Nivolumab + DAY101 for Craniopharyngioma

(PNOC029 Trial)

Recruiting at 16 trial locations

Overseen By PNOC Operations Office

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Sabine Mueller, MD, PhD

Must not be taking: Strong CYP2C8 inhibitors

Disqualifiers: Uncontrolled neuroendocrine dysfunction, Cardiovascular disease, Autoimmune disorder, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

57 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for children and young adults with craniopharyngioma, a type of brain tumor. The researchers aim to evaluate the effectiveness of Tovorafenib (also known as DAY101, a pan-RAF-kinase inhibitor) alone or in combination with other treatments. Participants will either be newly diagnosed or have recurring craniopharyngioma, and the trial assesses the tumor's response to the drug before or after surgery. Eligible participants include those with a confirmed diagnosis of craniopharyngioma who are candidates for surgery or have undergone past treatments. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, participants must not have had chemotherapy or radiotherapy within 3 weeks prior to entering the study, and certain medications may need to be discussed with the study chairs. It's best to consult with the trial coordinators about your specific medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Tovorafenib, also known as OJEMDA™, was generally well-tolerated in past studies. In a safety review involving young patients aged 1 to 24, the drug's side effects were manageable. Most patients continued treatment without major issues, and any side effects were usually mild or moderate.

Nivolumab, a type of immunotherapy, has been used safely in other conditions. Many patients tolerate it well, though some may experience side effects like tiredness or a rash, which are typically mild and manageable.

Both Tovorafenib and Nivolumab have been studied for their safety, and current evidence suggests they are safe for many people. However, like any treatment, risks may exist, so discussing any concerns with the trial team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for craniopharyngioma because they offer a fresh approach compared to traditional options like surgery and radiation therapy. DAY101 (also known as Tovorafenib) is a novel inhibitor that targets specific signaling pathways crucial for the growth of these tumors. This targeted approach could mean more effective treatment with potentially fewer side effects compared to conventional therapies. Meanwhile, Nivolumab is an immunotherapy that boosts the body's natural defenses to fight cancer, representing a shift from traditional methods to more personalized medicine. Together, these treatments have the potential to improve outcomes for patients with this challenging condition.

What evidence suggests that this trial's treatments could be effective for craniopharyngioma?

Research has shown that Tovorafenib, a type of medication, may help treat tumors like craniopharyngioma. Participants in this trial will receive Tovorafenib as part of different treatment groups. Studies have found it effective in shrinking tumors with characteristics similar to those in craniopharyngioma. The drug has been approved for use because it significantly reduces tumor size in other conditions, suggesting it might work well in this study too. Although specific data for craniopharyngioma is limited, existing research indicates it could be effective. ^{2 6 7 8 9}

Who Is on the Research Team?

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Cassie Kline, MD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 to 39 with craniopharyngioma, who can undergo surgery. They should not have had certain treatments recently, must be able to provide tissue samples, and have good organ function. Pregnant or breastfeeding women are excluded, as well as those with immune disorders or severe cardiovascular issues.

Inclusion Criteria

I still have visible signs of my disease while on maintenance therapy.

Participants must agree to use adequate contraception if of child-bearing potential

I have been newly diagnosed with craniopharyngioma based on imaging.

Exclusion Criteria

Participants with a history of allergic reactions to study drugs or compounds with similar composition are excluded

I have not received any treatment for my cancer yet.

I do not have unmanaged symptoms from neuroendocrine issues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive one dose of nivolumab and/or Tovorafenib prior to planned biopsy or resection

2 weeks

1 visit (in-person)

Combination Maintenance Therapy

Participants continue on combination maintenance therapy of nivolumab every 2 weeks and Tovorafenib once weekly

Up to 24 months

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• DAY101
• Nivolumab

Trial Overview The study tests the safety and effectiveness of combining Nivolumab (a PD-1 inhibitor) with DAY101 (a pan-RAF kinase inhibitor) in treating craniopharyngioma. It's designed for patients who may be newly diagnosed or have recurrent disease after prior treatments.

How Is the Trial Designed?

Group I: Group 2, Arm B: Non-biopsy/resection participants Experimental Treatment 1 Intervention

Non-biopsy/resection participants with recurrent disease will receive monotherapy of Tovorafenib given once weekly at the respected RP2D.

Group II: Group 2, Arm A: Neoadjuvant Tovorafenib Experimental Treatment 1 Intervention

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 maintenance monotherapy of Tovorafenib given once weekly at the respected RP2D.

