A PHASE I-II STUDY OF NIACIN IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA: SAFETY AND INTERIM PHASE II ANALYSIS
TITLE PAGE
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RoldanUrgoiti1
G1
P
de
Robles1,2TsangRY1
MWillson2,3
SGhosh4,8
MFaruqi5
GLim5
LoewenSK5
RNordal5
GCairncross1,2
CLeckie1
PoonCC1,2,6,7
YongVW1,2,6,7
Dr.
GloriaRoldanUrgoiti9✉Phone587 231 5098Emailgloria.roldanurgoiti@albertahealthservices.ca1
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Department of Oncology, Division of Medical Oncology, Arthur Child Comprehensive Cancer CentreUniversity of Calgary, Cancer Care AlbertaCalgaryAB2
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Department of Clinical NeurosciencesUniversity of CalgaryCalgaryAB3
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Department of Diagnostic ImagingUniversity of CalgaryCalgaryAB4
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Department of Medical oncologyUniversity of AlbertaEdmontonAB5
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Department of Oncology, Division of Radiation Oncology, Arthur Child Comprehensive Cancer CentreUniversity of CalgaryCalgaryAB6
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Hotchkiss Brain InstituteCalgaryAB7
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Arnie Charbonneau Cancer InstituteCalgaryAB8Division of Biostatistics, Department of Public Health SciencesHenry Ford HealthDetroitMichiganUSA
9Department of Oncology, Division of Medical Oncology, Arthur Child Comprehensive Cancer CentreUniversity of Calgary3395 Hospital Drive NWT2N 5G2Calgary, CalgaryAB, ABCanada
Authors: Roldan Urgoiti G (1,6,7), de Robles P (1,2), Tsang RY (1), Willson M (2,3), Ghosh S (4,8), Faruqi M (5), Lim G (5), Loewen SK (5), Nordal R (5), Cairncross G (1,2), Leckie C (1), Poon CC (1,2,6,7), Yong VW (1,2,6,7).
Department of Oncology, Division of Medical Oncology, University of Calgary, and Arthur Child Comprehensive Cancer Centre, Cancer Care Alberta, Calgary, AB
Department of Clinical Neurosciences, University of Calgary, Calgary, AB
Department of Diagnostic Imaging, University of Calgary, Calgary, AB
Department of Medical oncology, University of Alberta, Edmonton,, AB
Department of Oncology, Division of Radiation Oncology, University of Calgary, and Arthur Child Comprehensive Cancer Centre, Calgary, AB.
Hotchkiss Brain Institute, Calgary, AB
Arnie Charbonneau Cancer Institute, Calgary, AB
Division of Biostatistics, Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA.
Corresponding author:
Dr. Gloria Roldan Urgoiti - ORCID 0000-0002-9762-5415
Department of Oncology, Division of Medical Oncology, University of Calgary and Arthur Child Comprehensive Cancer Centre, Calgary AB
3395 Hospital Drive NW, Calgary, AB, Canada T2N 5G2
Telephone: 587 231 5098; Fax: 587 231 5077
Email: gloria.roldanurgoiti@albertahealthservices.ca
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Acknowledgement
We are grateful to the patients and their families for participating. We appreciate the customer support of Designs For Health. This study was conducted with operating funds from the Canadian Institutes of Health Research and the Alberta Cancer Foundation.
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ABSTRACT
PURPOSE
Survival of patients with glioblastoma (GB) treated with standard of care (SOC) surgery, radiotherapy, and temozolomide is 15 months with progression free survival at 6 months (PFS-6M) of 53.9%. In vivo studies showed increased survival in mice with GB treated with niacin. This is a first in human Phase I-II study aiming to evaluate safety and efficacy of controlled-release niacin (NiacinCRT ™) added to SOC.
METHODS
Patients 18–75 years old with newly diagnosed glioblastoma eligible for SOC treatment were included. Phase I evaluated intra-patient dose escalation of niacin (500–3000 mg/d) to determine dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Phase II aims to determine if niacin adds ≥ 20% absolute increase in PFS-6M over historical controls. Interim/futility analysis was planned when 24 patients become evaluable for PFS-6M. The study would stop if the conditional power (one-sided Z test) < 20% or futility index > 80%.
RESULTS
Phase I included 15 patients; median age: 57 years (37–68), 40% women, and 47% with MGMT promoter methylated. The most common side effect was flushing (10/15; 9 grade 1). Two DLTs occurred at 2,500 mg/d niacin (grade 3 thrombocytopenia and hyperbilirubinemia). Niacin dose escalated up to 2000 mg/d is the ongoing RP2D. Interim analysis by central radiology review reported PFS-6M of 82.3% (CI95% 82.14–82.46%).
