Clinical Trials /

Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma

NCT01896999

Description:

This phase I/II trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin, and how well they work in treating patients with Hodgkin lymphoma that has returned after a period of improvement or has not responded to previous treatment. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Brentuximab vedotin is a combining monoclonal antibody with an anticancer drug that binds to a protein on the surface of lymphoma cells called cluster of differentiation (CD)30 and may kill the cells. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab may kill more cancer cells.

Related Conditions:
  • Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma
  • Official Title: A Phase I Study With an Expansion Cohort/Randomized Phase II Study of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin in Patients With Relapsed/Refractory Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2013-01275
  • SECONDARY ID: NCI-2013-01275
  • SECONDARY ID: E4412
  • SECONDARY ID: S14-00011
  • SECONDARY ID: E4412
  • SECONDARY ID: E4412
  • SECONDARY ID: U10CA180820
  • SECONDARY ID: U24CA196172
  • NCT ID: NCT01896999

Conditions

  • Recurrent Classic Hodgkin Lymphoma
  • Refractory Classic Hodgkin Lymphoma

Interventions

DrugSynonymsArms
Brentuximab VedotinADC SGN-35, Adcetris, Anti-CD30 Antibody-Drug Conjugate SGN-35, Anti-CD30 Monoclonal Antibody-MMAE SGN-35, Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35, cAC10-vcMMAE, SGN-35Phase I Arm I (brentuximab vedotin, ipilimumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyPhase I Arm I (brentuximab vedotin, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoPhase I Arm II (brentuximab vedotin, nivolumab)

Purpose

This phase I/II trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin, and how well they work in treating patients with Hodgkin lymphoma that has returned after a period of improvement or has not responded to previous treatment. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Brentuximab vedotin is a combining monoclonal antibody with an anticancer drug that binds to a protein on the surface of lymphoma cells called cluster of differentiation (CD)30 and may kill the cells. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the
      combinations of brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and
      brentuximab vedotin, ipilimumab, and nivolumab. (Phase I) II. To evaluate the complete
      response (CR) rate for the regimens of brentuximab vedotin and nivolumab compared to
      brentuximab vedotin, ipilimumab, and nivolumab. (Phase II)

      SECONDARY OBJECTIVES:

      I. To evaluate complete response (CR) rate, partial response (PR) rate and overall response
      rate (ORR), for the combinations of brentuximab vedotin and ipilimumab, brentuximab vedotin
      and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab. (Phase I) II. To evaluate
      the duration of remission (DOR) to these combinations and compare with the DOR achieved with
      the most recent prior systemic therapy. (Phase I) III. To evaluate the progression-free
      survival (PFS) and the overall survival (OS) in patients receiving the combination of
      brentuximab vedotin and ipilimumab, brentuximab vedotin and nivolumab, and brentuximab
      vedotin, ipilimumab, and nivolumab. (Phase I) IV. To evaluate the ORR, PR, and stable disease
      (SD) rate for the combinations of brentuximab vedotin and nivolumab and brentuximab vedotin,
      ipilimumab, and nivolumab. (Phase II) V. To evaluate the DOR to these combinations and
      compare with the DOR achieved with the most recent prior systemic therapy. (Phase II) VI. To
      evaluate the 5 year PFS and OS in patients receiving the combinations of brentuximab vedotin
      and nivolumab and brentuximab vedotin, ipilimumab, and nivolumab. (Phase II) VII. To further
      evaluate the safety and characterize the toxicity for the combinations of brentuximab vedotin
      and nivolumab, and brentuximab vedotin, ipilimumab, and nivolumab. (Phase II)

      CORRELATIVE STUDY OBJECTIVES:

      I. To evaluate the ability of these combinations to alter tumor specific T cell immunity.
      (Phase I) II. To evaluate the effects of these combinations on systemic immunity. (Phase I)
      III. To evaluate a panel of cytokine and T cell specific biomarkers from the peripheral blood
      as a potential immune signature of treatment response to therapy with these combinations for
      patients with relapsed/refractory Hodgkin lymphoma (HL). (Phase I) IV. To evaluate using gene
      expression profiling (GEP) a signature of response to these novel combinations of an antibody
      drug conjugate with immunomodulatory therapy. (Phase I) V. To evaluate the ability of these
      combinations to alter tumor specific T cell immunity, and circulating T cell phenotypes, in
      patients as a function of treatment response at multiple timepoints during therapy. (Phase
      II) VI. To evaluate peripheral blood cytokine profiles in responding and resistant patients
      at multiple timepoints during therapy. (Phase II) VII. To evaluate using GEP a signature of
      response versus (vs.) resistance to these novel combinations of an antibody drug conjugate
      with immunomodulatory therapy. (Phase II) VIII. To evaluate the influence of human gut
      microbiome dysbiosis on HL lymphomagenesis and the systemic immune response. (Phase II)

      IMAGING CORRELATIVE STUDY OBJECTIVES:

      I. To evaluate atypical response patterns with currently available response evaluation
      criteria. (Phase II) II. To correlate response evaluated using currently available response
      evaluation criteria with duration of response (PFS, event free survival [EFS], failure free
      survival [FFS]). (Phase II) III. To evaluate response patterns in different immunotherapy
      treatment schemes and correlate with historical data using chemotherapy. (Phase II) IV. To
      correlate imaging changes in all treatment schemes quantitatively with PFS. (Phase II)

      OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin, ipilimumab, and
      nivolumab followed by a phase II study.

      PHASE I: Patients are assigned into 1 of 3 arms.

      ARM I: Patients receive brentuximab vedotin intravenously (IV) over 90 minutes on day 1 and
      ipilimumab IV over 30 minutes on day 1 of cycles 1-4, 8, 12, and 16. Treatment repeats every
      21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and
      nivolumab IV over 30 minutes on day 1 of cycles 1-46. Treatment repeats every 21 days for up
      to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of
      disease progression or unacceptable toxicity.

      ARM III: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16,
      nivolumab IV over 30 minutes on day 1 of cycles 1-46, and ipilimumab IV over 30 minutes on
      day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 16 cycles
      and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease
      progression or unacceptable toxicity.

      PHASE II: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and
      nivolumab IV over 30 minutes on day 1 of cycles 1-34. Treatment repeats every 21 days for up
      to 34 cycles in the absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16,
      nivolumab IV over 30 minutes on day 1 of cycles 1-34, and ipilimumab IV over 30 minutes on
      day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 34 cycles
      in the absence of disease progression or unacceptable toxicity.

      After completion of phase I study treatment, patients are followed up every 3 months for 1
      year, then every 6 months for 2 years. After completion of phase II study treatment, patients
      are followed up for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I Arm I (brentuximab vedotin, ipilimumab)ExperimentalPatients receive brentuximab vedotin IV over 90 minutes on day 1 and ipilimumab IV over 30 minutes on day 1 of cycles 1-4, 8, 12, and 16. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.
  • Brentuximab Vedotin
  • Ipilimumab
Phase I Arm II (brentuximab vedotin, nivolumab)ExperimentalPatients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and nivolumab IV over 30 minutes on day 1 of cycles 1-46. Treatment repeats every 21 days for up to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease progression or unacceptable toxicity.
  • Brentuximab Vedotin
  • Nivolumab
Phase I Arm III (brentuximab vedotin, nivolumab, ipilimumab)ExperimentalPatients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16, nivolumab IV over 30 minutes on day 1 of cycles 1-46, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 16 cycles and every 14 days beginning cycle 17 for up to 46 cycles in the absence of disease progression or unacceptable toxicity.
  • Brentuximab Vedotin
  • Ipilimumab
  • Nivolumab
Phase II Arm I (brentuximab vedotin, nivolumab)ExperimentalPatients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16 and nivolumab IV over 30 minutes on day 1 of cycles 1-34. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or unacceptable toxicity.
  • Brentuximab Vedotin
  • Nivolumab
Phase II Arm II (brentuximab vedotin, nivolumab, ipilimumab)ExperimentalPatients receive brentuximab vedotin IV over 90 minutes on day 1 of cycles 1-16, nivolumab IV over 30 minutes on day 1 of cycles 1-34, and ipilimumab IV over 30 minutes on day 1 every 12 weeks for up to 9 doses. Treatment repeats every 21 days for up to 34 cycles in the absence of disease progression or unacceptable toxicity.
  • Brentuximab Vedotin
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  PHASE I (ARMS A, B, C, D, E, F, G, H, I, X, Y, Z)

          -  Patients must have pathologically confirmed relapsed or refractory classical Hodgkin
             lymphoma (cHL); a biopsy at any relapse is acceptable; other histologies including
             lymphocyte predominant (LP) HL are not permitted

          -  Patients must have relapsed after first line chemotherapy; may have relapsed after
             autologous or allogeneic stem cell transplant, or have primary refractory disease; no
             upper limit for number of prior therapies; if status post allogeneic stem cell
             transplant, no active graft versus host disease

          -  Patients may have received prior brentuximab vedotin, but must not have received
             brentuximab vedotin within 6 months prior to registration, and must not have relapsed
             within 6 months of receiving previous brentuximab vedotin; patients may not have
             received prior nivolumab or PD1/PDL1 axis agents; patients in the
             nivolumab/brentuximab cohorts ONLY (D, E, F, Y) may have received prior ipilimumab

          -  Patients may have received other prior activating immunotherapies (i.e. checkpoint
             inhibitors), but must not have received them within 6 months prior to registration,
             and there must be no serious unresolved complication of therapy at the time of
             registration; for the purposes of this study monoclonal antibodies and antibody drug
             conjugates are not considered to be activating immunotherapies and there are no
             additional time restrictions on prior exposure to these agents (except prior
             brentuximab vedotin)

          -  Eastern Cooperative Oncology Group (ECOG)-American College of Radiology Imaging
             Network (ACRIN) performance status between 0-2

          -  Patients must have measurable disease; baseline measurements and evaluations must be
             obtained within 4 weeks of registration to the study; abnormal positron emission
             tomography (PET) scans will not constitute evaluable disease unless verified by a
             diagnostic quality computed tomography (CT) scan; patients must use the same imaging
             modality (CT or PET/CT) throughout the study

          -  Women must not be pregnant or breast-feeding due to risk of fetal harm by the
             chemotherapeutic agents prescribed in this protocol; all females of childbearing
             potential must have a blood test or urine study within 2 weeks prior to registration
             to rule out pregnancy; a female of childbearing potential is any woman, regardless of
             sexual orientation or whether they have undergone tubal ligation, who meets the
             following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or
             2) 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)

          -  Women of childbearing potential (WOCBP) and sexually active males must either abstain
             from sexual intercourse for the duration of their participation in the study or agree
             to use both single barrier contraception and birth control pills or implants for at
             least one week prior to the start of the study drug and continuing for 5 months after
             the last dose of study drug (for female patients) and for 7 months after the last dose
             of study drug (for male patients who are sexually active with WOCBP); should a woman
             become pregnant or suspect she is pregnant while she or her partner is participating
             in this study, she (or the participating partner) should inform the treating physician
             immediately

          -  Patients must have no evidence of dyspnea at rest and a pulse oximetry > 92% while
             breathing room air

          -  Patients must have forced expiratory volume in 1 second (FEV1)/forced vital capacity
             (FVC) > 60% by pulmonary function test (PFT), unless due to large mediastinal mass
             from HL; carbon monoxide diffusion capacity (DLCO), FEV1, and FVC all > 50% predicted
             value; all pulmonary function tests must be obtained within one month prior to
             registration

          -  Absolute neutrophil count (ANC) >= 1500/mcL (1.5 x 10^9/L) (obtained within 2 weeks
             prior to registration)

          -  Platelets >= 75,000/mcL (75 x 10^9/L) (obtained within 2 weeks prior to registration)

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
             of normal (ULN) (obtained within 2 weeks prior to registration)

          -  Bilirubin =< 2 x upper limit of normal (ULN) (unless documented Gilbert's syndrome,
             for which bilirubin =< 3 x upper limit of normal [ULN] is permitted) (obtained within
             2 weeks prior to registration)

          -  Calculated creatinine clearance by Cockcroft-Gault formula >= 30 ml/min (obtained
             within 2 weeks prior to registration)

          -  No evidence of prior malignancy except adequately treated non-melanoma skin cancer, in
             situ cervical carcinoma or any surgically- or radiation-cured malignancy continuously
             disease free for >= 5 years so as not to interfere with interpretation of radiographic
             response

          -  Patient must have no current or prior history of central nervous system (CNS)
             involvement

          -  All prior therapy must have been completed at least 21 days prior to enrollment; no
             concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose
             of treatment of lymphoma are allowed; topical steroids are allowed

          -  No history of Steven's Johnson's syndrome, toxic epidermal necrolysis (TEN)s syndrome,
             or motor neuropathy

          -  Human immunodeficiency virus (HIV) positive patients are allowed on this study if they
             have a CD4 count > 400, and are on a stable antiviral regimen; patients with poorly
             controlled HIV or other chronic active viral infections will be excluded

          -  Patients must not have autoimmune disorders or conditions of immunosuppression that
             require current ongoing treatment with systemic corticosteroids (or other systemic
             immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone) or
             continuous use of topical steroid creams or ointments or ophthalmologic steroids; a
             history of occasional (but not continuous) use of steroid inhalers is allowed

               -  Replacement doses of steroids for patients with adrenal insufficiency are
                  allowed; patients who discontinue use of these classes of medication for at least
                  2 weeks prior to initiation of study treatment are eligible if, in the judgment
                  of the treating physician investigator, the patient is not likely to require
                  resumption of treatment with these classes of drugs during the study

               -  Exclusion from this study also includes patients with a history of symptomatic
                  autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis
                  [scleroderma], systemic lupus erythematosus, Sjogren's syndrome, autoimmune
                  vasculitis [e.g., Wegener's Granulomatosis]); motor neuropathy considered of
                  autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia Gravis); other
                  CNS autoimmune disease (e.g., Multiple sclerosis); patients with autoimmune
                  hypothyroid disease or type I diabetes on replacement treatment are eligible

          -  Patients must not have grade 2 or greater peripheral sensory neuropathy

          -  Patients must not have New York Heart Association (NYHA) class III or IV heart
             failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
             electrocardiographic evidence of acute ischemia

          -  Patients must not have previously existing hypersensitivity to brentuximab vedotin or
             ipilimumab

          -  Patients must not have a serious medical or psychiatric illness likely to interfere
             with study participation

          -  Patients must not be participating in any other clinical trial or taking any other
             experimental medications within 21 days prior to registration

          -  Routine vaccinations, including seasonal influenza, should be given at least 2 weeks
             prior to study treatment; vaccines are not prohibited on study, but must be given at
             least 6 weeks after cycle 1 and not within 7 days of treatment

          -  Patients registering to Arms D, E, F, G, H, I, X, Y must not currently be smoking
             tobacco or other substances and must not have smoked within the past 6 months

          -  RANDOMIZED PHASE II (ARMS K AND L): Patients must have pathologically confirmed
             relapsed or refractory classical Hodgkin lymphoma (cHL); a biopsy at any relapse is
             acceptable; other histologies including lymphocyte predominant (LP) HL are not
             permitted

          -  RANDOMIZED PHASE II (ARMS K AND L): Patients must have relapsed after first line
             chemotherapy; may have relapsed after autologous stem cell transplant, or have primary
             refractory disease; no upper limit for number of prior therapies; patient must not
             have received a prior allogeneic stem cell transplant

          -  RANDOMIZED PHASE II (ARMS K AND L): Patients may have received prior brentuximab
             vedotin, but must not have received brentuximab vedotin within 6 months prior to
             registration, and must not have relapsed within 6 months of receiving previous
             brentuximab vedotin; patients may not have received prior nivolumab or PD1/PDL1 axis
             agents; patients may not have received prior ipilimumab

          -  RANDOMIZED PHASE II (ARMS K AND L): Patients may not have received other prior
             activating immunotherapies (i.e. checkpoint inhibitor therapies); for the purposes of
             this study monoclonal antibodies and antibody drug conjugates are not considered to be
             activating immunotherapies and there are no additional time restrictions on prior
             exposure to these agents (except prior brentuximab vedotin)

          -  RANDOMIZED PHASE II (ARMS K AND L): ECOG-ACRIN performance status between 0-2

          -  RANDOMIZED PHASE II (ARMS K AND L): Patients must have measurable disease; baseline
             measurements and evaluations must be obtained within 4 weeks of registration to the
             study; abnormal PET scans will not constitute evaluable disease unless verified by a
             diagnostic quality CT scan; patients must use the same imaging modality (CT or PET/CT)
             throughout the study

          -  RANDOMIZED PHASE II (ARMS K AND L): Women must not be pregnant or breast-feeding due
             to risk of fetal harm by the chemotherapeutic agents prescribed in this protocol; all
             females of childbearing potential must have a blood test or urine study within 24
             hours prior to enrollment to rule out pregnancy; a female of childbearing potential is
             any woman, regardless of sexual orientation or whether they have undergone tubal
             ligation, who meets the following criteria: 1) has not undergone a hysterectomy or
             bilateral oophorectomy; or 2) 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)

          -  RANDOMIZED PHASE II (ARMS K AND L): Women of childbearing potential (WOCBP) and
             sexually active males must either abstain from sexual intercourse for the duration of
             their participation in the study or agree to use both double barrier contraception and
             birth control pills or implants for at least one week prior to the start of the study
             drug and continuing for 5 months after the last dose of study drug (for female
             patients) and for 7 months after the last dose of study drug (for male patients who
             are sexually active with WOCBP); should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she (or the
             participating partner) should inform the treating physician immediately

          -  RANDOMIZED PHASE II (ARMS K AND L): Patients must have no evidence of dyspnea at rest
             and a pulse oximetry > 92% while breathing room air

          -  RANDOMIZED PHASE II (ARMS K AND L): Patients must have FEV1/FVC > 60% by pulmonary
             function test (PFT), unless due to large mediastinal mass from HL; carbon monoxide
             diffusion capacity (DLCO), FEV1, and FVC all > 50% predicted value; all pulmonary
             function tests must be obtained within one month prior to registration

          -  RANDOMIZED PHASE II (ARMS K AND L): ANC >= 1500/mcL (1.5 x 0^9/L) (obtained within 2
             weeks prior to registration)

          -  RANDOMIZED PHASE II (ARMS K AND L): Platelets >= 75,000/mcL (75 x 10^9/L) (obtained
             within 2 weeks prior to registration)

          -  RANDOMIZED PHASE II (ARMS K AND L): AST/ALT =< 2.5 x upper limit of normal (ULN)
             (obtained within 2 weeks prior to registration)

          -  RANDOMIZED PHASE II (ARMS K AND L): Bilirubin =< 2 x upper limit of normal (ULN)
             (unless documented Gilbert's syndrome, for which Bilirubin =< 3 x upper limit of
             normal [ULN] is permitted) (obtained within 2 weeks prior to registration)

          -  RANDOMIZED PHASE II (ARMS K AND L): Calculated creatinine clearance by Cockcroft-Gault
             formula >= 30 ml/min (obtained within 2 weeks prior to registration)

          -  RANDOMIZED PHASE II (ARMS K AND L): No evidence of prior malignancy except adequately
             treated non-melanoma skin cancer, in situ cervical carcinoma or any surgically- or
             radiation-cured malignancy continuously disease free for >= 5 years so as not to
             interfere with interpretation of radiographic response

          -  RANDOMIZED PHASE II (ARMS K AND L): Patient must have no current or prior history of
             CNS involvement

          -  RANDOMIZED PHASE II (ARMS K AND L): All prior therapy must have been completed at
             least 21 days prior to enrollment (6 weeks for nitrosoureas or mitomycin C); no
             concomitant anti lymphoma therapy, including systemic corticosteroids for the purpose
             of treatment of lymphoma are allowed; topical steroids are allowed

          -  RANDOMIZED PHASE II (ARMS K AND L): No history of Steven's Johnson's syndrome, TENs
             syndrome, or motor neuropathy

          -  RANDOMIZED PHASE II (ARMS K AND L): HIV positive patients are eligible provided they
             meet the other protocol criteria including the following:

               -  Long term survival expected were it not for the cHL

               -  HIV viral loads undetectable by standard clinical HIV testing

               -  Willing to adhere to effective combination antiretroviral therapy

          -  RANDOMIZED PHASE II (ARMS K AND L): Patients must not have autoimmune disorders or
             conditions of immunosuppression that require current ongoing treatment with systemic
             corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e.,
             prednisone, dexamethasone) or continuous use of topical steroid creams or ointments or
             ophthalmologic steroids; a history of occasional (but not continuous) use of steroid
             inhalers is allowed; replacement doses of steroids for patients with adrenal
             insufficiency are allowed; patients who discontinue use of steroid medication for at
             least 2 weeks prior to initiation of therapy are eligible if, in the judgment of the
             treating physician investigator, the patient is not likely to require resumption of
             treatment with these classes of drugs during the study; exclusion from this study also
             includes patients with a history of symptomatic autoimmune disease (e.g., rheumatoid
             arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus,
             Sjogren's syndrome, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); motor
             neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and
             Myasthenia Gravis); other CNS autoimmune disease (e.g., Multiple sclerosis); patients
             with autoimmune hypothyroid disease or type I diabetes on replacement treatment are
             eligible

          -  RANDOMIZED PHASE II (ARMS K AND L): Patients must not have grade 2 or greater
             peripheral sensory n
      
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 each combination (Phase I)
Time Frame:21 days
Safety Issue:
Description:MTD defined as the highest dose level at which less than 33% of 6 patients experience a dose limiting toxicity (DLT), will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Upon completion of the trial, frequency of subjects experiencing toxicities will be tabulated. Toxicities will be assessed and graded according to CTCAE version 4.0 terminology. Exact 95% confidence intervals (CI) around the toxicity proportions will be calculated.

Secondary Outcome Measures

Measure:Complete response (CR) rate (Phase I)
Time Frame:Up to 3 years
Safety Issue:
Description:Assessed using the Revised Response Criteria for Malignant Lymphoma and reported along with the 95% CI.
Measure:Partial response (PR) rate (Phase I)
Time Frame:Up to 3 years
Safety Issue:
Description:Assessed using the Revised Response Criteria for Malignant Lymphoma and reported along with the 95% CI.
Measure:Overall response rate (ORR) rate (Phase I)
Time Frame:Up to 3 years
Safety Issue:
Description:Assessed using the Revised Response Criteria for Malignant Lymphoma and reported along with the 95% CI.
Measure:Duration of response (DOR) (Phase I)
Time Frame:From the documented beginning of response up to 3 years
Safety Issue:
Description:DOR will be estimated using Kaplan-Meier methodology. Greenwood's formula will be used to calculate 95% CI for the Kaplan-Meier estimates. Descriptive statistics will be used to evaluate the DOR achieved with the protocol therapy and with the most recent prior systemic therapy.
Measure:Overall survival (OS) (Phase I)
Time Frame:From the date of study entry up to 3 years
Safety Issue:
Description:OS will be estimated using Kaplan-Meier methodology. Greenwood's formula will be used to calculate 95% CI for the Kaplan-Meier estimates.
Measure:Progression-free survival (PFS) (Phase I)
Time Frame:From entry onto study up to 3 years
Safety Issue:
Description:PFS will be estimated using Kaplan-Meier methodology. Greenwood's formula will be used to calculate 95% CI for the Kaplan-Meier estimates.
Measure:ORR (Phase II)
Time Frame:Up to 5 years
Safety Issue:
Description:Assessed using Revised Response (Cheson) and Deauville criteria. The analysis of ORR between two arms will be performed using the CMH test stratifying on prior BV (Yes vs. No). Multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.
Measure:PFS (or modified PFS) (Phase II)
Time Frame:From randomization up to 5 years
Safety Issue:
Description:PFS will be estimated using Kaplan-Meier methodology and compared between arms using stratified log-rank test. Greenwood's formula will be used to calculate 95% confidence intervals for the Kaplan-Meier estimates. Cox proportional regression model will be used to estimate hazard ratios (95% CI) and assess the relationship between other prognostic factors with time-to-event outcome. Point estimates of all endpoints will be accompanied by the corresponding 90% confidence intervals.
Measure:OS (Phase II)
Time Frame:From randomization up to 5 years
Safety Issue:
Description:OS will be estimated using Kaplan-Meier methodology and compared between arms using stratified log-rank test. Greenwood's formula will be used to calculate 95% confidence intervals for the Kaplan-Meier estimates. Cox proportional regression model will be used to estimate hazard ratios (95% CI) and assess the relationship between other prognostic factors with time-to-event outcome. Point estimates of all endpoints will be accompanied by the corresponding 90% confidence intervals.
Measure:DOR (Phase II)
Time Frame:From the documented beginning of response up to 5 years
Safety Issue:
Description:DOR, will be estimated using Kaplan-Meier methodology and compared between arms using stratified log-rank test. Greenwood's formula will be used to calculate 95% confidence intervals for the Kaplan-Meier estimates. Cox proportional regression model will be used to estimate hazard ratios (95% CI) and assess the relationship between other prognostic factors with time-to-event outcome. Point estimates of all endpoints will be accompanied by the corresponding 90% confidence intervals. The DOR achieved with the most recent prior systemic therapy will be collected on the case report forms, and descriptive statistics will be used to evaluate the DOR achieved with the protocol therapy and with the most recent prior systemic therapy.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 6, 2020