. One-year progression-free survival rates for patients with ACP who are treated with binimetinib single-agent therapy who have not been previously received radiation (Stratum 2) will be determined.

Background:

Adamantinomatous craniopharyngioma (ACP) is a neurologically devastating tumor that accounts for 4% of all central nervous system (CNS) tumors in children less than 14 years of age. ACPs sellar/suprasellar location and propensity for cyst formation and hypothalamic infiltration lead to severe disability. As such, the social and economic burdens of ACP far outweigh the mortality risk (2-year overall survival ~90%). Therapy for ACP is principally limited to surgical resection and radiation therapy (RT). This paradigm has remained largely stagnant for over 50 years, in large part due to a lack of appropriate preclinical models for biologic discovery and a resultant paucity of clinical trials. Though complete resection of ACP can be curative, it is often not attainable given the proximity of this tumor to critical neurologic structures. Further, regardless of extent of resection, the recurrence risk remains considerable (20-50%). RT, though effective, carries significant morbidity. Permanent deleterious effects on behavior, learning, vision, and endocrine function following surgery and/or RT are common in children with ACP. Hypothalamic damage including obesity, impaired socialization, and poor academic performance are often not remediable and are associated with decreased life expectancy. Hence, ACP, as currently treated, is associated with the lowest quality of life scores of any pediatric brain tumor[Foreman 99]. Effective chemo- or immunotherapeutic strategies as an alternative to RT and/or aggressive surgery, particularly for young children, would be of tremendous benefit both in terms of overall survival and quality of life. This proposal leverages the combination of one of North America’s leading translational research laboratories in Craniopharyngioma with an agile international clinical trials consortium to execute an unprecedented international clinical trial of targeted therapy against ACP. This trial is paired with a parallel trial that is detailed in a companion proposal.

Binimetinib is an oral, highly selective reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity.  Binimetinib’s biological activity has been evaluated through in vitro and animal xenograft studies involving a wide variety of tumor types. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cell-free assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models^{[Mektovi, Pfizer]}.

Apps and Martinez-Barbera have demonstrated activation of the MAPK/ERK pathway in both genetically engineered mouse models of ACP and human ACP tissue.  Short term treatment of xenograft ACP models or patient-derived ACP specimens with MEK inhibitors, trametinib or binimetinib, decreased levels of the downstream effector, pERK 1/2^{[Apps ‘18]}. Importantly, reduction of pERK1/2 was associated with a significant reduction in tumor cell proliferation and a significant increase in tumor cell apoptosis, thereby offering evidence that MEK inhibition may have a role in ACP tumor control. Additionally, recent data from our group suggests that the MAPK pathway remains active in both primary and relapsed tumors (Martinez-Barbera JP, unpublished data).

Binimetinib Experience in Children

Binimetinib is a member of a class of drugs, MEK1/2 inhibitors that is increasingly used in pediatric oncology

To date, no formal studies of MEK inhibitors have been conducted in patients with ACP.  Patel and colleagues reported a case of a 26 year old patient who was diagnosed with ACP at 6 years of age^{[Patel ‘21]}.  After multiple failed therapies, including surgery and radiation, the patient demonstrated a radiographic response to single agent binimetinib, which overall was tolerated well but did require dose reduction during the course of therapy.

 

Clinical Significance

This proposal has the potential to dramatically alter the management options for patients and families afflicted with ACP, a tumor that has been associated with the lowest quality of life scores of any pediatric brain tumor. Treatment advances for these patients are long overdue and lag behind those of other pediatric cancers, largely due to a lack of biological insight and well-designed clinical trials. Through multi-institutional collaboration, we have recently begun to obtain actionable biological insight regarding ACP. This trial represents the first multicenter translation of these insights into patient care.  Due to the great need for systemic ACP therapies that may be associated with fewer long-term toxicities than standard-of-care treatments of surgery and radiation, there is significant enthusiasm for this trial in the ACP community, including patients, clinicians and researchers. 

