Smart 3: A Multi-Center Phase 2 Trial Of Golcadomide, Glofitamab And Polatuzumab Vedotin (G2P) For Patients With Newly Diagnosed Large B-Cell Lymphoma

Eligibility Criteria

Participants must meet the following criteria for study entry:

• Age ≥18 years

• Histologically diagnosed

  • Diffuse large B-cell lymphoma, not otherwise specified (NOS) or
  • High grade B-cell lymphoma (NOS or MYC and BCL2 rearrangements) o Transformed indolent lymphomas are eligible

• Ann Arbor stage II bulky (maximum dimension ≥7.5cm), III or IV

• International Prognostic Index score ≥2

• Participants must have bi-dimensional measurable disease, as defined as radiographically apparent disease with the longest dimension of ≥1.5cm

• Performance status ≤2 on the ECOG scale, or 3 if related to lymphoma

• Participants must have adequate organ and marrow function as defined below:

  • Absolute neutrophil count (ANC) ≥1.0 × 109 /L
  • Platelet count ≥75 × 109 /L
  • Hemoglobin ≥ 8 g/dL
  • Total bilirubin ≤ 3 ULN, unless consistent with Gilbert's
  • AST and ALT ≤ 5x upper limit of normal (ULN)
  • Alkaline phosphatase < 2.5 ULN
  • Creatinine clearance >30 ml/min calculated by modified Cockcroft-Gault formula or eGFR > 30 ml/min/1.73m2
  • Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion (except trace or physiological) as determined by an echocardiogram (ECHO) or MUGA, and no clinically significant electrocardiogram (ECG) findings

• All subjects must

  • Have an understanding that the study drug could have a potential teratogenic risk
  • Agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 12 months following the last dose of study treatment
  • Agree not to share study medication with another person
  • Agree to follow all requirements defined in the Pregnancy Prevention Program (see for golcadomide Pregnancy Prevention Plan for Subjects in Clinical trials
  • Females must refrain from donating egg while on study and for at least 28 days after the last dose of golcadomide.

• Females must agree to abstain from breastfeeding while taking golcadomide and for at least 28 days after the last dose of golcadomide

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114 and ARMM Checklist Appendix 14.6). This includes all female patients, between the onset of menses (as early as 8 years of age) and 50 years unless the Participant presents with an applicable exclusionary factor which may be one of the following:

  • Postmenopausal (no menses in greater than or equal to 12 consecutive months)
  • History of hysterectomy or bilateral salpingo-oophorectomy
  • Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy)
  • History of bilateral tubal ligation or another surgical sterilization procedure

• Females of childbearing potential (FCBP§) must:

  • Have two negative pregnancy tests as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact
  • a negative serum or urine pregnancy test at Screening (within 10-14 days prior to Cycle 1 Day 1) of study treatment
  • a negative serum or urine pregnancy test (Investigator's discretion) within 24 hours prior to Cycle 1 Day 1 of study treatment
  • Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting IP, during the study treatment (including dose interruptions), and for 28 days after the last dose of golcadomide, 2 months after the last dose of glofitamab, 9 months after the last dose of polatuzumab and for 18 months after the last dose of obinutuzumab or 3 months after the last dose of tocilizumab (if applicable), whichever is longer. Contraception requirements are detailed in

• Male subjects must:

  • Participants must agree to either remain completely abstinent or to use two effective contraceptive methods that result in a failure rate of < 1% per year from screening until at least 28 days after the last dose of golcadomide, 3 months after pre-treatment with obinutuzumab, 2 months after the last dose of glofitamab, 6 months after the last dose of polatuzumab, or 2 months after the last dose of tocilizumab (if applicable), whichever is longer

    ), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study

  • Must agree to refrain from donating sperm while on study treatment, during dose interruptions, and for at least 3 months and 2 weeks after the last dose of golcadomide or obinutuzumab, whichever is longer

  • Sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study

• The investigator is responsible for: ensuring that the Participant understands the potential risks and benefits of participating in the study; ensuring that informed consent is given by each patient, this includes obtaining the appropriate signatures and dates on the informed consent document prior to the performance of any study procedures and prior to the administration of study treatment; answering any questions the Participant may have throughout the study and sharing in a timely manner any new information that may be relevant to the patient's willingness to continue his or her participant in the trial. Subjects will undergo a brief physical exam including a brief exam to determine cognitive review. No one without capacity to personally consent will be enrolled. Patients have medical decision-making capacity if they can demonstrate understanding of the situation, appreciation of the consequences of their decision, and reasoning in their thought process, and if they can communicate their wishes

