Trial Title:
Phase II Study of Pirtobrutinib, Rituximab (PR) in Previously Untreated Low and Intermediate Risk MCL (Mantle Cell Lymphoma) Patients
NCT ID:
NCT06263491
Condition:
Mantle Cell Lymphoma
Conditions: Official terms:
Lymphoma
Lymphoma, Mantle-Cell
Rituximab
Pirtobrutinib
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Rituximab
Description:
Given by PO
Arm group label:
Cohort A
Arm group label:
Cohort B
Other name:
Rituxan
Intervention type:
Drug
Intervention name:
Pirtobrutinib
Description:
Given by PO
Arm group label:
Cohort A
Arm group label:
Cohort B
Summary:
To learn if the chemotherapy-free combination of pirtobrutinib (also called LOXO-305) and
rituximab can help provide long term remission in low and intermediate risk MCL.
Detailed description:
Primary Objectives
- To determine the efficacy measured by ORR (CR + PR) at the end of cycle 3 of
combination of PR (Pirtobrutinib plus rituximab) in MCL patients with low and
intermediate risk.
- To determine the safety profile of Pirtobrutinib with rituximab combination in MCL
participants with low and intermediate risk.
Secondary Objectives
- To evaluate the CR, best overall response (OR: CR + PR), progression-free and
overall survival from PR combination in MCL.
- To assess MRD negative CR rates
Criteria for eligibility:
Criteria:
Inclusion Criteria:
The study will enroll 50 previously untreated low and medium risk MCL patients. Estimated
3 patients per month at minimum for enrollment.
1. Age ≥ 18 years old
2. Pathology confirmed diagnosis of mantle cell lymphoma. CD20 positivity is needed.
Cyclin D1 negative MCL are allowed after confirming the diagnosis of MCL from
hem-path at MDACC.
3. Newly diagnosed MCL with no prior therapy for MCL (age >= 18 years)
• Low risk - Ki-67% (<= 30%), no features of high-risk disease (see below in
exclusion), largest tumor size <= 3 cm.
- Medium risk - Ki-67% (<=50%), largest tumor size <=5 cm, no features of
high-risk disease (see below in exclusion)
4. Participants with preexisting well-controlled cardio-vascular comorbidities -
participants on anticoagulants (excluding warfarin and vitamin K antagonists),
antiplatelet, anti-hypertensive, prior ablation, anti-arrhythmia, prior arrhythmias,
baseline EKG abnormalities and cardiology clearance are allowed. Ejection fraction
>=50% and cardiology evaluation may be needed. (Echo and EKG and cardiology
consultation within 2 months prior to C1D1 are allowed).
5. Understand and voluntarily sign an IRB-approved informed consent form.
6. Participants may have at least 1 site of radiographically assessable disease (i.e.,
lymph node longest diameter [LDi] >= 1.5 cm, not necessary for disease assessable by
positron emission tomography [PET]/computerized tomography [CT], extra nodal site >=
1.0 cm in LDi. But participants with isolated gastrointestinal, bone marrow or
spleen only disease patients are allowed.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less (See
Appendix III).
8. Prothrombin time (or international normalized ratio) and partial thromboplastin time
not to exceed 1.2 times the institutional upper limit of normal range (participants
with an elevated prothrombin time and known lupus anticoagulant may be eligible for
participation after consulting the study PI).
9A. Adequate BM function independent of growth factor or PRBC or platelet transfusion
support (within 14 days of Screening assessment and criteria must be met on C1D1 without
transfusion/G-CSF within 7 days of assessment, per local laboratory reference range at
screening as follows:
a. platelet count >=75,000/mm3; b. absolute neutrophil count (ANC) >= 1000/mm3 unless
cytopenia is clearly due to marrow involvement from MCL c. total hemoglobin >= 8 g/dL
(without transfusion support within 2 weeks of screening); If any of the above-mentioned
cytopenias (a-c) are present due to significant BM involvement, at least 30% BM
involvement by MCL (requiring transfusion or granulocyte colony-stimulating factor
[G-CSF] support) MCL patients may proceed with enrollment after discussion with the PI or
Co-PI. Cytopenias may not be due to evidence of myelodysplastic syndrome (MDS) or
hypoplastic BM.
9B. Adequate organ function as defined by the following laboratory values:
a. Creatinine clearance. >=30 mL/min (by Cockcroft-Gault method, APPENDIX I), b. Total
bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver involvement and/or Gilbert's
Disease or controlled immune hemolysis or considered an effect of regular blood
transfusions.
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3 x ULN, or < 5 x
upper limit of normal if hepatic metastases are present.
