Clinical Trials /

Modified VR-CAP and Acalabrutinib as First Line Therapy for the Treatment of Transplant-Eligible Patients With Mantle Cell Lymphoma

NCT04626791

Description:

This phase II trial investigates how well modified VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin hydrochloride, prednisone, and cytarabine hydrochloride) and acalabrutinib as first line therapy work in treating transplant-eligible patients with mantle cell lymphoma. Modified VR-CAP is a combination of drugs used as standard first line treatment for mantle cell lymphoma. Chemotherapy drugs, such as bortezomib, cyclophosphamide, doxorubicin hydrochloride, and cytarabine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody that binds and depletes malignant B cells, by inducing immune responses and direct toxicity. Acalabrutinib blocks a key enzyme which is needed for malignant cell growth in mantle cell lymphoma. Combining modified VR-CAP and acalabrutinib as first line therapy may be more useful against mantle cell lymphoma compared to the usual treatment.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Modified VR-CAP and Acalabrutinib as First Line Therapy for the Treatment of Transplant-Eligible Patients With Mantle Cell Lymphoma
  • Official Title: A Phase II Study of Modified VR-CAP and Acalabrutinib as First Line Therapy for Transplant-Eligible Patients With Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-LY-1804
  • SECONDARY ID: NCI-2020-04428
  • SECONDARY ID: ACCRU-LY-1804
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04626791

Conditions

  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
AcalabrutinibACP-196, Bruton Tyrosine Kinase Inhibitor ACP-196, CalquenceTreatment (modified VR-CAP, acalabrutinib)
Bortezomib[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, VelcadeTreatment (modified VR-CAP, acalabrutinib)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (modified VR-CAP, acalabrutinib)
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-Cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (modified VR-CAP, acalabrutinib)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexTreatment (modified VR-CAP, acalabrutinib)
Prednisone.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-PrednisoneTreatment (modified VR-CAP, acalabrutinib)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, TruximaTreatment (modified VR-CAP, acalabrutinib)
Rituximab and Hyaluronidase HumanRituxan Hycela, Rituximab Plus Hyaluronidase, Rituximab/Hyaluronidase, Rituximab/Hyaluronidase HumanTreatment (modified VR-CAP, acalabrutinib)

Purpose

This phase II trial investigates how well modified VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin hydrochloride, prednisone, and cytarabine hydrochloride) and acalabrutinib as first line therapy work in treating transplant-eligible patients with mantle cell lymphoma. Modified VR-CAP is a combination of drugs used as standard first line treatment for mantle cell lymphoma. Chemotherapy drugs, such as bortezomib, cyclophosphamide, doxorubicin hydrochloride, and cytarabine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody that binds and depletes malignant B cells, by inducing immune responses and direct toxicity. Acalabrutinib blocks a key enzyme which is needed for malignant cell growth in mantle cell lymphoma. Combining modified VR-CAP and acalabrutinib as first line therapy may be more useful against mantle cell lymphoma compared to the usual treatment.

Detailed Description

      PRIMARY OBJECTIVE:

      I. Measure the proportion of complete metabolic responses according to Lugano criteria at the
      end of study therapy.

      SECONDARY OBJECTIVES:

      I. Evaluate the safety of this combination. II. Proportion proceeding to autologous stem cell
      transplant (ASCT). III. Feasibility and results of stem cell mobilization and successful
      collection.

      IV. Progression-free survival (PFS) and overall survival (OS) (event monitoring phase),
      assessed up to 2 years after registration.

      CORRELATIVE RESEARCH OBJECTIVE:

      I. Assess minimal residual disease level after 3 and 6 cycles of therapy using the ClonoSEQ
      (Adaptive Biotechnologies, Seattle, Washington [WA]), and explore relationship with
      radiographic complete response (CR) rate and baseline features.

      OUTLINE:

      CYCLES 1, 3, AND 5: Patients receive acalabrutinib orally (PO) twice daily (BID) on days
      1-21. Patients also receive bortezomib subcutaneously (SC) on days 1, 8, and 15, rituximab
      (or rituximab and hyaluronidase human) intravenously (IV), cyclophosphamide IV, and
      doxorubicin hydrochloride IV on day 1, and prednisone PO on days 1-5.

