Study of Tazemetostat in Lymphoid Malignancies

Sponsor

University of Alabama at Birmingham (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05983965

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Tazemetostat is an oral EZH2 inhibitor which has been FDA approved for adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) whose tumors are positive for an EZH2 and who have received at least 2 prior systemic therapies, and for adult patients with R/R FL who have no satisfactory alternative treatment option. Tazemetostat has demonstrated preclinical activity as monotherapy in T-cell lymphomas and in combination with BTK inhibitors in B-cell lymphomas and CLL. Therefore, the investigators propose a study to evaluate the safety of tazemetostat as monotherapy in T-cell lymphomas and in combination with acalabrutinib in CLL.

Condition or Disease	Intervention/Treatment	Phase
T-cell Lymphoma CLL/SLL	Drug: Tazemetostat Drug: Acalabrutinib and Tazemetostat	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Study to Evaluate Safety and Tolerability of Tazemetostat Alone or in Combination With Acalabrutinib in Lymphoid Malignancies

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2027

Anticipated Study Completion Date :

Dec 1, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A T-cell Lymphomas	Drug: Tazemetostat Treatment: On day 1 and day 15 of the first cycle, and day 1 of all following cycles, the subject will have office visit with physical exam, vital signs, and lab tests. The subject will take tazemetostat twice a day by mouth continuously as an outpatient. If continuing on the treatment for more than 6 cycles, visits change to every 3 months.
Experimental: Cohort B CLL-Chronic Lymphocytic Leukemia/SLL-Small Lymphocytic Leukemia	Drug: Acalabrutinib and Tazemetostat Treatment: On day 1 and day 15 of the first cycle, and day 1 of all following cycles, the subject will have office visit with physical exam, vital signs, and lab tests. The subject will take tazemetostat and acalabrutinib by mouth continuously as an outpatient. If continuing on the treatment for more than 6 cycles, visits change to every 3 months.

Arm

Intervention/Treatment

Experimental: Cohort A

T-cell Lymphomas

Drug: Tazemetostat

Treatment: On day 1 and day 15 of the first cycle, and day 1 of all following cycles, the subject will have office visit with physical exam, vital signs, and lab tests. The subject will take tazemetostat twice a day by mouth continuously as an outpatient. If continuing on the treatment for more than 6 cycles, visits change to every 3 months.

Experimental: Cohort B

CLL-Chronic Lymphocytic Leukemia/SLL-Small Lymphocytic Leukemia

Drug: Acalabrutinib and Tazemetostat

Treatment: On day 1 and day 15 of the first cycle, and day 1 of all following cycles, the subject will have office visit with physical exam, vital signs, and lab tests. The subject will take tazemetostat and acalabrutinib by mouth continuously as an outpatient. If continuing on the treatment for more than 6 cycles, visits change to every 3 months.

Outcome Measures

Primary Outcome Measures

Identify the recommended phase II dose of Tazemetostat [28 days]
The measurement will be the occurrence of a dose limiting toxicity (DLT) in the first cycle (28 days) after treatment initiation from the start of cycle 1 day 1. Measurements will be graded on a Hematologic Toxicity scale from grades 1 through 4 with grade 4 being worst grade.
Identify the recommended phase II dose of Tazemetostat and Acalabrutinib [28 days]
The measurement will be the occurrence of a dose limiting toxicity (DLT) in the first cycle (28 days) after treatment initiation from the start of cycle 1 day 1. Measurements will be graded on a Hematologic Toxicity scale from grades 1 through 4 with grade 4 being worst grade.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Inclusion criteria for all patients

Age ≥ 18.
Patients with Hepatitis C can be included if they have completed therapy for hepatitis C with undetectable viral load.
Patients with Hepatitis B can be included if they are on suppressive therapy for hepatitis B infection and with no detectable viral load.
Patients with HIV can be included if they are on appropriate antiretroviral therapy, there is no interaction with the study drug, a CD4+ T-cell counts ≥ 350 cells/µL and no detectable viral load.
Adequate organ function as defined below unless attributed to disease involvement (Note: transfusions and growth factors allowed during screening; however, transfusion-dependency defined as requiring blood products ≥once per week not allowed): i. Liver function: No more than moderate hepatic impairment per NCI ODWG criteria - Total bilirubin ≤ 3X upper limit of normal (ULN), AST ≤ ULN (unless attributed to fatty liver or disease involvement).

