IRB Study Number 25-378
Status Recruiting
Phase Phase 2
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
1.1 Primary Objective(s)
o To evaluate the efficacy (complete response rate) of Nem-R in patients with treatment-naïve MCL
1.2 Secondary Objective(s)
o To evaluate objective response rate (ORR), median progression-free survival (PFS), overall survival (OS) and duration of response (DOR)
o To evaluate safety and tolerability of Nem-R in patients with treatment-naïve MCL
1.3 Exploratory Objective(s)
o To conduct preliminary assessment of the predictive value of MRD in MCL treated with a novel regimen
o To explore immune cell populations in patients treated with Nem-R
o To explore mechanisms of resistance to Nem-R therapy in MCL
o To estimate the second PFS after salvage therapy for patients who progress after Nem-R therapy
Inclusion Criteria
Informed Consent and Willingness to Participate
- Documented informed consent of the participant and/or legally authorized representative.
Assent, when appropriate, will be obtained per institutional guidelines
Age Criteria, Performance status
Age: ≥ 18 years
ECOG ≤ 2 (Appendix A)
Nature of Illness and Illness Related Criteria
- Diagnosis of MCL established by histologic assessment including one of the following:
Immunohistochemistry of the biopsy
Flow cytometry of the biopsy
- Requiring treatment for MCL, and for which no prior systemic anticancer therapies have been received
local radiotherapy not exceeding a total dose of 20 Gy at least 2 weeks prior the first dose of study therapy is allowed
- Laboratory, radiographic, physical exam findings and/or symptoms attributable to MCL.
Asymptomatic patients with blastoid or pleomorphic variant can be enrolled
- Radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (as defined by Lugano Classification for NHL, Appendix C) [1]
Clinical Laboratory and Organ Function Criteria: (acceptable windows for tests are indicated in the Study Calendar Section 10.0).
- Without bone marrow involvement: ANC ≥ 1,000/mm3
With bone marrow involvement: ANC ≥ 500/mm3
NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement.
- Without bone marrow involvement: Platelets ≥ 75,000/mm3
With bone marrow involvement: Platelets ≥ 30,000/mm3
NOTE: Platelet transfusions are not permitted within 7 days of platelet assessment unless cytopenia is secondary to disease involvement.
Total bilirubin ≤1.5×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels >1.5×ULN
AST 2.5 x ULN
ALT 2.5 x ULN
Creatinine clearance of ≥30 mL/min per 24-hour urine test or the Cockcroft-Gault formula or estimated GFR ≥30 mL/min/1.73 m2 per the CDK-EPI creatinine equation (2021)
If not receiving anticoagulants: International Normalized Ratio (INR) OR Prothrombin (PT) ≤1.5×ULN
If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
- If not receiving anticoagulants: Activated Partial Thromboplastin Time (aPTT) ≤1.5×ULN
If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants
- Seronegative for HCV, HBV (Surface Antigen Negative) OR If seropositive for HBV or HCV, nucleic acid quantitation must be performed. Viral load must be undetectable.
Patients with occult or prior HBV infection (defined as negative HBsAg and positive hepatitis B core antibody (HBcAb) may be included if HBV DNA is undetectable, if they are willing to undergo DNA testing on Day 1 of every cycle and every three months for at least 12 months after the last cycle of study treatment
- Participants with HIV are eligible if they meet ALL the following:
CD4 count > 350 cells/μL at screening
The HIV viral load is below the detectable level as per locally available testing
Are on a stable ART regimen for at least 4 weeks prior to study entry
NOTE: ART includes drugs, which are NOT strong CYP3A4 inducers (participants receiving ART that are strong CYP3A4 inducers are not eligible to be included in the study).
HIV screening tests are not required unless:
o Known history of HIV infection
o As mandated by local health authority
Are compliant with their ART
NOTE: If the participant has had an AIDS defining opportunistic infection in the past 12 months prior to screening, they are not eligible to be included in the study.
- Person of childbearing potential (POCBP): negative urine or serum pregnancy test
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (See Appendix D)
Contraception (See Appendix D)
- Participants assigned male sex at birth: If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:
Nemtabrutinib: 12 days
Rituximab: 3 months
Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent OR
Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) as detailed below:
Uses a penile/external condom plus nonparticipant of childbearing potential who is not currently pregnant and should also be advised of the benefit for that partner to use an additional method of contraception, as a condom may break or leak.
Note: Participants capable of producing ejaculate whose partner is pregnant or breastfeeding must agree to use penile/external condom during each episode of sexual activity in which the partner is at risk of drug exposure via ejaculate.
Contraceptive use by participants capable of producing sperm should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.
- Participants assigned female sex at birth: A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:
Is not a person of childbearing potential (POCBP) OR
Is a POCBP and:
o Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 3 during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:
o Nemtabrutinib: 1 month
o Rituximab: 12 months
o The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.
Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for urine test) or 72 hours (for serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention are in Section X.
Abstains from breastfeeding during the study intervention period and for at least 30 days after study intervention with nemtabrutinib.
Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.
Exclusion Criteria
Prior and concomitant therapies
Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 2 weeks of the first day of study therapy.
Chronic systemic corticosteroid use >20 mg/day of prednisone or equivalent. Patients who received corticosteroid treatment with 20 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks’ duration prior to Day 1 of Cycle 1. Patients may have received a brief ( 14 days) course of systemic steroids (≤100 mg prednisone equivalent per day) prior to initiation of study therapy for control of lymphoma-related symptoms.
Other illnesses or conditions
History of severe bleeding disorder defined as an ongoing congenital or acquired condition that leads to an increased likelihood of bleeding.
Unstable cardiac disease as defined by one of the following:
Acute myocardial infarction (MI) within the past 6 months
NYHA (New York Heart Association) heart failure class III-IV (Appendix B)
Unstable angina (angina symptoms at rest) or new-onset angina (begun within the last 3 months)
QTc prolongation (defined as a QTcF >450 msecs) or other significant ECG abnormalities including second degree AV block type II, third degree AV block, or bradycardia (ventricular rate less than 50 beats/min)
Positive for hepatitis C virus (HCV) virus by PCR at screening. Testing only required if the Hep C antibody is positive.
AIDS-defining opportunistic infection in the past 12 months prior to screening
Known allergy/sensitivity to nemtabrutinib or any of the excipients; history of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents
Clinically significant uncontrolled illness
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episode of infection (as evaluated by the investigator) within 4 weeks prior to the first study treatment.
Primary or secondary central nervous system (CNS) lymphoma at the time of recruitment or history of CNS lymphoma
Other active malignancy. Exceptions include malignancy treated with curative intent and no known active disease present for ≥ 2 years prior to initiation of protocol therapy; adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease; adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without evidence of disease; asymptomatic prostate cancer managed with “watch and wait” strategy.
POCBP: Pregnant or breastfeeding
Patients with gastrointestinal dysfunction and/or clinically significant medical condition of malabsorption, inflammatory bowel disease, chronic conditions which manifest with diarrhea, refractory nausea, vomiting or any other condition that will interfere significantly with drug absorption (e.g., gastric bypass surgery, gastrectomy)
Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns with clinical study procedures.
Noncompliance
- Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).
