Clinical Trials /

Copanlisib and Combination Chemotherapy for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma or Relapsed Grade 3b Follicular Lymphoma

NCT04156828

Description:

This phase I trial studies the best dose of copanlisib when given together with combination chemotherapy (R-GCD) in treating patients with diffuse large B-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory) or grade 3b follicular lymphoma that has come back (relapsed) after 1 prior line of therapy. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as rituximab, gemcitabine, carboplatin, and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving copanlisib together with R-GCD as second line therapy may improve the complete response rate for patients with diffuse large B-cell lymphoma or follicular lymphoma.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Grade 3b Follicular Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Copanlisib and Combination Chemotherapy for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma or Relapsed Grade 3b Follicular Lymphoma
  • Official Title: A Phase I Study Evaluating Copanlisib in Combination With R-GCD (Gemcitabine, Carboplatin, Dexamethasone, and Rituximab) With Relapsed/Refractory Diffuse Large B-Cell Lymphoma and High-Risk Follicular Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: RG1005097
  • SECONDARY ID: NCI-2019-07286
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT04156828

Conditions

  • Grade 3b Follicular Lymphoma
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Follicular Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Non-Hodgkin's Lymphoma

Interventions

DrugSynonymsArms
Copanlisib1032568-63-0, BAY 80-6946, PI3K Inhibitor BAY 80-6946Treatment (copanlisib, R-GCD)
GemcitabinedFdCyd, Difluorodeoxycytidine, 1-(2-Oxo-4-amino-1Treatment (copanlisib, R-GCD)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Nealorin, Novoplatinum, Paraplatin, Paraplatine, Platinwas, RibocarboTreatment (copanlisib, R-GCD)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin Depot, Auricularum, Auxiloson, Baycadron, Baycuten, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decalix, Decameth, Decasone, Deltafluorene, Desameton, Dexa-Mamallet, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDexTreatment (copanlisib, R-GCD)
Rituximab174722-31-7, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, rituximab-abbs, RTXM83, TruximaTreatment (copanlisib, R-GCD)
Pegfilgrastim208265-92-3, Filgrastim SD-01, filgrastim-SD/01, Fulphila, HSP-130, Jinyouli, Neulasta, Pegfilgrastim Biosimilar HSP-130, Pegfilgrastim Biosimilar Pegcyte, Pegfilgrastim-jmdb, SD-01, SD-01 sustained duration G-CSFTreatment (copanlisib, R-GCD)

Purpose

This phase I trial studies the best dose of copanlisib when given together with combination chemotherapy (R-GCD) in treating patients with diffuse large B-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory) or grade 3b follicular lymphoma that has come back (relapsed) after 1 prior line of therapy. Copanlisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as rituximab, gemcitabine, carboplatin, and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving copanlisib together with R-GCD as second line therapy may improve the complete response rate for patients with diffuse large B-cell lymphoma or follicular lymphoma.

Detailed Description

      This is a dose-escalation study of copanlisib.

      Patients receive copanlisib intravenously (IV) and gemcitabine IV on days 1 and 8,
      carboplatin IV and rituximab IV on day 1, and dexamethasone orally (PO) in the morning (AM)
      or 30-60 minutes prior to chemotherapy on days 1-4. Patients also receive pegfilgrastim
      subcutaneously (SC) on day 8 or 9. Treatment repeats every 21 days for up to 3 cycles in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed for up to 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (copanlisib, R-GCD)ExperimentalPatients receive copanlisib IV and gemcitabine IV on days 1 and 8, carboplatin IV and rituximab IV on day 1, and dexamethasone PO in AM or 30-60 minutes prior to chemotherapy on days 1-4. Patients also receive pegfilgrastim SC on day 8 or 9. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
  • Copanlisib
  • Gemcitabine
  • Carboplatin
  • Dexamethasone
  • Rituximab
  • Pegfilgrastim

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects must meet one of the following criteria:

               -  Histologically confirmed relapsed/refractory DLBCL or grade 3b follicular
                  lymphoma.

               -  Follicular lymphoma that has relapsed within 2 years of primary therapy that
                  included an anti-CD20 antibody in combination with chemotherapy as measured from
                  the date of the last dose of chemotherapy

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Previous exposure to other PI3K inhibitors (except copanlisib) is acceptable provided
             there is no resistance (resistance defined as no response (response defined as partial
             response [PR] or CR) at any time during therapy, or progressive disease (PD) after any
             response (PR/CR) or after stable disease within 6 months from the end of the therapy
             with a PI3K inhibitor

          -  Willingness and ability to comply with study and follow-up procedures, and give
             written informed consent

          -  Female subjects of childbearing potential must be surgically sterile, be
             post-menopausal (per institutional guidelines), or must have a negative pregnancy test
             within 3 days prior to cycle 1 day 1 and agree to use medically acceptable
             contraception throughout the study period and for 4 months after the last dose of
             either study drug. Men of reproductive potential may not participate unless they agree
             to use medically acceptable contraception throughout the study period and for 4 months
             after the last dose of either study drug

          -  Patients must be expected to receive at least 2 cycles of therapy

          -  Patients should have an expected survival if untreated of >= 90 days

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (< 3 x ULN for patients with
             Gilbert-Meulengracht syndrome or for patients with cholestasis due to compressive
             adenopathies of the hepatic hilum) (collected no more than 7 days before starting
             study treatment)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5
             x ULN for patients with liver involvement by lymphoma (collected no more than 7 days
             before starting study treatment)

          -  Lipase =< 1.5 x ULN (collected no more than 7 days before starting study treatment)

          -  Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 according to the Modification
             of Diet in Renal Disease (MDRD) abbreviated formula (collected no more than 7 days
             before starting study treatment). If not on target, this evaluation may be repeated
             once after at least 24 hours either according to the MDRD abbreviated formula or by 24
             hour sampling. If the latter result is within acceptable range, it may be used to
             fulfill the inclusion criteria instead

          -  International normalized ratio 9INR) =< 1.5 and partial thromboplastin time (PTT) =<
             1.5 x ULN. PT can be used instead of INR if =< 1.4 x ULN (collected no more than 7
             days before starting study treatment)

          -  Platelet count >= 75,000 /mm^3. For patients with lymphomatous bone marrow
             infiltration, platelet count >= 50,000 /mm^3 (collected no more than 7 days before
             starting study treatment)

          -  Hemoglobin (Hb) >= 8 g/dl (collected no more than 7 days before starting study
             treatment). Packed red blood cell transfusion or erythropoietin should not be given
             less than 7 days before the exam collection

          -  Absolute neutrophil count (ANC) >= 1,000/mm^3 (collected no more than 7 days before
             starting study treatment). For patients with confirmed lymphomatous bone marrow
             infiltration, ANC count >= 750/mm^3. Myeloid growth factors should not be given less
             than 7 days before the exam collection

        Exclusion Criteria:

          -  More than one prior line of therapy for DLBCL

          -  More than one prior line of chemoimmunotherapy

          -  Prior treatment with copanlisib

          -  Documented evidence of resistance to prior treatment with idelalisib or other PI3K
             inhibitors defined as: No response (response defined as partial response [PR] or
             complete response [CR]) at any time during therapy, or Progression (PD) after any
             response (PR/CR) or after stable disease within 6 months from the end of the therapy
             with a PI3K inhibitor

          -  Prior treatment including systemic therapy or radiotherapy within 21 days of study
             initiation

          -  Poorly controlled diabetes mellitus defined as hemoglobin A1c > 8.5%

          -  Known lymphomatous involvement of the central nervous system

          -  Known history of human immunodeficiency virus (HIV) infection. All patients must be
             screened for HIV up to 28 days prior to study drug start using a blood test for HIV
             according to local regulations

          -  Hepatitis B (HBV) or C (HCV) infection. All patients must be screened for HBV and HCV
             up to 28 days prior to study drug start using the routine hepatitis virus laboratorial
             panel. Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core
             antibody (HBcAb) will be eligible if they are negative for HBV-deoxribonucleic acid
             (DNA), these patients should receive prophylactic antiviral therapy. Patients positive
             for anti-HCV antibody will be eligible if they are negative for HCV-ribonucleic acid
             (RNA)

          -  Previous or concurrent history of malignancies within 3 years prior to study. Any
             exceptions beyond those listed below must be approved by the principal investigator:

               -  Cervical carcinoma in situ

               -  Non-melanoma skin cancer

               -  Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and
                  T1 [tumor invades lamina propria])

               -  Localized prostate cancer

          -  Active, clinically serious infections (> Common Terminology Criteria for Adverse
             Events [CTCAE] grade 2)

          -  Known hypersensitivity to any of the study drugs, study drug classes, or excipients in
             the formulation.

          -  Proteinuria of >= CTCAE grade 3 as assessed by a 24 h total urine protein
             quantification or estimated by urine protein : creatinine ratio > 3.5 on a random
             urine sample

          -  Unresolved toxicity from prior therapy higher than National Cancer Institute
             (NCI)-CTCAE grade 1 attributed to any prior therapy/procedure excluding alopecia or
             sensory neuropathy. Concurrent diagnosis of pheochromocytoma

          -  Pregnant or breast-feeding patients. Women of childbearing potential must have a
             pregnancy test performed a maximum of 7 days before start of treatment, and a negative
             result must be documented before start of treatment

          -  Substance abuse, medical, psychological or social conditions that may interfere with
             the patient's participation in the study or evaluation of the study result

          -  Congestive heart failure > New York Heart Association (NYHA) class 2

          -  Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
             months)

          -  Myocardial infarction less than 6 months before start of test drug

          -  Uncontrolled arterial hypertension despite optimal medical management (per
             investigator's assessment)

          -  Arterial or venous thrombotic or embolic events such as cerebrovascular accident
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
             within 3 months before the start of study treatment

          -  Non-healing wound, ulcer, or bone fracture

          -  Active, clinically serious infections > CTCAE grade 2

          -  Patients with seizure disorder requiring medication

          -  Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding
             event >= CTCAE grade 3 within 4 weeks prior to the start of study treatment

          -  Any illness or medical conditions that are unstable or could jeopardize the safety of
             the patients and their compliance in the study

          -  History of having received an allogeneic bone marrow or organ transplant

          -  Anti-arrhythmic therapy (beta blockers or digoxin are permitted)

          -  Major surgical procedure or significant traumatic injury (as judged by the
             investigator) less than 28 days before start of treatment, open biopsy less than 7
             days before start of treatment

          -  Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg
             prednisone or equivalent is not allowed. Patients may be using topical or inhaled
             corticosteroids. Previous corticosteroid therapy must be stopped or reduced to the
             allowed dose at least 7 days performing the screening computed tomography
             (CT)/magnetic resonance imaging (MRI). If a patient is on chronic corticosteroid
             therapy, corticosteroids should be de-escalated to the maximum allowed dose before the
             screening. Patients may be using topical or inhaled corticosteroids

          -  Use of CYP3A4 inhibitors and inducers. Copanlisib is primarily metabolized by CYP3A4.
             Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole,
             itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and
             strong inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital,
             St. John's wort) are not permitted from day -14 of cycle 1 until the safety follow-up
             visit
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT)
Time Frame:Up to 21 days
Safety Issue:
Description:Will assess the presence of a DLT in the first cycle of treatment The dose that estimate of the maximum tolerated dose (MTD) will be obtained using the continuous reassessment method (CRM). Moreover, the proportion of DLT at each dose level will be reported along with the final estimates of the probability of DLT at the MTD based on the CRM along with the 95% confidence interval.

Secondary Outcome Measures

Measure:Complete response rate
Time Frame:Up to 1 year after 3 cycles of treatment (each cycle is 21 days)
Safety Issue:
Description:Will be defined by the Lugano Criteria using positron emission tomography (PET)/computed tomography (CT). Will be calculated for patients assigned to the MTD and reported along with an exact binomial 95% confidence interval.
Measure:Objective response rate
Time Frame:Up to 1 year after 3 cycles of treatment (each cycle is 21 days)
Safety Issue:
Description:Will be defined by the Lugano Criteria using PET/CT. Will be calculated for patients assigned to the MTD and reported along with an exact binomial 95% confidence interval.
Measure:Ability to mobilize an adequate number of CD34+ stem cells for autologous stem cell transplant (ASCT)
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:For those who initially planned to consolidate treatment with an ASCT, will evaluate the proportion who are able to mobilize an adequate number of CD34+ stem cells for ASCT defined as >= 2 x 10^6 CD34+ cells/kg.
Measure:Ability to proceed with ASCT
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Will also evaluate the proportion of patients who initially planned to consolidate treatment with ASCT that are actually able to do so.
Measure:Progression free survival (PFS)
Time Frame:At 1 year
Safety Issue:
Description:Will also evaluate the 1-year PFS of this population.
Measure:Overall survival (OS)
Time Frame:At 1 year
Safety Issue:
Description:Will also evaluate the 1-year OS of this population.
Measure:Cell of origin (COO)
Time Frame:Up to 1 year post treatment
Safety Issue:
Description:Will stratify results based on COO as determined by Hans algorithm or gene expression profiling by nanostring.
Measure:Incidence of adverse events
Time Frame:Up to 28 days after cycle 3 day 1 (each cycle is 21 days)
Safety Issue:
Description:The National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 will be used to classify and grade toxicities.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Washington

Last Updated

January 29, 2020