Group III: Group 1: Neoadjuvant Tovorafenib Experimental Treatment 1 Intervention

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 maintenance monotherapy of Tovorafenib given once weekly at the respected recommended phase 2 dose (RP2D). Participants having undergone a gross total resection (GTR) will enter into follow-up only and will be part of the exploratory cohort.

DAY101 is already approved in United States for the following indications:

Approved in United States as Ojemda for:

• Pediatric low-grade glioma with BRAF gene mutations

Who Is Running the Clinical Trial?

Sabine Mueller, MD, PhD

Lead Sponsor

Trials

9

Recruited

440+

Day One Biopharmaceuticals, Inc.

Industry Sponsor

Trials

8

Recruited

1,100+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

Vemurafenib combined with cobimetinib has shown effectiveness in treating patients with BRAF-mutant papillary craniopharyngioma, a type of brain tumor.

This combination therapy targets specific mutations, suggesting a tailored approach to treatment that could improve outcomes for affected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF-MEK Inhibition Is Effective in BRAFV600E-Mutant Papillary Craniopharyngioma. [2023]

Both adamantinomatous (ACP) and papillary craniopharyngiomas (PCP) express PD-L1, with ACP showing PD-L1 in the cyst lining and intrinsic PD-1 in certain tumor cells, suggesting a potential target for immunotherapy.

The study indicates that targeting the PD-1/PD-L1 immune checkpoint pathway could be a promising therapeutic strategy for both ACP and PCP, as both subtypes exhibit characteristics that may respond to such treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma. Coy, S., Rashid, R., Lin, JR., et al.[2019]

A 35-year-old man with a BRAF-V600E-positive papillary craniopharyngioma experienced a remarkable 95% reduction in tumor size over 21 months while being treated with the BRAF-V600 inhibitor dabrafenib and trametinib, indicating the efficacy of this targeted therapy.

The treatment was well-tolerated with no negative side effects reported, suggesting that BRAF-V600E inhibition could be a safe and effective non-invasive option for managing this type of tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case report and literature review of BRAF-V600 inhibitors for treatment of papillary craniopharyngiomas: A potential treatment paradigm shift. Nussbaum, PE., Nussbaum, LA., Torok, CM., et al.[2022]

In a comparison of anti-PD-1 drugs for recurrent/metastatic nasopharyngeal carcinoma (RM-NPC), camrelizumab showed the highest objective response rate (34.1%) among second-line therapies, while first-line nivolumab achieved a 40% response rate, indicating its effectiveness in treating this cancer.

Nivolumab and pembrolizumab demonstrated the best safety profiles for managing adverse events, particularly for lower-grade side effects, while camrelizumab combined with chemotherapy resulted in a significantly higher response rate (90.9%) compared to chemotherapy alone (64.1%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative safety and efficacy of anti-PD-1 monotherapy, chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from recent advances in landmark trials. Lv, JW., Li, JY., Luo, LN., et al.[2020]

The JAVELIN Head and Neck 100 study is a Phase III clinical trial investigating the effectiveness of avelumab, a PD-L1 inhibitor, combined with standard chemoradiotherapy (CRT) for high-risk, locoregionally advanced squamous cell carcinomas of the head and neck.

This study addresses a critical gap in research, as there are currently no prospective studies evaluating immune checkpoint inhibitors in the definitive treatment of nonmetastatic HNSCC, which is important for improving outcomes in patients with poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAVELIN Head and Neck 100: a Phase III trial of avelumab and chemoradiation for locally advanced head and neck cancer. Yu, Y., Lee, NY.[2020]

Nivolumab demonstrated a 20.5% objective response rate in patients with recurrent or metastatic nasopharyngeal carcinoma, with a 1-year overall survival rate of 59%, indicating its potential effectiveness as a treatment option.

The study found that patients with PD-L1 positive tumors had a higher response rate, and those with a loss of human leukocyte antigen class 1 proteins experienced better progression-free survival, suggesting that these biomarkers may help predict treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742). Ma, BBY., Lim, WT., Goh, BC., et al.[2022]

In a study of 87 children with craniopharyngioma, hypothalamic obesity was found in 24.7% of patients, and 71.3% experienced panhypopituitarism with diabetes insipidus after a median follow-up of 6.5 years, indicating significant long-term complications from the condition.

