IRB Study Number 25-148
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
To evaluate the MTD and select the recommended Phase II dose (RP2D) of Mosun + Len
Secondary Objective
To evaluate treatment efficacy by measuring response and long-term efficacy outcomes
Inclusion Criteria
Signed Informed Consent Form
Age 18 years
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
R/R FL after treatment with at least one prior systemic lymphoma therapy, which includes prior immunotherapy or chemoimmunotherapy
For patients who have only received one prior line of systemic therapy, patients must either have FLIPI score 25, be refractory to prior anti-CD20 MAb, or have progression of disease within 24 months after initiation of prior therapy (POD24); these restrictions do not apply for patients who have received two or more prior lines of systemic therapy
Previously untreated patients with FL must require systemic therapy assessed by investigator based on GELF criteria and have a FLIPI score of 25
Histologically documented FL of Grade 1, 2, or 3a, and that expresses CD20 as determined by the local laboratory Fluorodeoxyglucose-avid lymphoma (i.e., PET-positive lymphoma) At least one bi-dimensionally measurable nodal lesion ( 1.5 cm in its largest dimension by PET-CT scan), or at least one bi-dimensionally measurable extranodal lesion ( 1.0 cm in its largest dimension by PET-CT scan)
Availability of a representative tumor specimen and the corresponding pathology report for confirmation of the diagnosis of FL.
If archival tissue is unavailable or unacceptable, a pretreatment sample of at least 1 core-needle, excisional or incisional tumor biopsy is required. Cytological or fine-needle aspiration samples are not acceptable. For patients in China, tissue samples may be submitted retrospectively upon Human Genetic Resources Administration of China approval of sample submission.
Adequate hematologic function defined as follows without growth factors or blood product transfusion within 14 days of first dose of study drug administration:
– Hemoglobin, without transfusion, 9 g/dL
– ANC 1.0 109/L
– Platelet count 75 109/L
Normal laboratory values defined as follows:
– Measured or estimated creatinine clearance 50 mL/min by institutional standard method
– AST or ALT 2.5 ULN
– Serum total bilirubin 1.5 ULN (or 3 ULN for patients with Gilbert syndrome)
Negative HIV test at screening, with the following exception:
Individuals with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy for at least 4 weeks, have a CD4 count 200/mL, have an undetectable viral load, and have not had a history of opportunistic infection attributable to AIDS within the last 12 months.
Agreement to comply with all local requirements of the lenalidomide risk minimization plan
In every country where lenalidomide has been approved, a risk minimization plan, which includes a pregnancy prevention program, is in place. The risk minimization plan should be followed by patients using lenalidomide.
All patients and health care providers will be trained and counseled on pregnancy prevention in accordance with the Lenalidomide Global Pregnancy Prevention Counseling Program prior to medication being dispensed to ensure that the patient has complied with all requirements, including use of birth control and pregnancy testing, and that the patient understands the risk of embryo-fetal toxicity associated with lenalidomide. This step will be documented with a completed Education and Counseling Guidance Document (refer to the Lenalidomide Pregnancy Prevention Risk Management Plans), and no drug will be dispensed until this step occurs. Counseling includes verification with the patient that required pregnancy testing was performed and results were negative. A Lenalidomide Information Sheet (refer to Lenalidomide Pregnancy Prevention Risk Management Plans) will be supplied with each medication dispensed. All requirements must be followed by each site as noted within the Lenalidomide Pregnancy Prevention Risk Management Plans.
In addition, because lenalidomide will be administered in combination with mosunetuzumab, patients must comply with contraceptive measures designed to ensure safe administration of all study treatments, as outlined below.
For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use two adequate methods of contraception, including at least one method with a failure rate of 1% per year, for at least 28 days prior to Day 1 of Cycle 1, during the treatment period (including periods of treatment interruption), and for at least 28 days after the last dose of lenalidomide, 3 months after the final dose of tocilizumab, and 3 months after the final dose of mosunetuzumab. Women must refrain from donating eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state ( 24 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Even in presence of infertility history, a reliable contraception, including two adequate methods of contraception, is indicated.
Examples of non-hormonal contraceptive methods with a failure rate of 1% per year include bilateral tubal ligation, male sterilization and copper intrauterine devices. Barrier methods must always be supplemented with the use of a spermicide.
Note: Combined oral contraceptives are not recommended because of the increased risk of venous and arterial thromboembolism (TE) in patients taking lenalidomide.
The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 28 days after last dose of lenalidomide, and 2 months after the final dose of tocilizumab. Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
Exclusion Criteria
Any history of Grade 3b FL
Any history of disease transformation and/or DLBCL
Suspicion or clinical evidence of transformed lymphoma at enrollment by investigator assessment (e.g., high standardized uptake values [SUV] in at least one lesion that was not biopsied, and discordant with SUV of biopsied lesion (at least double of the average SUV), LDH 2.5 x ULN especially in a context of rapidly progressive disease).
