Clinical Trials /

Trial of Duvelisib in Combination With Either Romidepsin or Bortezomib in Relapsed/Refractory T-cell Lymphomas

NCT02783625

Description:

The purpose of this study is to test the safety of a study drug called duvelisib.

Related Conditions:
  • T-Cell Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Trial of Duvelisib in Combination With Either Romidepsin or Bortezomib in Relapsed/Refractory T-cell Lymphomas
  • Official Title: A Phase I Trial of Duvelisib in Combination With Either Romidepsin or Bortezomib in Relapsed/Refractory T-cell Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: 16-042
  • NCT ID: NCT02783625

Conditions

  • Lymphoma
  • Relapsed/Refractory T-cell Lymphomas

Interventions

DrugSynonymsArms
RomidepsinRomidepsin + duvelisib
BortezomibBortezomib + duvelisib
duvelisibIPI-145Romidepsin + duvelisib

Purpose

The purpose of this study is to test the safety of a study drug called duvelisib.

Detailed Description

      The phase I portion of the study is designed to determine the MTD of duvelisib with
      romidepsin and duvelisib with bortezomib. All patients must have a relapsed or refractory
      T-cell lymphoma. The design is a standard 3+3 dose escalation of two parallel phase I
      studies. Patients will be enrolled in Arms A (Romidepsin + duvelisib) and B (Bortezomib +
      duvelisib) of the study starting at dose level 1.

      Three to six patients will be initially treated in each dose level until the MTD is
      determined. If dose level 3 is achieved without exceeding one dose limiting toxicity (DLT)
      after 1 cycle that dose level will be deemed the "optimal dose" and the study will proceed
      to the cohort expansion phase. Should patients be found to develop significant toxicity or
      not tolerate therapy at the MTD with repeated cycles of therapy, the "optimal dose" may be
      determined to be at dose levels less than the MTD. Patients with measurable disease treated
      in the phase I at the optimal dose will be counted towards the accrual of the expansion
      cohorts by disease subtype and all efficacy and toxicity endpoints.

      Cohort Expansion Phase: The expansion cohorts will further assess toxicity and safety and
      allow a preliminary assessment of the efficacy of the combination to provide background for
      a potential future subtype specific phase II study. The assessment of efficacy will be
      descriptive.
    

Trial Arms

NameTypeDescriptionInterventions
Romidepsin + duvelisibExperimentalRomidepsin/duvelisib: Cycle 1 and beyond Days 1, 8, 15* Romidepsin IVPB over 4 hours, days 1, 8, 15 duvelisib by mouth twice daily, days 1-28
  • Romidepsin
  • duvelisib
Bortezomib + duvelisibExperimentalBortezomib/duvelisib: Cycle 1 and beyond Days 1, 4, 8, and 11* Bortezomib subcutaneous injection, days 1, 4, 8, 11** duvelisib by mouth twice daily, days 1-28
  • Bortezomib
  • duvelisib

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed T-cell lymphomas at the enrolling institution, including
             stage ≥ Ib CTCL, which has relapsed or progressed after at least one systemic
             therapy.

          -  Age ≥ 18

          -  Previous systemic anti-cancer therapy must have been discontinued at least 3 weeks
             prior to treatment. For the cohort expansion phase, in progressing subjects, a 2 week
             washout may be allowed after discussion with the MSK Principal Investigator.

          -  Previous radiation and/or surgery must have been discontinued or completed at least 2
             weeks prior to treatment in this study and adverse effects must have resolved to
             Grade 1 or baseline. Lymph node or other diagnostic biopsies within 2 weeks are not
             considered exclusionary.

          -  ECOG ≤ 2

          -  Meet the following laboratory criteria without use of growth factor support or
             platelet transfusions for 1 week:

             i) Absolute neutrophil count ≥ 1.0 K/mcl, ii) Platelet count ≥ 80 K/μl (in the
             expansion cohorts, if thrombocytopenia is due to bone marrow involvement platelet
             count must be ≥ 50 K/μL), iii) Phase 1 patients who are not enrolled on the expansion
             cohorts must have calculated creatinine clearance ≥ 50ml/min by Cockcroft-Gault
             formula. Expansion cohort subjects must have calculated creatinine clearance ≥
             40ml/min by Cockcroft-Gault formula.

        iv) Total bilirubin ≤ 1.5 x upper limit of normal (ULN);AST (SGOT) and ALT (SGPT) ≤ 3 x
        ULN

          -  Measurable disease for expansion cohorts and lead in phases only. i) Lymphoma
             (includes CTCL patients who are without evidence of the disease in the skin): CT or
             PET/CT by modified Cheson criteria with incorporation of PET.

        ii) CTCL: mSWAT >0, or absolute Sezary count ≥ 1000 cells/μL.

          -  Short course systemic corticosteroids for disease control, improvement of performance
             status or non-cancer indication (< 7 days) must have been discontinued at least 6
             days prior to study treatment. Stable ongoing corticosteroid use (≥ 30 days) up to an
             equivalent dose of 20 mg of prednisone is permissible.

             i) Topical steroids that have been used for > 3 weeks may be continued (CTCL only).

          -  Women of reproductive potential† must have a negative serum or urine β human
             chorionic gonadotropin (βhCG) pregnancy test. All women of reproductive potential,
             all sexually active male patients, and all partners of patients must agree to use
             adequate methods of birth control (e.g. latex condoms) throughout the study and for
             30 days after the last dose of study drug.

