Trial Title:
A Pilot "Window-3" Study of Acalabrutinib Plus Rituximab Followed by Brexucabtagene Autoleucel Therapy in Patients With Previously Untreated High-risk Mantle Cell Lymphoma
NCT ID:
NCT05495464
Condition:
Lymphoma
Mantle Cell Lymphoma
Conditions: Official terms:
Lymphoma
Lymphoma, Mantle-Cell
Cyclophosphamide
Rituximab
Fludarabine
Fludarabine phosphate
Acalabrutinib
Brexucabtagene autoleucel
Study type:
Interventional
Study phase:
Early Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Acalabrutinib
Description:
Given by PO
Arm group label:
Acalabrutinib and Rituximab (Part 1)
Intervention type:
Drug
Intervention name:
Rituximab
Description:
Given by IV (vein)
Arm group label:
Acalabrutinib and Rituximab (Part 1)
Other name:
Rituxan
Intervention type:
Other
Intervention name:
Brexucabtagene Autoleucel
Description:
Given by IV (vein)
Arm group label:
Brexucabtagene Autoleucel (Part 2)
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Given by IV (vein)
Arm group label:
Acalabrutinib and Rituximab (Part 1)
Arm group label:
Brexucabtagene Autoleucel (Part 2)
Other name:
Cytoxan®
Other name:
Neosar®
Intervention type:
Drug
Intervention name:
Fludarabine Phosphate
Description:
Given by IV (vein)
Arm group label:
Acalabrutinib and Rituximab (Part 1)
Arm group label:
Brexucabtagene Autoleucel (Part 2)
Other name:
Fludarabine
Other name:
Fludara®
Summary:
To learn if giving acalabrutinib, rituximab, and brexucabtagene autoleucel to patients
with previously untreated high-risk mantle cell lymphoma (MCL) can help to control the
disease.
Detailed description:
PRIMARY OBJECTIVES:
To determine the safety profile of the acalabrutinib plus rituximab combination followed
by CAR T-cell therapy in newly diagnosed high risk MCL patients.
SECONDARY OBJECTIVES:
To evaluate efficacy measured by complete response (CR) rate and progression free
survival (PFS) of the acalabrutinib plus rituximab combination followed by CAR T-cell
therapy in newly diagnosed high risk MCL patients.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
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 (See Appendix I, footnote 10).
2. Newly diagnosed high risk patient without any prior therapy for MCL and are eligible
to receive AR and CART cell therapy.
3. High risk MCL (Blastoid/pleomorphic histology, high Ki-67 (≥50%), TP53/NOTCH1/2,
NSD2, UBR5, FAT1, TRAF2, SP140, POT1, 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 disease >= 5 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 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. (We will not use any assay which is not
FDA approved or not CLIA certified to determine the eligibility of these patients)
4. Patients who are eligible to receive CAR T therapy
5. Patients who are willing and able to participate in all required evaluations and
procedures in this study protocol, including swallowing capsules and tablets without
difficulty.
6. Understand and voluntarily sign an IRB-approved informed consent form.
7. Age ≥ 18 years at the time of signing the informed consent.
8. Bi-dimensional measurable disease using the 2014 Cheson criteria (Measurable disease
by PET-CT scan defined as at least 1 lesion that measures ≥ 1.5 cm in single
dimension.) Spleen only involved (>=20 cm), these patients are allowed if they meet
other high-risk features, determined by the study PI.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less (See
Appendix IV).
10. An absolute neutrophil count (ANC) > 1,000/mm3 and platelet count >100,000/mm3
(Patients 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. These patients should be discussed with the PI of the study
for final approval).
11. Serum bilirubin <1.5 mg/dl and Cr Clearance ≥ 60 mL/min by Cockroft-Gault Formula
(Appendix VIII) or by >=60 ml/min by 24 hour urine Cr clearance test (Appendix VIII)
, 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.