Active or history of CNS lymphoma or leptomeningeal infiltration
Documented refractoriness to lenalidomide, defined as no response (PR or CR) within 6 months of therapy Prior standard or investigational anti-cancer therapy as specified below:
– Lenalidomide exposure within 12 months prior to Day 1 of Cycle 1
– Fludarabine or alemtuzumab within 12 months prior to Day 1 of Cycle 1
– Radioimmunoconjugate within 12 weeks prior to Day 1 of Cycle 1
– Prior anti-lymphoma treatment with MAb or antibodydrug conjugate within 4 weeks prior to Day 1 of Cycle 1
– Treatment with any chemotherapeutic agent, or treatment with any other anti-cancer agent (investigational or otherwise) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to first dose of study treatment
Clinically significant toxicity (other than alopecia) from prior treatment that has not resolved to Grade 2 (per NCI CTCAE v5.0) prior to Day 1 of Cycle 1
Known history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis or evidence of active pneumonitis on screening chest CT scan
Treatment with systemic immunosuppressive medications, including, but not limited to, prednisone, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents within 2 weeks prior to Day 1 of Cycle 1
The use of inhaled corticosteroids is permitted.
The use of mineralocorticoids for management of orthostatic hypotension is permitted.
The use of physiologic doses of corticosteroids for management of adrenal insufficiency is permitted.
If corticosteroid treatment is urgently required for lymphoma symptom control prior to the start of study treatment, 100 mg of prednisone or equivalent can be given for a maximum of 5 days.
History of solid organ transplantation
History of severe allergic or anaphylactic reaction to humanized, chimeric or murine MAbs
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the mosunetuzumab, lenalidomide, or thalidomide formulation, including mannitol
History of erythema multiforme, Grade 3 rash, or blistering following prior treatment with immunomodulatory derivatives
Known active bacterial, viral, fungal, or other infection, or any major episode of infection requiring treatment with IV antibiotics within 4 weeks of Day 1 of Cycle 1
Known or suspected chronic active Epstein-Barr virus (EBV) infection
Known or suspected hemophagocytic syndrome
Active Hepatitis B infection
Patients who are hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (HBcAb) positive, must be negative for hepatitis B virus (HBV) polymerase chain reaction (PCR) to be eligible for study participation.
Active Hepatitis C infection
Patients who are positive for hepatitis C virus (HCV) antibody must be negative for HCV by PCR to be eligible for study participation.
History of progressive multifocal leukoencephalopathy (PML)
Administration of a live, attenuated vaccine within 4 weeks before first dose of study treatment or anticipation that such a live attenuated vaccine will be required during the study
Patients must not receive live, attenuated vaccines (e.g., FluMist) while receiving study treatment or after the last dose until B-cell recovery to the normal ranges. Killed vaccines or toxoids should be given at least 4 weeks prior to the first dose of study treatment to allow development of sufficient immunity.
Refer to Section 4.4.1.3 for additional information about SARS-CoV-2 vaccines.
Inactivated influenza vaccination should be given during influenza season only.
Investigators should review the vaccination status of potential study patients being considered for this study and follow the U.S. Centers for Disease Control and Prevention guidelines, or local guidelines for sites outside the U.S., for adult vaccination with any other non-live vaccines intended to prevent infectious diseases prior to study.
Other malignancy that could affect compliance with the protocol or interpretation of results, with the exception of the following:
– Any of the following malignancies previously curatively treated: carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of the breast, basal, or squamous cell skin cancer – Stage I melanoma, low-grade, early-stage localized prostate cancer, or any other previously treated malignancy that has been in remission without treatment for 2 years prior to enrollment
Active autoimmune disease requiring treatment.
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
Patients with a history of disease-related immune thrombocytopenic purpura, or autoimmune hemolytic anemia, or other stable autoimmune diseases may be eligible.
Patients with a history of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis, with treatmentfree interval from immunosuppressive therapy for 12 months, may be eligible.
Prior allogeneic hematopoietic stem cell transplant
Grade 2 neuropathy
Evidence of any significant, uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including, but not limited to significant cardiovascular disease (e.g., New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or unstable angina) or significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm)
Major surgical procedure other than for diagnosis within 28 days prior to Day 1 of Cycle 1 or anticipation of a major surgical procedure during the course of the study
Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis
Pregnant or lactating or intending to become pregnant during the study
Women of childbearing potential must have two negative pregnancy test results (minimum sensitivity, 25 mIU/mL) prior to initiating therapy: at 10 to 14 days prior to Day 1 of Cycle 1 and within 24 hours prior to Day 1 of Cycle 1. If serum pregnancy test has not been performed within 14 days to receive first study treatment, a urine pregnancy test must be performed 7 days prior to study treatment and within 24 hours prior to Day 1 of Cycle 1. In addition, a pregnancy test must be performed at approximately 14 days after treatment discontinuation in patients of reproductive age and irregular menses. Women with irregular menstrual cycles must have pregnancy test 14 days after the last dose of lenalidomide.
Unable to comply with the study protocol, in the investigator’s judgment
History of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator’s judgment
Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results.
