Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Eligibility Criteria

Participants must meet the following criteria for study entry:

1. Confirmed diagnosis of mantle cell lymphoma by hematopathology. MCL should have CD20
positivity (by flow or IHC in tissue or in BM) with presence of chromosome
translocation t (11;14), (q13;q32) and/or overexpression of cyclin D1 in tissue
biopsy. Cyclin D negative MCL are allowed after discussion with study PI.

2. Participants should have a life expectancy >= 12 weeks.

3. Newly diagnosed, untreated, high risk participant without any prior therapy for MCL
and are eligible to receive BTKi-R and glofitamab therapy.

4. High risk MCL (Blastoid/pleomorphic histology, high Ki-67 (≥50%), TP53/NOTCH1/2,
NSD2, UBR5, TRAF2, SP140, SMARCA4, KMT2D, BIRC3 mutated or any of these mutations or
more than 2 mutations with some evidence of prognostic impact, complex karyotype
and/or Bulky nodal disease >= 5 cm or spleen >= 20 cm, FISH positive for TP53 or MYC
from involved tissues or TP53 and MYC positive intensity in lymphoma cells in
involved tissues (positive by hem-path criteria at MDACC), high risk MIPI score
(with/without Ki-67%). Presence of any or all of these features would qualify as
high risk but will need to be reviewed and approved by the study PI.

6. Participants who are willing and able to participate in all required evaluations and
procedures in this study protocol, including swallowing capsules and tablets without
difficulty.

7. Understand and voluntarily sign an IRB-approved informed consent form. 8. Age ≥ 18
years at the time of signing the informed consent. 9. Bi-dimensional measurable disease
using the 2014 Cheson criteria (Measurable disease by PETCT scan or CT scan (if PET-CT
not approved and study PI approves) defined as at least 1 lesion that measures ≥ 1.5 cm
in single dimension.) and/or spleen only involved (>=20 cm). Leukemic phase MCL are
allowed without bulky measurable disease if they have other high-risk features after
discussion with the study PI. These participants are allowed if they meet any other
high-risk features, determined by the study PI.

10. Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. 11.
Participants with preexisting well-controlled cardio-vascular comorbidities -
participants on anticoagulants (excluding warfarin and vitamin K antagonists),
antiplatelet, antihypertensive, prior ablation, anti-arrhythmia, prior arrhythmias,
baseline EKG abnormalities and cardiology clearance are allowed. Ejection fraction >=50%
and cardiology evaluation is needed. (Echo and EKG and cardiology consultation within 2
months prior to C1D1 are allowed).

12. An absolute neutrophil count (ANC) > 1,000/mm3 and platelet count >100,000/mm3
(Participants who have >50% bone marrow or spleen infiltration by MCL are eligible if
their ANC is ≥ 500/mm3 [growth factor allowed] or their platelet level is equal to or >=
than 30,000/mm3 (transfusions allowed) These participants should be discussed with the PI
of the study for final approval). Hemoglobin > 8.0 g/dL (> 80 g/L), unsupported for 2
days before first treatment (unless attributable to the underlying disease as determined
by the study PI) 13. Serum bilirubin <1.5 mg/dl, AST (SGOT) and ALT (SGPT) < 2.5 x upper
limit of normal or < 5 x upper limit of normal if hepatic metastases are present.
Gilbert's disease is allowed.

14. Creatinine clearance. >=30 mL/min (by 2021 chronic kidney disease epidemiology
(CKD-EPI) creatinine equation or 2021 CKD-EPI creatinine-cystatin C equation., APPENDIX
VI I) 15. Contraception in female participants of childbearing potential- female
participants must remain abstinent or use contraceptive methods with a failure rate of <
1% per year during the treatment period and for at least 6 months after pretreatment with
obinutuzumab, 2 months after the final dose of glofitamab and 2 months after the final
dose of tocilizumab (as applicable), whichever is longer. Women must refrain from
donating eggs during this same period.

16. A female participant is considered to be of childbearing potential if she is
postmenarchal, has not reached a postmenopausal state (³ 12 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). Per this
definition, a female participant with tubal ligation is considered to be of childbearing
potential. The definition of childbearing potential may be adapted for alignment with
local guidelines or regulations.

17. Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation in female of child-bearing potential, male sterilization,
hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
and copper intrauterine devices.

18. Hormonal contraceptive methods are also recommended to be supplemented by a barrier
method.

19. 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 individual. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not adequate 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.

