Clinical Trials /

Avo In R/R And Previously Untreated MCL

NCT04855695

Description:

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

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Avo In R/R And Previously Untreated MCL
  • Official Title: A Phase 1/2 Study of Acalabrutinib, Venetoclax, and Obinutuzumab in Patients With Relapsed/Refractory and Previously Untreated Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 21-040
  • NCT ID: NCT04855695

Conditions

  • Mantle Cell Lymphoma
  • Refractory Lymphoma

Interventions

DrugSynonymsArms
AcalabrutinibCalquenceAcalabrutinib, Venetoclax, and Obinutuzumab
VenetoclaxVenclextaAcalabrutinib, Venetoclax, and Obinutuzumab
ObinutuzumabGazyvaAcalabrutinib, Venetoclax, and Obinutuzumab

Purpose

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

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Acalabrutinib, Venetoclax, and ObinutuzumabExperimentalThis study will consist of 2 parts (Parts A and B) and begin in the relapsed/refractory (R/R) MCL setting (Part A) with the phase 1 portion consisting of a dose finding stage to determine the recommended phase 2 dose (RP2D).The phase 1 dose finding stage will follow a 3+3 dose finding schema, such that there will be a safety pause and evaluation after the first 3 participants at any given dose level have completed therapy through cycle 5, day 1. If there are no dose limiting toxicities (DLTs) seen, an additional 3 participants will be treated at the same dose level and if there are 0 or 1 DLTs seen, the RP2D will have been determined. Each study drug is given according to a different schedule. Each treatment cycle lasts 28 days (4 weeks). Acalabrutinib: Obinutuzumab: Venetoclax:
  • Acalabrutinib
  • Venetoclax
  • Obinutuzumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 Dose for acalabrutinib
Time Frame:5 months
Safety Issue:
Description:The RP2D will be defined as the highest dose level for which there are no more than 1/6 DLTs observed.

Secondary Outcome Measures

Measure:Complete Remission (CR) rate after 7 cycles in the entire study population
Time Frame:7 months
Safety Issue:
Description:Complete remission (CR) is defined radiographically using 2014 Lugano criteria and a negative bone marrow biopsy by histology, immunohistochemistry, and flow cytometry, if bone marrow was initially involved by MCL at screening. CR, a primary endpoint measured after 7 cycles of AVO, does not incorporate minimal residual disease (MRD) testing
Measure:CR rate after 7 cycles cohort A
Time Frame:7 Months
Safety Issue:
Description:Complete remission (CR) is defined radiographically using 2014 Lugano criteria and a negative bone marrow biopsy by histology, immunohistochemistry, and flow cytometry, if bone marrow was initially involved by MCL at screening. CR, a primary endpoint measured after 7 cycles of AVO, does not incorporate minimal residual disease (MRD) testing
Measure:Partial Response (PR) Rate after 7 cycles
Time Frame:7 months
Safety Issue:
Description:2014 Lugano Criteria
Measure:Stable Disease Rate after 7 cycles
Time Frame:7 months
Safety Issue:
Description:Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
Measure:Progressive Disease Rate after 7 Cycles
Time Frame:7 months
Safety Issue:
Description:Lugano 2014 criteria
Measure:Progression Free Survival-Median
Time Frame:Up to 5 Years
Safety Issue:
Description:Kaplan Meier Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation
Measure:Progression Free Survival
Time Frame:Up to 5 years
Safety Issue:
Description:Kaplan Meier Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation
Measure:Overall Survival
Time Frame:Up to 5 years
Safety Issue:
Description:Kaplan Meier- Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.
Measure:Overall Survival-Median
Time Frame:Up to 5 years
Safety Issue:
Description:Kaplan Meier Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive.
Measure:Rate of peripheral blood MRD-negativity after 7 cycles
Time Frame:7 months
Safety Issue:
Description:Minimal residual disease (MRD) negativity is defined as 0 residual clonal cells per 1 x 106 nucleated cells in the peripheral blood assessed by the clonoSEQ® assay. The clonoSEQ assay uses next generation sequencing (NGS) to identify rearranged IgH (VDJ), IgH (DJ), IgK, and IgL receptor gene sequences, as well as translocated BCL1/IgH (J) sequences in a sample
Measure:Time to Minimal Residual Disease (MRD)-positive disease recurrence in the peripheral blood
Time Frame:Up to 8 months
Safety Issue:
Description:Time to MRD-positive disease recurrence, in patients who have achieved MRD negativity
Measure:Time to clinical disease progression
Time Frame:Up to 5 years
Safety Issue:
Description:Time to Progression (TTP) is defined as the time from randomization (or registration) to progression, or censored at date of last disease evaluation for those without progression reported
Measure:Rate of infusion related reactions
Time Frame:Up to 5 years
Safety Issue:
Description:Some participants may develop hypersensitivity or other infusion-related reactions (IRRs) to obinutuzumab, pre-medication is recommended to reduce the risk of infusion reactions. Premedication will be given as outlined in protocol. Cycle numbers are specific to this trial
Measure:Rate of tumor lysis syndrome
Time Frame:7 Months
Safety Issue:
Description:criteria of laboratory TLS or clinical TLS according to the Cairo-Bishop definition of TLS
Measure:Rate of therapy discontinuation
Time Frame:10 Months
Safety Issue:
Description:descriptive analysis of rates of therapy discontinuation after 10 cycles will be performed, with subjects grouped by reasons for discontinuation (e.g. achievement of MRD-negative CR, progressive disease, or intolerability). Rates of discontinuation of individual components of the regimen will also be included in this analysis.
Measure:Number of Participants with Treatment Related Adverse Events CTCAE 5.0 criteria
Time Frame:up to 30 days after the last dose of study treatment or until resolution of toxicity to grade 1 or baseline, whichever occurs last up to 5 years
Safety Issue:
Description:Grade 3 and higher toxicities, both regardless of attribution, and at least possibly attributed to the study treatment Grade 2 or higher toxicity at least probably related to study treatment Adverse events leading to discontinuation due to toxicity NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Austin I Kim

Trial Keywords

  • Mantle Cell Lymphoma
  • Refractory Lymphoma

Last Updated

April 22, 2021