Neoplasms

All Conditions

Musculoskeletal Diseases

Rare Diseases

Craniopharyngioma

Adamantinoma

Ameloblastoma

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Bone Neoplasms

Bone Diseases

Neuroepithelioma

Pediatrics who have a tumor specimen that is suspected to be craniopharyngioma, but is deemed superfluous to the clinical care of the patient (e.g. pathological diagnosis).

If available, specimen will be sampled from within the tumor, and not include portions of the tumor capsule. If the tumor includes a cyst, fluid from the cyst will be sampled if available. For each tumor specimen, a companion sample of blood that would otherwise be disposed of through usual clinical practice in the operating room will also be collected.

Tumor and Blood Specimens

Todd Hankinson, MD

New data suggests that the current treatment for pediatric adamantinomatous craniopharyngioma (CPA) may not be as effective as it could be.

Current treatment regimens for pediatric CPA are limited to surgery and radiation therapy. This pilot study seeks to identify biologically rational therapeutics for the medical treatment of adamantinomatous CPA by confirming the overexpression of specific molecules.

Prospective Pilot Study Identifying Clinically Relevant Biological Targets for Medical Therapy

Advancing Treatment for Pediatric Craniopharyngioma: Prospective Pilot Study Identifying Clinically Relevant Biological Targets for Medical Therapy

Investigators will identify potential therapeutic targets through mRNA expression.

Investigators will identify potential therapeutic targets through microarray analysis.

Investigators will identify potential therapeutic targets immunohistochemistry.

Investigators will identify potential therapeutic targets through quantitative PCR.

Investigators will also perform immunostaining for beta-catenin and use DNA SNaPshot analysis to determine what parts of the tumor are responsible for observed gene signatures.

The amount of time the patient survives with or without the disease.

The amount of time the patient survives without advancement of disease.

With regard to visual deficits, investigators will compare the rates of functional blindness, unilateral blindness, and visual field deficit.

With regard to pituitary function, investigators will assess patients based on the quality of life impairment that is associated with their dysfunction. Assessment will be divided among 4 groups:

1. No dependence on hormone supplementation or evidence of diabetes insipidus
2. Dependence on 1 or 2 hormone supplements without diabetes insipidus
3. The presence of diabetes insipidus with or without the need for 2 or fewer hormone supplements
4. Diabetes Insipidus with panhypopituitarism

University of Colorado, Denver

Symptoms and General Pathology

Recurrence

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Participants with newly diagnosed craniopharyngioma will receive one (1) dose of nivolumab within 14 days - 5 days prior to planned biopsy or resection. At completion of biopsy or resection, participants having undergone biopsy only or sub-total (STR) or near-total resection (NTR) will continue on combination maintenance therapy of nivolumab given every 2 weeks and Tovorafenib once weekly at the respected recommended phase 2 dose (RP2D) for each agent. Participants having undergone a gross total resection (GTR) will enter into follow-up only and will be part of the exploratory cohort.

Participants with newly diagnosed craniopharyngioma will receive one (1) dose of Tovorafenib within 7 days +/- 2 days prior to planned biopsy or resection. At completion of biopsy or resection, participants having undergone biopsy only or sub-total (STR) or near-total resection (NTR) will continue on combination maintenance therapy of nivolumab given every 2 weeks and Tovorafenib once weekly at the respected RP2D for each agent . Participants having undergone a gross total resection (GTR) will enter into follow-up only and will be part of the exploratory cohort.

Participants with newly diagnosed craniopharyngioma will receive one (1) dose of nivolumab (14 days -5 days prior) and one dose of Tovorafenib (7days +/- 2 days prior) to planned biopsy or resection. At completion of biopsy or resection, participants having undergone biopsy only or sub-total (STR) or near-total resection (NTR) will continue on combination maintenance therapy of nivolumab given every 2 weeks and Tovorafenib once weekly at the respected RP2D for each agent. Participants having undergone a gross total resection (GTR) will enter into follow-up only and will be part of the exploratory cohort.

Participants with recurrent craniopharyngioma will receive one (1) dose of nivolumab within 14 days - 5 days prior to planned biopsy or resection. At completion of biopsy or resection, participants having undergone biopsy only or STR or NTR will continue on combination maintenance therapy of nivolumab given every 2 weeks and Tovorafenib once weekly at the respected RP2D for each agent. If participants are eligible based on archival tissue alone, these participants will go directly on to receive combination therapy only.

Participants with recurrent craniopharyngioma will receive one (1) dose of Tovorafenib within 7 days +/- 2 days prior to planned biopsy or resection. At completion of biopsy or resection, participants having undergone biopsy only or STR or NTR will continue on combination maintenance therapy of nivolumab given every 2 weeks and Tovorafenib once weekly at the respected RP2D for each agent.

Participants with recurrent craniopharyngioma will receive one (1) dose of nivolumab (14 days -5 days prior) and one (1) dose of Tovorafenib (7 days +/- 2 days) prior to planned biopsy or resection. At completion of biopsy or resection, participants having undergone biopsy only or STR or NTR will continue on combination maintenance therapy of nivolumab given every 2 weeks and Tovorafenib once weekly at the respected RP2D for each agent.

Non-biopsy/resection participants with recurrent disease will receive combination maintenance therapy of nivolumab given every 2 weeks and Tovorafenib once weekly at the respected RP2D for each agent.