• A determination of lack of decision-making capacity shall be made after an appropriate medical evaluation that concludes there is little or no likelihood that the participant will regain decisionmaking capacity in a reasonable period of time

• §A FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months

• Participants must be willing and able to comply with the protocol treatment and procedures

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Subjects will be ineligible for this study if they meet any of following criteria:

• Central nervous system involvement of lymphoma

  > Suspicious cases at the time of diagnosis should be evaluated with brain MRI with or without lumbar puncture

• Any prior history of other malignancy besides B-NHL, unless the Participant has been free of disease for ≥ 2 year and felt to be at low risk for recurrence by the treating physician, except:

  • Adequately treated localized skin cancer without evidence of disease
  • Adequately treated cervical carcinoma in situ without evidence of disease
  • Adequately treated localized breast cancer without evidence of disease
  • Adequately treated localized prostate cancer without evidence of disease

• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of golcadomide, or put the study outcomes at undue risk

• Requires chronic treatment with strong CYP3A inhibitors (List in Table 8). Participants can be eligible after discontinuation of the perpetrator and a sufficient washout period of 7-days or 5 half-lives, whichever is longer.

• Uncontrolled human immunodeficiency virus (HIV) with positive viral load, or active Hepatitis C Virus, or active Hepatitis B Virus infection, or any uncontrolled active significant infection within 4 weeks before the start of treatment, including suspected or confirmed JC virus infection and SARSCoV2.

• Participants with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis unless contraindicated. The treatment and monitoring of hepatitis B will follow the institutional standard of practice. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded. Subjects with a history of Hepatitis C who received antiviral treatment are eligible as long as PCR is negative.

• History of severe allergic or anaphylactic reactions or intolerance to anti-CD20 monoclonal antibody therapy or any bispecific antibody.

• History of immunodeficiency (with the exception of hypogammaglobulinemia) or concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc., or chronic administration glucocorticoid equivalent of >20mg/day of prednisone) within 28 days of the first dose of study drug with exception of steroid used for IV contrast allergy. In addition, use of inhaled, topical, intranasal corticosteroids or local steroid injection (eg, intra- articular injection) is permitted.

• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association NYHA) Functional Classification. Subjects with controlled, asymptomatic heart failure during screening can enroll on study.

• Significant screening electrocardiogram (ECG) abnormalities including left bundle branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree block.

• QTcF ≥ 470 msec

• History of stroke, seizure disorder or Participants requiring antiepileptic therapy or intracranial hemorrhage within 6 months prior to study entry.

• Vaccinated with live, attenuated vaccines within 4 weeks of study entry

• Lactating or pregnant subjects. Pregnant women are excluded from this study for potential teratogenic or abortifacient effects by golcadomide or glofitamab.

• Had blood transfusion within 14 days of first dose of study drug

• Administration of any investigational agent within 28 days of first dose of study drug

• Participants who have undergone major surgery within 28 days or minor surgery within 3 days of first dose of study drug

• Participants taking chronic corticosteroids for other diseases, unless administered at a dose equivalent to < 20 mg/day prednisone. For corticosteroids, prednisolone >20 mg daily (or equivalent) qualifies as immunosuppressive and thus is excluded for this use. Note: corticosteroids at any dose are permitted for control of lymphoma-related symptoms or potential immune related complication from the treatment, including during screening, and for prophylaxis or AE management during the trial

• Prior exposure to IMiDs, CD20 x CD3 bispecific antibodies, independently from indication

• Participants who have difficulty with or are unable to swallow oral medication, or have disease significantly affecting gastrointestinal function that would limit absorption of oral medication

• Participants who have any contraindication for prophylaxis against venous thromboembolism

• Participants for whom accurate assessment of neurologic toxicity is not feasible in the opinion of the investigator

• Participants who have an active autoimmune disease that has required systemic treatment in past 12 months (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed

• Participants with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment)

• Known history of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) or drug rash with eosinophilia and syst