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 41 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.
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 (part B).
- 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 part B, 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
- Participants in part B 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 part B who have a molecular marker identified from the peripheral blood will be
eligible for minimal residual disease (MRD) driven treatment interruptions.
- Participants in part B 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 in parts A and B 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 treatment with proton pump inhibitors. Subjects receiving
proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
for enrollment on this study.
- 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.
