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R-MPV Followed by Nivolumab in Older (≥65) Pts With Previously Untreated Primary CNS Lymphoma

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ClinicalTrials.gov Identifier: NCT04022980
Recruitment Status : Recruiting
First Posted : July 17, 2019
Last Update Posted : July 26, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Steven Park, MD, Atrium Health

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Brain and Nervous System Eye and Orbit Drug: Nivolumab Drug: Rituximab Drug: Methotrexate Drug: Vincristine Drug: Procarbazine Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 25, 2019
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021


Arm Intervention/treatment
Experimental: Stage 1
Safety Run-In
Drug: Nivolumab
R-MPV induction followed by Nivolumab consolidation.

Drug: Rituximab
R-MPV induction followed by Nivolumab consolidation.

Drug: Methotrexate
R-MPV induction followed by Nivolumab consolidation.

Drug: Vincristine
R-MPV induction followed by Nivolumab consolidation.

Drug: Procarbazine
R-MPV induction followed by Nivolumab consolidation.

Experimental: Stage 2
Expansion Cohort
Drug: Nivolumab
R-MPV induction followed by Nivolumab consolidation.

Drug: Rituximab
R-MPV induction followed by Nivolumab consolidation.

Drug: Methotrexate
R-MPV induction followed by Nivolumab consolidation.

Drug: Vincristine
R-MPV induction followed by Nivolumab consolidation.

Drug: Procarbazine
R-MPV induction followed by Nivolumab consolidation.




Primary Outcome Measures :
  1. 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. ]
    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).

  2. The primary objective of Stage 2 is to evaluate the efficacy of Nivolumab consolidation after R-MPV [ Time Frame: 2 years. ]
    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.


Secondary Outcome Measures :
  1. 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. ]
  2. 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. ]
  3. To estimate objective and complete response rates in this subject population. [ Time Frame: Through study completion, an average of 2 years. ]
  4. 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. ]


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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04022980


Contacts
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Contact: Kelly Bumgarner 704-403-2520 Kelly.Bumgarner@atriumhealth.org

Locations
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United States, North Carolina
Levine Cancer Institute Recruiting
Charlotte, North Carolina, United States, 28204
Contact: Kelly Bumgarner, RN    704-403-2520    Kelly.Bumgarner@atriumhealth.org   
Sponsors and Collaborators
Steven Park, MD
Bristol-Myers Squibb
Investigators
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Principal Investigator: Steven Park, MD Atrium Health

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Responsible Party: Steven Park, MD, Sponsor Investigator, Atrium Health
ClinicalTrials.gov Identifier: NCT04022980     History of Changes
Other Study ID Numbers: LCI-HEM-PCNSL-RMPV-001
00036735
First Posted: July 17, 2019    Key Record Dates
Last Update Posted: July 26, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Rituximab
Nivolumab
Methotrexate
Vincristine
Procarbazine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Nucleic Acid Synthesis Inhibitors
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators