Clinical Trials /

Nivolumab Consolidation in Older (≥ 65) Patients With Primary CNS Lymphoma

NCT04022980

Description:

The primary objective of Stage 1 is to evaluate the safety of nivolumab consolidation after completion of HD-MTX containing induction chemotherapy in older subjects with PCNSL in terms of a tolerated dose (based on dose-limiting toxicities) for the expansion phase of the study (Stage 2).The primary objective of Stage 2 is to evaluate the efficacy of nivolumab consolidation after completion of HD-MTX containing induction chemotherapy in terms of the 2-year progression-free survival rate and compare to relevant historical controls

Related Conditions:
  • Primary Central Nervous System Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: R-MPV Followed by Nivolumab in Older (≥65) Pts With Previously Untreated Primary CNS Lymphoma
  • Official Title: A Phase 1B Trial of R-MPV (Rituximab, Methotrexate, Procarbazine, Vincristine) Induction Chemotherapy Followed by Nivolumab Consolidation in Older (65 Years or Older) Patients With Previously Untreated Primary CNS Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: LCI-HEM-PCNSL-RMPV-001
  • SECONDARY ID: 00036735
  • NCT ID: NCT04022980

Conditions

  • Brain and Nervous System
  • Eye and Orbit

Interventions

DrugSynonymsArms
NivolumabStage 1
RituximabStage 1
MethotrexateStage 1
VincristineStage 1
ProcarbazineStage 1

Purpose

The primary objective of Stage 1 is to evaluate the safety of nivolumab consolidation after R-MPV induction chemotherapy in older subjects with previously untreated PCNSL in terms of a tolerated dose (based on dose-limiting toxicities) for the expansion phase of the study (Stage 2). The primary objective of Stage 2 is to evaluate the efficacy of nivolumab consolidation after R-MPV induction chemotherapy in terms of the 2-year progression-free survival rate.

Detailed Description

      This is a 2-stage phase 1B study of R-MPV (rituximab, methotrexate, procarbazine,
      vincristine) induction chemotherapy followed by nivolumab consolidation in older (≥ 65 years
      old) patients with previously untreated primary CNS lymphoma. Stage 1 is designed to evaluate
      the safety of nivolumab consolidation after R-MPV induction chemotherapy. We plan to use 3+3
      design and start at the FDA approved single agent dose of nivolumab 480 mg intravenously
      every 4 weeks. Stage 2 is designed to evaluate the safety as well as efficacy of nivolumab
      consolidation after R-MPV induction chemotherapy in an expansion cohort.
    

Trial Arms

NameTypeDescriptionInterventions
Stage 1ExperimentalSafety Run-In
  • Nivolumab
  • Rituximab
  • Methotrexate
  • Vincristine
  • Procarbazine
Stage 2ExperimentalExpansion Cohort
  • Nivolumab
  • Rituximab
  • Methotrexate
  • Vincristine
  • Procarbazine

Eligibility Criteria

        Subjects must meet all of the following criteria to participate in this study:

          1. Written informed consent and HIPAA authorization for release of personal health
             information of subject or subject's legally authorized representative.

          2. Age ≥ 65 years at the time of consent

          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 3 within 14 days
             prior to day 1 of treatment

          4. Previously untreated histological or cytological confirmation of PCNSL, CD20 positive
             by immunohistochemistry

          5. Measurable disease including lesions that can be accurately measured in 2 dimensions
             by CT or MRI of brain and with a greatest transverse diameter of ≥ 1 cm.

          6. Deemed poor candidate for whole brain irradiation (WBI) or autologous stem cell
             transplant (ASCT) due to advanced age, ECOG performance status of 2, or in the opinion
             of the treating physician, subject would not tolerate the administration of WBI or
             ASCT for other reasons

          7. Life expectancy of at least 3 months

          8. Demonstrate adequate organ function as defined below (all screening labs to be
             obtained within 14 days prior to day 1 of treatment):

               1. Absolute Neutrophil Count (ANC) ≥ 1000K/mm3

               2. Platelet Count ≥ 75 K/mm3

               3. Hemoglobin (Hgb) ≥ 8 g/dL

               4. Serum creatinine ≥ 1.5 mg/dL OR creatinine clearance ≥ 50 cc/minute as measured
                  by a 24-hour urine collection or estimated by the Cockcroft and Gault formula

