This phase I trial tests the safety, side effects and best dose of azacitidine in combination with belinostat and how well the combination works in treating patients with follicular helper T cell lymphoma (TFH) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). This phase I trial also tests the safety, side effects and best dose of pralatrexate in combination with belinostat and how well the combination works in treating patients with relapsed or refractory peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL) with large cell transformation and cytotoxic phenotype. Azacitidine stops cells from making deoxyribonucleic acid (DNA) and may kill cancer cells. It is a type of antimetabolite. Pralatrexate stops cells from using folic acid to make DNA. This may help keep cancer cells from growing and may kill them. Pralatrexate is a type of antimetabolite and a type of dihydrofolate reductase inhibitor. Belinostat blocks certain enzymes needed for cell division and may kill cancer cells. It may also prevent the growth of new blood vessels that tumors need to grow and may help make cancer cells easier to kill with other anticancer drugs. It is a type of histone deacetylase inhibitor, a type of antiangiogenesis agent, and a type of chemosensitizer. Giving azacitidine in combination with belinostat may be safe, tolerable, and/or effective in treating patients with relapsed/refractory (R/R) TFH. In additional, giving pralatrexate in combination with belinostat may be safe, tolerable, and/or effective in treating patients with R/R PTCL and CTCL with large cell transformation and cytotoxic phenotype.
PRIMARY OBJECTIVES: I. To evaluate the safety and feasibility of combining azacitidine with belinostat in R/R nodal TFH cell lymphoma. (Arm A) II. To evaluate the safety and feasibility of combining pralatrexate with belinostat in R/R PTCL and CTCL with large cell transformation. (Arm B) SECONDARY OBJECTIVES: I. To measure the clinical efficacy as measured by overall response rate (ORR), complete response (CR) rate, and time to next treatment (TTNT) of belinostat and azacitidine. (Arm A) II. Patient-reported outcomes as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health37 and Functional Assessment of Cancer Therapy (FACT)-Item GP5 scale. (Arm A) III. To measure the clinical efficacy as measured by ORR, CR rate, and TTNT of belinostat and pralatrexate. (Arm B) IV. Patient-reported outcomes as measured by the PROMIS Global Health37 and FACT-Item GP5 scale. (Arm B) EXPLORATORY OBJECTIVES: I. To measure survival outcomes by progression-free survival (PFS) and overall survival (OS) of belinostat and azacitidine. (Arm A) II. Examine the association between biomarkers (e.g., genomic proofing, minimal residual disease \[MRD\]) and clinical outcomes (ORR, PFS). (Arm A) III. To measure survival outcomes by PFS and OS of belinostat and pralatrexate. (Arm B) IV. Examine the association between biomarkers (e.g., genomic profiling, MRD) and clinical outcomes (ORR, PFS). (Arm B) OUTLINE: Patients are assigned to 1 of 2 arms. ARM A: Patients receive azacitidine subcutaneously (SC) on days 1-5 and belinostat intravenously (IV) over 30-45 minutes on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and fludeoxyglucose F-18 (FDG)-positron emission tomography (PET), and computed tomography (CT) or PET/CT throughout the study. ARM B: Patients receive pralatrexate SC on days 8 and 15 and belinostat IV over 30-45 minutes on days 1-3 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and FDG-PET, and CT or PET/CT throughout the study. After completion of study treatment, patients in Arm A are followed up at 30 days, every 3 months for up to 2 years, then for up to 5 years. Patients in Arm B are followed up at 30 days, every 3 months for up to one year from start of treatment, every 6 months for up to 2 years then every 5 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Given SC
Given IV
Undergo blood sample collection
Undergo CT or PET/CT
Undergo FDG-PET
Given FDG
Undergo PET/CT
Given SC
Ancillary studies
City of Hope Medical Center
Duarte, California, United States
Occurrence of dose-limiting toxicities (DLT) (Arm A)
Observed toxicities will be summarized by type, severity, timing of onset, and attribution, and will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 6.0.
Time frame: Prior to cycle 2 day 1 (cycle length = 28 days)
Occurrence of DLT (Arm B)
Observed toxicities will be summarized by type, severity, timing of onset, and attribution, and will be graded according to the CTCAE, version 6.0.
Time frame: Prior to cycle 2 day 1 (cycle length = 21 days)
Maximum tolerated dose (MTD) (Arm A)
Will be defined as the highest dose of azacitidine tested in which at most 1 out of 6 DLT-evaluable patients treated at that dose experience a DLT. The MTD will be designated as the recommended phase 2 dose (RP2D), provided no additional safety concerns are identified.
Time frame: During the first cycle of treatment (cycle length = 28 days)
MTD (Arm B)
Will be defined as the highest dose of pralatexate tested in which at most 1 out of 6 DLT-evaluable patients treated at that dose experience a DLT. The MTD will be designated as the RP2D, provided no additional safety concerns are identified.
Time frame: During the first cycle of treatment (cycle length = 21 days)
Overall response rate (ORR) (Arm A)
Will be estimated using simple binary proportions with corresponding two-sided 95% confidence intervals.
Time frame: Up to 5 years
ORR (Arm B)
Will be estimated using simple binary proportions with corresponding two-sided 95% confidence intervals.
Time frame: Up to 5 years
Complete response (CR) rate (Arm A)
Will be defined as the proportion of patients achieving a complete response according to standard response criteria. Will be estimated using simple binary proportions with corresponding two-sided 95% confidence intervals.
Time frame: Up to 5 years
CR rate (Arm B)
Will be defined as the proportion of patients achieving a complete response according to standard response criteria. Will be estimated using simple binary proportions with corresponding two-sided 95% confidence intervals.
Time frame: Up to 5 years
Time to next treatment (TTNT) (Arm A)
Continuous variables will be summarized using measures such as mean, standard deviation, median, range, and standard error, as appropriate. Categorical variables will be summarized using counts and percentages.
Time frame: From the first dose of study treatment to initiation of subsequent anti-lymphoma therapy, assessed up to 5 years
TTNT (Arm B)
Continuous variables will be summarized using measures such as mean, standard deviation, median, range, and standard error, as appropriate. Categorical variables will be summarized using counts and percentages.
Time frame: From the first dose of study treatment to initiation of subsequent anti-lymphoma therapy, assessed up to 5 years
Patient reported outcomes (Arm A) - PROMIS Global Health37
Will be measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health37. Will be summarized descriptively.
Time frame: Up to 5 years
Patient reported outcomes (Arm A) - FACT Item GP5
Will be measured by the Functional Assessment of Cancer Therapy (FACT)-Item GP5 scale. Will be summarized descriptively.
Time frame: Up to 5 years
Patient reported outcomes (Arm B) - PROMIS Global Health37
Will be measured by the PROMIS Global Health37. Will be summarized descriptively.
Time frame: Up to 5 years
Patient reported outcomes (Arm B) - FACT Item GP5
Will be measured by the FACT-Item GP5 scale. Will be summarized descriptively.
Time frame: Up to 5 years
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