CONCLUSION
The MTD dose of niacin added to first line treatment in patients with GB is 2000 mg/d. The interim analysis already showed an absolute increase in PFS-6M of 28%.
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Trial Registration number:1. Local ethics board approval - HREBA cc 20–0402
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Clinicaltrials.gov - NCT04677049. Registered 15 Dec 2020
Keywords:
glioblastoma
niacin
Phase I-II
immunotherapy
Introduction
Glioblastoma (GB or glioma WHO grade IV IDH wild-type) [1] is one of the most aggressive solid tumors in humans. Standard treatment of patients with newly diagnosed GB includes maximal safe resection followed by external beam radiotherapy and oral temozolomide chemotherapy. Unfortunately, GB is not curable and this intensive treatment renders a median overall survival of 14.6 months with less than 10% of the patients alive at 5 years [2]. Attempts to improve outcomes significantly in GB have been unsuccessful during the last 2 decades. While the addition of tumor treating fields in a very selected population of patients with glioblastoma resulted in overall survival of 20.9 months, this device is not publicly available in Canada [3].
Immunotherapy that has been so successful in improving outcomes for other tumor types has not been useful in GB thus far. Chimeric antigen receptor-T cell therapy has not significantly improved lifespan in GB above standard of care[4, 5], nor has the use of immune checkpoint inhibitors [6]. Nonetheless, progress continues to be made on these research fronts[7, 8]. In this context, there is interest in the repurposing of drugs for the treatment of patients with GB [9, 10].
The immune system is suppressed in people with GB, both in the tumor microenvironment [11–13] and in the circulation [14]. In previous work, we described niacin (vitamin B3) to rejuvenate compromised immune cells. For example, the failure of GB patient-derived myeloid cells to curb the growth of brain tumor-initiating cells in culture could be rectified by niacin[15]. Importantly, the growth of patient-derived brain tumor-initiating cells in the brain of mice was slowed by systemic niacin treatment resulting in prolonged lifespan of mice with intracranial tumor[15].
Based on this preclinical data we designed a Phase I-II clinical trial to evaluate the safety of adding niacin to the standard of care of patients with newly diagnosed GB. We sought to identify the maximum tolerated dose and determine if this strategy would improve clinical outcomes.
Materials and Methods
The primary objective of the phase I study was to evaluate tolerance and determine the maximum tolerated dose (MTD) of niacin added to concurrent radiotherapy (RT) and temozolomide (TMZ) in patients with newly diagnosed GB, considered standard of care. For Phase II we aimed to determine if adding niacin to standard of care of GB improves progression free survival at 6 months (PFS6).
Extended-release formulations of niacin are known to have increased tolerability with less flushing and hepatotoxicity than immediate-release products [16]. The formulation used for this study was selected based on published safety data from clinical studies using NiacinCRT™ for the management of dyslipidemias[17–20].
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Selection and Description of Participants
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The study included adult patients from 18–75 years old with newly diagnosed GB (IDH-wild type, CNS WHO grade 4) and ECOG 0–2, considered candidates for standard of care treatment. Patients had adequate hematological, renal and liver function without active HIV, infectious hepatitis or serious medical comorbidities. Exclusion criteria included active peptic ulcer or active gastrointestinal bleeding, or symptomatic gout. Patients on statins (HMG-COA reductase inhibitors) required a washout period of 2 weeks. Patients that had received any prior systemic treatment for GB (standard, evidence based or experimental) or radiotherapy/radiosurgery were excluded. Patients with a history of other malignancies were not included except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years. The protocol was amended to clarify that, any low grade or low risk malignancy not requiring treatment would not exclude a patient from participation in the trial. All eligible patients were offered participation at time of RT consultation and signed informed consent before any trial-related intervention occurred.ii.
Treatment, data collection and measurements
Patients received standard of care of RT (60.0 Gy in 30 daily fractions over 6 weeks; one treatment of 2 Gy daily, five days per week) and temozolomide (75 mg/m2 daily during radiotherapy followed by 150/200 mg/m2 Day 1 to Day 5 monthly for 6 months), referred to as the Stupp protocol [2]. Extension of monthly TMZ to 12 cycles was allowed at the treating physician discretion. Figure 1 describes the trial design.
Fig. 1
– Clinical trial design.