20. Contraception for male participants: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods, and agree to refrain from
donating sperm, as defined below: 21. With a female partner of childbearing potential or
pregnant female partners, male participants must remain abstinent or use a condom plus an
additional contraceptive method that together result in a failure rate of < 1% per year
during the treatment period and for at least 6 months after pretreatment with
obinutuzumab, 2 months after the final dose of glofitamab or 2 months after the last dose
of tocilizumab (as applicable), whichever is longer. Male participants must refrain from
donating sperm during this same period.

22. 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 individual. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not adequate 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. ..

a. Females must agree to abstain from breastfeeding during study participation and for at
least 12 months after glofitamab discontinuation. Women of childbearing potential (WOCBP)
must have a negative serum or urine pregnancy test. WOCBP and males must be willing to
use highly effective methods of birth control. Woman of childbearing potential (WOCBP)
who are sexually active must use highly effective methods of contraception during
treatment and 1 week after the last dose of acalabrutinib b. Females of childbearing
potential (FCBP§ ) must: i. Have one negative pregnancy tests via serum in some cases
urine (as clinically indicated) one week or immediately prior to starting study therapy.
She must agree to ongoing pregnancy testing during the course of the study, prior to day
1 of each cycle, and after end of study therapy. This applies even if the subject
practices true abstinence* from heterosexual contact.

ii. Not engaging in sexual activity for the total duration of the trial and the drug
washout period is an acceptable practice. Otherwise, she must agree to use, and be able
to comply with highly effective contraception.

c. Male subjects must: i. A male subject who is sexually active with a female with
reproductive potential is also recommended to use a barrier method of birth control, eg,
either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive
cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ suppository
(including dose interruptions), even if they have undergone a successful vasectomy, from
the time of signing consent and for at least 2 months after the last dose of glofitamab,
6 months after treatment with obinutuzumab, or 2 months after the last dose of
tocilizumab (if applicable), whichever is longer. For male participants with a pregnant
or non-pregnant WOCBP partner, should use barrier contraception, during treatment and for
1 week after the last dose of acalabrutinib, 180 days following the last dose of
rituximab, 2 months following the last dose of glofitamab,6 months following the last
dose of obinutuzumab, 2 months following the last dose of tocilizumab (if applicable), ,
whichever is longer, even if they have had a successful vasectomy.) d. Participant must
be willing and able to comply with protocol-mandated hospitalization upon administration
of the first dose of glofitamab. e. f. Have achieved complete metabolic response by
Lugano criteria[35] to go to part 2 for glofitamab consolidation g. Performance status ≤1
on the ECOG scale h. All subjects must i. 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.

Exclusion Criteria Having radiologically confirmed relapsed/refractory disease.

1. Isolated bone marrow or GI only disease MCL participants and/or lack of any
measurable disease, except if participants have leukemic phase MCL with any high
risk features.

2. Pregnant or breast-feeding females.

3. Participants who are primary refractory to BTKi-R (No response/progressive disease
within first 3 months of BTKi-R)

4. Received any investigational drug within 30 days or 5 half-lives (whichever is
shorter) before first dose of study drug.

5. Current life-threatening illness, medical condition, or organ system dysfunction
which, in the Investigator's opinion, could compromise the subject's safety or put
the study at risk.

6. Known HIV infection.

7. Known history of hemophagocytic lymphohistiocytosis (HLH)

8. Known or suspected chronic active Epstein-Barr virus infection (clearance with
infectious disease is needed to allow these participants)

9. Positive SARS-CoV-2 test within 7 days prior to enrollment. Rapid antigen test
result is also acceptable.

10. Participants who do not meet high risk features as indicated above in inclusion.

11. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody
(anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will
need to have a negative polymerase chain reaction (PCR) and must be willing to
undergo DNA PCR testing during the study to be eligible. Those who are HBsAg
positive or hepatitis B PCR positive will be excluded (unless cleared by hepatology
and ID team after discussion with study PI). Subjects who are hepatitis C antibody
positive will need to have a negative PCR result to be eligible. Those who are
hepatitis C PCR positive will be excluded.

12. Prior malignancy (or any other malignancy requiring active treatment), except for
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
in situ ca prostate, in situ melanoma (> 5 mm margins) or other cancer from which
the subject has been disease free for ≥ 3 years or which will not limit survival to
< 3 years or not on active systemic chemotherapy.