This trial and the underlying process are highly innovative in the context of ACP. This study, along with the companion trial described in a parallel proposal, will be the second ever trial of systemic therapy against ACP, and the first that builds on a rationale rooted in the cell biology of ACP. The use of a basic multicenter consortium (Advancing Treatment for Pediatric Craniopharyngioma) combined with an international laboratory collaboration (Hankinson and Martinez-Barbera labs) to derive the basic science foundations of this study is unique in ACP. To subsequently translate these findings through a sophisticated international clinical trials organization (CONNECT) demonstrates a thoughtful stepwise progression and commitment to improving the plight of children with ACP.

 

Design and Methods

This proposal describes one of two paired clinical trials, both for therapies with a biological rationale for the treatment of ACP. While beyond the scope of this proposal, a trial of combination therapy will be designed if the results of these 2 trials support the concept.

This Phase 2 study is designed to assess whether MAPK/ERK pathway blockers demonstrate clinical efficacy in the treatment of pediatric ACP. It is well established that current state therapies are not associated with optimal outcomes, especially with regard to quality of life. No targeted systemic therapies have been established for the treatment of ACP. Recent preclinical data and one case report indicate that MEK inhibition (binimetinib) may have efficacy against ACP. Due to the epidemiology of this uncommon tumor, a multicenter, international study cohort is ideal to test the hypothesis that single-agent binimetinib will be safe and effective at inducing tumor response in children with ACP. In addition, this study will provide valuable feasibility data for future clinical trials involving ACP. The study design includes two enrolling arms based on prior therapy, acknowledging that prior treatment with radiation is both common, and may alter the efficacy of MEK inhibition. The study design also leverages the fact that pediatric dosing and safety data are established. Eligibility will include patients aged >1 year and <25 years with ACP who have been treated with any combination of surgery +/- radiation. If surgical intervention is clinically indicated at the time of enrollment, or subsequently, tissue (cyst fluid/solid tumor or both) will be collected and analyzed using appropriate methods, as described below. Of note, support for these correlative studies is not requested herein, and will be provided through other means.  

 

Up to 19 patients on each stratum will receive binimetinib at the recommended phase 2 pediatric dose (32 mg/m² PO every 12 hours). Cycles will last 28 days. Therapy may continue for up to two years (26 cycles).

 

Study Schema Personnel

Todd C. Hankinson: Study Chair

Dr. Hankinson is professor and head of pediatric neurosurgery at Children’s Hospital Colorado/University of Colorado. He established and leads Advancing Treatment for Pediatric Craniopharyngioma (ATPC), a North American consortium dedicated to ACP research. He has developed multiple local, national and international collaborations and a record of external funding. His laboratory contributed to the initial data indicating that MEK inhibition may have benefit against ACP, which was led by the laboratory of Dr. Juan Pedro Martinez-Barbera. Dr. Martinez-Barbera is a close collaborator of Dr. Hankinson and is based at a CONNECT institution, University College London/Great Ormond Street Hospital. Together with Dr. Dorris and the CONNECT team, Dr. Hankinson developed the clinical trial protocol in this proposal.

Kathleen Dorris: Co-Investigator

Dr. Dorris is an Associate Professor of Pediatrics at University of Colorado School of Medicine.  She is the Clinical Lead for the Neuro-Oncology group at Children’s Hospital Colorado.  She has extensive training and experience with clinical trial design, activation and conduct and has a Master of Science degree in Clinical Research. She collaborates with laboratory-based researchers to pursue the most rational molecular targets in the context of early phase clinical trials. She is the CHCO Site Principal Investigator (PI) for the Pediatric Brain Tumor Consortium (PBTC) and CONNECT Consortium.

COllaborative Network for NEuro-oncology Clinical Trials (CONNECT)

Established in 2018, CONNECT is an international collaborative network that fills a critical gap between Phase I and Phase II/III trials by conducting smaller, scientifically rational trials that demonstrate the safety and feasibility of novel agents and therapeutic modalities for children with high-risk brain tumors.

The CONNECT Operations staff of eight brings over 50 years of clinical trial experience in protocol coordination and trial design, regulatory, study management and biostatistics. Based at Nationwide Children’s Hospital, the consortium has three trials that are open or recently completed, and is funded by support from the FDA, industry and philanthropy.

Description of Research Proposal

Budget

Collaborations and Conflicts of Interest