CLINICAL TRIAL / NCT04855695
Avo In R/R And Previously Untreated MCL
- Interventional
- Recruiting
- NCT04855695
Contact Information
A Phase 1/2 Study of Acalabrutinib, Venetoclax, and Obinutuzumab in Patients With Relapsed/Refractory and Previously Untreated Mantle Cell Lymphoma
This research study is evaluating the combination of three drugs - acalabrutinib, venetoclax, and obinutuzumab - as a possible treatment for relapsed or refractory and untreated mantle cell lymphoma (MCL). The names of the study drugs involved in this study are: - Acalabrutinib - Venetoclax - Obinutuzumab
This is an open-label, investigator-initiated, single-arm, multi-cohort phase 1/2 study
to assess the safety and efficacy of the combination of acalabrutinib, venetoclax, and
obinutuzumab (AVO) in relapsed/refractory (R/R) and untreated mantle cell lymphoma (MCL).
The research study procedures include screening for eligibility and study treatment
including evaluations and follow up visits.
The names of the study drugs involved in this study are:
- Acalabrutinib
- Venetoclax
- Obinutuzumab
Participants will receive study treatment for as long as there are no serious side
effects and the disease does not get worse. Participants will be followed for 5 years.
It is expected that 53 people will take part in this research study.
This is a Phase I/II clinical trial. Phase I clinical trials test the safety of
investigational drugs and also tries to define the appropriate dose of investigational
drugs to use for further studies. "Investigational" means that the drugs are being
studied.
- The U.S. Food and Drug Administration (FDA) has not approved venetoclax and
obinutuzumab for this specific disease but it has been approved for other uses.
- The U.S. Food and Drug Administration (FDA) has approved acalabrutinib as a
treatment option for this disease.
Gender
All
Age Group
18 Years and up
Accepting Healthy Volunteers
No
Inclusion Criteria:
- Participants must meet the following criteria on screening examination to be
eligible to participate in the study:
- Participants must have histologically determined mantle cell lymphoma with
pathologic review at the participating institutions, that has either:
- Relapsed or primary refractory after at least one line of therapy including
anti-CD20 monoclonal antibody treatment (part A) or; Had no previous
anti-lymphoma therapy other than corticosteroids or radiotherapy (parts B and
C).
- Participants in part A, relapsed or refractory following prior therapy, may
have had a prior autologous or allogeneic stem cell transplant and may have
been treated with chimeric antigen receptor T-cells (CAR T-cells).
- Participants in parts B and C, without prior anti-lymphoma therapy, must require
treatment as defined by any of the following criteria:
- Symptomatic adenopathy or splenomegaly
- Local symptoms due to extranodal disease
- Organ function impairment due to disease involvement, including cytopenias due
to marrow involvement (WBC <1.5x109/L; absolute neutrophil count [ANC]
<1.0x109/L, Hgb <10g/dL; platelets <100x109/L)
- Presence of systemic B symptoms (fever, drenching night sweats, or
unintentional weight loss ≥ 10% body weight over previous 6 months) or
functionally significant fatigue
- Participants in part B without prior anti-lymphoma therapy should be deemed to be
ineligible for autologous stem cell transplant by the treating physician and/or have
a TP53 mutation detected by next generation sequencing at a variant (mutant) allele
fraction above the validated threshold for calling a new variant or high TP53
expression on immunohistochemistry (>50% positive lymphoma cells)
- Participants in part C without prior anti-lymphoma therapy should be deemed to be
eligible for autologous stem cell transplant by the treatment physician and have no
evidence of TP53 mutation (TP53 wild type) detected by next generation sequencing
and no evidence of high TP53 expression on immunohistochemisty
- Participants in parts B and C must have an archived formalin-fixed paraffin-embedded
(FFPE) tumor tissue specimen from the original diagnostic biopsy and peripheral
blood available for submission to Adaptive Biotechnologies for ClonoSEQ®ID molecular
marker identification of a unique clonal immunoglobulin DNA sequence. Only those
participants in parts B and C who have a molecular marker identified from the
peripheral blood will be eligible for minimal residual disease (MRD) driven
treatment interruptions.
