This randomized phase I/II trial studies the best dose and side effects of durvalumab and to see how well it works with or without lenalidomide in treating patients with cutaneous or peripheral T cell lymphoma that has come back and does not respond to treatment. Monoclonal antibodies, such as durvalumab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving durvalumab and lenalidomide may work better in treating patients with cutaneous or peripheral T cell lymphoma.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (recommended phase 2 dose, RP2D) of lenalidomide, when given in combination with fixed-dose durvalumab. (Phase 1) II. To assess the safety and tolerability of the lenalidomide/durvalumab regimen, and accompanying dose modification plan, by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration. (Phase 1) III. To evaluate the anti-tumor activity durvalumab (MEDI4736) as single agent therapy and as part of combination therapy (+lenalidomide); activity assessed by overall response rate (ORR). (Phase 2) SECONDARY OBJECTIVES: I. To estimate and assess response duration and survival probabilities (overall and event-free). (Phase 2) II. To summarize and assess toxicities by type, frequency, severity, attribution, time course and duration. (Phase 2) III. To assess clinically meaningful reduction in pruritus (CMRP) in patients with CTCL (critical quality of life measure). (Phase 2) TERTIARY OBJECTIVES: I. To identify the malignant CD4+ T cells within the skin microenvironment. II. To characterize the spatial and functional relationship of malignant T cells with other immune cells, their expression of key immune checkpoints and correlate with response. III. To identify aberrantly expressed micro(mi) ribonucleic acid (RNA)s involved in cutaneous T-cell lymphoma (CTCL) and messenger (m)RNAs that may predict response and/or treatment-related toxicity. IV. To evaluate whether or not the identified miRNAs are involved in regulating key immune checkpoints. OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II study. Patients are randomized to 1 of 2 arms, ARM I: Patients receive durvalumab intravenously (IV) over 1 hour on day 1. Treatment repeats every 28 days (+/- 3) for up to 13 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive durvalumab IV over 1 hour on day 1 and lenalidomide orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 (+/- 3) days for up to 13 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for up to 12 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
38
City of Hope Medical Center
Duarte, California, United States
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, United States
M D Anderson Cancer Center
Houston, Texas, United States
CTCL specific response assessed by Lugano Classification
CTCL response was used to establish global response, which incorporates nodal, visceral and cutaneous lesions/disease. mSWAT tool was used for documenting responses in skin of patients with CTCL. PTCL specific response assessment criteria per Lugano Classification was used.
Time frame: Up to 12 months
Dose limiting toxicity assessed by CTCAE version 4.03
Observed toxicities was summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Time frame: Up to 84 days
Duration of Complete Response
Duration of complete response (CR) was defined as the time interval from the date of first documented complete response to the date of first documented disease relapse, progression or death whichever occurs first.
Time frame: Date when criteria for CR first met until time of loss of CR (relapse/recurrence) or death (as a result of MF/SS or acute toxicity of treatment), assessed up to 12 months
Event-Free Survival
Event-free survival was defined as the time interval from date of first dose of study drug to first documented disease relapse, progression or death from any cause, whichever occurs first. Event-free survival was estimated using the product-limit method of Kaplan and Meier.
Time frame: From date of first dose of study drug to first documented disease relapse, progression or death from any cause, whichever occurs first, assessed up to 12 months
Incidence of adverse events assessed by National Cancer Institute CTCAE version 4.03
Observed toxicities was summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Time frame: Up to 90 days post-treatment
Overall Response Rate (ORR)
ORR was defined as proportion of patients with complete response (CR) and partial response (PR). The overall response rate and 95% Clopper Pearson binomial confidence interval (CI) was calculated.
Time frame: Up to 12 months
Overall survival (OS)
OS was defined as the time interval from date of first dose of study drug to date of death from any cause. OS was estimated using the product-limit method of Kaplan and Meier.
Time frame: From date of first dose of study drug to date of death from any cause, assessed up to 12 months
Progression Free Survival (PFS)
PFS was date of initiation of treatment to first date meets criteria for PD or death as a result of any cause.
Time frame: Date of initiation of treatment to first date meets criteria for progressive disease or death as a result of any cause, assessed up to 12 months
Response duration
95% Clopper Pearson binomial confidence interval will be calculated. Response rates will also be explored based on number/type of prior therapies.
Time frame: From the date of first documented response to the date of first documented disease relapse, progression or death whichever occurs first, assessed up to 12 months
Time to response
Time frame: Date of initiation of treatment to date when criteria for response (PR or CR) first met, assessed up to 12 months
Clinically Meaningful Reduction in Pruritus (CMRP)
CMRP was defined as a decrease in VAS score of at least 30 for at least two consecutive cycles for patients with moderate-to-severe pruritus at baseline. Changes in pruritus VAS score was assessed using descriptive statistics.
Time frame: Baseline up to 12 months
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