Clinical Trial: NCT02048813 - My Cancer Genome

NCT02048813

Description:

This randomized phase III trial studies ibrutinib and rituximab to see how well they work compared to fludarabine phosphate, cyclophosphamide, and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, 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. Monoclonal antibodies, such as rituximab, interfere with the ability of cancer cells to grow and spread. It is not yet known whether fludarabine phosphate, cyclophosphamide, and rituximab may work better than ibrutinib and rituximab in treating patients with untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Related Conditions:

Chronic Lymphocytic Leukemia

Recruiting Status:

Active, not recruiting

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT02048813

Trial Eligibility

Document

Title

Brief Title: Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Official Title: A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy vs Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients With Chronic Lymphocytic Leukemia (CLL)

Clinical Trial IDs

ORG STUDY ID: NCI-2014-00118
SECONDARY ID: NCI-2014-00118
SECONDARY ID: E1912
SECONDARY ID: ECOG-E1912
SECONDARY ID: E1912
SECONDARY ID: E1912
SECONDARY ID: R01CA193541
SECONDARY ID: U10CA180820
SECONDARY ID: U10CA021115
SECONDARY ID: U24CA196172
NCT ID: NCT02048813

Conditions

Anemia
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma

Interventions

Drug	Synonyms	Arms
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- 138719	Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
Fludarabine Phosphate	2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586	Arm B (rituximab, fludarabine phosphate, cyclophosphamide)
Ibrutinib	BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765	Arm A (ibrutinib, rituximab)
Rituximab	ABP 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 SIBP-02, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, Truxima	Arm A (ibrutinib, rituximab)

Purpose

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the ability of Ibrutinib-based induction therapy to prolong progression free
      survival (PFS) compared to standard fludarabine phosphate, cyclophosphamide, and rituximab
      (FCR) chemoimmunotherapy for younger patients with chronic lymphocytic leukemia (CLL).

      SECONDARY OBJECTIVES:

      I. Evaluate overall survival (OS) of patients based on treatment arm. II. Monitor and assess
      toxicity of treatment with Ibrutinib-based induction relative to standard FCR chemotherapy.

      III. To compare quality of life (QOL) in CLL patients during the first 6 months of treatment
      among patients receiving Ibrutinib-based induction therapy relative to standard FCR
      chemoimmunotherapy.

      IV. To compare QOL over the long-term in CLL patients receiving continuous therapy using
      Ibrutinib to that of CLL patients who completed FCR therapy.

      V. Determine the effect of pretreatment clinical and biological characteristics (e.g. disease
      stage, immunoglobulin heavy chain variable region gene [IGHV] mutation status, fluorescent in
      situ hybridization [FISH]) on clinical outcomes (e.g. complete response, PFS) of the
      different arms.

      VI. Determine if the minimal residual disease (MRD) status as assessed by flow cytometry at
      different time points during and after treatment is an effective surrogate marker for
      prolonged PFS and overall survival.

      VII. Compare the genetic abnormalities and dynamics of intra-clonal architecture of CLL
      patients before and after treatment with chemoimmunotherapy (CIT) and non-CIT approaches and
      explore relationships with treatment resistance.

      VIII. Explore the effects of FCR and Ibrutinib-based therapy on T-cell immune function.

      IX. Conduct confirmatory validation genotyping of single nucleotide polymorphisms (SNPs)
      associated with the efficacy and toxicity of fludarabine-based therapy as in a prior Eastern
      Cooperative Oncology Group (ECOG) genome-wide association study (GWAS) analysis in the E2997
      trial.

      X. Evaluate the ability of prognostic model that incorporates clinical and biologic
      characters to predict a response to therapy and clinical outcome (PFS, OS).

