Clinical Trials /

Check Point Inhibition After Autologous Stem Cell Transplantation in Patients at High Risk of Post Transplant Recurrence

NCT02681302

Description:

The goal of this study is to determine the safety and clinical effect of combined checkpoint inhibition administered after autologous hematopoietic stem cell transplantation in each of six clinical cohorts of high risk and recurrent disease. In addition to assessing the incidence and severity of adverse events and rates of complete response and progression free survival, investigators intend to monitor immune reconstitution, phenotype and TCR repertoire throughout treatment and at the time of disease progression. Investigators will also analyze the gut microbiome prior to conditioning, throughout treatment, post-transplant and at time of relapse.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Multiple Myeloma
  • Myeloma
  • T-Cell Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Check Point Inhibition After Autologous Stem Cell Transplantation in Patients at High Risk of Post Transplant Recurrence
  • Official Title: Phase Ib-IIA Study of Combined Check Point Inhibition After Autologous Hematopoietic Stem Cell Transplantation in Patients at High Risk for Post-transplant Recurrence

Clinical Trial IDs

  • ORG STUDY ID: 2016-0048
  • NCT ID: NCT02681302

Conditions

  • Multiple Myeloma
  • Lymphoma

Interventions

DrugSynonymsArms
IpilimumabYervoyAll Participants
NivolumabOpdivoAll Participants

Purpose

The goal of this study is to determine the safety and clinical effect of combined checkpoint inhibition administered after autologous hematopoietic stem cell transplantation in each of six clinical cohorts of high risk and recurrent disease. In addition to assessing the incidence and severity of adverse events and rates of complete response and progression free survival, investigators intend to monitor immune reconstitution, phenotype and TCR repertoire throughout treatment and at the time of disease progression. Investigators will also analyze the gut microbiome prior to conditioning, throughout treatment, post-transplant and at time of relapse.

Detailed Description

      This is a phase Ib-IIA study of post-transplant combined check point inhibitors for patients
      with a high risk of relapse (>50%) after an autologous hematopoietic stem cell transplant.

      Patients will accrue to study by disease groups and followed separately by group for
      incidence and severity of toxicity, ability to receive intended schedule of combined check
      point inhibitors and for complete response and progression free survival (PFS) rates.
      Complete response and progression free survival rates will be compared to published standards
      for each disease group. Expected PFS at 18 months for all post-transplant groups without
      check point inhibitors is less than 50%. Each group with PFS at 18 months in 4 or more
      patients (57%) will be considered for eligibility in a successor phase IIB expansion trial.
    

Trial Arms

NameTypeDescriptionInterventions
All ParticipantsExperimentalIpilimumab 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22 Nivolumab 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. Voluntary signed and dated IRB/IEC approved written informed consent form in
             accordance with regulatory and local guidelines.

          2. Be 18 years or older and 80 years or younger on the day of signing consent

          3. Have a confirmed diagnosis of:

               -  (GROUP A) De novo diffuse large B cell lymphoma that fails to achieve a PET
                  negative complete response to primary rituximab and anthracycline based
                  multi-agent chemotherapy and at least maintains stable disease after salvage
                  chemotherapy or present double/triple hit features defined by overexpression by
                  standard immunohistochemistry of c-MYC plus BCL2 and/or BCL6 or presence of
                  chromosomal translocations as detected by break-apart FISH involving IGH/MYC plus
                  IGH/BCL2 and/or IGH/BCL6 and who only received standard chemoimmunotherapy with
                  rituximab, cyclophosphamide, vincristine and prednisone (R-CHOP) for induction
                  and present at least stable disease after consolidation or salvage chemotherapy.
                  Stable disease (SD) for lymphoma is defined in Appendix B: Lugano Classification
                  for Response Assessment of Non-Hodgkin Lymphoma.

               -  (GROUP B) Recurrent high-risk diffuse large B cell lymphoma defined as relapsing
                  within one year of completion of rituximab and anthracycline based multi-agent
                  chemotherapy or a sAAIPI (second-line age-adjusted International Prognostic
                  Index) intermediate or high at relapse or acquisition of double/triple hit
                  features upon relapse (as defined in group A) and at least stable disease after
                  salvage chemotherapy. Patients with an initial diagnosis of low-grade/indolent
                  non-Hodgkin lymphoma (i.e. follicular, marginal zone) who present relapse with
                  histologic transformation to diffuse large B cell lymphoma (confirmed by biopsy)
                  and meet the definition for high-risk as presented above, are also eligible.

               -  (GROUP C) De novo high-risk T cell lymphoma with at least stable disease after
                  primary therapy. High risk T cell lymphoma is defined as Stage III or IV disease
                  at presentation and/or failure to achieve CR after frontline chemotherapy.
                  Patients with ALK-positive ALCL will be excluded from the trial. Patients with
                  ALK-negative ALCL in complete response will be excluded from the trial.

               -  (GROUP D) Recurrent T cell lymphoma with at least stable disease after salvage
                  therapy. Patients with ALK-positive ALCL will be excluded from the trial.

          4. Be deemed eligible for an autologous stem cell transplantation according to the
             institutional guidelines of the Blood and Marrow Transplantation Program at John
             Theurer Cancer Center at Hackensack University Medical Center

          5. Have an ECOG performance status of 2 or lower

          6. Women of childbearing potential (WOCBP) must use appropriate method(s) of
             contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30
             days plus the time required for nivolumab to undergo five half-lives) after the last
             dose of investigational drug.

          7. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
             the start of nivolumab. If the urine test is positive or cannot be confirmed as
             negative, a serum pregnancy test will be required. Female subjects of childbearing
             potential should agree to ongoing pregnancy testing, to be performed prior to each
             dosing of ipilimumab and nivolumab. See Note below for definition of WOCBP.

          8. Women must not be breastfeeding.

          9. Men who are sexually active with WOCBP must use any contraceptive method with a
             failure rate of less than 1% per year. Men receiving nivolumab, and who are sexually
             active with WOCBP will be instructed to adhere to contraception for a period of 31
             weeks after the last dose of investigational product, even if they have had a
             vasectomy. Women who are not of childbearing potential (ie, who are postmenopausal or
             surgically sterile as well as azoospermic men do not require contraception). See Note
             below for definition of WOCBP.

         10. Females of childbearing potential must be willing to use two methods of birth control
             or be surgically sterile, or abstain from heterosexual activity for the course of the
             study through 120 days after the last dose of study medication. Subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 2 years. See Note below for definition of WOCBP.

         11. Allowable transplant preparative regimens are the following:

               -  For non-Hodgkin lymphoma groups (A, B,C,D) BEAM: carmustine 300 mg/m2 day -6,
                  etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 mg/m2
                  day -1

               -  For Myeloma groups (E and F) Melphalan 200 mg/m2 day -1

        Exclusion Criteria:

          1. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment. There must also be no
             requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day
             prednisone equivalents) for at least 2 weeks prior to study drug administration. This
             exception does not include carcinomatous meningitis, which is excluded regardless of
             clinical stability. Note: Subjects are permitted to use topical, ocular,
             intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic
             absorption). Physiologic replacement doses of systemic corticosteroids are permitted,
             even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for
             prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions
             (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.

          2. Is unable or unwilling to sign informed consent.

          3. Has an active, known, or suspected autoimmune disease. Subjects are permitted to
             enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
             autoimmune condition only requiring hormone replacement, psoriasis not requiring
             systemic treatment, or conditions not expected to recur in the absence of an external
             trigger

          4. Patients should be excluded if they have a condition requiring systemic treatment with
             either corticosteroids (> 10 mg daily prednisone equivalents) or other
             immunosuppressive medications within 14 days of study drug administration. Inhaled or
             topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents
             are permitted in the absence of active autoimmune disease. Note: Subjects are
             permitted to use topical, ocular, intra-articular, intranasal, and inhalational
             corticosteroids (with minimal systemic absorption). Physiologic replacement doses of
             systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A
             brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for
             treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction
             caused by contact allergen) is permitted.

          5. As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab
             combinations, drugs with a predisposition to hepatoxicity should be used with caution
             in patients treated with nivolumab-containing regimen.

          6. Has received an allogeneic stem cell transplant.

          7. Has a history of hypersensitivity to nivolumab, ipilimumab, or any of its excipients,
             or severe hypersensitivity reaction to any previous monoclonal antibody.

          8. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Day 1 of
             checkpoint inhibitor treatment administration or who has not recovered (i.e., t
             administration mAb) within 4 weeks prior to dose of trial treatment. Rituximab within
             that period is allowed.

          9. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg. thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment. Note: Subjects are permitted to use topical, ocular,
             intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic
             absorption). Physiologic replacement doses of systemic corticosteroids are permitted,
             even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for
             prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions
             (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.

         10. Has known history of, or any evidence of active, non-infectious pneumonitis.

         11. Has an active infection requiring intravenous systemic therapy.

         12. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

         13. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         14. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 23 weeks for females and 31 weeks for males after the last dose of trial
             treatment.

         15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent,
             anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell
             costimulation or immune checkpoint pathways.

         16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or
             known acquired immunodeficiency syndrome (AIDS).

         17. Has positive test for Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected) indicating acute or chronic infection, as tested for
             transplant.

         18. Has received a live vaccine within 30 days of planned start of study therapy.
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of combined check point inhibition therapy via assessment of adverse events and lab findings
Time Frame:26 weeks
Safety Issue:
Description:To assess the safety of combined check point inhibition with nivolumab and ipilimumab after autologous hematopoietic stem cell transplantation in patients at high risk for post-transplant recurrence including patients with persistent and recurrent high risk diffuse large B cell lymphoma, high risk and recurrent T cell lymphoma and high risk and recurrent multiple myeloma

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hackensack Meridian Health

Last Updated