Neoplasms

All Conditions

Rare Diseases

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Pharmaceutical Solutions

Carboplatin

Vincristine

Vinblastine

Fluorophosphate

Investigator's choice of one of the following current standard of care for pediatric patients with low-grade gliomas:

1. Children's Oncology Group - Vincristine/Carboplatin (COG-V/C)
2. International Society for Paediatric Oncology - Low-Grade Glioma Vincristine/Carboplatin (SIOPe-LGG-V/C)
3. Vinblastine (VBL)

Tovorafenib

Chemotherapeutic Agent

Day One Clinical Trials Information

This is a 2-arm, randomized, open-label, multicenter, global, Phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy versus standard of care (SoC) chemotherapy in patients with pediatric low-grade glioma (LGG) harboring an activating rapidly accelerated fibrosarcoma (RAF) alteration requiring front-line systemic therapy.

Approximately 400 treatment-naïve low-grade glioma patients will be randomized 1:1 to either tovorafenib (Arm 1) or an Investigator's choice of SoC chemotherapy (Arm 2).

Arm 1 (tovorafenib): treatment cycles will repeat every 28 days in the absence of disease progression. Patients will continue tovorafenib until any of the following occurs: disease progression based on Response Assessment in Neuro-Oncology (RANO-LGG) criteria, unacceptable toxicity, withdrawal of consent to treatment, or end of study.

Arm 2 (Investigator's Choice of SoC Chemotherapy): patients will receive one of 3 SoC chemotherapy options selected by the treating Investigator: Children's Oncology Group - Vincristine/Carboplatin (COG-V/C) regimen, International Society for Paediatric Oncology - Low-Grade Glioma Vincristine/Carboplatin (SIOPe-LGG-V/C) regimen, or vinblastine (VBL) regimen. The choice of SoC chemotherapy regimen will be selected prior to patient randomization. Treatment will continue until completion of therapy or until any of the following occurs: disease progression based on RANO-LGG criteria, unacceptable toxicity, withdrawal of consent to treatment, or end of study.

Patients who discontinue treatment due to disease progression will have (1) radiographic evidence of progressive disease based on RANO-LGG, as determined by the Investigator and confirmed by the IRC, or (2) clinical progression based on RANO-LGG criteria determined by the Investigator. Investigators are encouraged to discuss cases of clinical progression and early radiographic progression without clinical symptom with the Sponsor Medical Monitor prior to treatment discontinuation or initiation of a different form of treatment for the malignancy. Patients may continue therapy beyond progressive disease

Tovorafenib versus standard of care chemotherapy

DAY101 vs. Standard of Care Chemotherapy in Pediatric Patients With Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)

LOGGIC/FIREFLY-2: A Phase 3, Randomized, International Multicenter Trial of DAY101 Monotherapy Versus Standard of Care Chemotherapy in Patients With Pediatric Low-Grade Glioma Harboring an Activating RAF Alteration Requiring First-Line Systemic Therapy

ORR, per RANO-LGG criteria, defined as the proportion of patients with overall confirmed response of complete response (CR) or partial response (PR)

PFS per RANO-LGG criteria, deﬁned as time from randomization to PD or death from any cause

DOR per RANO-LGG criteria, deﬁned as time from confirmed response to PD or death from any cause for patients with confirmed response

OS, defined as time from randomization up to death from any cause

Type, frequency, and severity of treatment-emergent adverse events

Measured by incidence of clinically significant laboratory abnormalities

Change from baseline in the Vineland Adaptive Behavior Composite Scales \[age-adjusted standard scores range between 20 to 140, with a mean of 100 and standard deviation of 15, and lower scores indicate worse functional outcomes\]

Measured by Teller Acuity Cards® or alternative

ORR, deﬁned as the proportion of patients with overall conﬁrmed response per RANO-HGG, RANO-LGG, or RAPNO-LGG criteria.

CBR, deﬁned as the proportion of patients with radiological tumor stabilization or regression per RANO-LGG, RANO-HGG or RAPNO-LGG criteria, as applicable

Measured by the time to ﬁrst response following initiation of therapy in patients with best overall conﬁrmed response per RANO-LGG, RANO-HGG or RAPNO-LGG criteria, as applicable

PFS per RANO-HGG or RAPNO-LGG (as applicable), deﬁned as time from randomization to progressive disease (PD) or death from any cause

DOR, deﬁned as time from conﬁrmed response to PD or death from any cause for patients with confirmed response per RANO or RAPNO criteria, as applicable

Measured by change from baseline in Total Score at 1, 2, 5 years

SIOPe Brain Tumor Group LOGGIC Consortium

Day One Biopharmaceuticals, Inc.