Kidney function: CrCl > 30ml/min using Cockroft-Gault, based on actual weight.
ANC ≥ 1,000/µL, Platelet Count ≥ 75,000/ µL, Hemoglobin ≥ 8.0 g/dl.

Left ventricular ejection fraction (LVEF) defined by multiple-gated acquisition (MUGA) scan or echocardiogram within the institutional limits of normal.
Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2.
A negative urine or serum pregnancy test is required for all women of childbearing potential within 1 week prior to enrolling on this trial and within 3 days of first dose of study drug. Note: Urine pregnancy tests that cannot be confirmed as negative require a confirmatory negative serum pregnancy test.

Non-childbearing potential is defined as:

Postmenopausal: Defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, FSH measurements indicating post-menopausal status must be documented in patient's medical history.
Permanently sterile: Documented permanent sterilization e.g., hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

If female of childbearing potential, subject must not be pregnant or be breastfeeding and is required to have a negative urine or serum pregnancy test within 3 days prior to the first dose of study drug. In addition, females of childbearing potential must either practice complete abstinence or agree to use two effective methods of contraception simultaneously, beginning ≥ 28 days prior to start of tazemetostat, during tazemetostat treatment, and for at least 6 months after final dose of tazemetostat. See Appendix F regarding contraception guidelines.
Male subjects must either practice complete abstinence or agree to use a latex or synthetic condom during any sexual contact with a female of childbearing potential, from first dose of tazemetostat, during study treatment including dose interruptions, and for 3 months after last dose of tazemetostat. This applies even to males who have undergone successful vasectomy with medically confirmed azoospermia.
Willing and able to participate in all required evaluations and procedures in this study protocol including receiving intravenous administration of investigational product and being admitted, when required, for at least 24 hours during investigational product administration.

Inclusion criteria for Cohort A (T-cell lymphomas)

Histologically confirmed peripheral T-cell lymphomas (PTCL) with allowed subtypes listed below as per the revised World Health Organization 2022 classification [7]:

PTCL subtypes allowed

PTCL-not otherwise specified (NOS)
Nodal T-follicular helper cell lymphoma - angioimmunoblastic type, follicular type, or NOS
Anaplastic Large Cell Lymphoma (ALK+)
Anaplastic Large Cell Lymphoma (ALK-)
Enteropathy-associated T-cell lymphoma
Monomorphic epitheliotropic intestinal T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Adult T-cell leukemia / lymphoma - lymphomatous, acute, or unfavorable chronic subtypes
Patients must have relapsed or refractory disease.
Relapsed disease is defined when a patient progressed (>3 months) after achieving CR with a previous treatment
Refractory disease is defined when a patient failed to achieve a CR or PR after a previous treatment
Patients received at least 1 prior therapy for PTCL.
At least one bi-dimensionally measurable nodal lesion, defined as ≥ 1.5 cm in its longest dimension, or one bi-dimensionally measurable extranodal lesion, defined as ≥ 1.0 cm in its longest diameter on fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) scan as defined by response criteria for PTCL

Inclusion criteria for Cohort B (CLL/SLL)

Diagnosis of CLL according to the IWCLL criteria or SLL according to the WHO criteria.

This includes previous documentation of:

Biopsy-proven small lymphocytic lymphoma OR
Diagnosis of CLL according to the IWCLL criteria as evidenced by all of the following:

Peripheral blood lymphocyte count of greater than 5 x109/L ii. Immunophenotype consistent with CLL defined as: The predominant population of lymphocytes share both B cell antigens [CD19, CD20 (typically dim expression), or CD23] as well as CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc).

