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Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive duvelisib PO QD or BID on days 1-28 or days 1-14 and nivolumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo PET-CT or CT scan at baseline. Patients also undergo punch biopsy and collection of blood samples throughout the trial.

Biospecimen Collection

Computed Tomography

Duvelisib

Positron Emission Tomography

Punch Biopsy

Site Public Contact

Allison C. Rosenthal

Bradley M. Haverkos

Jonathan H. Schatz

Muhamad Alhaj Moustafa

Jason T. Romancik

Jonathan Moreira

Eric D. Jacobsen

Nabila N. Bennani

Neha Mehta-Shah

Jia Ruan

Oleg E. Akilov

This phase I trial identifies the best dose, possible benefits, and/or side effects of duvelisib in combination with nivolumab in treating patients with stage IIB-IVB mycosis fungoides and Sezary syndrome. Duvelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving duvelisib in combination with nivolumab may work better than giving each of these drugs individually, or treating with the usual approach in patients with mycosis fungoides and Sezary syndrome.

PRIMARY OBJECTIVE:

I. To determine the recommended phase II dose (RP2D) or maximum tolerated dose (MTD) of the combination of duvelisib with nivolumab in patients with advanced mycosis fungoides/Sezary syndrome (MF/SS).

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. Ia. To determine the overall response rate at four months to the combination of nivolumab and duvelisib.

Ib. To determine the time to maximum response, best overall response rate, complete remission rate, and duration of response among responding patients.

EXPLORATORY OBJECTIVES:

I. To evaluate whether intra-patient changes in serum cytokines (soluble CD40L, TNF-beta, IL-17alpha, IL-15, CXCL13, IL-12p40) predict response to duvelisib in combination with nivolumab in cutaneous T-cell lymphoma (CTCL).

II. To explore whether the combination of duvelisib and nivolumab changes the T-cell repertoire including T-cell receptor sequencing pre- and post- treatment with duvelisib and nivolumab in effort to better understand skin flare and other immunogenic reactions to this combination therapy.

OUTLINE: This is a dose-escalation study of duvelisib in combination with fixed dose nivolumab followed by a dose-expansion study.

Patients receive duvelisib orally (PO) once daily (QD) or twice daily (BID) on days 1-28 or days 1-14 and nivolumab intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo positron emission tomography (PET)-computed tomography (CT) or CT scan at baseline. Patients also undergo punch biopsy and collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up every 6 months for 2 years.

Duvelisib and Nivolumab for the Treatment of Stage IIB-IVB Mycosis Fungoides and Sezary Syndrome

A Phase I Study With an Expansion Cohort of Duvelisib and Nivolumab in Mycosis Fungoides (MF) and Sézary Syndrome (SS)

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will evaluate the changes in the immune composition by CyTOF and MIBI and in serum cytokine profiles (Olink) on samples before the start of treatment, on treatment, at end of treatment, and at the time of flare. For comparing biomarkers pre- and post-treatment we will use paired Wilcoxon signed-rank tests for each marker comparing to baseline earlier timepoints. Will correct for multiple hypothesis testing using the Benjamini-Hochberg procedure. Will also use logistic regression to assess the relationship between biomarkers and response.

If one dose-limiting toxicity (DLT) is seen in the first three patients treated at a given dose level, then three additional patients will be evaluated at that same dose level. If DLTs are present at \< 2 of 6 patients, the next dose level will be explored. If 3 patients are treated at the maximal dose level without DLT, three more patients will be enrolled to that dose level to evaluate for DLT. If \< 2/6 DLTs are seen at that dose level, it will be deemed the RP2D.

Defined as the proportion of patients having achieved partial response (PR) or complete response (CR) at any time prior to the four-month time point. ORR will be estimated as a sample proportion with a 95% confidence interval using the method of Agresti and Coull around the point estimate. Will be assessed using the Global Response Criteria for cutaneous T-cell lymphoma which includes a skin-based assessment (modified severity-weighted assessment tool), peripheral blood evaluation for circulating Sezary cells by flow cytometry, and radiographic evaluation (contrast-enhanced computed tomography \[CT\] chest/abdomen/pelvis or positron emission tomography \[PET\]/CT).

Defined as the percentage of patients who achieve CR at any timepoint. CRR will be estimated as a sample proportion with associated confidence intervals.

Defined as the percentage of patients who achieve CR or PR at any timepoint. ORR will be estimated as a sample proportion with associated confidence intervals. Will be assessed using the Global Response Criteria for cutaneous T-cell lymphoma which includes a skin-based assessment (modified severity-weighted assessment tool), peripheral blood evaluation for circulating Sezary cells by flow cytometry, and radiographic evaluation (contrast-enhanced CT chest/abdomen/pelvis or PET/CT).