Tovorafenib

PNOC Operations Office

Lanipua Yeh-Nayre

Jennifer Elster, MD

Carole Johnson

Sabine Mueller, MD, PhD, MAS

Alex Newhouse

Ashley Plant-Fox, MD

Daniel Runco, MD, MS

Runco Daniel, MD, MS

Lianne Greenspan

Susan Chi, MD

Lisa Murray

Mohamed Shebl Abdelbaki, MD

Anna Yaffe

Jessica Clymer, MD

Cassie Kline, MD, MAS

Susan Burlingame

Manju George

Fatema Malbari, MD

Cassie Kline, MD

The current study assesses the tolerability and efficacy of combination therapy with PD-1 (nivolumab) and pan-RAF-kinase (Tovorafenib) inhibition for the treatment of children and young adults with craniopharyngioma.

PRIMARY OBJECTIVE:

I. To determine progression free survival and maintenance of quality of life at 12 months as based on physical function and compared to historical controls.

SECONDARY OBJECTIVES:

I. To identify proportion of participants with visual deficits at 1-year, 2-year, and 3-year follow-up.

II. To identify proportion of participants with neuroendocrine deficits at 1-year, 2-year, and 3-year follow-up.

EXPLORATORY OBJECTIVES:

I. To assess Quality of Life (QOL) and cognitive measures in children and young adults with newly diagnosed or recurrent craniopharyngioma.

II. To perform Immunohistochemistry (IHC)/Multiplexed ion beam imaging on pre-and post-treatment tumor tissue (as available), including at time of progression, to assess for patterns of protein density and spatial relationship in intact tumor tissue and elucidate changes in tumor tissue over the course of therapy and disease evolution.

III. To perform single-cell (scRNA) RNA sequencing on pre- and post-treatment tumor tissue (as available), including at time of progression, to identify and characterize distinct cell subsets that make up the components of craniopharyngioma and elucidate changes in cell subsets over the course of therapy and disease evolution.

IV. To perform proteomic analysis on pre- and post-treatment tumor tissue, including at time of progression, to characterize distinct proteins and transcriptome pathways that are active in different tumor compartments and elucidate changes in proteomic profiles over the course of therapy and disease evolution.

V. To perform ELISA array/multiplex analysis on pre- and post-treatment cyst fluid, including at time of progression, to characterize distinct cytokine profiles and elucidate changes in cytokine profile over the course of therapy and disease evolution.

VI. Microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistic.

VII. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures.

VIII. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures in the context of race ethnicity and other health related social risks.

IX. To assess on therapy toxicity in the context of race, ethnicity and other health related social risks.

TREATMENT GROUPS:

Participants will be divided into 2 Groups (newly diagnosed craniopharyngioma, recurrent craniopharyngioma without histological diagnosis) with 3 treatment arms within each group (Neoadjuvant nivolumab, Neoadjuvant Tovorafenib, Neoadjuvant combination nivolumab plus Tovorafenib). There will also be a separate Non-biopsy/resection arm within the Recurrent Craniopharyngioma group.

Participants will be randomized in a 1:1:1 and will receive one dose of assigned drug prior to planned biopsy or resection. Participants with measurable disease will then continue on combination maintenance therapy. Participants may continue treatment for up to 24 months total and will be followed up for 3 years after enrollment into the study.

Nivolumab and Tovorafenib for Treatment of Craniopharyngioma in Children and Young Adults

Nivolumab and Tovorafenib for the Treatment of Newly Diagnosed or Recurrent Craniopharyngioma in Children and Young Adults

Individual participant data after de-identification may be shared with other researchers.

Progression-free survival is defined as the time of documented response until disease progression as defined by Response assessment in neuro-oncology criteria (RANO) criteria. PFS will be reported by overall group at 12 months.

Scores over time from the PedsQL 4.0 Generic Core physical function domain rating form, which have multidimensional child self-report and parent proxy report scales to assess health-related quality of life (QOL) in children, adolescents, and young adults ages 2 - 25 years will be reported. Physical functioning, is the sub-scale of interest for this protocol. Items on the physical functioning sub-scale are scored on a 5-point Likert scale with raw scores ranging from 0- 4. Items are reversed scored and linearly transformed to a 0-100 scale. If more than 50% of the items in the scale are missing, the Scale Scores should not be computed. Higher scores indicate a higher level of physical functioning

Teller acuity testing using Teller Acuity Cards® (TAC) II will be performed on every time participants undergo a radiographic disease assessment. Visual acuity (VA) testing will be performed in each eye separately at a distance of 55 centimeters in all participants. The tester will use the "two down, one up" protocol to achieve the best VA score. Acuity will be reported in logarithm of the minimum angle of resolution (logMAR). Visual field testing will be performed by confrontation and reported as the number of quadrants (0, 1, 2, 3, or 4) with visual field deficits. Optic discs will be assessed for the presence or absence of pallor and edema.The proportion of participants with recorded visual deficits over time based on these assessments will be reported.

The proportion of participants with presence of new neuroendocrine deficits defined as hypothalamic obesity, diabetes insipidus, growth hormone deficiency, adrenal insufficiency from baseline will be reported.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Prospective Pilot Study Identifying Clinically Relevant Biological Targets for Medical Therapy	NCT03610906	Craniopharyngio...	Tumor and Blood...	30 Days - 21 Years	University of Colorado, Denver
Prospective Pilot Study Identifying Clinically Relevant Biological Targets for Medical Therapy	NCT03610906	Craniopharyngio...	Tumor and Blood...	30 Days - 21 Years	University of Colorado, Denver
Nivolumab and Tovorafenib for Treatment of Craniopharyngioma in Children and Young Adults	NCT05465174	Craniopharyngio... Craniopharyngio... Recurrent Crani...	Nivolumab Tovorafenib	1 Year - 39 Years	University of California, San Francisco

Spots Global Cancer Trial Database for craniopharyngioma, child