Nivolumab + DAY101 for Craniopharyngioma

(PNOC029 Trial)

Recruiting at 15 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

56 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug combination Nivolumab and DAY101 for treating craniopharyngioma?

Research shows that papillary craniopharyngiomas with BRAF V600E mutations respond well to BRAF/MEK inhibitors, and both craniopharyngioma types express PD-L1, suggesting potential effectiveness of immune checkpoint inhibitors like Nivolumab. ^{1 2 3 4 5}

How is the drug combination of Nivolumab and DAY101 unique for treating craniopharyngioma?

The combination of Nivolumab and DAY101 is unique because Nivolumab is an immunotherapy drug that helps the immune system attack cancer cells, and DAY101 is a targeted therapy that inhibits specific proteins involved in tumor growth. This combination may offer a novel approach for craniopharyngioma, a condition with limited standard treatment options. ^{6 7 8 9 10}

Research Team

Sabine Mueller, MD, PhD, MAS

Principal Investigator

University of California, San Francisco

Cassie Kline, MD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Group 2, Arm D: Non-biopsy/resection participants Experimental Treatment 2 Interventions

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.

Group II: Group 2, Arm C: Neoadjuvant combination nivolumab and Tovorafenib Experimental Treatment 2 Interventions

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.

Group III: Group 2, Arm B: Neoadjuvant Tovorafenib Experimental Treatment 2 Interventions

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.

Group IV: Group 2, Arm A: Neoadjuvant nivolumab Experimental Treatment 1 Intervention

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.

Group V: Group 1, Arm C: Neoadjuvant combination nivolumab and Tovorafenib Experimental Treatment 2 Interventions

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.

Group VI: Group 1, Arm B: Neoadjuvant Tovorafenib Experimental Treatment 2 Interventions

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.

Group VII: Group 1, Arm A: Neoadjuvant nivolumab Experimental Treatment 1 Intervention

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.

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. Germany 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). [2022]

2. United States pubmed.ncbi.nlm.nih.gov

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

3. England pubmed.ncbi.nlm.nih.gov

Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Treatment and outcome of the Dutch Childhood Craniopharyngioma Cohort study: First results after centralization of care. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Case report and literature review of BRAF-V600 inhibitors for treatment of papillary craniopharyngiomas: A potential treatment paradigm shift. [2022]

6. England 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. [2020]

7. England 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. [2020]

8. England 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. [2020]

9. United States 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). [2022]

10. England 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. [2023]