               -  A female of reproductive potential is a sexually mature female who: has not
                  undergone a hysterectomy or bilateral oophorectomy; or has not been naturally
                  postmenopausal for at least 24 consecutive months (i.e. has had menses at any
                  time in the preceding 24 consecutive months).

        Exclusion Criteria:

          -  Any serious medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from signing the informed consent form.

          -  Pregnant females. (Lactating females must agree not to breast feed while taking the
             study medications).

          -  Prior use of duvelisib if discontinued due to toxicity.

          -  For the romidepsin arm of the study, prior therapy with romidepsin if discontinued
             due to toxicity.

          -  For the bortezomib arm of the study, prior therapy with a proteasome inhibitor if
             discontinued due to toxicity.

          -  For the bortezomib arm of the study, patients with grade ≥2 peripheral neuropathy.

          -  Concurrent use of other anti-cancer agents or treatments. History of chronic liver
             disease, veno-occlusive disease, or current alcohol abuse.

          -  Administration of a live vaccine within 6 weeks of first dose of study drug.

          -  Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g.,
             gastric bypass surgery, gastrectomy)

          -  Known seropositive and requiring anti-viral therapy for human immunodeficiency virus
             (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects with chronic
             hepatitis B or C as defined as test .

          -  Subjects with positive Hep B serology. Subjects with a negative HBsAg and a positive
             HBcAb require an undetectable/negative hepatitis B DNA test (e.g., polymerase chain
             reaction [PCR] test) to be enrolled, and will require prophylactic antiviral
             treatment (e.g., F) initiated prior to the first dose of study drug, an continued
             until approximately 6 to 12 months after completion of study drug(s).

          -  Patients with positive hepatitis C virus Ab

          -  Subjects with active EBV unrelated to underlying lymphoma (positive serology for
             anti-EBV VCA IgM antibody and negative for anti-EBV EBNA IgG antibody, or clinical
             manifestations and positive EBV PCR consistent with active EBV infection.

          -  Subject with active CMV (positive serology for anti-CMV IgM antibody and negative for
             anti-CMV IgG antibody and positive CMV PCR with clinical manifestations consistent
             with active CMV infection) and requiring therapy will be excluded from participation
             in the study. Carriers will be monitored per institutional guidelines.

          -  Concurrent malignancy requiring active therapy.

          -  Patients with more than one type of lymphoma may be enrolled after discussion with
             the MSK Principal Investigator.

          -  Known central nervous system or meningeal involvement (in the absence of symptoms,
             investigation into central nervous system involvement is not required).

          -  The following known cardiac abnormalities:

               1. Congenital long QT syndrome.

               2. QTc/QTf interval ≥ 480 milliseconds; unless secondary to pacemaker or bundle
                  branch block.

               3. Myocardial infarction within 6 months. (Subjects with a history of myocardial
                  infarction within the last 6 to12 months who are asymptomatic and have had a
                  negative cardiac risk assessment (treadmill stress test, nuclear medicine stress
                  test, or stress echocardiogram) since the event may participate.)

               4. Other significant ECG abnormalities including 2nd degree atrio- ventricular (AV)
                  block (AV) block type II, 3rd degree AV block.

               5. Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV
                  (see Appendix B). In any patient in whom there is doubt, the patient should have
                  a stress imaging study and, if abnormal, angiography to define whether or not
                  CAD is present.

                  II-IV (see Appendix B). In any patient in whom there is doubt, the patient
                  should have a stress imaging study and, if abnormal, angiography to define
                  whether or not CAD is present.

               6. An ECG recorded at screening showing evidence of cardiac ischemia (ST depression
                  of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt,
                  the patient should have a stress imaging study and, if abnormal, angiography to
                  define whether or not CAD is present.

               7. Congestive heart failure (CHF) that meets New York Heart Association (NYHA)
                  Class II to IV definitions (see Appendix C) and/or ejection fraction <45% by
                  MUGA, echocardiogram, or cardiac MRI.

               8. A known history of sustained ventricular tachycardia (VT), ventricular
                  fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently
                  addressed with an automatic implantable cardioverter defibrillator (AICD).

               9. Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or
                  other causes.

              10. Uncontrolled hypertension, i.e., blood pressure (BP) of ≥170/95; patients who
                  have a history of hypertension controlled by medication must be on a stable dose
                  (for at least one month prior to study registration) and meet all other
                  inclusion criteria.

              11. Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
                  doses of beta-blockers)

              12. For patients enrolling on the Romidepsin arm; taking drugs associated with
                  significant QTc/QTf prolongation, unless able to be switched to non-QTc/QTf
                  prolonging medication or on a stable dose without significant QT prolongation
                  (>470 msec). Caution should be used when administering study drugs to patients
                  taking medications significantly metabolized by these enzymes refer to
                  (http://medicine.iupui.edu/clinpharm/ddis/clinical-table/) for clinically
                  relevant medications. Particular attention should be paid to patients receiving
                  warfarin. Patient should have coagulation parameters monitored regularly, and
                  warfarin dose adjusted accordingly. If these drugs cannot be discontinued or
                  replaced enrollment may be allowed after discussion with MSK PI.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:maximum tolerated dose (MTD)
Time Frame:1 year
Safety Issue:
Description:There will be two parallel phase I studies using the 3+3 dose escalation scheme

Secondary Outcome Measures

Measure:overall response rate (ORR)
Time Frame:6 months
Safety Issue:
Description:Response and progression of disease will be evaluated in this study using a modification of the international criteria proposed by the modified Cheson criteria with incorporation of PET/CT.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • Duvelisib
  • Romidepsin
  • Bortezomib
  • 16-042

Last Updated

March 2, 2017