      CYCLES 2, 4, AND 6: Patients receive acalabrutinib PO BID on days 1-21. Patients also receive
      rituximab (or rituximab and hyaluronidase human) IV on day 1 and cytarabine IV on days 1-2.

      Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months for up to 2
      years after registration.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (modified VR-CAP, acalabrutinib)ExperimentalCYCLES 1, 3, AND 5: Patients receive acalabrutinib PO BID on days 1-21. Patients also receive bortezomib SC on days 1, 8, and 15, rituximab (or rituximab and hyaluronidase human) IV, cyclophosphamide IV, and doxorubicin hydrochloride IV on day 1, and prednisone PO on days 1-5. CYCLES 2, 4, AND 6: Patients receive acalabrutinib PO BID on days 1-21. Patients also receive rituximab (or rituximab and hyaluronidase human) IV on day 1 and cytarabine IV on days 1-2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
  • Acalabrutinib
  • Bortezomib
  • Cyclophosphamide
  • Cytarabine
  • Doxorubicin Hydrochloride
  • Prednisone
  • Rituximab
  • Rituximab and Hyaluronidase Human

Eligibility Criteria

        Inclusion Criteria:

          -  No prior therapy for mantle cell lymphoma (MCL)

          -  MCL in need of systemic therapy, and potentially eligible for ASCT as assessed by the
             treating physician

          -  Documented histological confirmation of MCL by local institutional review

          -  Documented, fludeoxyglucose F-18 (FDG)-avid measurable disease (at least 1 lesion >=
             1.5 cm in diameter) as detected by positron emission tomography (PET)/computed
             tomography (CT) and as defined and includes measurable nodal and extranodal disease
             sites, or splenomegaly measuring more than 13 cm in vertical length

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2

          -  Absolute neutrophil count (ANC) >= 1000/mm^3 or >= 500/mm^3 if due to lymphomatous
             marrow or spleen involvement (obtained =< 30 days prior to registration)

          -  Platelet count >= 100,000/mm^3 or >= 75,000/mm^3 if due to lymphomatous marrow or
             spleen involvement (obtained =< 30 days prior to registration)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless documented Gilbert's
             syndrome, for which total bilirubin =< 3 x upper limit of normal [ULN] is permitted)
             (obtained =< 30 days prior to registration)

          -  Aspartate transaminase (AST) =< 3 x ULN (obtained =< 30 days prior to registration)

          -  Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin
             time (PTT) =< 2 x ULN, unless elevated due to a lupus anticoagulant (obtained =< 30
             days prior to registration)

          -  Calculated creatinine clearance must be >= 30 ml/min using the Cockcroft-Gault formula
             (obtained =< 30 days prior to registration)

          -  Negative pregnancy test done within =< 14 days prior to registration for women of
             childbearing potential only

          -  For women childbearing potential (WOCBP, defined as premenopausal women capable of
             becoming pregnant): Must agree to use of highly effective method of birth control
             during study therapy and until 12 months after last dose of study therapy.
             ('Acceptable' methods are not adequate. Highly effective methods are defined by
             Clinical Trials Facilitation and Coordination Group [CTFG] as having a failure rate of
             < 1% per year)

          -  Men must agree to use barrier contraception starting with the first dose of study
             therapy and through 180 days after completion of study therapy

          -  Provide informed written consent

          -  Willing to return to enrolling institution for follow-up (during the Active Monitoring
             Phase of the study)

          -  Hematologic labs must be obtained within =< 14 days of registration

          -  Willing and able to participate in all required evaluations and procedures in this
             study protocol

          -  Ability to understand the purpose and risks of the study and provide signed and dated
             informed consent and authorization to use protected health information

        Exclusion Criteria:

          -  Prior systemic treatment for mantle cell lymphoma. Short course of steroids (=< 7
             days) for symptom management or localized radiation is permissible, as long as
             measurable disease outside of the radiation field exists

          -  Peripheral neuropathy or neuropathic pain of grade 2 or worse as assessed by the
             investigator

          -  Prior exposure to bortezomib or a BTK inhibitor

          -  Prior anthracycline exposure unless cumulative prior exposure is under 150 mg per
             square meter

          -  Requiring anticoagulation with warfarin or equivalent vitamin k antagonist

          -  Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenia
             purpura)