Clonality as evidenced by κ or λ light chain restriction (typically dim immunoglobulin expression) Negative FISH analysis for t(11;14) (IgH/CCND1) on peripheral blood or tissue biopsy (e.g. marrow aspirate) or negative immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g.

marrow aspirate or lymph node biopsy)

Patients must meet criteria for treatment as defined by 2018 IWCLL guidelines [Hallek et al] which includes at least one of the following criteria:
Evidence of marrow failure as manifested by the development or worsening of anemia or thrombocytopenia.
Massive (≥6 cm below the costal margin), progressive or symptomatic splenomegaly
Massive nodes (≥10 cm) or progressive or symptomatic lymphadenopathy
Progressive lymphocytosis with a lymphocyte doubling time < 6 months or an increase of ≥ 50% over a 2-month period
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy
Symptomatic or functional extranodal involvement (e.g. skin, kidney, lung, spine)
Constitutional symptoms, which include any of the following:

Unintentional weight loss of 10% or more within 6 months ii. Significant fatigue

Fevers >100.5 degrees F for 2 weeks or more without evidence of infection iv. Night sweats ≥1 month without evidence of infection

Eligible to receive Acalabrutinib.
Patients must have relapsed or refractory disease.
Relapsed disease is defined when a patient progressed (>3 months) after achieving CR with a previous treatment
Refractory disease is defined when a patient failed to achieve a CR or PR after a previous treatment

Exclusion Criteria:

Exclusion criteria for all patients

Current evidence of central nervous system involvement.
Completion of an autologous hematopoietic stem cell transplantation within 3 months prior to first dose of study drug.
Prior allogeneic stem cell transplant within 6 months. The patient should not have any active GVH or should be on immune suppressive agents.
Completion of treatment with any radiotherapy, chemotherapy, antibody, immunoconjugates and/or another investigational drug ≤4 weeks (or 5 half-lives of the drug, whichever is shorter) prior to first dose of study drug.

Patients may be enrolled after a minimum of 2 weeks of radiation if radiation was for palliative intent.

Prior therapy with an EZH2 inhibitor.
Inability to swallow and retain oral medications.
Pregnant women are excluded from this study.
Any active, concurrent, significant illness or disease (other underlying lymphoma) or clinically significant findings including psychiatric and behavioral problems, medical history and/or physical examination findings that would preclude the patient from participation in the study such as: i. Active infection requiring systemic therapy ≤10 days before the first dose of study drug; ii. Unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association [NYHA] II, III, IV;), myocardial infarction ≤6 months prior to first study drug, uncontrolled cardiac arrhythmia e.g., atrial fibrillation/flutter, cerebrovascular accidents ≤6 months before first dose of study drug; iii. Any severe or uncontrolled other disease or condition which might increase the risk associated with study participation.
Vaccination with live, attenuated vaccines within 28 days prior to the first dose of study medication.
Receiving systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents). The use of inhaled corticosteroids is permitted.
Corticosteroids ≥ 10 mg of prednisone within the last 7 days.
Has had a solid organ transplant within the last 3 years. Note: Patients who have had a solid organ transplant >3 years ago are eligible if there are no signs/symptoms of graft versus host disease (GvHD) and off immunosuppressive medications as per above.
Any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN).
Any prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL).
Any other malignancy known to be active, with the exception of i. Cervical carcinoma of Stage 1B or less ii. Non-invasive basal cell or squamous cell skin carcinoma iii. Non-invasive, superficial bladder cancer iv. Prostate cancer with a current PSA level < 0.1 ng/mL v. Any curable or localized cancer with a CR of > 2 years' duration.
Any malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat.
Major surgery within 4 weeks before the first dose of study intervention. Note: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrolment.

Exclusion criteria for Cohort A (T-cell lymphoma)

Patients with the following subtypes of lymphoma: i. T-cell prolymphocytic leukemia ii. T-large granular lymphocytic leukemia iii. NK-large granular lymphocytic leukemia iv. Aggressive NK-cell leukemia v. Breast implant-associated anaplastic large-cell lymphoma

Exclusion criteria for Cohort B (CLL/SLL)

Barriers to commercially available acalabrutinib.
Known histological transformation from CLL to an aggressive lymphoma such as Richter's Transformation. Prolymphocytic leukemia is not excluded.
For patients with prior treatment with BTK inhibitors, presence of resistance associated mutation with BTK inhibitors as documented by presence of C481S or PLCG2 mutations.
QTcF interval> 480ms or other remarkable abnormality of ECG, including second-degree type II atrioventricular block, third-degree atrioventricular block, or bradycardia (ventricular rate consistently less than 50 beats per minute).