      XI. Evaluate signaling networks downstream of the B-cell receptor in patients receiving
      Ibrutinib-based therapy.

      XII. Collect relapse samples to study mechanisms of resistance to both FCR and
      Ibrutinib-based therapy.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM A: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Beginning course
      2, patients also receive rituximab intravenously (IV) over 4 hours on day 1 (days 1 and 2 of
      course 2 only). Treatment repeats every 28 days for 7 courses. In the absence of disease
      progression, patients may continue ibrutinib PO QD.

      ARM B: Patients receive rituximab as seen in Arm A and fludarabine phosphate IV over 30
      minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days
      for 6 courses.

      After completion of study treatment, patients are followed up for 10 years.

Trial Arms

Name	Type	Description	Interventions
Arm A (ibrutinib, rituximab)	Experimental	Patients receive ibrutinib PO QD on days 1-28. Beginning course 2, patients also receive rituximab IV over 4 hours on day 1 (days 1 and 2 of course 2 only). Treatment repeats every 28 days for 7 courses. In the absence of disease progression, patients may continue ibrutinib PO QD.	Ibrutinib Rituximab
Arm B (rituximab, fludarabine phosphate, cyclophosphamide)	Experimental	Patients receive rituximab as seen in Arm A and fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 courses.	Cyclophosphamide Fludarabine Phosphate Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of CLL according to the National Cancer Institute (NCI)/Internal Workshop on
             Chronic Lymphocytic Leukemia (IWCLL) criteria or small lymphocytic lymphoma (SLL)
             according to the World Health Organization (WHO) criteria; this includes previous
             documentation of:

               -  Biopsy-proven small lymphocytic lymphoma or

               -  Diagnosis of CLL according to the NCI/IWCLL criteria as evidenced by all of the
                  following:

                    -  Peripheral blood lymphocyte count of greater than 5 x 10^9/L

                    -  Immunophenotype consistent with CLL defined as:

                         -  The predominant population of lymphocytes share both B-cell antigens
                            (cluster of differentiation [CD]19, CD20 [typically dim expression], or
                            CD23) as well as CD5 in the absence of other pan-T-cell markers (CD3,
                            CD2, etc)

                         -  Clonality as evidenced by kappa or lambda light chain restriction
                            (typically dim immunoglobulin expression)

               -  Negative FISH analysis for t(11;14)(immunoglobulin heavy locus [IgH]/cyclin D1
                  [CCND1]) on peripheral blood or tissue biopsy (e.g. marrow aspirate) or negative
                  immunohistochemical stains for cyclin D1 staining on involved tissue biopsy (e.g.
                  marrow aspirate or lymph node biopsy)

          -  No prior chemotherapy, Bruton's tyrosine kinase (BTK) inhibitor therapy, or monoclonal
             anti-body therapy for treatment of CLL or SLL

          -  Has met at least one of the following indications for treatment:

               -  Evidence of progressive marrow failure as manifested by the development of
                  worsening anemia (hemoglobin [Hg] < 11 g/dl) and/or thrombocytopenia (platelets <
                  100 x 10^9/L)

               -  Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly

               -  One or more of the following disease-related symptoms:

                    -  Weight loss >= 10% within the previous 6 months

                    -  Grade 2 or 3 fatigue attributed to CLL

                    -  Fevers > 100.5 Fahrenheit (F) for 2 weeks without evidence of infection

                    -  Clinically significant night sweats without evidence of infection

               -  Progressive lymphocytosis (not due to the effects of corticosteroids) with an
                  increase of > 50% over a two-month period or an anticipated doubling time of less
                  than six months

          -  ECOG performance status between 0-2

          -  Life expectancy of >= 12 months

          -  Ability to tolerate FCR based therapy

          -  No deletion of 17p13 on cytogenetic analysis by FISH

          -  Glomerular filtration rate (GFR) > 40 mL/minute as calculated by the Cockcroft-Gault
             formula

          -  Total bilirubin =< 2.5 x upper limit of normal (ULN) unless due to Gilbert's disease;
             for those with a total bilirubin > 2.5 x ULN, a direct bilirubin should be performed
             and must be < 1.5 mg/dL for Gilbert's to be diagnosed; if value is higher due to
             hepatic involvement by CLL, patient is eligible