- Participants in parts B and C who do not have a molecular marker identified by
ClonoSEQ from the peripheral blood will be deemed to be MRD indeterminate and are
not eligible for peripheral blood MRD driven treatment interruptions. These
participants will be able to enroll in the study assuming all other eligibility
criteria are met but will receive 7 cycles of AVO combination therapy followed by 17
cycles of acalabrutinib and venetoclax therapy (24 total cycles of AV) and 2 years
of maintenance obinutuzumab for a total of 31 cycles of therapy.
- Measurable disease with a lymph node or tumor mass ≥ 1.5 cm in at least one
dimension by CT, PET/CT, or MRI. Patients without measurable disease will be
eligible if they have marrow involvement and cytopenias related to their lymphoma
(hemoglobin <10 g/dL, absolute neutrophil count < 1.0 x 109/L, or platelets < 100 x
109/L) OR symptomatic splenomegaly > 15cm in craniocaudal diameter.
- Age ≥ 18 years.
- ECOG performance status ≤2 (Karnofsky ≥60%)
- Participants must have adequate organ and marrow function as defined below:
- Absolute neutrophil count ≥ 750 cells/mm3 (0.75 x109/L) unless due to marrow
involvement by lymphoma in which case ANC must be ≥ 500 cells/mm3 (0.5x109/L)
- Platelet count without transfusional support must be ≥ 75,000 cells/mm3 (75
x109/L), unless due to marrow involvement by lymphoma, in which case platelets
must be ≥ 50,000 cells/mm3 (50 x109/L)
- Hemoglobin without transfusional support must be ≥ 8.0 g/dL (80 g/L) unless due
to marrow involvement by lymphoma, in which case hemoglobin must be ≥ 7.0 g/dL
(70 g/L)
- Creatinine clearance (CrCl) ≥ 50 ml/min using 24-hour urine collection for
creatinine clearance or calculated CrCl or calculated glomerular filtration
rate (GFR) ≥ 50 ml/min/1.73 m2 using the CKD-EPI equation
- Total bilirubin ≤ 2 times the upper limit of normal, unless there is disease
involvement of the liver, hemolysis, or a known history of Gilbert's disease,
in which case direct bilirubin must be ≤ 3 times the upper limit of normal
- AST and ALT ≤ 2.5 times the upper limit of normal, unless documented liver
involvement by lymphoma, in which case AST and ALT must be ≤ 5 times the upper
limit of normal
- PT/INR ≤ 2 times the upper limit of normal and PTT ≤ 2 times the upper limit of
normal
- Willingness to provide pre-treatment bone marrow (or recent archival w/o intervening
therapy) and on-treatment bone marrow and peripheral blood samples
- The effects of the study drugs on the developing human fetus are unknown. Women of
child-bearing potential must agree to remain abstinent or use highly effective
contraception (defined as contraceptive measures that result in a failure rate of
<1% per year) during the treatment period and for at least 2 days after the last
dose of acalabrutinib, 90 days after the last dose of venetoclax or 18 months after
the last dose of obinutuzumab, whichever is longer. Men with female sexual partners
of childbearing potential should agree to remain abstinent or use contraceptive
measures which include 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 90 days after the last dose of venetoclax or 6 months after the last
dose of obinutuzumab, whichever is longer. Men should refrain from donating sperm
during the same period. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately.
- Ability to understand and the willingness to sign a written informed consent
document.
Exclusion Criteria:
- Participants who exhibit any of the following conditions at screening will not
eligible for admission into the study:
- Participants who have progressed or relapsed after receiving either a BTK inhibitor
or BCL2 inhibitor.
- Participants who are receiving any other investigational agents, or have received
investigational agents within 4 weeks (or 3 half-lives, whichever is longer) of
beginning treatment.
- Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus,
etc., within 28 days of the first dose of study drug or chronic administration of
>20 mg/day of prednisone equivalent corticosteroid within 7 days of the first dose)
-- Note: Glucocorticoids for lymphoma symptom palliation are allowed but must be
discontinued at time of initiation of protocol therapy.
- History of severe allergic reactions attributed to compounds of similar chemical or
biologic composition to obinutuzumab, venetoclax, or acalabrutinib. Patients with
reactions to other CD20 monoclonal antibodies (e.g. rituximab, ofatumumab) are not
excluded if they were able to eventually tolerate treatment in an outpatient setting
without grade 2 or higher infusion reactions.
- Participants who have a history of other malignancies except:
- Malignancy treated with curative intent and with no known active disease
present and felt to be at low risk for recurrence by treating physician.
Current adjuvant hormonal therapy for disease treated with curative intent is
permissible.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
- Adequately treated carcinoma in situ without evidence of disease.
- Low-risk prostate cancer on active surveillance
- Other exceptions may be made after consultation with the study chair
- Participants with known leptomeningeal or brain metastases. Imaging or spinal fluid
analysis to exclude CNS involvement is not required, unless there is clinical
suspicion by the treating investigator.
- Participants who have had a major surgery or significant traumatic injury within 4
weeks of start of study drug, participants who have not adequately recovered from
the side effects of any major surgery (defined as requiring general anesthesia), or
participants that may require major surgery during the course of the study.
- Vaccinated with live, attenuated vaccines within 28 days of study entry or need for
live virus vaccines at any time during study period.
- Patients with human immunodeficiency virus (HIV) or active hepatitis C virus (HCV)
or hepatitis B virus (HBV) infection. HIV-positive participants are ineligible
because of the potential for pharmacokinetic interactions between certain components
of anti-retroviral therapy and venetoclax. Patients who are positive for hepatitis B
core antibody or hepatitis B surface antigen must have a negative polymerase chain
reaction (PCR) result before enrollment. Those who are PCR positive will be
excluded. Those who are positive for either hepatitis B surface antigen and/or
hepatitis B core antibody but negative for HBV DNA will be managed. Patients who are
positive for HCV antibody must be negative for HCV by polymerase chain reaction
(PCR) to be eligible for study participation.
- Ongoing or recent infection requiring intravenous antimicrobials at time of
screening. Patients with ongoing use of prophylactic antibiotics are eligible as
long as there is no evidence of active infection and the antibiotic is not included
on the list of prohibited medications.
- Uncontrolled intercurrent illness or psychiatric illness/social situations that
would limit compliance with study requirements, compromise the subject's safety, or
put the study outcomes at undue risk.
- Lactating or pregnant women are excluded from this study because venetoclax has been
shown to decrease implantation, litter size, live fetuses, and fetal body weight in
animal models. Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with venetoclax, breastfeeding
should be discontinued if the mother is treated with venetoclax. These potential
risks may also apply to other agents used in this study.
- Known bleeding disorders (e.g. von Willebrand's disease) or hemophilia.
- Presence of a bleeding gastrointestinal ulcer diagnosed by endoscopy within 3 months
prior to enrollment.
- History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
- Participants who require warfarin or other vitamin K antagonists for anticoagulation
(other anticoagulants are allowed).
- Currently active, clinically significant cardiovascular disease, such as
uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the
New York Heart Association Functional Classification; or a history of myocardial
infarction, unstable angina, or acute coronary syndrome within 6 months prior to
randomization. Patients with atrial fibrillation are allowed as long as they are
adequately rate controlled.
- Participants who require concurrent treatment with strong CYP3A inhibitors or strong
CYP3A inducers are excluded from the study. If patients are receiving strong CYP3A
inhibitors/inducers at time of screening but do not require continuous
administration of these agents, these patients are eligible if there is a 7-day
washout period between discontinuation of the strong CYP3A inhibitor/inducer and
initiation of the first study drug, acalabrutinib.
- Participants who require concurrent treatment with P-gp inhibitors or narrow
therapeutic index P-gp substrates are excluded from the study. If patients are
receiving P-gp inhibitors or narrow therapeutic index P-gp substrates at time of
screening but do not require continuous administration of these agents, these
patients are eligible if there is a 7-day washout period between discontinuation of
the P-gp inhibitor and initiation of venetoclax.
- Unable to swallow capsules, a large number of tablets, or malabsorption syndrome,
disease significantly affecting gastrointestinal function, or resection of the
stomach or small bowel if thought by the investigator to compromise systemic
absorption, active, symptomatic inflammatory bowel disease or ulcerative colitis, or
partial or complete bowel obstruction.
- Significant co-morbid condition or disease which in the judgment of the Principal
Investigator would place the participant at undue risk or interfere with the study.
- History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).