               5. Bilirubin ≤ 1.5 x upper limit of normal (ULN) (except subjects with Gilbert
                  Syndrome who must have a total bilirubin level of < 3.0 x ULN)

               6. Aspartate aminotransferase (AST) ≤ 3 x ULN

               7. Alanine aminotransferase (ALT) ≤ 3 x ULN

          9. Females of childbearing potential (FCBP) must have a negative serum pregnancy test
             within 3 days prior to day 1 of treatment. NOTE: Females are considered of child
             bearing potential unless they are surgically sterile (have undergone a hysterectomy,
             bilateral tubal ligation, or bilateral oophorectomy) or are postmenopausal (at least
             12 consecutive months with no menses without an alternative medical cause).

         10. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a
             failure rate of <1% per year when used consistently and correctly) from the time of
             informed consent until 5 months after treatment discontinuation. Contraceptive methods
             with low user dependency are preferable but not required.
             (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/
             2014_09_HMA_CTFG_Contraception.pdf)

         11. Male subjects must be willing to use condoms from the time of treatment initiation
             until 7 months after treatment discontinuation. For a non-pregnant FCBP partner,
             contraception recommendations should also be considered.

         12. As determined by the enrolling physician, ability of the subject to understand and
             comply with study procedures for the entire length of the study.

        Subjects must not meet any of the following criteria:

          1. Any concurrent systemic involvement by lymphoma outside CNS or intraocular lymphoma
             without evidence of brain disease

          2. Any previous chemotherapy or radiation therapy for PCNSL. Subjects treated with
             corticosteroids for PCNSL are allowed.

          3. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
             mother is being treated on study)

          4. Has a known additional malignancy within the past 5 years that is active and/or
             progressive requiring treatment; exceptions include basal cell or squamous cell skin
             cancer, in situ cervical or bladder cancer.

          5. Treatment with any investigational drug (including drugs not FDA-approved for the
             indication for which they are given) within 28 days prior to day 1 of treatment

          6. Subjects with active, uncontrolled infections (subjects must be afebrile for >48 hours
             off systemic antibiotics).

          7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
             psychiatric illness/social situations that would limit compliance with study
             requirements as determined by the investigator.

          8. Major surgery and/or radiotherapy within 14 days prior to initiation of study
             treatment

          9. Known history of positive test for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at
             sites where mandated locally.

         10. Active infectious hepatitis, type B or C. Subjects with a past or resolved HBV
             infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence
             of HBsAg) may be included if HBV DNA is undetectable. If enrolled, subjects must be
             willing to undergo monthly HBV DNA testing.

         11. Subjects with active interstitial pneumonitis.

         12. Subjects with active, known or suspected autoimmune disease. Subjects with 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 are permitted
             to enroll.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:65 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Stage 1 is to evaluate the safety of Nivolumab consolidation after R-MPV
Time Frame:Until up to 6 subjects can be adequately assessed for DLT.
Safety Issue:
Description:Stage 1 is to evaluate the safety of Nivolumab consolidation after R-MPV induction chemotherapy in older subjects with previously untreated PCNSL in terms of a tolerated dose (based on dose-limiting toxicities (DLT)) for the expansion phase of the study (Stage 2).

Secondary Outcome Measures

Measure:To evaluate progression-free survival (PFS) in older subjects with previously untreated PCNSL who received R-MPV induction chemotherapy followed by Nivolumab consolidation therapy.
Time Frame:2 years.
Safety Issue:
Description:
Measure:To evaluate overall survival (OS) and estimate the OS rate at 2 years in older subjects with previously untreated PCNSL who received R-MPV induction chemotherapy followed by Nivolumab consolidation therapy.
Time Frame:2 years.
Safety Issue:
Description:
Measure:To estimate objective and complete response rates in this subject population.
Time Frame:Through study completion, an average of 2 years.
Safety Issue:
Description:
Measure:To estimate conversion rate from partial to complete response before and after Nivolumab consolidation therapy.
Time Frame:Through study completion, an average of 2 years.
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Steven Park, MD

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