Effects of Nicotinamide in Patients With Chronic Lymphocytic Leukemia (CLL) With History of Non-melanoma Skin Cancers (NMSC)

Sponsor

University of Utah (Other)

Overall Status

Recruiting

CT.gov ID

NCT04844528

Collaborator

(none)

Enrollment

Location

Arms

59.9

Anticipated Duration (Months)

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomized, phase II, double-blind, placebo-controlled trial with planned crossover to the intervention arm after 1 year.

Consenting patients with CLL who have had at least one NMSC diagnosed in the past year will be randomized to receive either oral nicotinamide 500 mg twice daily (BID) for 1 year or oral placebo 1 tablet twice daily for 1 year. Patients will be stratified according to CLL therapy and the number of prior NMSC. At the end of 1 year, patients will undergo dermatologic examination and the number of new NMSC will be quantified. The number of patients who develop new NMSC in each arm will be documented. At this time, patients will be unblinded and all patients will receive Nicotinamide 500 mg BID for an additional year. At the end of this second year, patients will again undergo dermatologic examination, and the number of new NMSC will be quantified. The number of patients who develop NMSC will be documented. Skin biopsies will be taken for correlative studies.

Enrollment will be split into two parts separated by an interim analysis. Part 1 will accrue 40 patients: 20 to each arm. After 40 patients have completed their 12 month visit an interim futility analysis will be conducted prior to recruiting more patients. The study will stop if the difference in the number of patients with NMSC between control and treatment arms is 0 or less (i.e., absolutely no evidence that the treatment is better than control). If the trial is not stopped, the investigators will proceed with Part 2 and recruit 46 more patients.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Drug: Nicotinamide Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

86 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Randomized Phase 2 Studying the Effects of Nicotinamide in Patients With Chronic Lymphocytic Leukemia (CLL) With History of Non-melanoma Skin Cancers (NMSC)

Actual Study Start Date :

Aug 5, 2021

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Aug 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment: all patients Consenting patients with CLL who have had at least one NMSC diagnosed in the past year will be randomized to receive either oral nicotinamide 500 mg twice daily (BID) for 1 year or oral placebo 1 tablet twice daily for 1 year. Patients will be stratified according to CLL therapy and the number of prior NMSC. At the end of 1 year, patients will undergo dermatologic examination and the number of new NMSC will be quantified. The number of patients who develop new NMSC in each arm will be documented. At this time, patients will be unblinded and all patients will receive Nicotinamide 500 mg BID for an additional year. At the end of this second year, patients will again undergo dermatologic examination, and the number of new NMSC will be quantified. The number of patients who develop NMSC will be documented. Skin biopsies will be taken for correlative studies.	Drug: Nicotinamide oral nicotinamide 500 mg twice daily (BID)
Placebo Comparator: Arm 2: Placebo Consenting patients with CLL who have had at least one NMSC diagnosed in the past year will be randomized to receive either oral nicotinamide 500 mg twice daily (BID) for 1 year or oral placebo 1 tablet twice daily for 1 year. Patients will be stratified according to CLL therapy and the number of prior NMSC. At the end of 1 year, patients will undergo dermatologic examination and the number of new NMSC will be quantified. The number of patients who develop new NMSC in each arm will be documented. At this time, patients will be unblinded and all patients will receive Nicotinamide 500 mg BID for an additional year. At the end of this second year, patients will again undergo dermatologic examination, and the number of new NMSC will be quantified. The number of patients who develop NMSC will be documented. Skin biopsies will be taken for correlative studies.	Drug: Placebo oral placebo twice daily for first year. Cross over to oral nicotinamide 500 mg twice daily (BID) for year two.

Arm

Intervention/Treatment

Experimental: Treatment: all patients

Drug: Nicotinamide

oral nicotinamide 500 mg twice daily (BID)

Placebo Comparator: Arm 2: Placebo

Drug: Placebo

oral placebo twice daily for first year. Cross over to oral nicotinamide 500 mg twice daily (BID) for year two.

Outcome Measures

Primary Outcome Measures

Proportion of CLL patients who develop a new NMSC after 1 year of nicotinamide therapy. [1 year]
evaluate whether nicotinamide can reduce the number of patients who develop one or more new NMSC versus placebo in CLL patients with a history of NMSC.