10. Projected life expectancy of >12 weeks pertaining to lymphoma. 11. Female
participants must be surgically sterile, postmenopausal (for at least 1 year), or
have confirmed negative results for a pregnancy test at screening, on a serum sample
obtained within 7 days prior to initiation of study treatment.
12. Women of childbearing potential and men with female partners of childbearing
potential must be willing to use a highly effective form of contraception for at
least 1 month after the last dose of study treatment. Participant enrolled into the
Pirtobrutinib+ rituximab study should use a highly effective form of contraception
for 1 month after the last dose of Pirtobrutinib and 12 months after the last dose
of rituximab, whichever time period is longer. Recommended methods of highly
effective birth control are:
1. Combined estrogen and progestin containing hormonal contraception associated with
inhibition of ovulation given orally, intravaginally, or transdermally
2. Progestin-only hormonal contraception associated with inhibition of ovulation given
orally, by injection, or by implant
3. Intrauterine device (IUD)
4. Intrauterine hormone-releasing system (IUS)
5. Vasectomized partner
6. Sexual abstinence: considered a highly effective method only if defined as
refraining from heterosexual intercourse during an entire period of risk associated
with the study treatment. The reliability of sexual abstinence will be evaluated in
relation to the duration of the study and to the usual lifestyles of the
participant.
7. Female sterilization
8. Fallopian tube implants (if confirmed by hysterosalpingogram) 13. Oocyte donation is
prohibited during the duration of participation on this protocol and for 1 month
after the last dose of Pirtobrutinib.
Exclusion Criteria:
1. Participants with central nervous system involvement with mantle cell lymphoma or
with suspected or confirmed progressive multifocal leukoencephalopathy (PML) are
excluded since those participants have very poor prognosis, need aggressive
intensive chemoimmunotherapy and intrathecal chemotherapy along with BTK inhibitors
and these participants would not be eligible for this study.
2. High risk MCL - any or all of the following (Blastoid/pleomorphic histology), High
Ki-67 (>50%), Bulky disease (nodes >5 cm, spleen >20 cm), lymphocytosis >=50,000
cells/uL, TP53 mutated or del17p by FISH. Presence of MYC rearrangement positive by
FISH or MYC, Bcl2 amplification, complex karyotype or high-risk biologic MIPI (with
Ki-67%)
3. Major surgery within 4 weeks prior to registration
4. History of bleeding diathesis
5. Known active CMV. Unknown or negative status are eligible
6. Evidence of other clinically significant uncontrolled condition(s) including but not
limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection
(except for fungal nail infection), or other clinically significant active disease
process which in the opinion of the investigator and medical monitor may pose a risk
for participant participation. Screening for chronic conditions is not required
7. Clinically significant cardiovascular diseases as determined after cardiology
consultation, including uncontrolled or symptomatic arrhythmias, congestive heart
failure or myocardial infarction within 6 months of screening or any Class 3
(moderate) or 4 (severe) cardiac disease following the New York Heart Association
Classification. Otherwise, significant screening electrocardiogram (ECG)
abnormalities including left bundle branch block, 2nd degree AV block type II, 3rd
degree block, bradycardia, or QTc >470 msec.
8. 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.
9. Pregnancy or plan to become pregnant during the study or within 1-month post
pirtobrutinib or 12 months post Rituxan. (Note: post rituxan, WOCBP should not
become pregnant for 12 months post last dose of rituxan).
10. Lactation during the study or for 1 week after last dose of pirtobrutinib (Note that
the USPI for rituxan recommends no lactation during treatment and for 6 months after
last dose)
11. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or
inducers and/or strong P-gp inhibitors. Because of their effect on CYP3A4, use of
any of the following within 3 days of study therapy start or planned use during
study participation is prohibited - grapefruit or grapefruit products, Seville
oranges or products from Seville oranges, star fruit
12. Participants taking warfarin and/or equivalent vitamin K antagonists
13. Has difficulty with or is unable to swallow oral medication or has significant
gastrointestinal disease that would limit absorption of oral medication.
14. History of stroke or intracranial hemorrhage within 6 months of C1D1
15. Vaccination with live vaccine within 28 days prior to enrollment.
16. Have a known hypersensitivity to any of the excipients of Pirtobrutinib or rituximab
17. Participants who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior
treatment with a BTK inhibitor. NOTE: Major bleeding is defined as bleeding having
one or more of the following features: potentially life-threatening bleeding with
signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in
the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or
organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial
bleeding or intramuscular bleeding with compartment syndrome).
18. Participants who have tested positive for Human Immunodeficiency Virus (HIV) are
excluded due to risk of opportunistic infections with both HIV and BTK-inhibitors.
For patients with unknown HIV status, HIV testing will be performed at Screening and
result must be negative for enrollment
19. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on
criteria below: Hepatitis B virus (HBV): Participants with positive hepatitis B
surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core
antibody (anti-HBc) and negative HBsAg require hepatitis B polymerase chain reaction
(PCR) evaluation before enrollment. Participants who are hepatitis B PCR positive
will be excluded unless cleared by infectious disease. If a participant is Hep B
core antibody positive, they must be on an approved nucleos(T)ide analogue to help
prevent reactivation. Hepatitis C virus (HCV): positive hepatitis C antibody. If
positive hepatitis C antibody result, participant will need to have a negative
result for hepatitis C ribonucleic acid (RNA) before enrollment, unless cleared by
infectious disease. Participants who are hepatitis C RNA positive will be excluded.
20. Evidence of other clinically significant uncontrolled condition(s) including but not
limited to, uncontrolled systemic bacterial, viral including CMV, fungal or
parasitic infection (except for fungal nail infection), or other clinically
significant active disease process which in the opinion of the investigator and IND
sponsor may pose a risk for patient participation. Screening for chronic conditions
is not required.
21. Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on one
electrocardiograms (ECGs), during Screening. EKG might be repeated same day to check
for any physiologic variation. QTcF is calculated using Fridericia's Formula (QTcF):
QTcF = QT/(RR0.33).
22. Correction of suspected drug induced QTcF prolongation can be attempted at the
investigator's discretion and only if clinically safe to do so with either
discontinuation of the offending drug or switch to another drug not known to be
associated with QTcF prolongation.
23. Correction for underlying bundle branch block (BBB) allowed. Note: Participants with
pacemakers are eligible if they have no history of fainting or clinically relevant
arrhythmias while using the pacemaker.
24. Concomitant malignancies or previous malignancies with less than a 1-year
disease-free interval at the time of signing consent. Subjects with adequately
treated basal or squamous cell carcinoma of the skin, or adequately treated
carcinoma in situ (e.g. cervix) may enroll irrespective of the time of diagnosis.
Patients with controlled, advanced prostate cancer (not on active chemotherapy) are
permitted. Active second malignancy unless in remission with life expectancy > 1
years. Examples include:
1. Adequately treated no melanomatous skin cancer or lentigo maligna melanoma
without current evidence of disease.
2. Adequately treated cervical carcinoma in situ without current evidence of
disease.
3. Localized (e.g., lymph node negative) breast cancer treated with curative
intent with no evidence of active disease present for more than 3 years and
receiving adjuvant hormonal therapy.
4. Localized prostate cancer undergoing hormonal therapy.
25. 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.
26. With known allergies to xanthine oxidase inhibitors and/or rasburicase.
27. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that, in the opinion of the investigator, may increase the risk
associated with study participation or study treatment administration or may
interfere with the interpretation of study results and/or would make the participant
inappropriate for enrollment into this study.
28. No concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy. No
major surgery within 4 weeks prior to first dose of study treatment.
29. Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia. Active
uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA],
idiopathic thrombocytopenic purpura [ITP]) is for which new therapy was introduced
or existing therapy was escalated within the 4 weeks prior to study enrollment to
maintain adequate blood counts.
30. Concomitant steroids for disease related pain control are allowed at any dose but
must be discontinued prior to any study treatment initiation. Chronic use of
corticosteroids is allowed up to 20 mg prednisone or equivalent daily for non-cancer
related conditions at the time of study start.
31. History of GVHD, allogeneic HSCT transplant, allogeneic organ transplant
32. Any serious medical condition including but not limited to, uncontrolled
hypertension, diabetes mellitus, active/symptomatic coronary artery disease, COPD,
renal failure, active infection, active hemorrhage, laboratory abnormality, or
psychiatric illness that places the participant at unacceptable risk and would
prevent the subject from signing the informed consent form.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
Accepts Healthy Volunteers
Locations:
Facility:
Name:
MD Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Preetesh Jain, MBBS, MD, DM, PhD
Phone:
(713) 563-8786
Email:
pjain@mdanderson.org
Investigator:
Last name:
Preetesh Jain, MBBS, MD, DM, PhD
Email:
Principal Investigator
Start date:
May 29, 2024
Completion date:
March 1, 2027
Lead sponsor:
Agency:
M.D. Anderson Cancer Center
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/NCT06263491
http://www.mdanderson.org