Since the centralization of care in 2018, there has been a trend towards improved body mass index (BMI) outcomes, with a decrease in hypothalamic obesity rates from 33.3% to 12.0% after one year, suggesting that centralized treatment may enhance patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment and outcome of the Dutch Childhood Craniopharyngioma Cohort study: First results after centralization of care. Van Schaik, J., Schouten-van Meeteren, AYN., Vos-Kerkhof, E., et al.[2023]

In a phase 3 trial (CheckMate 141) involving 361 patients with recurrent/metastatic squamous cell carcinoma of the head and neck, nivolumab significantly improved overall survival compared to investigator's choice of chemotherapy, with 30-month survival rates of 11.2% for patients under 65 and 13.0% for those 65 and older.

Nivolumab demonstrated a favorable safety profile, with lower rates of treatment-related adverse events compared to traditional chemotherapy, making it a viable option for older patients who may have difficulty tolerating standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab versus investigator's choice in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: Efficacy and safety in CheckMate 141 by age. Saba, NF., Blumenschein, G., Guigay, J., et al.[2020]

The study investigates the safety and efficacy of combining avelumab, an anti-PD-L1 monoclonal antibody, with cetuximab in patients with recurrent or metastatic squamous cell head and neck carcinoma, aiming to improve outcomes beyond the current standard of care.

Up to 16 participants will be enrolled in this phase II trial to assess the safety of the drug combination and determine the optimal dose of cetuximab, with secondary objectives focusing on tumor response and overall survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protocol for the EACH trial: a multicentre phase II study evaluating the safety and antitumour activity of the combination of avelumab, an anti-PD-L1 agent, and cetuximab, as any line treatment for patients with recurrent/metastatic head and neck squamous cell cancer (HNSCC) in the UK. Ng, K., Metcalf, R., Sacco, J., et al.[2023]

In a study of 52 craniopharyngioma cases, adamantinomatous craniopharyngiomas (ACPs) were found to express PD-1 and showed aberrant β-catenin activity, while papillary craniopharyngiomas (PCPs) predominantly had BRAF mutations, indicating distinct molecular profiles that could guide treatment strategies.

Both ACPs and PCPs exhibited high levels of PD-L1 expression, suggesting potential for immunotherapy; however, there was no significant difference in clinical outcomes between the two variants, highlighting the need for personalized approaches in managing these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Craniopharyngiomas: A clinicopathological and molecular study of 52 cases - Experience in the Complejo Hospitalario de Toledo and Hospital Universitario 12 de Octubre (Madrid). Moreno-Torres, B., Campos-Martín, Y., Meléndez, B., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/show/NCT05465174

Study Details | NCT05465174 | Tovorafenib for Treatment ... The current study assesses the tolerability and efficacy of monotherapy with pan-RAF-kinase (Tovorafenib) inhibition for the treatment of children and young ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11937174/

Current clinical trials for craniopharyngiomas - PubMed Central Case studies have demonstrated efficacy of this approach in ACP but there remains limited prospective data on toxicity and clinical outcomes in ...

3. pharmaceutical-technology.com pharmaceutical-technology.com/data-insights/tovorafenib-day-one-biopharmaceuticals-craniopharyngioma-likelihood-of-approval/

Tovorafenib by Day One Biopharmaceuticals for ... According to GlobalData, Phase II drugs for Craniopharyngioma does not have sufficient historical data to build an indication benchmark PTSR for ...

4. ojemdahcp.com ojemdahcp.com/efficacy

Efficacy Results - OJEMDA™ (tovorafenib) OJEMDA was studied in patients like Emily. LOCATION: 51% had an optic pathway glioma1. HISTOLOGY: 94% had tumors with astrocytic histology3.

5. ir.dayonebio.com ir.dayonebio.com/news-releases/news-release-details/day-ones-ojemdatm-tovorafenib-receives-us-fda-accelerated

Day One's OJEMDA™ (tovorafenib) Receives US FDA ... The approval of OJEMDA was based, in part, on the major efficacy outcome measure of overall response rate (ORR), defined as the proportion ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05465174

Study Details | NCT05465174 | Tovorafenib for Treatment ... 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 ...

7. eocco.com eocco.com/-/media/EOCCO/PDFs/Formulary/EOCCO-tovorafenib-Ojemda-Policy.pdf

tovorafenib (Ojemda™) There is currently no active trial evaluating the use of tovorafenib (Ojemda) in patients with high grade glioma (HGG). There is insufficient ...

8. fda.gov fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-ojemda

Drug Trials Snapshots: OJEMDA In the safety population, the demographics of the patients who received OJEMDA were: median age was 9 years (range: 1 to 24); 53% male; 58% ...

9. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/tovorafenib?pn=1

Clinical Trials Using Tovorafenib - NCI Clinical Trials Using Tovorafenib. Review the clinical trials studying tovorafenib on this list and use the filters to refine the results by age and location.