One week before starting RT, niacin was initiated at 500 mg orally (po) at bedtime (qhs) and escalated every 4 weeks as shown Fig. 1. This design allowed the evaluation of safety/tolerance of monotherapy with niacin before standard of care treatment was started. During the phase I part of the study, further escalation to 2500 mg qhs and 4 weeks later to 3000 mg qhs was planned but (as described in Results) the latter level was discontinued for phase II. The 2500 and 3000 mg doses required close monitoring of hematological and liver parameters as they exceeded the standard amount of niacin used for the management of dyslipidemias. Thus, in Phase II, dose escalation occurred as in Phase I, but the highest and subsequent maintenance dose was 2000 mg.
During the concurrent RT-TMZ and niacin, patients had weekly evaluations of bone marrow, and liver and kidney functions. As part of standard of care patients had a weekly review with their radiotherapy oncologist. During this period there was an additional review with the medical oncologist before dose escalation of niacin. During the monthly concurrent niacin and TMZ administration, patients had blood work and a clinical appointment prior to each cycle of TMZ and subsequent escalation of niacin. The dose escalation of niacin must occur 2 days after finishing the 5 days of TMZ. This facilitated the investigator to identify the drug responsible for any side effects that might have occurred. If treatment with niacin needed to be held for more than 4 weeks (> 28 days) during concurrent phase RT-TMZ-Niacin or during niacin monotherapy or more than 4 weeks + the safety period of 2 additional weeks (more than 6 weeks; >42 days) during monthly TMZ-Niacin, then it was permanently discontinued. After completing SOC TMZ treatment, niacin was continued until progression of the disease, intolerance or patient withdrawal of consent. Low dose (81 mg) or 325 mg ASA was recommended for the management of flushing or pruritus if needed. Patients received prophylaxis for pneumocystis pneumonia during radiotherapy as standard of care.
All patients who received at least one cycle of monthly temozolomide/niacin therapy and had their disease re-evaluated with MRI were considered evaluable for response. The first MRI was requested at 6 weeks post radiotherapy completion and subsequent MRIs were done q 8 weeks as SOC. A central radiology review was conducted by a blinded individual for the interim analysis of Phase II (by MW). To assess tumor response, the modified Response Assessment in Neuro-Oncology (RANO) criteria [21] was used. The PFS6 was calculated from the date of patient registration to the date of progression, loss in follow up or death.
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Statistics and Ethics
For the calculation of sample size and design of the Phase II portion of the trial, we planned to compare our cohort’s PFS6 and overall survival to historical controls. The trial would be considered positive if the PFS6 was shown to increase 20% compared to SOC. Available results with current first line treatment report 53.9% of patients with PFS6 [2]; therefore, the Phase II trial would be considered positive if a PFS6 of 73.9% was achieved. Using 80% power, the one-sided binomial test, a significance level of 0.05, and adjusting for 20% dropout, we calculated the required sample size to be 48 patients.
Interim analysis was planned after 50% of the information was obtained: when 24 patients were evaluated for response at 6 months. Conditional power was calculated for one sided Z test to detect a 20% increase in PFS6 based on the observed data. The study was planned to stop if the conditional power was less than 20% or futility index was greater than 80%.
This trial is being conducted in accordance with the International Conference on Harmonization- Data cutoff for the interim analysis was May 28/2025. The interim analysis was presented to DSMC on June 18/2025.
Descriptive statistics were reported for the study variables. Mean and standard deviation or median and interquartile range were reported for continuous variables. Frequency and proportions were reported for categorical variables. Overall survival (OS) was calculated from the date of study registration to the date of death or last follow up for patients who were alive. Two definitions of progression were calculated, progression as determined by radiologist were calculated from the date of registration to the date of progression as confirmed by radiologist. Progression as determined by investigators, was calculated from the date of study registration to date of disease progression confirmed by investigator. Kaplan-Meier estimates and the corresponding 95% confidence intervals were reported for OS and PFS. If median was not reached, then the survival probability at 6 months, 12 months and 18 months along with the 95% confidence intervals were reported. OS and PFS survival curves were compared for mgmt. status (yes vs. no) using log-rank tests. A p-value < 0.05 was used for statistical significance. SAS (SAS Institute Inc., Cary, NC, USA) version 9.4 was used for all statistical analysis.
Good Clinical Practice (ICH-GCP) Guidelines under a Clinical Trial Application (CTA) for a natural health product (NHP) with Health Canada. It obtained local ethics board approval (HREBA cc 20–0402) before starting. Data Safety Monitoring Committee (DSMC) meetings were planned per protocol at the completion of phase I, after the interim analysis and at the end of phase II. The trial is registered in clinicaltrials.gov as NCT04677049.
Niacin was obtained from Designs For Health and bought at public price (NiacinCRT™). A contract was not in place and the company did not have any input in the design or analysis of this trial. This study was supported by grants from Canadian Institutes of Health Research and Alberta Cancer Foundation.
Results
Phase I
Patients were enrolled from March 1, 2021 to June 30, 2023. Table 2 shows the safety/tolerance data was available for 14 of the 17 patients recruited. Three (3) patients were considered not evaluable for toxicity: 2 withdrew consent prior to receiving a dose of niacin and another patient presented with hydrocephalus after 1 dose of niacin that was considered not related to the drug, but this precluded the patient from continuing in the trial. Patients’ characteristics are included in Table 1 as all patients in Phase I were included in Phase II.
Characteristic | Patients (n = 24) |
|---|---|
Median age (range), years | 57.5 years old (37–69) |
Gender | |
Female | 7 (29%) |
Male | 17 (71%) |
Performance status (ECOG) | |
0 | 9 (37.5%) |
1 | 15 (62.5%) |
MGMT promoter methylation status | |
Methylated | 8 (33.3%) |
Unmethylated | 14 (58.3%) |
Indeterminate | 2 (8.3%) |
Extension of Surgery | |
Gross total | 16 (66.7%) |
Near Gross total | 3 (12.5%) |
Subtotal | 2 (8.3%) |
Biopsy | 3 (12.5%) |
Toxicity of niacin increased with dose. Table 2 shows the toxicities observed that were possibly, probably or definitely attributed to niacin at each dose level, as determined by the treating physician. The number of patients reporting each toxicity at each dose level is presented in brackets.
GRADE 1 | GRADE 2 | GRADE 3 |
|---|---|---|
At 500 mg/d | ||
Nausea (5) | Nausea (1) | Thrombocytopenia (1) DLT |
Fatigue (2) | Fatigue (1) | |
Anorexia (1) | ||
Pruritus (1) | ||
Flushing (1) | ||
At 1000 mg/d | ||
Flushing (6) | Nausea (1) | |
Fatigue (3) | Fatigue (1) | |
Increased INR (1) | ||
Nausea (1) | ||
Thrombocytopenia (2) | ||
Dyspepsia (1) | ||
Pruritus (1) | ||
At 1500 mg/d | ||
Neutropenia (2) | ||
Dyspepsia (1) | ||
Flushing (1) | ||
Increased INR (1) | ||
Pruritus (1) | ||
At 2000 mg/d | ||
Nausea (1) | ||
Vomiting (1) | ||
Increased INR (2) | ||
ALT elevated (1) | ||
Flushing (1) | ||
At 2500 mg/d | ||
Thrombocytopenia (1) | INR elevated (1) | Thrombocytopenia (1) (DLT) |
Nausea (1) | Hypophosphatemia (1) | |
Flushing (1) | Nausea/increased bilirubin (1) (DLT) | |
Neutropenia (1) | ||
Pruritus (1) |
DLT: Dose limiting toxicity. (number of patients)
As detailed, two patients had severe toxicity (thrombocytopenia grade 3 and liver failure requiring admission) at 2,500 mg/day of niacin leading to stopping the escalation and staying at that dose level. These were considered Dose Limiting Toxicities (DLT). The only other grade 3 toxicity, thrombocytopenia, presented in one patient at 500 mg/d of niacin. While niacin could contribute to this, temozolomide was considered the most probable culprit. In any case, no other patients presented this toxicity at such a low dose before analysis.
On June 22, 2023, the DSMC met to review toxicity/safety and based on available information, decided that the clinical trial could continue and that the recommended dose for Phase II was 2000 mg of niacin daily.
Phase II interim analysis
Patients from the phase I part were included in Phase II. Figure 2 shows study enrollment. A total of 29 patients were enrolled and 24 were eligible to become evaluable for PFS6. Two patients withdrew consent before starting any treatment in the context of the trial and 2 more during trial but before becoming eligible for this analysis. One patient developed hydrocephalus after 1 dose of niacin, before starting RT, and required surgical management.
Fig. 2
– Study enrollment
According to the central radiology review PFS6 was 82.3% (95% CI 82.14–82.46). Median PFS was 10 months (95% CI 5.77–14.23) and median overall survival was 17 months (95% CI: 15.07–18.93). Overall survival at 1 year was 77.5%. PFS6 evaluated by investigator was 79.2%. The conditional power for the study based on one-sided z-test for a difference of 28.4% (53.9% vs. 82.3%) was 93.28%.