          -  Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand
             disease)

          -  History of stroke or intracranial hemorrhage within 6 months prior to enrollment

          -  Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer

          -  Requiring treatment with a proton pump inhibitor. Examples include: dexlansoprazole,
             esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, or therapeutic
             class equivalents

               -  Note: H2-receptor agonists are not exclusionary

          -  History of allergic reactions attributed to acalabrutinib, cytarabine, bortezomib,
             boron, or any of the other agents administered as part of the therapeutic regimen in
             this study

          -  Active systemic fungal, bacterial, viral, or other infection that is worsening
             (defined as increasing signs/symptoms of infection during screening) or, requires
             intravenous antibiotic therapy

          -  Active or chronic uncontrolled hepatitis B or hepatitis C infection. Patients with
             positive hepatitis B core antibody positive require negative polymerase chain reaction
             (PCR) prior to enrollment. Hepatitis B surface antigen positive or PCR positive
             patients will be excluded. Patients with hepatitis C must have negative hepatitis C
             virus (HCV) ribonucleic acid (RNA) for inclusion

          -  Co-morbid systemic illnesses or other severe concurrent disease (including major
             surgery within 2 weeks) which, in the judgment of the investigator, would make the
             patient inappropriate for entry into this study or interfere significantly with the
             proper assessment of safety and toxicity of the prescribed regimens

          -  Known to be human immunodeficiency virus (HIV) positive since antiretroviral therapy
             has a potential for drug interactions with acalabrutinib

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure or low cardiac ejection fraction (New
             York Heart Association [NYHA] class 3-4 or ejection fraction [EF] < 45%), unstable
             angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
             would limit compliance with study requirements

          -  Receiving any other investigational agent which would be considered as a treatment for
             the primary neoplasm

          -  Other active malignancy =< 2 years prior to registration. EXCEPTIONS: Non-melanotic
             skin cancer localized prostate cancer, or carcinoma-in-situ of the breast or cervix.
             NOTE: If there is a history or prior malignancy, patients must not be receiving other
             specific treatment for their cancer

          -  Pregnant and/or breastfeeding

          -  Has difficulty with or is unable to swallow oral medication, or has significant
             gastrointestinal disease that would limit absorption of oral medication

          -  Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
             screening. unless directly due to MCL Involvement by endoscopic or histologic
             evaluation

          -  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

          -  Concurrent participation in another therapeutic clinical trial
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of complete responses to therapy (complete metabolic response [CMR])
Time Frame:At completion of study treatment, up to 5 years from registration
Safety Issue:
Description:Measured according to Lugano criteria. A success is defined as a CMR as the objective status at the end of treatment. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. 92% confidence intervals for the true success proportion will be calculated according to the approach of Clopper Pearson.

Secondary Outcome Measures

Measure:Minimal residual disease (MRD) rate
Time Frame:At completion of study treatment, up to 5 years from registration
Safety Issue:
Description:Measured by flow. MRD results will be reported descriptively, and explored for correlation with clinical factors and patient outcomes.
Measure:MRD rate
Time Frame:At completion of study treatment, up to 5 years from registration
Safety Issue:
Description:Measured by sequencing. MRD results will be reported descriptively, and explored for correlation with clinical factors and patient outcomes.
Measure:Incidence of adverse events
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be reported.
Measure:Progression-free survival
Time Frame:From the date of registration to the date of progression (or relapse),or death due to any cause, whichever comes first, assessed at 2 years post-registration
Safety Issue:
Description:The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Measure:Overall survival
Time Frame:From registration to death due to any cause, assessed at 2 years post-registration
Safety Issue:
Description:The distribution of survival time will be estimated using the method of Kaplan-Meier.
Measure:Feasibility of stem cell collection
Time Frame:At completion of study treatment, up to 5 years from registration
Safety Issue:
Description:The proportion of patients successfully collecting at least 2 x 10^6 CD34 cells/kg pt body weight will be calculated and reported.
Measure:Successful proceeding to autologous stem cell transplant (ASCT)
Time Frame:At completion of study treatment, up to 5 years from registration
Safety Issue:
Description:The proportion of patients successfully proceeding to ASCT will be calculated and reported.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Academic and Community Cancer Research United

Last Updated

November 13, 2020