Defined as the proportion of patients who achieve CR, PR, or stable disease (SD) at the four-month time point. DCR will be estimated as a sample proportion with associated confidence intervals.

DOR will be determined on intention-to-treat basis and will be estimated using Kaplan-Meier analysis.

Time to maximum response will be determined on intention-to-treat basis and will be estimated using Kaplan-Meier analysis.

OS will be determined on intention-to-treat basis and will be estimated using Kaplan-Meier analysis.

PFS will be determined on intention-to-treat basis and will be estimated using Kaplan-Meier analysis.

National Cancer Institute (NCI)

Pembrolizumab

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 cycles or until complete response in the absence of disease progression or unacceptable toxicity.

Jason C. Sluzevich, M.D.

This phase II trial studies how well pembrolizumab works in treating patients with stage IB-IV mycosis fungoides. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

PRIMARY OBJECTIVE:

I. To evaluate the antitumor activity of pembrolizumab in patients with advanced mycosis fungoides (MF) as initial systemic therapy.

SECONDARY OBJECTIVES:

I. To evaluate safety of pembrolizumab in this patient population. II. To evaluate response rates of pembrolizumab in this patient population. III. To determine the progression free survival, duration of response, time to response and overall survival of pembrolizumab in this patient population.

CORRELATIVE OBJECTIVE:

I. To characterize the histologic features of the anti-tumor response in patients with advanced MF before and after treatment with pembrolizumab.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 cycles or until complete response in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 and 90 days, and then every 3 months for up to 1 year.

Pembrolizumab in Treating Patients With Stage IB-IV Mycosis Fungoides

A Phase II, Open-Label, Single-Arm Trial Using KEYTRUDA (Pembrolizumab) as Initial Systemic Therapy in the Treatment of Advanced Mycosis Fungoides

Immunohistochemistry will be used to quantify levels of CD4 before and after treatment with pembrolizumab

Immunohistochemisty will be used for change in baseline calculations of CD4 at baseline and end of cycle 2

Immunohistochemisty will be used for change in baseline calculations of CD8 at baseline and end of cycle 2

Immunohistochemisty will be used for change in baseline calculations of PD-1/CD279 at baseline and end of cycle 2

Immunohistochemisty will be used for change in baseline calculations of PD-1 at baseline and end of cycle 2

Qualitative measures of the strength of PD-1 expression will use published standardized grading scales for categorical classification purposes.

Immunohistochemistry will be used to quantify levels of CD8 before and after treatment with pembrolizumab.

Immunohistochemistry will be used to quantify levels of PD-1/CD279 before and after treatment with pembrolizumab

Immunohistochemistry will be used to quantify levels of PD- L1 expression before and after treatment with pembrolizumab

Will be assessed by the Modified Severity Weighted Assessment Tool (mSWAT). All calculated values will use the last-observation-carried forward for any participants who withdraw, are lost to follow up, or exit the study per protocol. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients will be analyzed using Mann-Whitney U for nonparametric data and the student t-test. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

Summary statistics will be calculated. Proportions of patients will be calculated and described using summary statistics. Proportions of interest are patients having CR, CR90 and PR; patients having stable subcutaneous disease; patients having progressive cutaneous disease; and patients having an overall systemic response rate.

The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. In addition, the progression-free survival rate at 5 years after registration will be reported.

The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.

The distribution of survival time will be estimated using the method of Kaplan-Meier.

The distribution of survival time will be estimated using the method of Kaplan-Meier. In addition, the overall survival rate at 2 years after registration will be reported.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Duvelisib and Nivolumab for the Treatment of Stage IIB-IVB Mycosis Fungoides and Sezary Syndrome	NCT04652960	Stage IIB Mycos... Stage III Mycos... Stage IV Mycosi...	Biospecimen Col... Computed Tomogr... Duvelisib Nivolumab Positron Emissi... Punch Biopsy	18 Years -	National Cancer Institute (NCI)
Pembrolizumab in Treating Patients With Stage IB-IV Mycosis Fungoides	NCT03695471	Mycosis Fungoid... Sezary Syndrome Stage IB Mycosi... Stage II Mycosi... Stage IIA Mycos... Stage IIB Mycos... Stage III Mycos... Stage IIIA Myco... Stage IIIB Myco... Stage IV Mycosi... Stage IVA1 Myco... Stage IVA2 Myco... Stage IVB Mycos...	Pembrolizumab	18 Years -	Mayo Clinic

Spots Global Cancer Trial Database for stage iv mycosis fungoides and sezary syndrome ajcc v8