Additional safety concerns or side effects were not identified in patients included after Phase I was completed. Flushing, pruritus, fatigue and nausea continued to be the most frequently reported adverse events. Discontinuation of niacin due to toxicity occurred in 4 additional patients and was related to prolonged transaminitis grade 2 (1), thrombocytopenia grade 4 (1) and neutropenia grade 3 (1). With this information DSMC has recommended to continue the study without changes.
A sub-analysis by methylation status showed that for patients with MGMT promoter methylation, PFS6 was 85.7% (CI 95%, 82.14–82.46). For those with MGMT promoter unmethylated, the PFS6 was 77.9%(CI 95% 77.68–78.12). The small sample size precludes significant sub-analysis by other known prognostic factors currently.
Discussion
In this first in human phase I-II study, using a intrapatient dose escalation design the maximum tolerated dose of niacin used in combination with temozolomide and radiotherapy as first line treatment in patients with GB was 2000 mg/d. The preplanned Phase II interim analysis already showed a PFS6 higher than expected.
The interim analysis was performed as per protocol to evaluate futility. It was intended to stop the trial if there was no possibility of identifying a clinically beneficial difference in PFS6 with the addition of niacin to our SOC treatment in patients with newly diagnosed glioblastoma. There was a 28.5% increase in PFS6 that was superior than expected.
During the Phase I part we evaluated the toxicity of adding niacin to TMZ and radiotherapy. Both temozolomide and niacin can cause liver disfunction and thrombocytopenia, so it was not unexpected that those toxicities were dose limiting. It is important, in general, to emphasize that this demonstrates that adding any other drug, supplement or vitamin to the treatment of patients raises the potential of elevating toxicity. While it is difficult to design and develop studies like the one presented here, mainly because we are dealing with orphan drugs in rare tumors, well designed studies can and must be done.
When working with supplements and vitamins, as the production/quality is not as regulated than other agents, the selection of the product to use is paramount. This is an investigator-initiated study that was intensively monitored by Alberta Health Services acting as sponsor and that is being conducted under the oversight of Health Canada. It constitutes evidence that rigorous clinical research evaluating supplements, vitamins and the benefit of repurposing drugs is feasible
The results of the Phase II interim analysis are very encouraging. Our stopping rule was based on futility and not for efficacy, so the DSMC recommended continuing the study. At the time of this futility analysis a total of 38 patients have been enrolled. The interim analysis is based on a central blinded radiology review, but it is reassuring that the analysis of PFS6 reported by the treating physicians, while slightly different, is still significant. While numbers are small, it is significant that the majority of the patients included in this study (58.3%) had GB with MGMT promoter unmethylated which would normally have a poorer prognosis than those with MGMT methylated.
We recognize there are limitations in this study. Some researchers may disagree with the significance of an increase in 20% PFS6 compared with SOC. In Canada, tumor treating fields have been approved by Health Canada in 2024 but they are not available to patients as it is not funded by the public system or private insurances, so it was not included in our study design. We consider that the small sample size precludes us from making comments about known prognostic factors like age, performance status, extension of resection at this time.
Patients with incurable diseases such as GB frequently receive supplements/vitamins that were not evaluated in clinical trials as the one presented here. One of the aims of publishing this interim analysis is to provide an early background for patients and providers. We hope the final analysis corroborates these results and leads to further research adding niacin to the tools used to control this aggressive disease. Finally, we want to encourage colleagues from the clinical and basic areas of research to design and conduct clinical trials repurposing drugs that seem promising in the treatment of cancer.
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Statements & Declarations:
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Funding
This study was supported by grants from Canadian Institutes of Health Research (Foundation Grant to VWY) and Alberta Cancer Foundation (Investigator Initiated Trial Grant to GRU) .
• Competing interests
Authors disclosed no conflict of interest. Niacin was obtained from Designs For Health and bought at public price (NiacinCRT™). A contract was not in place and the company did not have any input in the design or analysis of this trial.
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Author Contribution
All authors contributed to the design of the study AND drafting/review of the intellectual content AND final approval of the version to be published (Roldan Urgoiti G, de Robles P, Tsang RY, Willson M, Ghosh S, Faruqi M, Lim G, Loewen SK, Nordal R, Cairncross G, Leckie C, Poon CC . Yong VW. Additionally, Ghosh S perfomed the statistical analysis and Willson M did the central radiology review.
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Data Availability
The protocol is available. Anonymized summarized original data can be made available upon reasonable request to [gloria.roldanurgoiti@albertahealthservices.ca]