Secondary Outcome Measures

Number of new NMSC on skin exam after 1 year of treatment [1 year]
assess the effect of oral nicotinamide on the number of new NMSC in patients with CLL who have previously been diagnosed with a NMSC.
proportion of CLL patients who develop squamous cell carcinoma (SCC) on skin exam after 1 and 2 years of treatment. [up to 2 years]
assess whether nicotinamide can reduce the number of patients who develop a SCC versus placebo in CLL patients with a history of NMSC.
proportion of CLL patients who develop basal cell carcinoma (BCC) on skin exam after 1 and 2 years of treatment. [up to 2 years]
assess whether nicotinamide can reduce the number of subjects who develop a BCC versus placebo in CLL patients with a history of NMSC
proportion of CLL patients who develop actinic keratosis (AK) on skin exam after 1 and 2 years of treatment. [up to 2 years]
evaluate whether nicotinamide can reduce the number of subjects who develop AK versus placebo in CLL patients with a history of NMSC
number of new NMSC developed during year 1 and year 2 for patients who receive placebo during the first year [2 years]
evaluate whether nicotinamide can reduce the number of recurrent NMSC in the same patient between year 1 on placebo therapy and year 2 on nicotinamide therapy
objective response rate (the proportion of subjects achieving a complete response [CR] or partial response [PR]) and complete response rate as calculated per International Workshop on CLL (IWCLL) 2018 Criteria at Month 6, 12, 18, and 24 [up to 24 months]
2.2.6 To compare objective response rates (CR + PR) and CR rates between patients not on active CLL therapy who receive nicotinamide versus placebo
objective response rate (the proportion of subjects achieving a CR or PR) and complete response rate as calculated per International Workshop on CLL (IWCLL) 2018 Criteria at Month 6, 12, 18, and 24 [up to 24 months]
2.2.7 To compare overall response rates (CR+ partial PR) and CR rates between patients not on active CLL therapy with and without mutations with DNA mismatch repair who receive nicotinamide versus placebo
frequency of adverse events (AEs) and serious adverse events (SAEs) characterized by type, severity (as defined by the NIH CTCAE, version 5.0 and iwCLL), seriousness, duration, and relationship to study treatment [up to 24 months]
evaluate the safety and tolerability of each arm

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female subject aged ≥ 18 years.
Histologically confirmed diagnosis of CLL per iwCLL criteria.
History of ≥1 non-melanoma skin cancer (NMSC) diagnosed within the last 5 years
Adequate liver function as defined as:
Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

---Subjects with a known diagnosis of Gilbert's Syndrome: direct bilirubin ≤ 1.5x ULN

AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
For female subjects: Negative pregnancy test or evidence of post-menopausal status. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

--Women < 50 years of age:

Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution; or
Underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
Women ≥ 50 years of age:
Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
Had radiation-induced menopause with last menses >1 year ago; or
Had chemotherapy-induced menopause with last menses >1 year ago; or
Underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
Female subjects of childbearing potential and male subjects with a sexual partner of childbearing potential must agree to use a highly effective method of contraception as described in Section 5.4.1.

Exclusion Criteria:

Received chemotherapy (such as fludarabine, cyclophosphamide, bendamustine, or chlorambucil) within the last 6 months
Received allogeneic stem cell transplant within the last 6 months.
Taking nicotinamide or niacin supplements within the last 4 weeks.
Taken acitretin or other oral retinoids within the past 6 months
Received field treatment for AKs (topical use of 5-fluorouracil, imiquimod, diclofenac, retinoids; topical photodynamic therapy for AKs; laser resurfacing or chemical peel treatments for AKs) within the previous 4 weeks
Large areas of confluent skin cancer at baseline preventing accurate assessment and counting of individual new skin cancers
Need for ongoing carbamazepine use (possible interaction with nicotinamide)
Severe GI malabsorption that may interfere with absorption of nicotinamide (per investigator's discretion)
Patients with an expected life expectancy < 2 years
Current evidence of uncontrolled, diabetes.
Current evidence or history of peptic ulcer disease.
Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment.

Note: Subjects on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.

Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice), or hepatitis C.

Note: Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.
Known prior severe hypersensitivity to investigational product (IP) or any component in its formulations (NCI CTCAE v5.0 Grade ≥ 3).
Subjects taking prohibited medications as described in Section 6.7.1. A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment.
Have ever received a solid organ transplant and are currently taking immunosuppressive medications.