Combination Therapy With Carfilzomib, Romidepsin, Lenalidomide in Patients With Relapsed or Refractory B- and T-cell Lymphomas

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Brief Title

Combination Therapy With Carfilzomib, Romidepsin, Lenalidomide in Patients With Relapsed or Refractory B- and T-cell Lymphomas

Official Title

Phase Ib/IIa Study of Combination Therapy With Carfilzomib, Romidepsin, Lenalidomide in Patients With Relapsed or Refractory B- and T-cell Lymphomas

Brief Summary

      This is an open label phase Ib/IIa study of patients with relapsed/refractory B- and T-cell
      lymphomas who are treated with carfilzomib, lenalidomide and romidepsin in a 3+3 design. The
      phase IIa portion of the study will involve a dose expansion at the MTD to better
      characterize the efficacy and to inform further disease specific studies.
    


Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

MTD (phase Ib)

Secondary Outcome

 overall response rate (orr)

Condition

T-cell Lymphomas

Intervention

Carfilzomib

Study Arms / Comparison Groups

 Carfilzomib, Romidepsin, Lenalidomide
Description:  All patients will be treated with romidepsin administered intravenously on days 1 and 8 of a 21-day cycle. Lenalidomide will be taken orally daily for days 1-14 of a 21-day cycle. The carfilzomib will be given weekly on days 1, and 8 of a 21-day cycle. Once a MTD is determined this dosing level will be used for the phase IIa portion. Cycles will be continued as above until the patient's wishes to be removed from the study, unacceptable toxicity develops, disease progression, treating physician recommends removal, or termination of study occurs.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

31

Start Date

January 2015

Completion Date

January 2022

Primary Completion Date

January 2022

Eligibility Criteria

        Inclusion Criteria:

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

          -  Hodgkin lymphoma is allowed and will be classified as a B-cell lymphoma in the phase
             IIA portion.

          -  Age ≥ 18,

          -  Previous systemic anti-cancer therapy must have been discontinued at least 3 weeks
             prior to treatment and adverse effects must have resolved to ≤Grade 1 or baseline. In
             the phase IIa portion, in progressing subjects, a 2 week washout may be allowed after
             discussion with the MSK Principal Investigator.

          -  Previous radiation, hormonal therapy, 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. Lymph node or other diagnostic biopsies within 2 weeks are not
             considered exclusionary.

          -  ECOG ≤ 2

          -  Meet the following laboratory criteria:

          -  Absolute neutrophil count 1.0/mm³,

          -  Platelet count 80 K/μ (in the Phase II portion, if thrombocytopenia is due to bone
             marrow involvement platelet count must be 50 K/μL),

          -  Phase Ib subjects must have calculated creatinine clearance 50ml/min by
             Cockcroft-Gault formula, phase IIa subjects must have calculated creatinine clearance
             ≥ 40ml4/min by Cockcroft-Gault formula.

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

          -  Measurable disease for phase IIa portion only.

          -  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.

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

          -  All study participants must be registered into the mandatory Revlimid REMS ® program,
             and be willing and able to comply with the requirements of the REMS ® program.

          -  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 15 mg of prednisone is permissible.

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

          -  Women of reproductive potential must adhere to the scheduled pregnancy testing as
             required in the Revlimid REMS® program. Men must agree to use a latex condom during
             sexual contact with a FCBP even if they have had a successful vasectomy. See Appendix
             A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control
             Methods.

          -  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:

          -  Patients who have a standard curative option for their lymphoid malignancy at current
             state of disease are excluded. For eligibility on this trial, allogeneic stem cell
             transplantation is not to be considered a standard curative option.

          -  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
             carfilzomib, lenalidomide or romidepsin).

          -  Known hypersensitivity to thalidomide.

          -  The development of erythema multiforme if characterized by a desquamating rash while
             taking thalidomide or similar drugs.

          -  Prior use of lenalidomide if discontinued due to toxicity.

          -  Prior therapy with romidepsin if discontinued due to toxicity.

          -  Prior therapy with carfilzomib if discontinued due to toxicity.

          -  Prior therapy with a proteasome inhibitor if discontinued due to toxicity.

          -  Concurrent use of other anti-cancer agents or treatments.

          -  Known seropositive and requiring anti-viral therapy for human immunodeficiency virus
             (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).

          -  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:

          -  Congenital long QT syndrome.

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

          -  Myocardial infarction within 6 months of cycle one, day one (C1D1). Subjects with a
             history of myocardial infarction between 6 and 12 months prior to C1D1 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.

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

          -  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.

          -  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.

          -  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, echocardiogram,
             or cardiac MRI.

          -  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).

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

          -  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) and meet all other inclusion criteria.

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

          -  Patients taking drugs that can cause 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).

          -  Concomitant use of significant CYP3A4 inhibitors unless able to be switched to a
             non-CYP3A4 inhibiting medication.

          -  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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Steven Horwitz, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02341014

Organization ID

14-179


Responsible Party

Sponsor

Study Sponsor

Memorial Sloan Kettering Cancer Center

Collaborators

 University of Nebraska

Study Sponsor

Steven Horwitz, MD, Principal Investigator, Memorial Sloan Kettering Cancer Center


Verification Date

February 2020