          -  Serum glutamic oxaloacetic transaminase (SGOT) aspartate transaminase (AST)/serum
             glutamate-pyruvate transaminase (SGPT) alanine transaminase (ALT) =< 3.0 x the
             institutional ULN; if value is higher due to hepatic involvement by CLL, patient is
             eligible

          -  Prothrombin time (PT)/international normalized ratio (INR) < 1.5 ULN and partial
             thromboplastin time (PTT) activated partial thromboplastin time (aPTT) < 1.5 X ULN; if
             value is higher due to hepatic involvement by CLL, patient is eligible

          -  No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic
             treatment; patients who have a positive Coombs test but no evidence of hemolysis are
             NOT excluded from participation

          -  No current use of corticosteroids; EXCEPTION: low doses of steroids (< 10 mg of
             prednisone or equivalent dose of other steroid) used for treatment of non-hematologic
             medical condition (e.g. chronic adrenal insufficiency) is permitted

          -  No previous use of corticosteroids for autoimmune complications that have developed
             since the initial diagnosis of CLL; prior use of corticosteroids for reasons other
             than treatment of autoimmune complications is allowed

          -  No other active primary malignancy (other than non-melanomatous skin cancer or
             carcinoma in situ of the cervix) requiring treatment or limiting expected survival to
             =< 2 years; NOTE: if there is a history of prior malignancy, they must not be
             receiving other specific treatment (other than hormonal therapy for their cancer)

          -  Able to adhere to the study visit schedule and other protocol requirements

          -  No major surgery within the last 4 weeks (28 days) of first dose of study drug or
             minor surgery within 3 days of first dose of study drug

          -  No radiation therapy =< 4 weeks prior to registration

          -  Patients with human immunodeficiency virus (HIV) infection may be eligible provided
             they meet the following criteria:

               -  CD4-positive cell count >= lower limit of institutional normal

               -  HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL (if not on anti-HIV
                  therapy) OR < 50 copies HIV RNA/mL (if on anti-HIV therapy)

               -  No evidence of hepatitis B or C infection

               -  No evidence of resistant strains of HIV

               -  No history of acquired immune deficiency syndrome (AIDS)-defining condition

          -  Patients must not have any of the following conditions:

               -  Congestive heart failure or New York Heart Association Functional Classification
                  III or IV congestive heart failure

               -  History of myocardial infarction, unstable angina, or acute coronary syndrome
                  within 6 months prior to registration

               -  Recent infections requiring systemic treatment; need to have completed
                  anti-biotic therapy > 14 days before the first dose of study drug

               -  Cerebral vascular accident or intracranial bleed within the last 6 months

               -  Infection with known chronic, active hepatitis C

               -  Serologic status reflecting active hepatitis B or C infection; patients that are
                  positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or
                  hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior
                  to enrollment (PCR positive patients will be excluded)

          -  Patients are not eligible if they require treatment with a strong cytochrome P450
             (CYP) family 3, subfamily A (3A) inhibitor

          -  Patients may not be on any other investigational agents

          -  Patients may not have received warfarin or another vitamin K antagonist in the
             preceding 30 days

          -  Women must not be pregnant or breast-feeding; female patients of childbearing
             potential must have a negative serum pregnancy test within 2 weeks prior to
             registration to rule out pregnancy; female patients who are of non-reproductive
             potential are those who are post-menopausal by history (i.e. no menses for >= 1 year);
             OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of
             bilateral oophorectomy

          -  Women of childbearing potential and sexually active males must be strongly advised to
             use an accepted and effective method of contraception or to abstain from sexual
             intercourse for 90 days after the last dose of study drug

          -  Patient must be able to swallow capsules and not have the following conditions:

               -  Disease significantly affecting gastrointestinal function

               -  Resection of the stomach or small bowel

               -  Symptomatic inflammatory bowel disease

               -  Ulcerative colitis

               -  Partial or complete bowel obstruction

          -  Patient must not be on any other systemic immunosuppressant therapy other than
             corticosteroids within 28 days of the first dose of study drug

          -  Patient must not be vaccinated with live, attenuated vaccines within 4 weeks of first
             dose of study drug

          -  Patient must not have any known bleeding disorders (e.g., von Willebrand's disease) or
             hemophilia

          -  Patient must not have currently active, clinically significant hepatic impairment (>=
             moderate hepatic impairment according to the NCI/Child Pugh)

Maximum Eligible Age:	70 Years
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Progression free survival (PFS)
Time Frame:	The time from randomization to progression or to death without documentation of progression, assessed up to 10 years
Safety Issue:
Description:	A stratified logrank test applied to all patients as randomized will be the primary analysis, with age, Eastern Cooperative Oncology Group (ECOG) performance status, disease stage, and baseline cytogenetic abnormalities as stratification factors. The same analysis applied to eligible patients only will also be performed as a sensitivity analysis. Cox proportional hazards models will be used to assess possible effects of clinical and biological characteristics on outcome, including age, gender, disease stage, cytogenetic abnormalities, ECOG performance status, and important mutations.

Secondary Outcome Measures

Measure:	Overall survival (OS)
Time Frame:	Time from randomization until death due to any cause, assessed up to 10 years
Safety Issue:
Description:	A stratified logrank test applied to all patients as randomized will be the primary analysis for OS, with age, ECOG performance status, disease stage, and baseline cytogenetic abnormalities as stratification factors. The same analysis applied to eligible patients only will also be performed as a sensitivity analysis. Cox proportional hazards models will be used to assess possible effects of clinical and biological characteristics on outcome, including age, gender, disease stage, cytogenetic abnormalities, ECOG performance status, and important mutations.

Measure:	Incidence of toxicity, defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment, graded according to the National Cancer Institute (NCI) Common Terminology for Adverse Events version 4.0
Time Frame:	Up to 10 years
Safety Issue:
Description:	The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, all adverse event data that is graded as 3, 4, or 5 will be reviewed and classified as either "unrelated or unlikely to be related" to study treatment in the event of an actual relationship developing. Effective April 1, 2018 adverse event reporting will use Common Terminology for Adverse Events (CTCAE) version 5.0.

Measure:	Change in FACT-Leu TOI score
Time Frame:	Baseline to 3 months after beginning therapy
Safety Issue:
Description:	The change in FACT-Leu TOI score will be compared between arm A and arm B to assess the short-term effect of the two therapies on quality of life (QOL).

Measure:	Change in FACT-Leu TOI score
Time Frame:	Baseline to 6 months after beginning therapy
Safety Issue:
Description:	The change in FACT-Leu TOI score from the time of randomization to 6 months after beginning therapy will be compared between the two treatment arms in order to provide additional information regarding the toxicity of the different regimens.

Measure:	Impact of chronic lymphocytic leukemia (CLL) on QOL
Time Frame:	Baseline
Safety Issue:
Description:	The social well-being and emotional well-being components of the FACT-General (G) will be administered at study entry. The entire FACT-Leukemia instrument (FACT-G and the leukemia subscale) at baseline will be analyzed using descriptive statistics to assess the impact of CLL on QOL independent of treatment.

Measure:	Adherence to prescription assessed by the Moriskey Adherence Scale (Arm A only)
Time Frame:	Up to 24 months
Safety Issue:
Description:	Descriptive statistics will be used to summarize trend in adherence to prescription.

Details

Phase:	Phase 3
Primary Purpose:	Interventional
Overall Status:	Active, not recruiting
Lead Sponsor:	National Cancer Institute (NCI)

Last Updated

August 5, 2021

Clinical Trials /

Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma