Clinical Trials /

Parsaclisib Plus the Standard Drug Therapy in Patients With Newly Diagnosed, High Risk Diffuse Large B-cell Lymphoma

NCT04323956

Description:

This phase I/Ib trial studies the side effects and best dose of parsaclisib plus the standard drug therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) and to see how well they work compared with R-CHOP alone in treating patients with newly diagnosed, high risk diffuse large B-cell lymphoma. Parsaclisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, and vincristine, 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. Anti-inflammatory drugs, such as prednisone, lower the body's immune response and are used with other drugs in the treatment of some types of cancer. It is not yet known if giving parsaclisib and R-CHOP together works better than R-CHOP alone in treating patients with high risk diffuse large B-cell lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Double-Hit Lymphoma
  • Triple-Hit Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Parsaclisib Plus the Standard Drug Therapy in Patients With Newly Diagnosed, High Risk Diffuse Large B-cell Lymphoma
  • Official Title: Phase I/Ib Study of Parsaclisib (INCB50465), Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (PaR-CHOP) Immunochemotherapy for Patients With Newly Diagnosed High Risk Diffuse Large B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: MC1986
  • SECONDARY ID: NCI-2020-01855
  • SECONDARY ID: MC1986
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04323956

Conditions

  • Ann Arbor Stage II Diffuse Large B-Cell Lymphoma
  • Ann Arbor Stage II Follicular Lymphoma
  • Ann Arbor Stage II Marginal Zone Lymphoma
  • Ann Arbor Stage III Diffuse Large B-Cell Lymphoma
  • Ann Arbor Stage III Follicular Lymphoma
  • Ann Arbor Stage III Marginal Zone Lymphoma
  • Ann Arbor Stage IV Diffuse Large B-Cell Lymphoma
  • Ann Arbor Stage IV Follicular Lymphoma
  • Ann Arbor Stage IV Marginal Zone Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements
  • High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements
  • High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements
  • Indolent Non-Hodgkin Lymphoma

Interventions

DrugSynonymsArms
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 (parsaclisib, R-CHOP)
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 (parsaclisib, R-CHOP)
Parsaclisib(4R)-4-(3-((1S)-1-(4-Amino-3-methyl-1H-pyrazolo(3,4-d)pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, INCB 50465, INCB-50465, INCB050465, INCB50465, WHO 10589Treatment (parsaclisib, R-CHOP)
PegfilgrastimFilgrastim SD-01, filgrastim-SD/01, Fulphila, HSP-130, Jinyouli, Neulasta, Neulastim, Pegfilgrastim Biosimilar HSP-130, Pegfilgrastim Biosimilar Pegcyte, Pegfilgrastim-jmdb, SD-01, SD-01 sustained duration G-CSFTreatment (parsaclisib, R-CHOP)
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 (parsaclisib, R-CHOP)
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 (parsaclisib, R-CHOP)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateTreatment (parsaclisib, R-CHOP)

Purpose

This phase I/Ib trial studies the side effects and best dose of parsaclisib plus the standard drug therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) and to see how well they work compared with R-CHOP alone in treating patients with newly diagnosed, high risk diffuse large B-cell lymphoma. Parsaclisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, and vincristine, 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. Anti-inflammatory drugs, such as prednisone, lower the body's immune response and are used with other drugs in the treatment of some types of cancer. It is not yet known if giving parsaclisib and R-CHOP together works better than R-CHOP alone in treating patients with high risk diffuse large B-cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To establish the maximum tolerated dose (MTD) of parsaclisib in combination with R-CHOP in
      newly diagnosed diffuse large B-cell lymphoma (DLBCL). (Phase I) II. To assess the complete
      metabolic response rate by positron emission tomography (PET) (PET complete response [CR]) of
      combining parsaclisib and R-CHOP in patients with newly diagnosed DLBCL. (Dose Expansion)

      SECONDARY OBJECTIVES:

      I. To describe the toxicities associated with parsaclisib in combination with R-CHOP. (Phase
      I) II. To assess the objective response rate (ORR) of parsaclisib in combination with R-CHOP.
      (Dose Expansion) III. To assess the duration of response (DOR), event-free survival (EFS),
      progression-free survival (PFS), and overall survival (OS). (Dose Expansion) IV. To further
      describe the toxicities associated with parsaclisib in combination with R-CHOP. (Dose
      Expansion)

      OUTLINE: This is a dose-escalation study of parsaclisib.

      Patients receive parsaclisib orally (PO) once daily (QD) on days 1-10 or 1-14, rituximab
      intravenously (IV), cyclophosphamide IV over 30 minutes, doxorubicin IV, and vincristine IV
      over 15 minutes on day 1. Patients also receive prednisone PO on days 1-5 and pegfilgrastim
      subcutaneously (SC) on day 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 3 months during year 1
      and every 4 months during year 2. Patients who experience disease progression before the end
      of year 2 are followed up every 6 months for 3 additional years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (parsaclisib, R-CHOP)ExperimentalPatients receive parsaclisib PO QD on days 1-10 or 1-14, rituximab IV, cyclophosphamide IV over 30 minutes, doxorubicin IV, and vincristine IV over 15 minutes on day 1. Patients also receive prednisone PO on days 1-5 and pegfilgrastim SC on day 2. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
  • Cyclophosphamide
  • Doxorubicin Hydrochloride
  • Parsaclisib
  • Pegfilgrastim
  • Prednisone
  • Rituximab
  • Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  Newly diagnosed, untreated, histologically confirmed diffuse large B-cell lymphoma
             expressing the CD20 antigen, with ANY of the following:

               -  Non-germinal center B-cell (GCB) subtype by Hans algorithm

               -  Myc expression >= 40% by immunohistochemistry (IHC)

               -  Bcl-2 expression >= 50% by IHC

               -  Myc expression >= 40% AND Bcl-2 expression >= 50% by IHC (double expressor)

               -  MYC rearrangement by fluorescence in situ hybridization (FISH)

               -  Or high-grade B-cell lymphoma with MYC rearrangement AND BCL2 and/or BCL6
                  rearrangement (double-hit or triple-hit lymphoma) but not a candidate for more
                  aggressive chemotherapy (such as cyclophosphamide, Oncovin [vincristine],
                  doxorubicin, [CODOX]-methotrexate [M]- ifosfamide, Vepesid [etoposide], Ara-C
                  [cytarabine] [IVAC])

                    -  NOTE: Patients with a new diagnosis of concurrent DLBCL and an indolent
                       lymphoma (previously undiagnosed, such as follicular lymphoma or marginal
                       zone lymphoma) are eligible. However, patients with a known prior diagnosis
                       of indolent lymphoma with new transformation to DLBCL (i.e., transformed
                       lymphoma) are not eligible

          -  Ann Arbor stages II (bulky disease, i.e., >= 5 cm, or not a candidate for combined
             modality treatment with R-CHOP plus radiotherapy), III, or IV

          -  Measurable disease (at least 1 lesion of >= 1.5 cm in one diameter) as detected by
             computed tomography (CT) or the CT images of PET/CT. Skins lesions can be used if the
             area is >= 2 cm in at least one diameter and photographed with a ruler

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

          -  Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 14 days prior to
             registration)

          -  Platelet count >= 100,000/mm^3 (obtained =< 14 days prior to registration)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN), or if total bilirubin is > 1.5 x
             ULN, the direct bilirubin must be normal (obtained =< 14 days prior to registration)

          -  Aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN for patients with direct liver
             involvement by lymphoma) (obtained =< 14 days prior to registration)

          -  Alkaline phosphatase =< 3 x ULN, unless evidence of the direct liver involvement by
             lymphoma, then =< 5 x ULN (obtained =< 14 days prior to registration)

          -  Calculated creatinine clearance of >= 30 mL/min using the Cockcroft-Gault formula
             (obtained =< 14 days prior to registration)

          -  Negative urine pregnancy test done =< 7 days prior to registration, for persons of
             childbearing potential only

               -  NOTE: If the urine test is positive or cannot be confirmed as negative, a serum
                  pregnancy test will be required

          -  Persons of childbearing potential must agree to use one reliable form of birth control

          -  Provide written informed consent

          -  Willingness to provide mandatory research blood specimens for banking

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

        Exclusion Criteria:

          -  Any of the following because this study involves an investigational agent whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown:

               -  Pregnant persons

               -  Nursing persons (lactating persons are eligible provided that they agree not to
                  breast feed while taking parsaclisib)

               -  Persons of childbearing potential who are unwilling to employ adequate
                  contraception

          -  Primary central nervous system (CNS) lymphoma, or parenchymal, meningeal or
             cerebrospinal fluid involvement with malignant lymphoma cells

          -  Co-morbid systemic illnesses or other severe concurrent disease 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

          -  Immunocompromised patients and patients known to be human immunodeficiency virus (HIV)
             positive and currently receiving antiretroviral therapy (except for patients on
             effective antiretroviral therapy with undetectable viral load within 6 months)

               -  NOTE: If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load
                  must be undetectable on suppressive therapy if indicated

               -  NOTE: If history of hepatitis C virus (HCV) infection, HCV viral load must be
                  undetectable

          -  Uncontrolled intercurrent illness including, but not limited to:

               -  Ongoing or active infection

               -  Symptomatic congestive heart failure requiring use of ongoing maintenance therapy
                  for life-threatening ventricular arrhythmias

               -  Unstable angina pectoris

               -  Cardiac arrhythmia

               -  Ongoing inflammatory bowel disease (such as ulcerative colitis) or other colitis
                  requiring active treatment

               -  Oxygen dependent baseline lung disease (such as interstitial lung disease or
                  chronic obstructive pulmonary disease [COPD])

               -  Or psychiatric illness/social situations that would limit compliance with study
                  requirements

          -  Received or receiving any other agent which would be considered as a treatment for the
             lymphoma (with the exception of corticosteroid)

          -  Other active malignancy requiring therapy such as radiation, chemotherapy or
             immunotherapy. Patients on hormonal therapy for treated breast or prostate cancer are
             permitted if they meet other eligibility criteria

               -  EXCEPTIONS: Localized non-melanotic skin cancer or any cancer that in the
                  judgment of the investigator has been treated with curative intent (e.g.,
                  disease-free survival equal or more than 5 years) and will not interfere with the
                  study treatment plan and response assessment

               -  NOTE: If there is a history of prior malignancy, they must not require therapy
                  such as radiation, chemotherapy or immunotherapy for their cancer

          -  History of myocardial infarction =< 6 months, or congestive heart failure requiring
             use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

          -  >= 25% of bone marrow radiated for other diseases

          -  Ejection fraction of < 45% by either multigated acquisition scan (MUGA) or
             echocardiogram (ECHO)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of parsaclisib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (Phase I)
Time Frame:Up to 21 days
Safety Issue:
Description:The MTD will be defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least 2 of a maximum of 6 patients.

Secondary Outcome Measures

Measure:Incidence of adverse events (AEs) (Phase I)
Time Frame:Up to 2 years
Safety Issue:
Description:The number and severity (grade) of all treatment related AEs will be tabulated and summarized. Non-hematologic AEs will be evaluated via the ordinal Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 standard AE grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTCAE v 5.0 standard AE grading. Both all grade and grade 3 and above AEs will be described and summarized in a similar fashion. Overall AE incidences as well as AE profiles by dose level and patient will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
Measure:Objective response rate (Dose Expansion)
Time Frame:Up to end of treatment (3-4 weeks after day 1 of cycle 6 [each cycle is 21 days])
Safety Issue:
Description:Will be estimated by the number of patients with an objective status of CMR or partial metabolic response (PMR) by the PET-CT based response criteria at the end of treatment divided by the total number of evaluable patients. All evaluable patients will be used for this analysis. Exact binomial 95% confidence intervals for the true objective response rate will be calculated.
Measure:Duration of response (Dose Expansion)
Time Frame:The date at which the patient's objective status is first noted to be either a CMR or PMR to the earliest date progression is documented by CT or PET/CT (progressive metabolic disease [PMD] or progressive disease [PD]), assessed up to 2 years
Safety Issue:
Description:The distribution of duration of response will be estimated using the method of Kaplan-Meier.
Measure:Event-free survival (Dose Expansion)
Time Frame:From registration to disease progression or relapse (PMD or PD), initiation of subsequent anti-lymphoma therapy, or death due to any cause, assessed up to 5 years
Safety Issue:
Description:The distribution of event-free survival time will be estimated using the method of Kaplan-Meier.
Measure:Progression-free survival (Dose Expansion)
Time Frame:From registration to progression (PMD or PD) or death due to any cause, assessed up to 5 years
Safety Issue:
Description:The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.
Measure:Overall survival (Dose Expansion)
Time Frame:From registration to death due to any cause, assessed up to 5 years
Safety Issue:
Description:The distribution of overall survival time will be estimated using the method of Kaplan-Meier.
Measure:Incidence of adverse events (Dose Expansion)
Time Frame:Up to 2 years
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 taken into consideration.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mayo Clinic

Last Updated

March 25, 2020