Symptoms and General Pathology

Recurrence

Tubulin Modulators

Antimitotic Agents

Tovorafenib for oral dosing is provided as an immediate-release tablet in 100 mg strength. The 100 mg tablets are red to yellowish red oval tablets. All products are labeled tovorafenib. In addition, tovorafenib is provided as a powder for reconstitution (PfR) in bottles (430mg per bottle to deliver 300 mg dose). Upon reconstitution with water, the concentration is 25 mg/mL.

Vinblastine is administered by intravenous route as IV push, sites to follow local administration guidelines, once weekly (central line, but peripheral line is also permitted)

Nirav Thacker

Aiman Siddiqi

Daniel Morgenstern

This is a Pilot, multicenter, open-label study of patients less than or equal to 25 years, with recurrent or progressive LGG harboring a CRAF or BRAF alteration, including BRAF V600 mutations and KIAA1549: BRAF fusions. Patients with BRAF or CRAF alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories.

The study will be conducted in two sequential phases:

Phase A: A Feasibility (combination dose finding) phase, followed by Phase B: An Efficacy phase. The maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of the combination as determined in Phase A would be the dose used in Phase B. The patients on Phase A who were below the MTD/RP2D would be eligible for intra-patient dose escalation to MTD/RP2D subject to criteria outlined later

Phase A (Feasibility Phase) A feasibility phase will be conducted to establish the maximum tolerated dose (MTD/RP2D) of the combination of vinblastine + tovorafenib using the Rolling 6 design.

Patients will receive vinblastine and tovorafenib on Days 1, 8, 15, 22 of each cycle for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days.

Treatment cycles will repeat every 28 days for a total of 24 cycles in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3.

The RP2D of tovorafenib of 420 mg/m2 once weekly (not exceeding 600 mg) in combination with vinblastine (4mg/m2) will be used as the starting dose and will be de-escalated/escalated as per Table 4. Dose of tovorafenib will not be escalated further.

Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression, unacceptable toxicity occurs, or withdrawal from the study occurs. Missed doses of either vinblastine or tovorafenib will not be made up.

Phase B (Expansion/Efficacy Phase) Once the MTD/RP2D of the combination, vinblastine + tovorafenib has been established, the expansion/efficacy phase will be initiated at the dose determined in Phase A.

Patient will receive vinblastine and tovorafenib weekly on Days 1, 8, 15, 22 of each cycle at dose determined in Phase A for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days.

Treatment cycles will repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3.

Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression or unacceptable toxicity occurs, unless disease progression, unacceptable toxicity or withdrawal from study occurs. Missed doses of either vinblastine or tovorafenib will not be made up.

Pilot Study of Vinblastine and Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas

VICTORY: A Pilot Study to Investigate Safety and Efficacy of Weekly Combination of Intravenous Vinblastine With Oral Type II RAF Inhibitor Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas

To determine the maximum tolerated dose (MTD/RP2D) of combination of vinblastine + tovorafenib for children with recurrent/progressive LGGs.

To assess safety and tolerability of combination of vinblastine and tovorafenib in pediatric patients with recurrent/progressive LGG through documentation of number of participants with treatment-related adverse events as assessed by CTCAE v5.0

To determine overall response rate (ORR) of CR, PR and MR in patients with LGG treated with combination of vinblastine + tovorafenib by RANO-LGG criteria.

To characterize pharmacokinetics of tovorafenib and vinblastine in combination in the study population. The following PK parameters will be determined for each agent: Cmax, Tmax, AUC and reported using descriptive summary statistics

DOR for patients with CR, PR or MR based on RANO-LGG criteria

CR, PR and MR plus stable disease which lasts a minimum of 24 weeks by RANO-LGG criteria

The Hospital for Sick Children

Senior Medical Officer

Musculoskeletal Diseases

Craniopharyngioma

Adamantinoma

Ameloblastoma

Bone Neoplasms

Bone Diseases

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.

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
DAY101 vs. Standard of Care Chemotherapy in Pediatric Patients With Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)	NCT05566795	Low-grade Gliom...	Tovorafenib Chemotherapeuti...	- 25 Years	Day One Biopharmaceuticals, Inc.
Pilot Study of Vinblastine and Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas	NCT06381570	Low-grade Gliom...	Tovorafenib	0 Weeks - 25 Years	The Hospital for Sick Children
DAY101 vs. Standard of Care Chemotherapy in Pediatric Patients With Low-Grade Glioma Requiring First-Line Systemic Therapy (LOGGIC/FIREFLY-2)	NCT05566795	Low-grade Gliom...	Tovorafenib Chemotherapeuti...	- 25 Years	Day One Biopharmaceuticals, Inc.
Pilot Study of Vinblastine and Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas	NCT06381570	Low-grade Gliom...	Tovorafenib	0 Weeks - 25 Years	The Hospital for Sick Children
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 tovorafenib

Every month we try and update this database with for tovorafenib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for tovorafenib

Every month we try and update this database with for tovorafenib cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for tovorafenib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.