12. Women of childbearing potential (WOBP) must have a negative serum or urine pregnancy
test. WOBP 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 for 2 days after the
last dose of acalabrutinib and for 12 months following the last dose of rituximab
and 6 months after the completion of CAR T infusion. For male patients with a
pregnant or non-pregnant WOCBP partner, should use barrier contraception, during
treatment and for 2 days after the last dose of acalabrutinib and for 1 month
following the last dose of rituximab and 6 months after the completion of CAR T
infusion even if they have had a successful vasectomy. (see Appendix VII).
13. Cardiology cleared for receiving acalabrutinib and CART
EXCLUSION CRITERIA PART 1:
1. Isolated bone marrow or GI only disease MCL patients and/or lack of measurable
disease.
2. Pregnant or breast-feeding females.
3. Patients who are primary refractory to AR (No response/progressive disease within
first 4 months of AR)
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. Patients who do not meet high risk features as indicated above. 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. 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.
8. 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.
9. 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.
10. History or presence of 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.
11. 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.
12. Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
purpura).
13. Malabsorption syndrome, disease significantly affecting gastrointestinal function,
or resection of the stomach or small bowel or 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 acalabrutinib.
14. Presence of a clinically significant gastrointestinal ulcer diagnosed by endoscopy
within 3 months before first dose of study drug.
15. 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.
16. History of symptomatic deep vein thrombosis (DVT) or pulmonary embolism requiring
systemic anticoagulation within the last 6 months of enrollment
17. Concomitant use of corticosteroids at > 20 mg prednisone or equivalent per day
longer than 2 weeks.
18. Primary immunodeficiency
19. 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 required for pts with remote history of auto-immune disease.
20. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
21. 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.
22. Requires treatment with strong CYP3A inhibitors or inducers (refer to list in
Appendix VI).
23. Any of the following cardiac related conditions:
- NYHA Class III and IV heart failure (Appendix IX),
- Active/symptomatic coronary artery disease,
- Myocardial infarction in the preceding 6 months,
- Significant conduction abnormalities, including but not limited to:
- Left bundle branch block,
- 2nd degree AV block type II,
- 3rd degree block,
- QT prolongation (QTc > 500 msec),
- Sick sinus syndrome,
- Ventricular tachycardia,
- Symptomatic bradycardia (heart rate < 50 bpm),
- Persistent and uncontrolled atrial fibrillation.
- Uncontrolled hypertension
- Uncontrolled Hypotension
- Light headedness and syncope,
24. 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. Patient who exhibit active uncontrolled infection on AR alone will not be
excluded but would await adequate infection control and then get CAR T, as long as
they have evidence of disease.
25. Vaccinated with live, attenuated vaccines within 6 weeks of first dose of study
drug.
26. Any other serious medical condition including, but not limited to, uncontrolled
diabetes mellitus, COPD, renal failure, psychiatric illness or social circumstances
that, in the investigator's opinion places the patient at unacceptable risk and
would prevent the patient from signing the informed consent form or complying with
study procedures.
27. Known history of hypersensitivity or anaphylaxis to study drug(s) including active
product or excipient components.
28. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) >2x ULN.
29. Concurrent participation in another therapeutic clinical trial.
30. Has difficulty with or is unable to swallow oral medication or has significant
gastrointestinal disease that would limit absorption of oral medication.
31. Known history of hypersensitivity or anaphylaxis to study drug(s) including active
product or excipient components.
32. 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
M D Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Preetesh Jain, MD, PHD
Phone:
713-563-8786
Email:
pjain@mdanderson.org
Investigator:
Last name:
Preetesh Jain, MD, PHD
Email:
Principal Investigator
Start date:
November 18, 2022
Completion date:
March 31, 2027
Lead sponsor:
Agency:
M.D. Anderson Cancer Center
Agency class:
Other
Collaborator:
Agency:
Kite, A Gilead Company
Agency class:
Industry
Collaborator:
Agency:
Acerta Pharma, LLC
Agency class:
Other
Source:
M.D. Anderson Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05495464
http://www.mdanderson.org