13. Central nervous system involvement with mantle cell lymphoma or with suspected or
confirmed progressive multifocal leukoencephalopathy (PML). Magnetic resonance
imaging (MRI) of the brain, if performed, showing evidence of central nervous system
(CNS) lymphoma or Lumbar puncture with flow cytometry, if performed, with CSF
involvement.

14. History or presence of uncontrolled CNS disorder, such as seizure disorder,
cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, cerebral edema,
posterior reversible encephalopathy syndrome, or any autoimmune disease with CNS
involvement.

15. Active bleeding, history of bleeding diathesis (such as Hemophilia or Von-Willebrand
disease), Any history of intracranial bleed or stroke within 6 months of first dose
of study drug.

16. Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
purpura).

17. Malabsorption syndrome, disease which is clinically significantly affecting
gastrointestinal function, or resection of the stomach or small bowel or active
ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete
bowel obstruction, or any other gastrointestinal condition that could interfere with
the absorption and metabolism of BTKi. These participants may be allowed after
discussion, clearance with GI team and discussion with the study PI.

18. Presence of a clinically significant gastrointestinal ulcer diagnosed by endoscopy
within 3 months before first dose of study drug.

19. Requires anticoagulation with warfarin or equivalent vitamin K antagonist, active
treatment for pulmonary embolism (PE)/ deep vein thrombosis (DVT) and persons with
mechanical cardiac valves. These participants may be allowed after review with
benign hematology and study PI.

20. Concomitant use of corticosteroids at > 20 mg prednisone or equivalent per day
longer than 2 weeks.

21. Primary immunodeficiency which is clinically active

22. History of confirmed autoimmune disease (e.g. Crohn's disease, rheumatoid arthritis,
systemic lupus) resulting in end organ injury or requiring systemic
immunosuppression/systemic disease modifying agents within the last 2 years.
Rheumatology clearance and approval by study PI is required for pts with remote
history of auto-immune disease.

23. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3
weeks of the first dose of study drug is prohibited.

24. Requires treatment with strong CYP3A inhibitors or inducers.

25. 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 and/or
any of the following cardiac related conditions, unless cleared by cardiology and
study PI:

26. NYHA Class III and IV heart failure,

27. Active/symptomatic coronary artery disease,

28. Myocardial infarction in the preceding 6 months,

29. Significant conduction abnormalities, including but not limited to:

30. Left bundle branch block,

31. 2nd degree AV block type II,

32. 3rd degree block,

33. QT prolongation (QTc > 500 msec),

34. Sick sinus syndrome,

35. Ventricular tachycardia,

36. Symptomatic bradycardia (heart rate < 50 bpm),

37. Persistent and uncontrolled atrial fibrillation.

38. Uncontrolled hypertension

39. Uncontrolled Hypotension

40. Light headedness and syncope,

41. Acute infection requiring systemic anti-infective treatment systemic antibiotics,
antivirals, or antifungals, or including subjects with positive cytomegalovirus
[CMV] DNA polymerase chain reaction [PCR] within 14 days prior to initiation of
therapy. Participant who exhibit active uncontrolled infection on BTKi-R alone will
not be excluded but would await adequate infection control and then get CAR T, as
long as they have evidence of disease.

42. Vaccinated with live, attenuated vaccines within 6 weeks of first dose of study
drug.

43. Any other serious medical condition including, but not limited to, clinically
significant uncontrolled diabetes mellitus, COPD, renal failure, psychiatric illness
or social circumstances that, in the investigator's opinion places the participant
at unacceptable risk and would prevent the participant from signing the informed
consent form or complying with study procedures.

44. Known history of hypersensitivity or anaphylaxis to study drug(s) including active
product or excipient components.

6. Concurrent participation in another therapeutic clinical trial. 47. Is unable to
swallow any oral medication or has clinically significant gastrointestinal disease
thatwould limit absorption of oral medication.

48. . 49. Major surgical procedure within 28 days of first dose of study drug. Note: If a
subject had major surgery, they must have recovered adequately from any toxicity and/or
complications from the intervention before the first dose of study drug.

50. Participants with inactive hepatitis B infection must adhere to hepatitis B
reactivation prophylaxis unless contraindicated. Hepatitis B or C serologic status:
subjects who are hepatitis B core antibody (antiHBc) 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.

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

2. History of immunodeficiency (except for hypogammaglobulinemia) or concurrent
systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc., or chronic
administration glucocorticoid equivalent of >10mg/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.